WO2017079003A1 - Deuterated compounds for treating blood cancers, and compositions and methods thereof - Google Patents

Abstract

The invention provides novel chemical compounds useful for treating various blood cancers, or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.

Description

DEUTERATED COMPOUNDS FOR TREATING BLOOD CANCERS, AND

COMPOSITIONS AND METHODS THEREOF

Priority Claims and Related Patent Applications

[0001] This application claims the benefit of priority from U.S. Provisional Application Serial No. 62/249,991, filed on November 3, 2015, the entire content of which is incorporated herein by reference in its entirety.

Technical Fields of the Invention

[0002] The invention generally relates to therapeutics and treatment methods for certain diseases and conditions. More particularly, the invention provides novel chemical compounds, including 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one with deuterium- substitutions at strategic positions, useful for treating various blood cancers and related diseases and conditions, and pharmaceutical compositions and methods of preparation and use thereof.

Background of the Invention

[0003] Blood cancers (a.k.a., hematologic malignancies or liquid tumors) are forms of cancer that begin in the cells of blood-forming tissue, for example, the bone marrow or in the cells of the immune system. Examples of hematologic cancers include acute and chronic leukemias, lymphomas, multiple myeloma and myelodysplastic syndromes.

[0004] Leukemia is a group of cancers that usually begin in the bone marrow and result in high numbers of abnormal white blood cells. There are two types of leukemia: Lymphocytic leukemia involves lymphocytes. Myelogenous leukemia involves granulocytes. These white blood cells are important in fighting infections. Lymphoma is a type of cancer that develops in the lymphatic system.

[0005] Leukemia can be of a type called acute leukemia, which is characterized by a rapid increase in the number of immature blood cells, making the bone marrow unable to produce healthy blood cells. Immediate treatment is needed to slow down the rapid progression and accumulation of the malignant cells, which can spread to other organs of the body via the bloodstream.

[0006] Leukemia can be of a type called chronic leukemia, for example, chronic lymphocytic leukemia (CLL), which is characterized by the excessive buildup of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Chronic forms are occasionally monitored for some time before treatment to ensure maximum effectiveness of therapy.

[0007] There are two general types of lymphoma depending on how cancer spreads. In Hodgkin lymphoma, the cancer spreads from one group of lymph nodes to another in a certain order. In non- Hodgkin lymphoma, the cancer spreads from one group of lymph nodes to another in a random order. Examples of non-Hodgkin lymphoma include follicular B-cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL). Myeloma is a cancer that causes the plasma cells to form a tumor in the bone marrow. Myeloma is usually found in multiple places in the body, thus often called multiple myeloma.

[0008] Blood cancers such as CLL, FL and SLL are placing an increasing burden on society, impairing the health and lives of those affected. Although medications have been developed to treat some of these diseases and conditions, the available treatments are often limited in terms of clinical effectiveness and at the same time have undesirable side effects.

[0009] There is an urgent and growing need for innovative therapeutics and treatment methods that provide improved clinical effectiveness with reduced side effects.

Summary of the Invention

[0010] The invention provides novel, orally available phosphoinositide 3-kinase (PI3K) delta inhibitors. The chemical compounds and pharmaceutical compositions disclosed herein are biochemically potent and physiologically active with improved pharmacokinetic and toxicological properties over idelalisib. The compounds disclosed herein are deuterium-substituted and improved versions of idelalisib, where hydrogen is substituted by deuterium at strategic locations of the molecule. The substitution locations are selected with the specific objective to impact

pharmacokinetic and toxicological properties of the molecule. The resulting compounds have up to 7 deuterium substitutions and exhibit more desirable profiles in terms of safety, efficacy and tolerability in the treatment of blood cancers and related diseases and conditions, such as CLL, FL and SLL.

[0011] In one aspect, the invention generally relates to a compound having the structural formula of:

(I)

wherein each of R_1; R₂, R3, R4, R5, R6 and R7 is D,

or a pharmaceutically acceptable salt or ester thereof.

[0012] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound having the structural formula of:

(I)

wherein each of R_1; R2, R3, R4, R5, R6 and R7 is D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more blood cancers, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0013] In yet another aspect, the invention generally relates to a unit dosage form comprising the pharmaceutical composition disclosed herein. The unit dosage is suitable for administration to a subject suffering from one or more blood cancers, including advanced hematologic malignancies, or a related disease or disorder thereof.

[0014] In yet another aspect, the invention generally relates to a method for treating, reducing, or preventing a disease or disorder. The method includes: administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

wherein each of R_1; R2, R₃, R4, R5, R6 and R7 is D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more blood cancers, or related a related disease or disorder thereof.

[0015] In certain embodiments, the one or more blood cancers include diseases and conditions that may benefit from treatment using the compounds, pharmaceutical composition, unit dosage form and treatment method disclosed herein include any diseases and disorders that may be addressed through inhibition of the delta isoform of PI3K, such as ALL, FL and SLL.

[0016] In certain preferred embodiments, the method of treatment includes administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

(I)

wherein each of R_1; R2, R₃, R4, R5, R6 and R7 is D, or a pharmaceutically acceptable salt or ester thereof, in combination with one or more other anti-cancer agents.

Brief Description of the Drawings

[0017] FIG. 1 shows certain exemplary ¹HNMR (CDCI₃) of a compound disclosed herein.

[0018] FIG. 2 shows certain exemplary ¹HNMR (CDCI₃) of a compound disclosed herein.

[0019] FIG. 3 shows certain exemplary LC-MS data of a compound disclosed herein.

[0020] FIG. 4 shows certain exemplary ¹HNMR (CDCI₃) of a compound disclosed herein.

[0021] FIG. 5 shows certain exemplary ¹HNMR (CDCI₃) of a compound disclosed herein.

[0022] FIG. 6 shows certain exemplary ¹HNMR (CDCI₃) of a compound disclosed herein.

[0023] FIG. 7 shows certain exemplary HPLC data of a compound disclosed herein.

[0024] FIG. 8 shows certain exemplary data on percentage of compound remaining vs. incubation time. After 4 hour, the concentration of D₇-idelalisib is approximately equal to 220% of idelalisib. [0025] FIG. 9 shows certain exemplary comparison of idelalisib vs. D_7-idelalisib in the formation of oxidative metabolites formed by purine ring oxidation on carbon-8.

Definitions

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0027] As used herein, "administration" of a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, as discussed herein.

[0028] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer. The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0029] As used herein, the terms "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred.

Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the

pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0030] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and/or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any

combination thereof.

[0031] As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0032] As used herein, the term "pharmaceutically acceptable enol ethers" include, but are not limited to, derivatives of formula -C=C(OR) where R can be selected from alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula -C=C(OC(0)R) where R can be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.

[0033] As used herein, a "pharmaceutically acceptable form" of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

[0034] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1 -19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of

pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate,

benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, gly colic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0035] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Ci_₄alkyl)⁴ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0036] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate" . Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0037] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "pro-drug") refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subj ect, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0038] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21 -24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," A. C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0039] As used herein, the term "pharmaceutically acceptable" excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol;

polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0040] As used herein, the term "subject" refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0041] As used herein, the "low dosage" refers to at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition. For example, a low dosage of an agent that reduces glucose levels and that is formulated for

administration by inhalation will differ from a low dosage of the same agent formulated for oral administration. [0042] As used herein, the "high dosage" is meant at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest standard recommended dosage of a particular compound for treatment of any human disease or condition.

[0043] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% ("substantially pure"), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0044] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

Detailed Description of the Invention

[0045] The invention provides novel chemical entities that are biochemically potent and physiologically active with improved pharmacokinetic and toxicological properties over 5-fluoro-3- phenyl-2-[(l S)-l-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one (Idelalisib), shown below.

Idelalisib

[0046] Idelalisib (Zydelig^®) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), approved for use in combination with rituximab for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other comorbidities. Idelalisib is also indicated to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.

[0047] The US FDA's prescribing information for Idelalisib contains a black box warning for fatal and/or severe adverse reactions. Recently, six clinical trials exploring combinations of idelalisib with other therapies were halted due to reports of an increased rate of adverse events, including death, for patients with hematologic malignancies.

(http://www.fda. gov/Drugs/DrugS afety/ ucm490618.htm)

[0048] Clinical studies have revealed serious toxicities associated with idelalisib, including hepatic, severe diarrhea, colitis, pneumonitis and intestinal perforation. Fatal and/or serious hepatotoxicity occurred in 14% of idelalisib-treated patients. Fatal and/or serious and severe diarrhea or colitis occurred in 14% of idelalisib-treated patients. In addition, fatal and serious pneumonitis can occur in idelalisib-treated patients.

[0049] Serious adverse reactions were reported also reported when is used with rituximab. For example, in 49% of patients treated with idelalisib and rituximab showed serious adverse reactions. The most frequent serious adverse reactions were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%) and diarrhea (5%). Adverse reactions that led to discontinuation of rituximab occurred in 10% of patients. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis. Thirty-five percent of patients had dose interruptions and 15% had dose reductions due to adverse reactions or laboratory abnormalities. The recommended maximum starting dose of idelalisib is 150 mg administered orally twice daily.

[0050] The compounds disclosed herein are deuterium-substituted versions of idelalisib, where hydrogen is replaced with deuterium at strategic locations of the molecule. The substitution locations are selected with the specific objective to impact pharmacokinetic and toxicological properties of the molecule.

Dy-Idelalisib [0051] The preferred compound, shown above, has 7 deuterium substitutions and exhibits superior safety, efficacy and tolerability profiles. The compound affords new and improved options in the treatment of blood cancers and related diseases and conditions, such as CLL. The compound may also be used to treat FL and SLL (e.g., relapsed FL or SLL, in particular after prior systemic therapies).

[0052] The major metabolite of idelalisib, GS-563117, did not significantly inhibit Class I PI3K kinase activity in in vitro enzyme assays at <10 μΜ (-17 times the clinical free Cmi_n for this metabolite). Therefore, this metabolite is not expected to contribute significantly to the efficacy of the drug.

GS-563117

[0053] While GS-563117 was a significant metabolite in humans (exposures [AUC] were 3.3 times those of idelalisib), it was only a minor metabolite in animal species (exposures [AUC] to GS- 563117 were 0.7-3.6%, 4.4-8.9% and 16-66% those of idelalisib in rats, rabbits and dogs, respectively). Researches to date indicated that this oxidation product (formed by purine ring oxidation on carbon-8) may be responsible for the skin toxicity, reproductive toxicity and phototoxicity of Idelalisib.

[0054] GS-563117 has significant inhibitory activity on Ste20-Like Kinase (SLK) and

Lymphocyte-Oriented Kinase (LOK) at clinically relevant concentrations. The pharmacological activity oxidation product at carbon-8 of the purine ring is against the LOK and SLK kinases that may activate lymphocytic response and lead to skin disorder.

[0055] The adverse embryofoetal effects are associated with inhibition of SLK by the idelalisib metabolite, GS-563117. SLK is expressed in the muscle and neuronal lineages in the developing embryo and inactivation of this kinase has led to embryofoetal deaths. The findings in rat experiments indicate a risk to the developing fetus if idelalisib is taken during pregnancy.

[0056] GS-563117 was clearly shown to be phototoxic to cultured cells (IC50 16-23 μg/mL; ERC_max 5-7) in in vitro experiment. In tissue distribution studies, there appeared to be some retention of drug related material in pigmented tissues. Since idelalisib and GS-563117 absorbs light, distributes and is retained in pigmented skin, and the metabolite GS-563117 was shown to be phototoxic in vitro, some phototoxic skin reactions may be seen in vivo.

[0057] An in vitro photo-toxicity study was reported to be conducted in the embryonic murine fibroblast BALB/c 3T3 cell line using Neutral Red uptake as a marker of cellular viability in the presence and absence of ultraviolet A (UVA) light exposure. The study showed that the primary human metabolite, GS-563117, induced photo-toxicity in the presence of UVA exposure. This metabolite has a very high exposure in humans (3.3 times of idelalisib) and is responsible for several serious toxicities.

[0058] Furthermore, GS-563117 inhibits the catalytic activities of cytochrome P450 enzymes CYP2C9, CYP3A, CYP2C8 and CYP2C19. Some patients were co-administered CYP2C8, CYP2C9 or UGT1 Al substrates, especially about 30% of patients enrolled in NHL and CLL trials were coadministered sensitive CYP2C19 substrates, including lansoprazole and omeprazole. The incidence of diarrhea and rash were higher in patients taking proton pump inhibitors (PPI). These adverse events are associated with both PPI and idelalisib. The exposure to idelalisib is similar in patients taking acid-reducing agents (ARA) as compared to patients not taking these agents. Overlapping adverse events or an increased exposure to PPI (CYP2C19 substrates) may explain the increased incidence of adverse events. Higher exposures (5-12 times) for PPI have been observed in poor CYP2C19 metabolizers and dose-response has been observed with diarrhea and infections.

Therefore, GS-56311, as its plasma concentration is much higher than idelalisib in human, may cause toxicities through drug-drug interaction (DDI) in patients taking other medicines. [0059] The invention aims at reducing metabolite caused toxicities while increasing parent drug exposure. The invention provides compounds that are orally available phosphoinositide 3-kinase (PI3K) delta inhibitors. In particular, the compounds target PI 105, the delta isoform of PI3K, one of the proteins responsible for leukemia and other cell growth.

[0060] In one aspect, the invention generally relates to a compound having the structural formula of:

(I)

wherein each of R_1; R2, R3, R4, R5, R6 and R7 is D,

or a pharmaceutically acceptable salt or ester thereof.

[0061] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound having the structural formula of:

wherein each of R_1; R2, R3, R4, R5, R6 and R7 is D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more blood cancers, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0062] In yet another aspect, the invention generally relates to a unit dosage form comprising the pharmaceutical composition disclosed herein. The unit dosage is suitable for administration to a subject suffering from one or more blood cancers, including advanced hematologic malignancies, or a related disease or disorder thereof.

[0063] In yet another aspect, the invention generally relates to a method for treating, reducing, or preventing a disease or disorder. The method includes: administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

(I)

wherein each of R_1; R₂, R₃, R4, R5, R6 and R7 is D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more blood cancers, or related a related disease or disorder thereof.

[0064] In certain embodiments, the one or more blood cancers include diseases and conditions that may benefit from treatment using the compounds, pharmaceutical composition, unit dosage form and treatment method disclosed herein include any diseases and disorders that may be addressed through inhibition of the delta isoform of PI3K, such as ALL, FL and SLL.

[0065] In certain preferred embodiments, the method of treatment includes administering to a subject in need thereof a pharmaceutical composition comprising compound having the formula of:

(I)

wherein each of R_1; R₂, R₃, R4, R5, R6 and R7 is D, or a pharmaceutically acceptable salt or ester thereof, in combination with one or more other anti-cancer agents. [0066] The one or more other anti-cancer agents may be a small molecule, a chemotherapeutic agent, a peptide, a polypeptide or protein, an antibody, an antibody-drug conjugate, an aptamer or nucleic acid molecule.

[0067] In certain embodiments, the one or more other anti-cancer agents are chemotherapeutic agents, chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole

(FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584

(Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin

(Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271 ; Sugen), alkylating agents such as thiotepa and

CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and

methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;

nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g. , calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemicin, including dynemicin A;

bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine,

ADRIAMYCIN^® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esonibicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;

amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK^® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2' ,2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara- C"); cyclophosphamide; thiotepa; taxoids, e.g. , TAXOL^® (paclitaxel; Bristol-Myers Squibb

Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and

TAXOTERE^® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR^® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE^® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine

(XELODA^®); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0068] In certain preferred embodiments, the one or more other anti-cancer agents are selected from monoclonal antibodies against CD20 protein, for example, rituximab.

[0069] Rituximab is a chimeric monoclonal antibody against CD20 protein, which is primarily found on the surface of immune system B cells. Rituximab is used to treat diseases characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells, including many lymphomas, leukemias, transplant rejection, and autoimmune disorders. [0070] The compounds disclosed herein may serve as second line drugs for patients whose CLL has relapsed. These compounds may be used in combination with rituximab in patients when CLL has come back after prior cancer treatment. These compounds are particularly effective in patients who have a p53 mutation, which otherwise tends to impart a poor prognosis in CLL patients.

[0071] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[0072] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alignates, gelatin,

polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv)

disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[0073] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[0074] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

[0075] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and frafts-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0076] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0077] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

Examples

Synthesis of D7-Idelalisib (Compound J-D7)

Synthesis of Compound D

[0078] 1.9 g L-2-aminobutyric acid d₆ (17.4 mmoL) was dissolved in 18 mL 1M sodium hydroxide solution and 13 mL MeOH, cooled with ice-bath, were dropped in 4.8 mL B0C2O (20.9 mmol). The reaction was stirred at room temperature overnight. Rotavap was used to remove MeOH, then the pH was adjusted to ~2 with 1M hydrochloride solution, extracted with ethyl acetate, combined organic layer, washed with brine, then dried with Magnesium Sulfate anhydrous, followed by filtration, rotavap removal of solvent, and vacuum dry with oil pump. The product was collected as colourless or slightly yellow sticky wax (3.5 g, 96% yield, including trace ethyl acetate residue). NMR (CDCI₃) is shown in FIG. 1. Synthesis of Compound E

[0079] 4.45 g (17.1 mmol) of compound C was suspended in 10 mL thionyl chloride, and 50 DMF was dropped in. The reaction mixture was refluxed for about 2 hours. Thionyl chloride was removed via rotavap. Toluene was used to help remove the residue.

[0080] 3.40 g (16.2 mmol) of compound D and 3.1 mL triethylamine (TEA) were dissolved in 20 mL anhydrous DCM and cool at ice bath for 5-10 min. The above intermediate from compound C was also dissolved in 20 mL dichloromethane (DCM). The intermediate solution was dropped to cold solution slowly. The reaction mixture was stirred at room temperature over a weekend. The reaction mixture was extracted with water, sodium bicarbonate (sat.), 5% citric acid, water and brine, and dried with MgSC>4 (anh.). After filtration and concentration, the target compound was purified with flash column. Compound E was collected as beige foam-like solid (6.4 g, yield 82%). ¹HNMR (CDCI₃) is shown in FIG. 2. LC-MS is shown in FIG. 3.

Synthesis of Compound G

[0081] A solution of compound E (14 mmol) in acetic acid (60 mL) was treated with zinc dust (5.13g, 6 eq.), which was added in 3 portions. The reaction mixture was allowed to cool to below 35 °C between additions. After stirring for overnight at ambient temperature, solids were filtered off and washed with acetic acid (5 mL). The filtrate was concentrated in vacuo, dissolved in EtOAc, and washed with water. The water layer was extracted with EtOAc. The combined organic layer was washed with water, saturated sodium bicarbonate and saturated brine, dried with magnesium sulfate anhydrous and then concentrated to a syrup. The syrup was purified by flash chromatography to yield compound G as an off-white foamy solid (3.74 g, 66% yield). ¹HNMR (CDC1₃) is shown in FIG. 4.

Synthesis of Compound H

[0082] A solution of compound G (9.17 mmol) in DCM (10 mL) was treated with

Trifluoroacetic acid (TFA) (10 mL). The reaction mixture was stirred for 1 hour, concentrated in vacuo, and partitioned between DCM and 10% potassium carbonate (aqueous layer pH -10 after extraction). The aqueous layer was extracted with additional DCM, and the combined organic layer was washed with water and brine, and dried with magnesium sulfate anhydrous. The solution was concentrated to provide compound H as an off-white solid (2.42 g, 87% yield). ¹HNMR (CDCI₃) is shown in FIG. 5.

Synthesis of Compound I [0083] To a 1 L flask, 6-chloropurine (30 g, 194.1 mmole, 1 equiv), 3, 4-dihydropyran (24.5 g, 291.1 mmol, 1.5 equiv) and PTSA monohydrate (2.95 g, 15.5 mmol, 8% equiv) were added, followed by EtOAc (240 mL). The mixture was refluxed for 2 hours. After the mixture cooled down, it was washed with NaHCCh (250 mL) to adjust pH = 7-8 and brine 150 mL x 3. The EtOAc layer was dried over Na2SC>4 and concentrated to dryness. The residue was purified by silica gel plug with hexane : EtOAc (2: 1, 1 : 1 and 1 :2 ) to get 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine as an off-white solid (31.6 g, 67%).

[0084] To a 100 mL round-bottom flask under N₂ at -40 °C, n-BuLi (2.5 M, 23.5 mL, 58.7 mmol, 1.4 equiv) was added drop-wise to diisopropylamine (5.94 g, 58.7 mmol, 1.4 equiv) in tetrahydrofuran (THF) (40 mL). The temperature of the mixture was raised to -10 °C. Then the mixture was cooled to -70 °C. 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (10 g, 41.9 mmol, 1 equiv) in THF (20 mL) solution was added drop-wise, while maintaining the temperature below -68 °C. The mixture was stirred for 1 hour and then 5 mL D₂0 was added. The temperature of the mixture rose to 10 °C, 2 N HC1 was added to the mixture to adjust to pH = 8. The separated THF layer was concentrated. The aqueous phase was extracted with EtOAc (100 mL x 2). The EtOAc layer was combined with concentred THF and washed with brine (75 mL x 2), and dried over Na₂S0₄. The solvent was evaporated to give a red oil. Repeat the above H-D exchange procedure twice. The crude product was purified by silica gel plug with hexane:EtOAc (5: 1, 4: 1, 3: 1, 2.5: 1) to afford compound I as yellow oil (5.6 g, 56% yield).

Synthesis of Compound K

[0085] Compound H (2. 5 g, 8.24 mmol, 1) and compound I (1.97 g, 8.24 mmol, 1 equiv) were mixed with Ν,Ν-Diisopropylethylamine (DIPEA) (3.2 g, 24.7 mmol, 3 equiv) and t-Butyl-OD (13 mL) in a 150 mL sealed tube. The mixture was heated by oil-bath at 88 °C. After 40 hours, the mixture was concentrated to dryness. The residue was recrystallized with isopropanol (50 mL) to give compound K as a yellow solid (3 g, 55% yield).

Synthesis of Compound J-D 7

[0086] To compound K (3.2 g, 6.3 mmol) in EtOH (4 mL), 6 N HC1 (3.5 mL) was added. The mixture was stirred at room temperature for 1 hour and diluted with water (20 mL). To the mixture, NaHC0₃ aqueous solution (3 g in 100 mL of water) was added drop-wise, and white solids precipitated. The suspension was stirred for 30 min and filtered. The solid was washed with water (25 mL x 2) and dried under vacuum at 50 °C to give compound K-D7 as an off-white solid (2. 3 g, 86% yield). ¹HNMR (CDC1₃) is shown in FIG. 6. ^XH-NMR (500 MHz, DMSO-d6): 12.93 (s, 1H), 8.17 (s, 1H), 7.74-7.81 (m, 2H), 7.48-7.54 (m, 5H), 7.41-7.43 (d, 1H), 7.22-7.27 (dd, 1H); HPLC 97.0% purity (method: 150 mm C18 reverse phase column with gradient method 5-95% ACN+0.1% trifluoroacetic acid in 11 min; Wavelength: 254 nm): retention time: 6.44 min. HPLC is shown in FIG. 7

Pharmacokinetic and Drug Metabolism Study of Idelalisib and D7-Idelalisib with Human Hepatocyte

[0087] This study was carried out to evaluate the stability of the test compounds upon metabolism by cryopreserved human hepatocytes.

[0088] Cryopreserved hepatocytes represent a well-accepted experimental system for the evaluation of drug properties including metabolic stability, metabolite identification, drug-drug interaction potential, and hepatotoxic potential. Cryopreserved human hepatocytes were obtained from IV AL LLC. The donor characteristics of the hepatocyte lot (HH1009) used for the study was as follows:

[0089] The test article was administered in vitro directly or through a solvent compatible with the test system. Studies were performed in uncoated 24-well plates.

[0090] The No-Cells (NC) Negative Control consisted of the addition of test article but no hepatocytes added. These samples represented possible chemical degradation and/or adsorbance to surfaces and "stickiness" of a particular compound. No Cells control was also run at similar time points (i.e. T= 0 min, 30 min, 60 min, 120 min, 180 min and 240 min). The no cell control was carried out in incubation media and was run as single incubation as per the request of the sponsor.

[0091] Cryopreserved hepatocytes were thawed in a 37 °C water bath and placed on ice. The thawed hepatocytes were recovered using Universal Cryopreserved Recovery Medium™ (UCRM™) and centrifuged at 100 x g for 5 minutes to remove residual cryopreservants. The hepatocyte pellet was re-suspended in William's E based medium HIM. Viability and cell concentration were determined based on trypan blue exclusion using a hemacytometer. The cell suspension was adjusted to 1.11 x 10⁶ cells per mL and placed on ice until use.

[0092] The final reaction mixture for hepatocyte metabolism consisted of HIM, hepatocytes at 1 x 10⁶ cells per mL and the test article or negative controls.

[0093] The study was designed such that a reference article (idelalisib) was used along with the test article (D₇-idelalisib) per group. The final concentration of reference article and the test article at the initiation of incubation was 2 μΜ. Each test article including reference article was prepared as 20,000 x stock in DMSO at concentration of 40 mM. Each test article was mixed with reference article in equal volume to prepare a combined 10,000 x DMSO stock of 20 mM each. This DMSO stock is diluted 1000 x in HIM to prepare a 10 x dosing stock of 20 μΜ. This dosing stock was diluted to 2 μΜ upon addition to medium containing hepatocytes or blank medium.

[0094] Incubation of the hepatocytes with 2 μΜ test article + reference article was performed in triplicates in a incubator maintained at constant temperature 37° C and humidified atmosphere of 5% CO2 and 95% balanced air for time periods of 0, 30, 60, 120, 180 and 240 minutes and with the concentrations of the hepatocytes at 1 x 10⁶ cells per mL. Negative controls included samples in the absence of hepatocytes (incubation media) but with 2 μΜ test article + reference article only at the same six time points. These controls were conducted under identical conditions. Total reaction volume was 500 μΐ. (0.450 mL hepatocytes suspension + 0.050 mL incubation buffer media with lOx test compound or positive control). All samples except negative control were run in triplicates.

[0095] Reactions were initiated with the addition of 0.050 mL of the appropriate test chemical in buffer (mixing -up and down motion of the multichannel pipet to mix well test article with incubation media mixture), and placed in a 37°C incubator. At designated time points, 50 μΐ. of samples were collected from each treatment group followed by addition of 100 μΐ. of ice-cold acetonitrile containing 1 μg/mL carbutamide (internal standard). Internal standards were added to all the samples.

[0096] Test article concentrations: One concentration (2.0 μΜ) of the test article+ reference article was used in all incubations.

[0097] Positive Controls: The reference article at 2 μΜ in each group served as positive control.

[0098] Termination: After incubation, the reaction was terminated with as described previously. The total mixture after termination was stored frozen for LCMS analysis.

[0099] FIG. 8 shows the percentage of compounds remaining vs. incubation time. After 4 hour, the concentration of D₇-idelalisib is approximately equal to 220% of idelalisib. The result showed D₇- idelalisib has longer half-life and AUC. This substantial difference indicates superior DMPK property of Dy-idelalisib.

Toxicity of Oxidation Product

[00100] As pointed herein, researches indicated that the oxidation product (formed by purine ring oxidation on carbon-8) may be responsible for the skin toxicity, reproductive toxicity and phototoxicity of Idelalisib. Selectively modify the molecular structure to reduce the formation of the metabolite may lead to minimize toxic side effects in human application. The samples generated from the procedure described herein (para. [0086]-[0097]) were analyzed to compare the formation of the metabolite.

[00101] FIG. 9 compares idelalisib vs. D₇-idelalisib in the formation of oxidative metabolites formed by purine ring oxidation on carbon-8. The results supported that D₇-idelalisib slowed the metabolism that may cause toxicity in human disease treatment.

Measurement of IC50 for PI3K delta

[00102] The study of measuring IC50 for lipid kinase PI3K delta was performed on

Homogeneous Time-Resolved Fluorescence (HTRF) platform. The PIP3 product was detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labeled anti- GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex resulted in an energy transfer to the APC and a fluorescent emission at 665 nm. The PIP3 product formed by PI 3- Kinase(h) activity displaced biotin-PIP3 from the complex resulting in a loss of energy transfer and thus a decrease in signal. It was a 3-step reaction: First, the kinase reaction with PIP2 substrate was carried out in the presence of ATP, and then the reaction was quenched with Stop Solution, and finally detected by adding Detection Mixture followed by incubation. The Control Inhibitor was PI- 103. The emission ratio was converted into μΜ PIP3 production based on PIP3 standard curves. The nonlinear regression to obtain the standard curve and IC50 values were performed using Graphpad Prism software.

[00103] Idelalisib and D₇-idelalisib were received as a 2 mg/mL stock in DMSO. Both compounds were tested against 1 PI3K isoform. These compounds were tested in 10-dose IC50 mode starting at a concentration of 2 μΜ. Control compound, PI-103, was tested in 10-dose IC50 with 3-fold serial dilution starting at 10 μΜ. Reactions were carried out at 10 μΜ ATP. HTRF assay format was used for POKs. Curve fits were performed where the enzyme activities at the highest concentration of compounds were less than 65%.

[00104] The calculated IC50 values for idelalisib and D₇-idelalisib were 3.5 nM and 1.1 nM.

Table 1 IC50 for PI3K delta

[00105] Applicant's disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to "one embodiment," "an embodiment," or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[00106] The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant's composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[00107] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[00108] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed. Incorporation by Reference

[00109] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

Equivalents

[00110] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

is claimed is: CLAIMS

A compound having the structural formula of:

or a pharmaceutically acceptable salt or ester thereof

2. A pharmaceutical composition comprising a compound having the structural formula of:

or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce or more hematologic malignancies, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

A unit dosage form comprising the pharmaceutical composition of claim 3.

4. A method for treating, reducing, or preventing a disease or disorder, comprising: administering to a subject in need thereof a pharmaceutical composition comprising a compound having the formu

or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more hematologic malignancies, or a related disease or disorder thereof.

5. The method of claim 4, wherein the one or more blood cancers are selected from chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL).

6. The method of any of claims 4 or 5, wherein the compound is administered in combination with one or more other anti-cancer agents.

7. The method of claim 6, wherein the one or more other anti-cancer agents is one or more other anti-cancer agents may be a small molecule, a chemotherapeutic agent, a peptide, a polypeptide or protein, an antibody, an antibody-drug conjugate, an aptamer or nucleic acid molecule.

8. The method of claim 6, wherein the one or more other anti-cancer agents are selected from monoclonal antibodies against CD20 protein.

9. The method of claim 8, wherein the one or more other anti-cancer agents is rituximab.