WO2017087207A1 - Deuterated compounds for treating hematologic malignant, inflammatory and autoimmune diseases - Google Patents

Abstract

The invention provides novel chemical compounds useful for treating various hematologic malignancies and inflammatory and autoimmune diseases or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.

Description

DEUTERATED COMPOUNDS FOR TREATING HEMATOLOGIC MALIGNANT, INFLAMMATORY AND AUTOIMMUNE DISEASES

Priority Claims and Related Patent Applications

[0001] This application claims the benefit of priority from U.S. Provisional Application Serial No. 62/255,704, filed on November 16, 2015, and Serial No. 62/312,499, filed on March 24, 2016, the entire content of each 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 (S)- 3-(l-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one with one or more deuterium-substitutions at strategic positions, that exhibit immunomodulating and antineoplastic activities and are useful for treating various hematologic malignancies and inflammatory and autoimmune diseases and related diseases and conditions, and pharmaceutical compositions and methods of preparation and use thereof.

Background of the Invention

[0003] Tens of millions of people are affected by immune system disorders, which include abnormally low activity or over activity of the immune system. In cases of overly active immune system, the body attacks and damages its own tissues (or autoimmune diseases). In the case of immune deficiency diseases where the immune system is overly inactive, the body's ability to fight invaders decease leaving the patient vulnerability to infections. Currently, treatment for autoimmune diseases focuses on relieving symptoms because there is no curative therapy.

[0004] 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.

[0005] 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 fight infections. Lymphoma is a type of cancer that develops in the lymphatic system.

[0006] 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. 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 sometimes 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] Immune system disorders and blood cancers are placing an increasing burden on society, impairing the health and lives of those affected. Although medications have been used to 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] 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 and R6 is independently selected from H and D, and at least Ri, R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof.

[0011] 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 and R6 is independently selected from H and D, and at least one of Ri, R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof, in a mammal, including a human, and a

pharmaceutically acceptable excipient, carrier, or diluent. [0012] 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 of hematologic malignancies, inflammatory and autoimmune diseases and related diseases and conditions.

[0013] 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 and R6 is independently selected from H and D, and at least one of Ri, R₂, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof.

[0014] The one or more 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 and/or gamma isoforms of PI3K, including hematologic malignancies (e.g., ALL, FL and SLL),

inflammatory and autoimmune diseases.

Brief Description of the Drawings

[0015] FIG. 1 shows certain exemplary ¹HNMR (DMSO-d6) of a compound disclosed herein.

[0016] FIG. 2 shows certain exemplary ¹HNMR (DMSO-d6) of a compound disclosed herein. [0017] FIG. 3 shows certain exemplary comparison of duvelisib vs. D₅-duvelisib in the formation of oxidative metabolites formed by purine ring oxidation on carbon-8.

[0018] FIG. 4 shows certain exemplary comparison of duvelisib vs. D₂-duvelisib in the formation of oxidative metabolites formed by purine ring oxidation on carbon-8.

Definitions

[0019] 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.

[0020] 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.

[0021] 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 herein. In some embodiments, for example, 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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 subject, 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] As used herein, the "low dosage" generally 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. By way of an 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. [0035] As used herein, the "high dosage" is generally 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.

[0036] 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.

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

[0037] The invention provides novel chemical entities that are biochemically potent and physiologically active with improved pharmacokinetic and toxicological properties over 8-Chloro-2- phenyl-3-[(15 -l-(3H-purin-6-ylamino)ethyl]-l(2H)-isoquinolinone (or 8-Chloro-2-phenyl-3-[(15 -l- (3H-purin-6-ylamino)ethyl]-l(2H)-isoquinolinone) (Duvelisib), shown below.

Duvelisib

[0038] The compounds disclosed herein are deuterium-substituted versions of the above compound, where hydrogen is substituted with deuterium at strategic locations of the molecule. The compounds disclosed herein are orally available phosphoinositide 3 -kinase (PI3K) delta and gamma inhibitors. The substitution locations are selected with the specific objective to impact

pharmacokinetic and toxicological properties of the molecule. The resulting compounds have 1 to 6 deuterium substitutions and exhibit more desirable profiles in terms of safety, efficacy and tolerability in the treatment of blood cancers, inflammatory diseases and immune system disorders and related diseases and conditions, including CLL, FL and SLL.

[0039] POKs, a lipid kinase family, are expressed in mammalian cells. They play a significant role in intracellular signaling of different receptor tyrosine kinases and GPCRs. Isoforms of POKs include delta (δ) and gamma (γ) isoforms, which have been shown to preferentially express in cells of the immune system. Inhibition of PI3K signaling presents a new pathway to therapeutic treatments of inflammatory and autoimmune diseases as well as hematological malignancies. (Okkenhaug 2013 Chem Biol. 20(11): 1309-1310; Winkler et al. 2013 Chem Biol. 20(11): 1364- 1374; Rommel, et al. 2007 Nat Rev Immunol. 7(3): 191-201 ; Vanhaesebroeck, et al. 2010 Nat Rev Mol Cell Biol.

11(5):329-341. Foster, et al. 2012 Pharmacol Rev. 64(4): 1027-54.)

[0040] The compounds disclosed herein 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. 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.

[0041] The compounds disclosed herein may also be used to treat relapsed FL, in particular after prior systemic therapies. The compounds disclosed herein may also be used to treat relapsed SLL, in particular after prior systemic therapies.

[0042] 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.

[0043] 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 C_mi_n for this metabolite). Therefore, this metabolite is not expected to contribute significantly to the efficacy of the drug.

GS-563117

[0044] 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). So far, researches 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.

[0045] 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 which may activate lymphocytic response andlead to skin disorder.

[0046] 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.

[0047] GS-563117 was clearly shown to be phototoxic to cultured cells (IC50 16-23 μg/mL; ERCmax 5-7) in in viteo experiment. In tissue distribution studies, there appeared to be some retention of drug related material in pigmented tissues. Since idelalisib and GS-563117 absorb light, distribute to and are retained in pigmented skin, and the metabolite GS-563117 has been shown to be phototoxic in vitro and some phototoxic skin reactions have been observed in vivo.

[0048] An in vitro photo-toxicity study was reportedly 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.

[0049] Duvelisib does generate the metabolite of CARBON-8 as Idelalisib. It is expected that the metabolite to cause the same toxicities. Thus, minimizing the formation of the toxic metabolite is key to improve the toxicological profile of the PI3K delta inhibitor.

[0050] 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 and R6 is independently selected from H and D, and at least one

Ri, R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof.

[0051] In certain embodiments of (I), R6 is H and the compound has the structural formula of:

(II)

[0052] In certain embodiments of (II), each of Ri and R5 is D and each of R2, R3 and R4 is H, having the structural formula of:

[0053] In certain embodiments of (II), each of R_1; R2, R3, R4 and R5 is D, having the structural formula of:

[0054] In certain embodiments of (II), each of R2, R3, R4 and R5 is D and Ri is H, having the structural formula of:

In certain embodiments of (II), each of R_1; R2, R3 and R4 IS H and R5 is D, having the formula of:

[0056] In certain embodiments of (II), one of R_1; R2, R3 and R4 is D and the others are H. In certain embodiments, two of R_1; R2, R3 and R4 are D, and the remaining one and R5 are H.

[0057] In certain embodiments of (I), R6 is D and the compound has the structural formula of:

(III)

In certain embodiments of (III), Ri is D and each of R2, R3, R4 and R5 is H, having the formula of:

[0059] In certain embodiments of (III), each of Ri and R5 is D and each of R2, R3 and R4 is H, having the structural formula of:

[0060] In certain embodiments of (III), each of R_1; R2, R3 and R4 is D, and R5 is H having the structural formula of:

[0061] In certain embodiments of (III), each of R_1; R2, R3, R4 and R5 is D, having the structural formula of:

[0062] In certain embodiments of (III), each of R2, R3 and R4 is D and each of Ri and R5 is H, having the structural formula of:

In certain embodiments of (III), each of R2, R3, R4 and R5 is D and Ri is H, having the formula of:

In certain embodiments of (III), each of R_1; R2, R3 and R4 IS H and R5 IS D, having the formula of:

[0065] In certain embodiments of (III), one of R_1; R2, R3 and R4 is D and the others are H. In certain embodiments, two of R_1; R2, R3 and R4 are D, and the remaining one and R5 are H.

[0066] 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 and R6 is independently selected from H and D, and at least one of Ri, R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof, in a mammal, including a human, and a

pharmaceutically acceptable excipient, carrier, or diluent. [0067] In certain embodiments, the invention provides a pharmaceutical composition comprising a compound having the structural formula of:

(II)

wherein each of R_1; R2, R3, R4 and R5 is independently selected from H and D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0068] In certain embodiments, the invention provides a pharmaceutical composition comprising a compound having the structural formula of:

(III)

wherein each of R_1; R2, R3, R4 and R5 is independently selected from H and D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0069] 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 of hematologic malignancies, inflammatory and autoimmune diseases and related diseases and conditions.

[0070] 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 and R6 is independently selected from H and D, and at least one of Ri, R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof.

[0071] In certain embodiments, the invention provides 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 and R5 is independently selected from H and D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0072] In certain embodiments, the invention provides 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:

(III)

wherein each of R_1; R2, R3, R4 and R5 is independently selected from H and D, or a pharmaceutically acceptable salt or ester thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies, inflammatory and autoimmune diseases, or related a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0073] In certain embodiments, the one or more 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 and/or gamma isoforms of PI3K, including hematologic malignancies (e.g., ALL, FL and SLL), inflammatory and autoimmune diseases.

[0074] 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 and R6 is independently selected from H and D, and at least one of Ri, R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof, in combination with one or more other anti-cancer agents.

[0001] In certain embodiments of (I), R6 is H and the compound has the structural formula of:

(II)

[0075] In certain embodiments of (I), R.6 is D and the compound has the structural formula

(HI)

[0076] 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.

[0077] 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 (SU1 1248, 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 fiudarabine, 6- mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fioxuridine; 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.

[0078] In certain preferred embodiments, the one or more other anti-cancer agents are selected from monoclonal antibodies against CD20 protein, for example, rituximab.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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

Compound Synthesis

[0087] Scheme 1 outlines exemplary synthetic procedures. Scheme 1

Synthetic Procedures

Step 1. Synthesis of compound 3

[0088] To a solution of 2-fluoro-6-nitrobenzoic acid 1 (100 g, 0.54 mol) and dimethylformamide (DMF) (5 mL) in dichloromethane (DCM) (600 mL) was added, dropwise, oxalyl chloride (2M in DCM, 410 mL, 1.5 equiv.) over 30 min. After stirring for 2 hrs. at room temperature, the reaction mixture was concentrated under reduced pressure to give an orange syrup. The residue was dissolved in dry dioxane (80 mL) and slowly added to a suspension of aniline 2 (49 mL, 1 equiv.) and sodium bicarbonate (90 g, 2 equiv.) in a mixture of dioxane (250 mL) and water (250 mL) cooled in an ice- water bath. After 30 min., the reaction mixture was treated with water (1.2 L). The precipitate was filtered, washed with water, airflow dried, and then dried under vacuum at 50 °C for 24 hrs. to afford an off-white solid 3 (139 g, 99%).

Steps 2 and 3. Synthesis of compound 6

[0089] A mixture of Compound 3 (1 equiv.) and anhydrous tetrahydrofuran (THF) (5 vol.) was prepared. Separately, a mixture of Compound 4 (1.3 equiv.) and anhydrous THF (5 vol.) was prepared. Both mixtures were stirred for about 15 min. at about 20 °C to about 25 °C and then cooled to -25 °C ± 15 °C. n-Hexyl lithium (2.05 equiv.) was added to the Compound 3 mixture, maintaining the temperature at > 5 °C. i-PrMgCl (1.33 equiv.) was added to the Compound 4 mixture, maintaining the temperature at > 5 °C.

[0090] The Compound 4 mixture was transferred to the Compound 3 mixture under anhydrous conditions at 0 °C ± 5 °C. The resulting mixture was warmed to 20 °C ± 2 °C and held for about 1 hr. Then, the reaction was cooled to -5 °C ± 5 °C, and 6 N HC1 (3.5 equiv.) was added to quench the reaction, maintaining temperature at below about 25 °C. The aqueous layer was drained, and the organic layer was distilled under reduced pressure until the volume was 2-3 volumes. i-PrOH (3 vol.) was added and vacuum distillation was continued until the volume was 2-3 volumes. IPA (8 vol.) was added and the mixture temperature was adjusted to about 60 °C to about 75 °C. Cone. HC1 (1.5 vol.) was added and the mixture was subsequently held for 4 hrs.

[0091] The mixture was distilled under reduced pressure until the volume was 2.5-3.5 volumes. The mixture temperature was adjusted to 30 °C ± 10 °C. DI water (3 vol.) and DCM (7 vol.) were added respectively to the mixture. Then, NH₄OH was added to the mixture, adjusting the pH to about 7.5 to about 9. The temperature was adjusted to about 20 °C to about 25 °C. The layers were separated and the aqueous layer was washed with DCM (0.3 vol.). The combined DCM layers were distilled until the volume was 2 volumes. i-PrOAc (3 vol.) was added and vacuum distillation was continued until the volume was 3 volumes. The temperature was adjusted to about 15 °C to about 30 °C. Heptane (12 vol.) was charged to the organic layer, and the mixture was held for 30 min. The mixture was filtered and filter cake was washed with heptane (3 vol.). The cake was vacuum dried at about 45 °C afford Compound 6. Then, MeOH (10 vol.) and Compound 6 (1 equiv.) were combined and stirred while the temperature was adjusted to 55 ± 5 °C. D-Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 °C ± 5 °C for about 30 min. and then cooled to about 20 °C to about 25 °C over about 3 hrs. The mixture was held for 30 min. and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. Water (16 vol.) was added to the cake and the mixture was stirred at 25 °C ± 5 °C. NH₄OH was charged over 1 hr. adjusting the pH to about 8 to about 9. The mixture was then filtered and the resulting cake washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 6.

Synthesis of compound 7

R-3 ⁼H, R-4 ⁼ H

[0092] 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 p-toluenesulfonic acid (PTSA) monohydrate (2.95 g, 15.5 mmol, 8% equiv.) were added, followed by EtOAc (240 mL). The mixture was refluxed for 2 hrs. 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 Na₂S0₄ and concentrated to dryness. The residue was purified by silica gel plug with hexane : EtOAc (2: 1, 1 : 1 and 1 :2 ) to afford 6-chloro-9-(tetrahydro-2H-pyran-2- yl)-9H-purine as an off-white solid (31.6 g , 67%).

R₃ = D

[0093] To a 100 mL round bottom flask under N₂, at -40 °C under N₂, 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 THF (40 mL). The mixture temperature 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 hr. and then 5 mL D₂0 was added. The mixture temperature rose to 10 °C. To the mixture, 2 N HC1 was added 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 THF dryness and washed with brine (75 mL x 2), 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 get compound 7 as yellow oil (5.6 g, 56%).

Step 4. Synthesis of compound 8

[0094] To a mixture of i-PrOH (4 vol.) and Compound 6 (1 equiv.) was added Compound 7 (1.8 equiv.), EtsN (2.5 equiv.) and i-PrOH (4 vol.). The mixture was agitated and the temperature was adjusted to 82 °C ± 5 °C. The mixture was held for 24 hrs. Then, the mixture was cooled to about 20 °C to about 25 °C over about 2 hrs. The mixture was filtered and the cake was washed with i-PrOH (2 vol.), DI water (25 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned and then vacuum dried at 50 °C ± 5 °C to afford Compound 8. Step 5. Synthesis of compound 9

[0095] To a mixture of EtOH (2.5 vol.) and Compound 8 (1 equiv.) was added EtOH (2.5 vol.) and DI water (2 vol.). The mixture was agitated at about 20 °C to about 25 °C. Cone. HC1 (3.5 equiv.) was added and the temperature was adjusted to 35 °C ± 5 °C. The mixture was held for about 1.5 hr. The mixture was cooled to 25 °C ± 5 °C and then polish filtered to a particulate free vessel. NH₄OH was added, adjusting the pH to about 8 to about 9. Crystal seeds were added to the mixture, which was held for 30 min. DI water (13 vol.) was added over about 2 hrs. The mixture was held for 1 hr. and then filtered. The resulting cake was washed with DI water (4 vol.) and n-heptane (2 vol.), respectively. The cake was conditioned for about 24 hrs. and then DCM (5 vol.) was added. This mixture was agitated for about 12 hrs. at about 20 °C to about 25 °C. The mixture was filtered and the cake washed with DCM (1 vol.). The cake was conditioned for about 6 hrs. The cake was then vacuum-dried at 50 °C ± 5 °C to afford compound 9.

[0096] In regard to particular compounds so synthesized:

In case of compound 9a, R¹ = CD₃, R² = R³ = H, R⁴ = H

In case of compound 9b, R¹ = CDs R² = D, R³ = H, R⁴ = = H

In case of compound 9c, R¹ = CDs, R² = D, R³ = D, R⁴ = H

In case of compound 9d, R¹ = CHs R² = D, R³ = D, R⁴ = = H

In case of compound 9e, R¹ = CHs, R² = H, R³ = D, R⁴ = H

In case of compound 9f, R¹ = CHs, R² = = D, R³ = = H, R⁴ = H

In case of compound 9g, R¹ = CDs, R² = H, R³ = D, R⁴ = H

In case of compound 9h, R¹ = CHs R² = H, R³ = H, R⁴ = = D

In case of compound 9i, R¹ = CDs, R² = = R³ = H, R⁴ = D

In case of compound 9j, R¹ = CDs, R² = = D, R³ = = H, R⁴ = D

In case of compound 9k, R¹ = CDs R² = D, R³ = D, R⁴ = = D

In case of compound 91, R¹ = CHs, R² = = D, R³ = = D, R⁴ = D

In case of compound 9m, R¹ = = CH_: , ² = H, R³ = D, R⁴ = = D

In case of compound 9n, R¹ = CHs R² = D, R³ = H, R⁴ = = D

In case of compound 9o, R¹ = CDs, R² = H, R³ = D, R⁴ = D

[0097] D4-Duvelisib, molecular formula: C₂2Hi₃D₄ClN₆0, Mass Spec: [M+H]⁺= 421.2. ^XH- NMR (300 MHz, DMSO-d6): 9.24 (broad, 1 H), 8.42 (s, IH), 8.35 (s, IH), 7.27-7.62 (m, 9 H), 6.76 (s, IH).

[0098] Dl -Duvelisib, molecular formula: C₂₂HI₆D IC1N₆0, Mass Spec: [M+H]⁺= 418.2. ^XH- NMR (300 MHz, DMSO-d6): 9.40 (broad, 1 H), 8.38 (s, IH), 7.27-7.58 (m, 8 H), 6.84 (s, lH); 4.82 (m, IH), 1.36 (m, 3H).

[0099] D2-Duvelisib, molecular formula: C₂2Hi5D₂ClN₆0, Mass Spec: [M+H]⁺= 419.2. ^XH- NMR (300 MHz, DMSO-d6): 12.9 (broad, 1 H), 8.14 (s, 1H), 7.40-7.56 (m, 8 H), 6.76 (s, lH); 4.71 (m, 1H), 1.36 (m, 3H).

[00100] D5-Duvelisib, molecular formula: C₂2Hi2D₅ClN₆0, Mass Spec: [M+H]⁺= 422.2. ^XH- NMR (300 MHz, DMSO-d6): 8.45 (s, 1 H), 8.20 (s, 1H), 7.37-7.57 (m, 8 H), 6.76 (s, 1H).

Measurement of IC50 for PI3K delta

[00101] 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.

[00102] Duvelisib and D₅- Duvelisib were prepared as a 2 mg/mL stock in dimethyl sulfoxide (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. The 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 PI3Ks. Curve fits were performed where the enzyme activities at the highest concentration of compounds were less than 65%.

[00103] The calculated IC50 values for duvelisib and deuterated compounds were listed in Table 1. The results indicated that selectively deuterarted compounds have similar potency as Duvelisib.

Table 1 IC50 for PI3K delta

Pharmacokinetic and Drug Metabolism Study of Duvelisib and Deuterated Duvelisib with Human Hepatocyte

[00104] This study was carried out to evaluate the stability of the test compounds upon metabolism by cryopreserved human hepatocytes.

[00105] 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. [00106] The test article was administered in vitro directly or through a solvent compatible with the test system.

[00107] 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 will be also run at similar time points. The no cell control was carried out in incubation media and was run as single incubation.

[00108] Cryopreserved hepatocytes will be thawed in a 37 °C water bath and placed on ice. The thawed hepatocytes will be recovered using Universal Cryopreserved Recovery Medium™ (UCRM™) and centrifuged at 100 x g for 5 min. to remove residual cry opreserv ants. 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.

[00109] The final reaction mixture for hepatocyte metabolism will consist of HIM, hepatocytes at 1 x 10⁶ cells per mL and the test article or negative controls.

[00110] The study was designed such that a reference article (duvelisib) was used along with a test article (a deuterated duvelisib) per group. The final concentration of reference article and the test article at the initiation of incubation was 2μΜ. 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 will be diluted 1000X in HIM to prepare a 10 x dosing stock of 20 μΜ. This dosing stock will be diluted to 2 μΜ upon addition to medium containing hepatocytes or blank medium.

[00111] Incubation of the hepatocytes with 2 μΜ test article + reference article was performed in triplicates in an 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, 240 and 360 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 10 x test compound or positive control). All samples except negative control were run in triplicates.

[00112] 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. One concentration (2 μΜ) of the test article+ reference article was used in all incubations. The reference article at 2 μΜ in each group served as positive control. After incubation, the reaction was terminated. The total mixture after termination was stored frozen for LCMS analysis.

[00113] LC-HRAM-MS/MS analysis was performed on a Bruker Q-Tof coupling with a HPLC system. LCMS quantitative analysis indicated that selectively deuterated compounds slowed down the metabolism. Table 2 listed the improvement of parent compound concentration remaining after 4 hr. incubation.

Table 2. Improvement of parent compound concentration remaining after 4 hr. incubation.

Toxicity of Oxidation Product

[00114] 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 PI3K delta compounds such as 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. [00xx]-[00xx]) were analyzed to compare the formation of the metabolite.

[00115] FIG. 3 and FIG. 4 compare duvelisib vs. D₂-duvelisib and duvelisib vs. D₅-duvelisib in the formation of oxidative metabolites formed by purine ring oxidation on carbon-8. The results supported that D₅-duvelisib and D₂-duvelisib slowed the metabolism that may cause toxicity in human disease treatment.

[00116] 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.

[00117] The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, 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.

[00118] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[00119] 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

[00120] 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

[00121] 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

What is claimed is:

1. A compound having the structural formula of:

(I)

wherein each of R_1; R2, R3, R4, R5 and R6 is independently selected from H and D, and at least one of R_1; R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof. The compound of claim 1, wherein R₆ is H and the compound has the structural formula of:

(II)

The compound of claim 2, wherein Ri is D and each of R₂, R3, R4 and R5 is H, having the structural formula of:

The compound of claim 2, wherein each of Ri and R₅ is D and each of R₂, R₃ and R₄ is H, having the structural formul

The compound of claim 2, w herein each of R R₂, R₃, R₄ and R₅ is D, having the structural formula of:

The compound of claim 2, wherein each of R2, R3, R4 and R5 is D and Ri is H, having the structural formula of:

The compound of claim 2, wherein each of R_1; R2, R3 and R4 is H and R5 is D, having the structural formula of:

The compound of claim 1, wherein R₆ is D and the compound has the structural formula of:

(III)

The compound of claim 8, wherein Ri is D and each of R2, R₃, R4 and R5 is H, having the structural formula of:

The compound of claim 8, wherein each of Ri and R5 is D and each of R2, R₃ and R4 is H, having the structural formula of:

The compound of claim 8, wherein each of R_1; R₂, R3 and R4 is D, and R5 is H having structural formula of:

The compound of claim 8, wherein each of R_1; R₂, R3, R4 and R5 is D, having the structural formula of:

The compound of claim 8, wherein each of R2, R3 and R4 is D and each of Ri and R5 is H, having the structural fo

The compound of claim 8, wherein each of R2, R3, R4 and R5 is D and Ri is H, having the structural formula of:

The compound of claim 8, wherein each of R_1; R2, R3 and R4 is H and R5 is D, having the structural formula of:

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

(I)

wherein each of R_1; R2, R3, R4, R5 and R6 is independently selected from H and D, and at least one of R_1; R2, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies and

inflammatory and autoimmune diseases, or a related disease or disorder thereof, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

The pharmaceutical composition of claim 16, wherein R₆ is H and the compound has the structural formula of:

(II)

The pharmaceutical composition of claim 17, wherein each of Ri and R5 is D and each of R2, R3 and R4 is H, having the structural formula of:

19. The pharmaceutical composition of claim 17, wherein each of R_1; R2, R3, R4 and R5 is D, having the structural formula of:

20. The pharmaceutical composition of claim 17, wherein each of R₂, R3, R4 and R₅ is D and Ri is H. having the structural formula of:

21. The pharmaceutical composition of claim 17, wherein each of R_1; R₂, R3 and R₄ is H and R₅ is D, having the structural formula of:

The pharmaceutical composition of claim 16, wherein R₆ is D and the compound has the structural formula of:

(III)

The pharmaceutical composition of claim 22, wherein Ri is D and each of R2, R3, R4 and R5 is H, having the structural formula of:

The pharmaceutical composition of claim 22, wherein each of Ri and R5 is D and each of R2, R3 and R₄ is H, having the structural formula of:

The pharmaceutical composition of claim 22, wherein each of Ri, R₂, R₃ and R₄ is D, and R₅ is H having the structural formula of:

The pharmaceutical composition of claim 22, wherein each of R_1; R2, R3, R4 and R5 is D, having the structural fo

The pharmaceutical composition of claim 22, wherein each of R2, R3 and R4 is D and each of Ri and R5 is H, having the structural formula of:

The pharmaceutical composition of claim 22, wherein each of R2, R3, R4 and R5 is D and Ri is H, having the structural formula of:

The pharmaceutical composition of claim 22, wherein each of R_1; R2, R3 and R4 is H and R5 D, having the structural fo

A unit dosage form comprising the pharmaceutical composition of any of claims 16-29. A method for treating, reducing, or preventing a disease or disorder, comprising:

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 and R6 is independently selected from H and D, and at least one of R_1; R₂, R3, R4, R5 and R6 is D, or a pharmaceutically acceptable form thereof, effective to treat, prevent, or reduce one or more of hematologic malignancies and inflammatory and autoimmune diseases, or a related disease or disorder thereof.

The method of claim 31, wherein R₆ is H and the compound has the structural formula of:

(II)

33. The method of claim 32, wherein each of Ri and R5 is D and each of R₂, R3 and R4 is H, having the structural formula of:

The method of claim 32, wherein each of R_1; R2, R3, R4 and R5 is D, having the structural formula of:

The method of claim 32, wherein each of R2, R3, R4 and R5 is D and Ri is H, having the structural formula of:

The method of claim 32, wherein each of R_1; R2, R3 and R4 is H and R5 is D, having the structural formula of:

The method of claim 31, wherein R₆ is D and the compound has the structural formula of:

(III)

The method of claim 37, wherein Ri is D and each of R2, R3, R4 and R5 is H, having the structural formula of:

The method of claim 37, wherein each of Ri and R5 is D and each of R2, R3 and R4 is H, having the structural formula of:

The method of claim 37, wherein each of R_1; R2, R3 and R4 is D, and R5 is H having the structural formula of:

The method of claim 37, wherein each of R_1; R2, R3, R4 and R5 is D, having the structural formula of:

The method of claim 37, wherein each of R₂, R3 and R4 is D and each of Ri and R5 is H, having the structural formul

The method of claim 37, wherein each of R₂, R3, R4 and R5 is D and Ri is H, having the structural formula of:

The method of claim 37, wherein each of R_1; R₂, R3 and R4 is H and R5 is D, having the structural formula of:

45. The method of any of claims 31 -44, wherein the one or more of hematologic malignancies are selected from chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL).

46. The method of any of claims 31 -45, wherein the compound is administered in combination with one or more other anti-cancer agents.

47. The method of claim 46, wherein the one or more other anti-cancer agents are selected from monoclonal antibodies against CD20 protein.

48. The method of claim 47, wherein the one or more other anti-cancer agents is rituximab.