WO2014028914A1 - Deuterated icotinib derivatives - Google Patents

Abstract

The invention relates to novel deuterated Icotinib derivatives and their pharmaceutically acceptable salts, solvates, and prodrugs thereof. This invention also provides compositions comprising any of the deuterated Icotinib derivatives and use of these compounds, or compositions thereof, in preparation of medicaments for treatment of hyperproliferative disorders and diseases.

Description

DEUTERATED ICOTINIB DERIVATIVES

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional

Application No. 61/684,439, filed on August 17, 2012, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to deuterated Icotinib derivatives, compositions thereof, methods of synthesizing these derivatives, and their use as therapeutic agents for the treatment of proliferative diseases or disorders.

BACKGROUND OF THE INVENTION

Receptor tyrosine kinases are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. It is known that such kinases are frequently aberrantly expressed in common human cancers, such as breast cancer, lung cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or over-expressed in many human cancers, such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.

Icotinib, also known as 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4- quinazoline, modulates EGF type receptor tyrosine kinases (EGFR-TK) (see WO/2003/082830 and WO/2010/003313). Icotinib was approved for treating advanced stage non-small cell lung cancer by the Chinese SFDA. It is also in clinical trials as either a single agent or as part of a combination treatment for various other cancers.

Although Icotinib is effective in treating lung cancer, there is a need to search for new agents with higher potency, increased terminal half-life, slow clearance, higher drug exposure, and less dosing frequency, among others. SUMMARY OF THE INVENTION

This invention provides deuterated 4-[(3-ethynylphenyl)amino]-6,7-benzo-12- crown-4-quinazoline ("Icotinib") derivatives and use of these derivatives as mono-therapy or in combination therapy with other chemotherapeutic agents to ameliorate or treat disorders/diseases mediated by EGFR kinase.

In one aspect, the present invention provides compounds of Formula I:

Formula I

and pharmaceutically acceptable salts, solvate, and prodrugs thereof, wherein:

R 1 -R 13 are independently selected from the group consisting hydrogen and deuterium; and at least one of R 1 -R 13 is deuterium. In another aspect, the present invention provides methods of synthesizing these novel deuterated Icotinib derivatives, as substantially described in the examples.

In another aspect, the present invention provides a pharmaceutical composition comprising a deuterated Icotinib derivative according to any of the embodiments disclosed herein, and one or more pharmaceutically acceptable carriers.

In another aspect, the present invention provides a method of treating or ameliorating a disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of the embodiments disclosed herein, or a pharmaceutical composition thereof, to a patient in need thereof. In one embodiment, the disease or disorder is a hyperproliferative disease or disorder, preferably an EGFR kinase- mediated hyperproliferative disease or disorder, such as various cancers.

In another aspect, the present invention provides use of a compound according to any of the embodiments disclosed herein, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of an EGFR kinase-mediated disease or disorder.

These and other aspects of the present invention will be better appreciated through the following description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention realizes the benefits of replacing hydrogen atoms at certain positions of the anti-cancer agent 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4- quinazoline ("Icotinib") with deuterium, providing deuterated Icotinib derivatives, methods of synthesizing them, pharmaceutical compositions comprising any of these deuterated derivatives, and use of these compounds or compositions for treatment of hyperproliferative diseases or disorders, in particular those mediated by EGFR kinase.

In one aspect, the present invention provides a compound of Formula I:

Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein R 1 to R 13 are each independently selected from the group consisting of hydrogen and deuterium; and at least one of R 1 to R 13 is deuterium.

In one embodiment of this aspect, at least one of R 1 to R 13 independently has deuterium enrichment of no less than about 45%.

In another embodiment of this aspect, at least one of R 1 to R 13 independently has deuterium enrichment of no less than about 75%.

In another embodiment of this aspect, sometimes preferably, at least one of R¹ to R 13 independently has deuterium enrichment of no less than about 90%. In another embodiment of this aspect, sometimes preferably, at least one of R to

R 13 independently has deuterium enrichment of no less than about 97%.

In another embodiment of this aspect, sometimes preferably, at least one of R¹ to

R 13 independently has deuterium enrichment of no less than about 99%.

In another embodiment of this aspect, sometimes preferably, at least two of R¹ to

R 13 are deuterium.

In another embodiment of this aspect, sometimes preferably, at least three of R¹ to

R 13 are deuterium.

In another embodiment of this aspect, sometimes preferably, at least four of R¹ to R 13 are deuterium.

In another embodiment of this aspect, sometimes preferably, at least five of R¹ to

R 13 are deuterium.

In another embodiment of the invention, R 13 is deuterium, preferably at least one

1 12 1 12

of R to R is also deuterium, more preferably at least two of R to R are also deuterium,

1 12

and most preferably R to R are all deuterium.

In another embodiment of this aspect, R 13 is deuterium.

In another embodiment of this aspect, R 13 is deuterium, and at least one of R 1 to

R 12 is deuterium.

In another embodiment of this aspect, R 13 is deuterium, and at least two of R 1 to R 12 are deuterium.

In another embodiment of this aspect, R 13 is deuterium, and R 1 to R12 are each deuterium.

In another embodiment of this aspect, the present invention provides a deuterated compound having the formula selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect, the present invention provides methods of synthesizing these novel deuterated Icotinib derivatives, as substantially described in the examples.

In another aspect, the present invention provides a pharmaceutical composition comprising a deuterated Icotinib derivative according to any of the embodiments disclosed herein, and one or more pharmaceutically acceptable carriers.

In another aspect, the present invention provides a method of treating or ameliorating a disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of the embodiments disclosed herein, or a pharmaceutical composition thereof, to a patient in need thereof.

In one embodiment, the disease or disorder is a hyperproliferative disease or disorder, preferably an EGFR kinase-mediated hyperproliferative disease or disorder.

In another embodiment, the hyperproliferative disease or disorder is selected from the group consisting of ovarian cancer, bladder cancer, colorectal cancer, head and neck cancer, brain cancer, endocrine cancer, prostate cancer, sarcoma, myeloid leukemia, solid tumors, small cell lung cancer, non-small cell lung cancer, astrocytoma, breast cancer, squamous cell carcinoma, pancreatic cancer, glioblastoma multiforme, renal cancer, gastric cancer, cancer of unspecified body location/system, and liver cancer.

In another embodiment, the method further comprises administering to the patient an additional therapeutic agent.

In one embodiment, the additional therapeutic agent is another anti-cancer agent.

In another embodiment, the additional therapeutic agent is selected from the group consisting of anastrozole, arimidex, cediranib, bexarotene, calcitriol, capecitabine, carboplatin, cefixime, celecoxib, canertinib, cisplatin, dexamethasone, docetaxel, erbitux, etoposide, everolimus, everolimus, faslodex, fluorouracil, fulvestrant, gemcitabine, irinotecan, leucovorin, loperamide, oxaliplatin, paclitaxel, PEG-interferon alpha, pemetrexed, raltitrexed, simvastatin, sirolimus, sunitinib, tamoxifen, temozolomide, topotecan, trastuzumab, vorinostat, and vinorelbine.

In another aspect, the present invention provides use of a compound according to any of the embodiments disclosed herein, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of an EGFR kinase-mediated disease or disorder.

In one embodiment, the disease or disorder is a hyperproliferative disease or disorder.

In a preferred embodiment, the hyperproliferative disease or disorder is selected from the group consisting of ovarian cancer, bladder cancer, colorectal cancer, head and neck cancer, brain cancer, endocrine cancer, prostate cancer, sarcoma, myeloid leukemia, solid tumors, small cell lung cancer, non-small cell lung cancer, astrocytoma, breast cancer, squamous cell carcinoma, pancreatic cancer, glioblastoma multiforme, renal cancer, gastric cancer, cancer of unspecified body location/system, and liver cancer.

The terms "ameliorate" and "treat", or the like, are used interchangeably and include both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

"Disease" means any conditions or disorders that could cause damages or interfere with the normal function of a cell, tissue, or organ. It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of Icotinib will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention.

The compounds of the present invention are distinguished from such naturally occurring minor forms in that the term "compound" as used in this invention refers to a composition of matter that has a minimum isotopic enrichment factor at least 3000 (45% deuterium incorporation) for each deuterium atom that is present at a site designated as a site of deuteration in Formula I.

In the present invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom unless otherwise stated. Unless otherwise stated, when a position is designated specifically as "FT or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance at least 3000 times the natural abundance of deuterium, which is 0.015% (i.e., at least 45% deuterium incorporation).

The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

In one embodiment of the invention, the compound has an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5%> deuterium incorporation), preferably at least 4000 (60%) deuterium incorporation), at least 4500 (67.5%> deuterium incorporation), or at least 5000 (75%o deuterium), more preferably at least 5500 (82.5%> deuterium incorporation), at least 6000 (90%> deuterium incorporation), at least 6333.3 (95%> deuterium incorporation), at least 6466.7 (97%> deuterium incorporation), or at least 6600 (99%> deuterium incorporation), and most preferably at least 6633.3 (99.5% deuterium incorporation).

The formula depicted herein may or may not indicate whether atoms at certain positions are isotopically enriched. In some embodiments, when a formula is silent with respect to whether a particular position is isotopically enriched, it is to be understood that the stable isotopes at the particular position are present at natural abundance, or, alternatively, that that particular position is isotopically enriched with one or more naturally occurring stable isotopes. In a more specific embodiment, the stable isotopes are present at natural abundance at all positions in a compound not specifically designated as being isotopically enriched.

The term "isotopologue" refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof. Isotopologues can differ in the level of isotopic enrichment at one or more positions and/or in the positions(s) of isotopic enrichment.

The term "compound," when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skilled in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in total will be less than 55% of the compound. In other embodiments, the relative amount of such isotopologues in total will be less than 50%, less than 47.5%, less than 40%>, less than 32.5%, less than 25%, less than 17.5%, less than 10%), less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

The invention also provides salts of the compounds of the invention. A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a basic and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

The compounds of the present invention (e.g., compounds of Formula I), may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound of the present invention will include both racemic mixtures, and also individual respective stereoisomers that are substantially free from another possible stereoisomer. The term "substantially free of other stereoisomers," as used herein, means less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers, and most preferably less than 2%, less than 1%, less than 0.5%, less than 0.25%>, or less than 0.1 % of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present. Methods of obtaining or synthesizing an individual enantiomer for a given compound are well known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

"D" refers to deuterium.

"Stereoisomer" refers to both enantiomers and diastereomers.

The term "combination therapy" or the like means the administration of compound of Formula I with one or more other therapeutic agents to treat a 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.

The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, immunogenicity, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient," or the like, refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).

The terms "active ingredient," "active compound," and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.

The terms "drug," "therapeutic agent," and "chemotherapeutic agent," or the like, refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.

The term "release controlling excipient" refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

The term "nonrelease controlling excipient" refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

The term "prodrug" refers to a compound functional derivative of the compound as disclosed herein and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al, Curr. Pharm. Design 1999, 5, 265-287; Pauletti et al, Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al, Pharm. Biotech. 1998, 11, 345-365; Gaignault et al, Pract. Med. Chem. 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et al, Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1- 12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al, Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al, Methods Enzymol. 1985, 112, 360-381; Farquhar et al, J. Pharm. Sci. 1983, 72, 324-325; Freeman et al, J. Chem. Soc, Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al, Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al, Drugs 1985, 29, 455-73; Tan et al, Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131- 148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; Waller et al, Br. J. Clin. Pharmac. 1989, 28, 497-507.

Without intending to be bound by any theory of operation, it is believed that 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 or fecal excretion. Such oxidative metabolic reactions mediated with CYPs frequently involve the oxidation of a carbon-hydrogen (C-H) bond to a carbon-oxygen (C-O). The resultant more polar metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, 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. The observed rapid clearance of Icotinib from cancer patients is likely resulted from oxidative metabolism mediated by various CYPs.

Without intending to be bound by any theory, it is also believed that carbon- hydrogen bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond strength increases. Since deuterium (D) has twice the mass of proton, a C-D bond is stronger than the corresponding C-H bond. If a C-H 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 proton will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for proton. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. Substitution of tritium for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. CYP mediated oxidative metabolism often go through formation of a radical cation, involving an oxidative C-H bond cleavage. Thus, substitution of protons with deuteriums at certain metabolic soft spots in a drug, such as Icotinib, may reduce the clearance of the drug, and lead to lower dose and less dosing frequency.

Without intending to be bound by theory, it is further believed that Icotinib is metabolized in humans extensively at the 12-crown ether moiety and the deuterated Icotinib would have reduced metabolism at these sites and increased half-life in patients. Limiting the production of these metabolites also has the potential to decrease the danger of the administration of such drugs and may even allow increased dosage and/or increased efficacy.

Additionally, certain compounds disclosed herein may possess useful EGFR kinase modulating activity, and may be used in the treatment or prophylaxis of a disorder in which EGFR kinase play 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 modulating EGFR kinase. Other embodiments provide methods for treating an EGFR 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 the modulation of RGFR kinase.

The compounds as disclosed herein may also contain less prevalent isotopes for other elements, including, but not limited to, ¹³C or ¹⁴C for carbon, ¹⁵N for nitrogen, and

17 O or 18 O for oxygen.

In certain embodiments, the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half-life, lowering the efficacious dose and thus decreasing the non-mechanism-related toxicity, and/or lowering the probability of drug-drug interactions.

While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, 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, supra; Modified- Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126).

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 a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof ("active ingredient") 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.

Formulations of the compounds disclosed herein 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.

Pharmaceutical preparations that 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.

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. Formulations for parenteral administration include aqueous and non-aqueous (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.

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.

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.

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.

Certain compounds disclosed herein 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. 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.

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 dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro ethane, 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, the compounds according to the invention 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.

Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the disorder being treated. Also, the route of administration may vary depending on the disorder and its severity.

In the case wherein the patient's condition does not improve, upon the doctor's discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disorder.

In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a "drug holiday").

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disorder is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

Disclosed herein are methods of treating an EGFR kinase-mediated disorder comprising administering to a subject having or suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In certain embodiments, a method of treating an EGFR kinase-mediated disorder comprises administering to the subject a therapeutically effective amount of a compound of as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to affect: (1) decreased inter-individual variation in plasma levels of the compound or a metabolite thereof; (2) increased average plasma levels of the compound or decreased average plasma levels of at least one metabolite of the compound per dosage unit; (3) decreased inhibition of, and/or metabolism by at least one CYP450 in the subject; (4) decreased metabolism via at least one polymorphically-expressed CYP450 isoform in the subject; (5) at least one statistically-significantly improved disorder-control and/or disorder-eradication endpoint; (6) an improved clinical effect during the treatment of the disorder.

In certain embodiments, inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof, is decreased; average plasma levels of the compound as disclosed herein are increased; average plasma levels of a metabolite of the compound as disclosed herein are decreased; inhibition of a CYP450 by a compound as disclosed herein is decreased; or metabolism of the compound as disclosed herein by at least one polymorphically-expressed CYP450 isoform is decreased; 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-isotopically enriched compound.

Examples of CYP450 iso forms 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, CYP2S1, 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.

Examples of polymorphically-expressed CYP450 iso forms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

In additional aspects, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, may be administered in combination with a second chemotherapeutic agent or other anti-cancer agents. The second chemotherapeutic agent includes any known agents useful for treating cancer.

Examples of such anti-cancer agent(s) include, but are not limited to, antiangiogenic agents, such as linomide, inhibitors of integrin α _νβ₃ function, angiostatin, and razoxane; antiestrogens, such as tamoxifen, toremifene, raloxifene, droloxifene, and iodoxifene; progestogens, such as megestrol acetate, hydroxyprogesterone, and medroxyprogesterone; aromatase inhibitors, such as anastrozole, testolactone, letrozole, borazole, and exemestane; antihormones, such as aminoglutethimide; synthetic estrogens, such as chlorotrianisene, diethylstilbestrol and 17 a-ethinylestradiol; synthetic androgens, such as dromostanolone propionate, fluoxymesterone, and methyltestosterone; antiprogestogens; antiandrogens, such as flutamide, nilutamide, bicalutamide, and cyproterone acetate; androgens, such as testosterone; synthetic glucocorticoids, such as methylprednisolone, triamcinolone, prednisolone, and prednisone; LHRH agonists and antagonists, such as gosereline acetate and leuprolide; inhibitors of testosterone 5 -dihydroreductase, such as finasteride; farnesyltransferase inhibitors; anti-invasion agents, such as metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function; VEGF inhibitors, such as anti-VEGF antibodies (Avastin) and small molecules, such as ZD6474, SU6668, Vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP- 7055; Her 1 and Her 2 inhibitors including, for example, anti-Her 2 antibodies (Herceptin); Eg5 inhibitors, such as SB-715992, SB-743921, and MKI-833; pan Her inhibitors, such as canertinib, EKB-569, CI-1033, AEE-788, XL-647, mAb 2C4, and GW-572016; Src inhibitors, such as Gleevac and Dasatinib; MEK-1 inhibitors; MAPK inhibitors; PI3 kinase inhibitors; Met inhibitors; other Aurora kinase inhibitors; PDGF inhibitors, such as imatinib; IGF1R inhibitors, such as those disclosed in United States Patent Application No. 2004/0044203 Al; other receptor and non-receptor tyrosine kinase inhibitors; other serine/threonine kinase inhibitors; CDK inhibitors; antimetabolites, such as methotrexate, idatrexate, trimetrexate, 5-fluorouracil, tegafur, cytarabine, gemcitabine, capetitabine, fludarabine, 6-thioguanine, DON (d-oxo-norleucine or AT-125) and 6-mercaptopurine; intercalating antitumor antibiotics, such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitoxantrone, and mithramycin; platinum derivatives, such as cisplatin, oxaliplatin, and carboplatin; alkylating agents, such as nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide nitrosoureas, dacarbazine, hexamethyl melamine, estramustine, and thiotepa; antimitotic agents, such as pemetrexed, vinblastine, vinflunine, Taxol® (paclitaxel), Taxotere® (docetaxel), 7-O-methylthiomethylpaclitaxel, 4-desacetyl-4-methylcarbonatepaclitaxel, 3'- tert-butyl-3'~N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debenzoyl-4-0- methoxycarbonyl-paclitaxel, C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, epothilone analogs, i.e., ixabepilone, and derivatives thereof; inhibitors of integrin signaling; topoisomerase inhibitors, such as etoposide, teniposide, amsacrine, doxorubicin, daunorubicin, irinotecan, and topotecan; cell cycle inhibitors, such as, flavopyridols; biological response modifiers, such as interferon-alpha; monoclonal antibodies, such as rituximab, and gemtuzumab ozogamicin; proteasome inhibitors, such as Velcade® (bortezomib); SN-8; procarbazine; L-asparaginase; pyridobenzoindole derivatives; ribonucleutide reductase inhibitors; mTOR inhibitors; leucovorin; VM-26; interleukins; and hematopoietic growth factors; histone deacetylase inhibitors, such as vorinostat, MG0103 and MS-275.

In another aspect, the second chemotherapeutic agent can be a cytokine, such as G- CSF (granulocyte colony stimulating factor).

In another aspect, a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, may be administered in combination with radiation therapy.

The invention is further illustrated by the following non-limiting examples. EXAMPLES Synthetic Methods

Isotopic hydrogen (deuterium) can be introduced into a compound as disclosed herein by synthetic techniques that employ deuterated reagents, whereby incorporation rates are pre-determined; and/or by exchange techniques, wherein incorporation rates are determined by equilibrium conditions, and may be highly variable depending on the reaction conditions. Synthetic techniques, where deuterium is directly and specifically inserted by deuterated reagents of known isotopic content, may yield high deuterium abundance, but can be limited by the chemistry required. Exchange techniques, on the other hand, may yield lower deuterium incorporation, often with the isotope being distributed over many sites on the molecule.

The compounds as disclosed herein can be prepared by methods known to a person skilled in the art and routine modifications thereof, and/or following procedures similar to those described in the Example section herein and routine modifications thereof. Compounds as disclosed herein can also be prepared as shown in any of the following schemes and routine modifications thereof. The following schemes can be used to synthesize the compounds of formula I. Any position shown as hydrogen may be optionally substituted with deuterium.

EXAMPLE 1

Synthesis ofN-(3-ethynylphenyl)(6,6, 7, 7,9,9,10,10,12, 12, 13, 13-²H₁₂)-6, 7,9,10,12,13- hexahydrof 1, 4, 7, 10]tetraoxacyclododecino[2, 3-d] pyrimidin-4-amine (11)

Scheme 1

Scheme 1 describes the synthesis of deuterated Icotinib derivative 11. The commercially available deuterated ethylene glycol 1 can be alkylated with a properly protected deuterated 2-bromoethanol 2 (e.g., with a benzyl or 2-tetrahydropyranyl (THP) group) to provide compound 3. Deprotection of 3 results the fully deuterated diol 4. Tosylation of 4, followed by macro-ether (crown-ether) formation under basic conditions with 3,4-dihydroxy-benzoic acid ethyl ester to give crown-ether 6. Nitration of 6, followed by palladium-catalyzed hydrogenation in the presence of HC1, yields amine-HCl salt 8. Ring-closure of 8 can be accomplished under re fluxing conditions with ammonium formate in formamide to afford 9. Treatment of 9 with POCI₃ gives chloride 10, which can react with 3-ethynyl-phenylamine and a base to yield the final product 11.

EXAMPLE 2

Synthesis ofN-(3-ethynylphenyl) (9, 9,10,10-²H₄)-6, 7, 9,10,12,13- hexahydrof 1, 4, 7, 10] tetraoxacyclododecinof 2, 3-d] pyrimidin-4-amine (21)

Scheme 2 describes the synthesis of another deuterated derivative of Icotinib 21 by employing a similar chemical sequence to that of Scheme 1, except using THP protected 2-bromoethanol 12 to react with deuterated ethylene glycol 2.

The synthetic method is largely similar to the synthesis of Icotinib hydrochloride as described in WO 2010/003313 and US 2011/0182882, both of which are hereby incorporated by reference.

As an illustrated example, the compound of formula 21 was synthesized in six steps from reaction of deuterated tris(ethylene glycol) bis-tosylate with ethyl 3,4- dihydroxybenzoate to form the macrocyclic compound (Step 4). The macrocyclic compound underwent nitration (Step 5), reduction (Step 6), cyclization (Step 7), chlorination (Step 8), and cross-coupling (Step 9) to give the desired compound 21.

The starting material, deuterated ethylene glycol bis-tosylate, was synthesized from the deuterated ethylene glycol in three steps as described below in Steps 1-3. Scheme 2

P = protecting group

Step 1. l,12-diphenyl(6,6,7,7- H₄)-2,5, 8,11-tetraoxadodecane

2

To a solution of 1.0 g of ( H4)ethane-l,2-diol in 25 mL of DMF was added lg of NaH (60% in mineral oil) and the suspension was stirred at 60 °C for 10 min. After being cooled to room temperature, 0.1 g of 18-crown-6 was added. In a separated flask, 5.2 g of (2-Bromo-ethoxymethyl)-benzene and 3.6 g of nBu₄NI were mixed in 15 mL of DMF and heated for 5 min at 50 °C. After cooling to room temperature, the solution was added to the suspension of the other reactant. After stirring for 24 h at room temperature, the reaction mixture was treated with additional 1 g NaH (60% in mineral oil) and 5.2 g of (2- Bromo-ethoxymethyl)-benzene. The reaction mixture was continued stirring for 24 h at room temperature and quenched with 5 mL of water and DMF was removed under vacuum. The residue was portioned between 300 mL of 2: 1 EtOAc/hexane and 100 mL of water. The organic layer was then washed with 50 mL brine and dried over Na₂S0₄ and the residue was purified by silica gel chromatography eluted with a gradient of EtOAc/hexane (up to 80%> EtOAc) to give 3.1 g of the title compound as a colorless oil. ¹FiNMR (400 MHz, acetone-d₆): δ 7.23-7.40 (10H, m), 4.53 (4H, s), 3.1-3.18 (8H, m). MS (ES-API, pos. scan): 357.25 (M+Na)⁺

2

Step 2. 2,2'-|Y H₄)ethane-l,2-diylbis(oxy)ldiethanol

The product of Step 1 (3 g) and 1.2 g of 10%> Pd/C were mixed in 100 mL of MeOH and the mixture was shaken on a Par apparatus under 40 psi of hydrogen for 36 h. The reaction mixture was then diluted with 50 mL of CH₂C1₂, and filtered through a pad of Celite^®, washed with additional 100 mL of MeOH. The filtrate was concentrated to afford the title compound (1.1 g) as a colorless oil. ¹HNMR (400 MHz, acetone-d₆): δ 3.20 (2H, bs), 3.64 (4H, t), 3.52 (4H, t).

Step 3. ( H4)ethane-l,2-diylbis(oxyethane-2J-diyl) bis(4-methylbenzenesulfonate)

The product of Step 2 (1.0 g, 6.5 mmol) was dissolved in CH₂CI₂ at 0 °C and to this solution was added pyridine (1.3 g, 19.5 mmol) followed by addition of p- toluenesufonyl chloride (3.1 g, 13 mmol) in CH₂CI₂. The reaction mixture was stirred under N₂ at room temperature overnight. The solvent was then evaporated and the residue was partitioned between ether and 2N HC1 aqueous solution, the organic was concentrated and purified on silica gel to yield title compound as a light yellow solid (1.68 g, 56.1%). 1H NMR (400 MHz, CDC1₃): δ 7.82 (d, 4H), 7.35 (d, 4H), 4.15 (t, 4H). 3.65 (t, 4H). 2.45 (s, 6H). MS (ES-API, pos. scan): 480.5 (M+NH₄)⁺.

H₄)-23,5 8,9-hexahvdro A7 0-benzoτetraoxacvclododecine-

12-carboxylaτe

Ethyl 3,4-dihydroxybenzoate (610 mg, 3.33 mmol) and potassium carbonate (920 mg, 6.66 mmol) were suspended in DMF (100 ml) and the suspension was heated to 85 °C with well-stirring under nitrogen. Then, the product of Step 3 (1.54 g, 3.33 mmol) in DMF (20 mL) was added very slowly over about 1 h. The suspension was stirred at 85 °C and monitored by TLC (20% EtOAc/Hexane), which showed the completion of the reaction in 3.5 h. The mixture was cooled to room temperature, and partitioned between ether and water. The organic was concentrated and purified on silica gel to yield the title compound as an off-white solid, 278 mg (28%). 1H NMR (400 MHz, CDC1₃): δ 7.72 (s, 1H), 7.68 (s, 1H), 6.96 (d, 1H), 4.36 (q. 2H), 4.35 (d. 4H), 3.85 (d, 4H), 1.49 (t, 3H). MS (GC-Scan): 300 (M exact). Step 5. ethyl 13-nitro(5,5,6,6-²H4 -2,3,5,6,8,9-hexahvdro-l,4,7,10- benzotetraoxacyclododecine- -carboxylate

The product of Step 4 (220 mg, 0.73 mmol) was dissolved in AcOH (2 ml) and the solution was cooled to 0 °C. To this solution was added HNO₃ (2 mL) and then H₂S0₄ (2 mL) dropwise. The dark yellow solution was stirred between 0 °C to 15 °C for 25 min. and then was poured to ice water and extracted with EtOAc. The organic was concentrated to give a light yellow oil which solidified on standing to yield the title compound as a light yellow solid, 220 mg (87.7%). 1H NMR (400 MHz, CDCI3): δ 7.57 (s, 1H), 7.20 (s, 1H), 4.35 (q, 2H), 4.28 (m, 2H), 3.87 (m, 4H), 1.37 (t, 3H). MS (GC-Scan): 345 (M exact). Step 6. ethyl 13-amino(5,5,6,6-²H4V2,3.5,6,8,9-hexahvdro-l,4J,10- benzotetraoxacyclododecine- 12-carboxylate

The product of Step 5 (210 mg, 0.61 mmol) was dissolved in EtOH (50 ml) and

Pd-C (10%, 50 mg) was added. The black suspension was stirred under H₂ (balloon) at room temperature for 1.5 h. The mixture was filtrated and the filtrate was concentrated to yield the title compound as a yellow solid, 155 mg (80.7%). 1H NMR (400 MHz, CDCI3): δ 7.57 (s, 1H), 7.26 (s, 1H), 4.29 (q, 2H), 4.10 - 3.73 (m, 8H), 1.36 (t, 3H). MS (GC-Scan): 315 (M exact). Ste 7. (10J0J l J l-²H4V7,8J0J l J3J4-hexahvdrori ,4JJ01tetraoxacvclododecinor2,3- glquinazolin-4(3H -one

The product of Step 6 (130 mg, 0.41 mmol) and ammonium formate (95 mg, 1.5 mmol) was suspended in formamide (2 mL). The brown mixture was stirred at 155 °C under N₂ for 3 h. The mixture was cooled and partitioned between EtOAc and water and the organic layer was concentrated to yield the title compound as an off-white solid, 98 mg (80.3%). 1H NMR (400 MHz, CDC1₃): δ 12.1(s, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.16 (s, 1H). 4.18 (tt, 4H), 3.55 (tt, 4H).

MS (ES-API, pos. scan): 319.4 (M+Na)⁺.

Step 8. 4-chloro(l 0.10.1 1.1 1 -²H₄V 7.8.10.1 1.13.14-hexahydror 1.4.7.101- tetraoxacyclododecino Γ2.3 -gl quinazoline

The product of Step 7 (50 mg, 0.17 mmol) and phosphorus oxychloride (520 mg, 3.4 mmol) and DMF (3 drops) were mixed in CH₂C1₂ (2 mL) at room temperature. The suspension was stirred under reflux under nitrogen for 2 h. It then was cooled to 0 °C and quenched with aqueous NaHC0₃ solution. The product was extracted with more CH₂C1₂ (5 mL). The organic was concentrated to dryness, which was rinsed with 50% ether/hexane to yield the title compound as an tan solid, 40 mg (75.2%). 1H NMR (400 MHz, CDC1₃): δ 8.96 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 4.98 (tt, 4H), 3.9 (tt, 4H). MS (ES - API, pos. scan): 315.3 (M+H)⁺ Ste 9. N-(3-Ethvnylphenviy9,9J0J0-²H4 -6J,9J0J2J3-hexahvdrori,4JJ01- tetraoxacyclododecino[2,3-(i pyrimidin-4-amine

The product of Step 8 (40 mg, 0.12 mmol) was suspended in EtOH (2 mL) and DMF (2 drops), to which was added 3 -aminophenyl acetylene (18 mg, 0.15 mmol). The suspension was stirred at room temperature for 5 min. It then was heated to 85 °C and stirred under nitrogen overnight. The orange solution was concentrated to give an orange solid residue which was recrystallized from EtOAc to yield the title compound as an off- white solid, 30 mg (63.8%). 1H NMR (400 MHz, CDC1₃): δ 11.25 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.52 (t, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 4.39 (d, 2H), 4.32 (s, 1H), 3.80 (d, 2H). MS (ES - API, pos. scan): 396.4 (M+H)⁺.

EXAMPLE 3

Synthesis ofN-(3-ethynylphenyl)(6,6, 7, 7,12,12,13,13- H₈)-6, 7,9,10,12,13- hexahydrof 1, 4, 7, 10]tetraoxacyclododecino[2, 3-d] pyrimidin-4-amine (31)

Scheme 3 describes the synthesis of another deuterated derivative of Icobinib 31 by employing a similar chemical sequence to that of Scheme 1, except using ethylene glycol to react with THP protected deuterated 2-bromoethanol 2. Scheme 3

EXAMPLE 4

Synthesis ofN-[3-( H)ethynylphenyl] -6, 7,9,10,12,13- hexahydrof 1, 4, 7, 10]tetraoxacyclododecino[2, 3-d] pyrimidin-4-c

Scheme 4

Icotinib

Scheme 4 describes the synthesis of deuterated Icotinib derivative 32. Deprotonation of Icotinib with 2 equivalents of strong base, such as n-BuLi, followed by quenching with D₂0 affords the desired deuterated Icotinib derivative 32.

EXAMPLE 5

Synthesis ofN-[3-(²H)ethynylphenyl](6,6, 7, 7,12,12,13,13-²H₈)-6, 7,9,10,12,13- hexahydrof 1, 4, 7 ,10]tetraoxacyclododecino[2, 3-d] pyrimidin-4-amine (33)

Scheme 5

Scheme 5 describes the synthesis of deuterated Icotinib derivative 33. Deprotonation of compound 31 with 2 equivalents of strong base, such as n-BuLi, followed by quenching with D₂0 affords the desired deuterated Icotinib derivative 33. EXAMPLE 6

Synthesis ofN-[3-(²H)ethynylphenyl](6,6, 7, 7,9,9,10,10,12, 12, 13, 13-²H₁₂)-6, 7,9,10,12,13- hexahydrof 1, 4, 7, 10]tetraoxacyclododecino[2, 3-d] pyrimidin-4-amine (34) heme 6

Scheme 6 describes the synthesis of deuterated Icotinib derivative 34.

Deprotonation of compound 11 with 2 equivalents of strong base, such as n-BuLi, followed by quenching with D₂0 affords the desired deuterated Icotinib derivative 34.

EXAMPLE 7

Synthesis of N-[3-(²H)ethynylphenyl] ( 9,9, 10,10-²H₄)-6, 7,9, 10,12, 13- hexahydrof 1, 4, 7, 10]tetraoxacyclododecino[2, 3-d] pyrimidin-4-amine (35)

Scheme 6 describes the synthesis of deuterated Icotinib derivative 35. Deprotonation of compound 21 with 2 equivalents of strong base, such as n-BuLi, followed by quenching with D₂0 affords the desired deuterated Icotinib derivative 35.

The various deuterated Icotinib derivatives synthesized according to the methods described herein are being subjected to biological assays, stability studies, pharmacokinetics, and pharmacodynamics studies, among others, in comparison with Icotinib itself, which are incorporated herein by reference, and the data from these studies are an integral part of the invention disclosure in this Application.

It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the various embodiments of the present invention described herein are illustrative only and not intended to limit the scope of the present invention.

All publications cited in the specification, both patent publications and non-patent literature, are herein fully incorporated by reference in their entireties.

Claims

CLAIMS What is claimed is

1. A compound of Formula I:

Formula I ,

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,

wherein R 1 to R 13 are each independently selected from the group consisting of hydrogen and deuterium; and at least one of R 1 to R 13 is deuterium.

2. The compound of claim 1, wherein at least one of R 1 to R 13 independently has deuterium enrichment of no less than about 45%.

3. The compound of claim 1, wherein at least one of R 1 to R 13 independently has deuterium enrichment of no less than about 75%.

4. The compound of claim 1, wherein at least one of R 1 to R 13 independently has deuterium enrichment of no less than about 90%.

5. The compound of claim 1, wherein at least one of R 1 to R 13 independently has deuterium enrichment of no less than about 97%.

6. The compound of claim 1, wherein at least two of R 1 to R 13 are deuterium.

7. The compound of claim 1, wherein at least three of R 1 to R 13 are deuterium.

8. The compound of claim 1, wherein at least four of R 1 to R 13 are deuterium.

9. The compound of claim 1, wherein R 13 is deuterium.

1 12

10. The compound of claim 9, wherein at least one of R to R is deuterium.

1 12

11. The compound of claim 9, wherein at least two of R to R are deuterium.

12. The compound of claim 9, wherein R 1 to R 12 are each deuterium.

13. A compound having the formula selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

14. A pharmaceutical composition comprising a compound of any one of claims 1 to 13, and one or more pharmaceutically acceptable carriers.

15. A method of treating an EGFR kinase-mediated disease or disorder, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 13, or a pharmaceutical composition thereof, to a patient in need thereof.

16. The method of claim 15, wherein said disease or disorder is a

hyperproliferative disease or disorder.

17. The method of claim 16, wherein said hyperproliferative disease or disorder is selected from the group consisting of ovarian cancer, bladder cancer, colorectal cancer, head and neck cancer, brain cancer, endocrine cancer, prostate cancer, sarcoma, myeloid leukemia, solid tumors, small cell lung cancer, non-small cell lung cancer, astrocytoma, breast cancer, squamous cell carcinoma, pancreatic cancer, glioblastoma multiforme, renal cancer, gastric cancer, cancer of unspecified body location/system, and liver cancer.

18. The method of any one of claims 15 to 17, further comprising administering to the patient an additional therapeutic agent.

19. The method of claim 18, wherein said additional therapeutic agent is an anti-cancer agent.

20. The method of claim 18 or 19, wherein said additional therapeutic agent is selected from the group consisting of anastrozole, arimidex, cediranib, bexarotene, calcitriol, capecitabine, carboplatin, cefixime, celecoxib, canertinib, cisplatin,

dexamethasone, docetaxel, erbitux, etoposide, everolimus, everolimus, faslodex, fluorouracil, fulvestrant, gemcitabine, irinotecan, leucovorin, loperamide, oxaliplatin, paclitaxel, PEG-interferon alpha, pemetrexed, raltitrexed, simvastatin, sirolimus, sunitinib, tamoxifen, temozolomide, topotecan, trastuzumab, vorinostat, and vinorelbine.

21. Use of a compound of any one of claims 1 to 13, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of an EGFR kinase-mediated disease or disorder.

22. The use of claim 21 , wherein said disease or disorder is a

hyperproliferative disease or disorder.

23. The use of claim 22, wherein said hyperproliferative disease or disorder is selected from the group consisting of ovarian cancer, bladder cancer, colorectal cancer, head and neck cancer, brain cancer, endocrine cancer, prostate cancer, sarcoma, myeloid leukemia, solid tumors, small cell lung cancer, non-small cell lung cancer, astrocytoma, breast cancer, squamous cell carcinoma, pancreatic cancer, glioblastoma multiforme, renal cancer, gastric cancer, cancer of unspecified body location/system, and liver cancer.