Lyophilized formulation of CD73 compound

Abstract

A lyophilized formulation is provided comprising a compound of formula (I) and one or more amino acids, wherein W, X, Y, Z, R a , R c , and each R g is as defined herein. Methods of preparation, methods of use, and dosage forms are also provided. The present disclosure also provides aqueous solutions (e.g., pre-lyophilized or reconstituted lyophilized formulations) comprising a compound of Formula (I) or (Ia), one or more amino acids, a pH adjuster, and, in some embodiments, a bulking agent. The present disclosure also relates to the use of reconstituted lyophilized formulations for the treatment and / or prevention of various diseases, disorders, and conditions mediated in whole or in part by CD73. TIFF2025536309000056.tif35128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 380,357, filed October 20, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Ectonucleotides catalyze the conversion of ATP to adenosine, an endogenous regulator affecting multiple systems, including the immune, cardiovascular, central nervous, and respiratory systems. Adenosine also promotes fibrosis in various tissues. In the first step of adenosine production, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also known as CD39 (cluster of differentiation 39), hydrolyzes ATP to ADP, which then hydrolyzes ADP to AMP. In the next step, AMP is converted to adenosine by ecto-5'-nucleotidase (NT5E or 5NT), also known as CD73 (cluster of differentiation 73).

[0003] The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to various cells (e.g., immune cells). Alterations in these enzyme activities may alter the course or determine the prognosis of several pathophysiological events, including cancer, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury, suggesting that these ectoenzymes represent novel therapeutic targets for the management of various disorders.

[0004] For example, CD73 inhibitors in clinical development have been antibodies, although the development of small molecules has been hindered by less than ideal metabolic and physical stability and the lack of availability of suitable formulations that can effectively deliver the drug.

[0005] Given the role that CD73 plays in cancer and a wide variety of other diseases, disorders, and conditions, and the current lack of effective small molecule formulations of CD73 inhibitors available to physicians, there is a need for such compositions and related methods. Summary of the Invention

[0006] In one aspect, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, and one or more amino acids, wherein W, X, Y, Z, R a , R c , and each R g is as defined herein. Also provided are methods of preparation, methods of use, and dosage forms, as described in detail below.

[0007] In one particular aspect, the present disclosure provides a lyophilized formulation of a compound having formula (Ia). [ka]

[0008] The present disclosure also provides aqueous solutions (e.g., pre-lyophilized or reconstituted lyophilized formulations) comprising a compound of Formula (I) or (Ia), one or more amino acids, a pH adjuster, and, in some embodiments, a bulking agent. The present disclosure also relates to the use of the reconstituted lyophilized formulations for the treatment and / or prevention of various diseases, disorders, and conditions mediated, in whole or in part, by CD73. CD73 inhibitors have been implicated in the treatment of various disorders, including cancer, fibrosis, neurological and neurodegenerative disorders (e.g., depression and Parkinson's disease), cerebral and cardiac ischemic diseases, immune-related disorders, and disorders with an inflammatory component. See, e.g., Sorrentino et al. (2013) OncoImmunol, 2:e22448, doi:10.4161 / onci.22448; and Regateiro et al. (2012) Clin. Exp. Immunol, 171:1-7. In certain embodiments, the formulations described herein are capable of inhibiting the immunosuppressive and / or anti-inflammatory activity of CD73 and are useful as therapeutic or prophylactic therapies where such inhibition is desired. Unless otherwise indicated, when use refers to the compounds described herein, it should be understood that such compounds can be in any solid form (crystalline, amorphous, or mixtures thereof) or non-solid form.

[0009] In some embodiments, the present disclosure contemplates a method for treating or preventing cancer in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation comprising a compound of Formula (I) or (Ia) described herein). The present disclosure includes methods of treating or preventing cancer in a subject by administering to the subject a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation described herein) in an amount effective to reverse, halt, or slow the progression of CD73-mediated immunosuppression.

[0010] The present disclosure further contemplates the use of a compound of Formula (I) or (Ia) described herein in combination with one or more additional agents. The one or more additional agents may have some CD73-modulating activity and / or they may function through separate mechanisms of action. In some embodiments, such agents include radiation (e.g., local or systemic radiation therapy) and / or other therapeutic modalities of a non-pharmacological nature (e.g., surgical resection). In yet other embodiments, when combination therapy is utilized, a reconstituted lyophilized formulation comprising a compound of Formula (I) or (Ia) described herein and one or more additional agents may be in the form of a single composition or multiple compositions, and the therapeutic modalities may be administered simultaneously, sequentially, or through some other regimen. As an example, the present disclosure contemplates a treatment regimen in which a radiation phase is followed by a chemotherapy phase, or in which treatment with a compound of Formula (I) or (Ia) over a period of time allows for subsequent surgical resection. The combination therapy may have additive or synergistic effects. Other advantages of combination therapy are described below. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a flow chart illustrating an exemplary process for bulk lyophilization of a formulation according to the present disclosure. WFI = water for injection, qs = quantity added sufficient, ingredients refer to excipients.

[0012] [Figure 2] Figure 1 shows population PK simulations following administration of 50 mg QW (once weekly), 100 mg Q2W (every 2 weeks), and 300 mg Q3W (every 3 weeks). The solid line indicates the population median, the shaded area indicates the 5th to 95th quantiles of interindividual variability in predicted compound of Formula (Ia) concentrations, and the dashed line represents the IC90 of Formula (Ia) for inhibition of measured plasma CD73 enzyme activity. DETAILED DESCRIPTION OF THE INVENTION

[0013] Before the present disclosure is further described, it is to be understood that the present disclosure is not limited to particular embodiments described herein, and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0014] As used herein, the term "about" has its inherent meaning of approximation and is used to provide literal support for a number near or approximately the number it precedes, as well as the exact number it precedes. In general, the term "about" refers to the normal error range for the respective value, readily known to those skilled in the art. If the degree of approximation is not clear from the context, "about" means either within ±10% of the provided value, or rounded to the nearest significant figure, and in all cases includes the provided value. When ranges are provided, they include the boundaries. Overview

[0015] The present disclosure relates to lyophilized formulations of CD73 inhibitors (e.g., compounds of Formula (I) or other nucleoside or nucleotide compounds) combined with one or more amino acids. Surprisingly, the described combinations prevent aggregation of the CD73 inhibitors. Lyophilized formulations according to the present disclosure may have certain advantages, such as reduced cracking, brittleness, and / or shrinkage. In some embodiments, the lyophilized formulations of the present disclosure are stable and can be stored at approximately 40°C / 75% relative humidity ("RH") or 25°C / 60% RH and 2-8°C for up to 3 months before reconstitution. In some embodiments, stored lyophilizates rapidly reconstitute to yield clear solutions, and the impurity profile of the reconstituted solution remains unchanged compared to the initial lyophilizate. In some embodiments, the compound of formula (I) is (((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2-fluorophenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid (also known as quemliculstat or AB680), which is represented by the following formula (Ia): [ka] definition

[0016] Unless otherwise indicated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

[0017] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C1-8 means 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0018] The term "cycloalkyl" refers to a group having a specified number of ring atoms (e.g., C 3-6 "Cycloalkyl" refers to a hydrocarbon ring that is fully saturated or has no more than one double bond between the ring vertices. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0019] The term "heterocycloalkyl" refers to a cycloalkyl ring having a specified number of ring vertices (or members) and having 1 to 5 heteroatoms selected from N, O, and S replacing 1 to 5 of the carbon vertices, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heterocycloalkyls can be monocyclic, bicyclic, or polycyclic ring systems. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon atom or a ring heteroatom, if chemically permissible.

[0020] As used herein, a wavy line crossing a single, double, or triple bond in any chemical structure shown herein; [ka] indicates that the point of attachment of a single, double, or triple bond to the rest of the molecule is through any one of the atoms that make up the single, double, or triple bond. Additionally, a bond extending to the center of a ring (e.g., a phenyl ring) is meant to indicate a bond to any available ring vertex, i.e., a bond such that attachment of a substituent to the ring results in a chemically stable configuration.

[0021] As referred to herein, a divalent moiety includes either orientation (forward or reverse) of the moiety. For example, the group "-C(O)NH-" is meant to include the bond in either orientation: -C(O)NH or -NHC(O)-; similarly, "-O-CHCH-" is meant to include both -O-CHCH- and -CHCH-O-.

[0022] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense to refer to alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Furthermore, for dialkylamino groups, the alkyl portions may be the same or different and may also form a 3- to 7-membered ring together with the nitrogen atom to which each is attached. Thus, dialkylamino or -NR a R b A group represented as: is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.

[0023] The terms "arylalkyl" and "heteroarylalkyl" are used in their conventional sense to refer to groups in which an aryl or heteroaryl group is attached to the remainder of the molecule via a C1-C4 alkylene linker. An exemplary embodiment of an "arylalkyl" is phenylmethyl (or benzyl). Similarly, an exemplary embodiment of a "heteroarylalkyl" is, for example, 3-pyridylpropyl. When "optionally substituted" is used to describe either the term "arylalkyl" or "heteroarylalkyl," it is meant to refer to a group in which the aryl or heteroaryl moiety is optionally substituted as defined below, and the alkyl moiety is optionally substituted as defined below.

[0024] The terms "cycloalkylalkyl" and "heterocycloalkylalkyl" are used in their conventional sense to refer to a cycloalkyl or heterocycloalkyl group attached to the remainder of the molecule via a C-C alkylene linker. When "optionally substituted" is used to describe either the term "cycloalkylalkyl" or "heterocycloalkylalkyl," it is meant to refer to a group in which the cycloalkyl or heterocycloalkyl moiety is optionally substituted as defined below, and the alkyl moiety is optionally substituted as defined below.

[0025] The term "alkylene" refers to a group having 1 to 4 alkyl groups (e.g., C 1-4 -(CH(CH3))- refers to a straight-chain or branched saturated hydrocarbon radical having carbon atoms of -(CH(CH3))- and linking at least two other groups, i.e., a divalent hydrocarbon radical. When two moieties are linked to an alkylene, they can be linked to the same carbon atom (i.e., geminal), e.g., -(CH(CH3))-, or to different carbon atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n - (n is 1, 2, 3, or 4) divalent radical (i.e., C 1-4 Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secbutylene, and the like.

[0026] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0027] The term "aryl," unless otherwise specified, refers to a polyunsaturated aromatic hydrocarbon group which may be a single ring or multiple rings (up to three rings) which are fused or covalently linked to each other. In some embodiments, an aryl can have 6 to 14 (i.e., C aryl), or 6 to 10 (i.e., C aryl), or 6 (i.e., C aryl) carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

[0028] The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. In some embodiments, a "heteroaryl" can have 5 to 14 (i.e., 5-14-membered heteroaryl), or 5 to 10 (i.e., 5-10-membered heteroaryl), or 5 to 6 (i.e., 5-6-membered heteroaryl) members (i.e., ring vertices) and can contain 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). A heteroaryl group can be attached to the remainder of the molecule through a ring carbon atom or ring heteroatom, if chemically permissible. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Substituents for the heteroaryl ring can be selected from the group of acceptable substituents described below.

[0029] The above terms (e.g., "alkyl," "aryl," and "heteroaryl") are, in some embodiments, optionally substituted. Selected substituents for each type of radical are provided below.

[0030] Optional substituents on alkyl radicals (including those groups often referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) can range in number from 0 to (2m'+1), where m' is the total number of carbon atoms in such radical, of a variety of groups selected from halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)R', -NH-C(NH)=NH, -NR'C(NH)=NH, -NH-C(NH)=NR', -S(O)R', -S(O)R', -S(O)NR'R'', -NR'S(O)R'', -CN, and -NO. R', R", and R'" each independently represent hydrogen, unsubstituted C1-8 alkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted C1-8 alkyl, C1-8 alkoxy, or C1-8 thioalkoxy group, or unsubstituted aryl-C1-4 alkyl group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl.

[0031] Similarly, the optional substituents on the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups vary and generally include -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -C02R', -CONR'R'', -C(O)R', -OC(O)NR'R'', -NR''C(O)R', -NR''C(O)2R', -NR'-C(O)NR''R'''', -N and R', R'', and R'' are independently selected from H-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, the number ranging from 0 to the total number of open valences on the aromatic ring system; 1-8Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, and C 2-8 alkynyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of 1 to 4 carbon atoms.

[0032] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). In some embodiments, the heteroatom is O or N.

[0033] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts. Furthermore, certain compounds that contain both acidic and basic functional groups may exist as zwitterions (i.e., internal salts).

[0034] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, for example, solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of this disclosure.

[0035] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes to provide the compounds of the present disclosure. Generally, prodrugs contain a moiety that is cleaved in vivo to provide the compounds of the present disclosure.

[0036] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms (e.g., ethanol or ethyl acetate solvates), including hydrated forms, all of which are intended to be encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms (see, for example, WO 2020 / 123772 and WO 2021 / 257643). In general, all physical forms are contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0037] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. Where stereochemistry is depicted (e.g., with a dash), [ka] and / or wedges [ka] "Substantially free" of another isomer indicates that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or greater. In some embodiments, one of the isomers is present in an amount of at least 99%. Solid line [ka] A chemical bond to an asymmetric carbon depicted as follows is intended to include all possible stereoisomers at that carbon atom (eg, enantiomers, diastereomers, racemic mixtures, etc.).

[0038] "Hydrate" refers to, for example, a complex formed by combining a compound of formula (I) (a CD73 inhibitor compound) with water. This term includes stoichiometric and non-stoichiometric hydrates.

[0039] "Solvate" refers to a complex formed by combining a compound of Formula (I) with a solvent. Exemplary solvents that form solvates include, but are not limited to, methanol, methyl tert-butyl ether, ethanol, isopropanol, DMSO, ethyl acetate, acetic acid, and acetonitrile. In some embodiments, the solvate is an ethanol, ethyl acetate, or acetonitrile solvate.

[0040] "Desolvated" refers to a compound of formula (I) that is a solvate, as described herein, from which solvent molecules have been partially or completely removed. Desolvation techniques for producing desolvated forms include, but are not limited to, exposing the compound of formula (I) (solvate) to a vacuum, exposing the solvate to high temperatures, exposing the solvate to a gas stream such as air or nitrogen, slurrying the solvate in a different solvent, or any combination thereof. Thus, a desolvated form of a compound of formula (I) may be completely free of solvent molecules, or may be partially solvated, with solvent molecules present in stoichiometric or non-stoichiometric amounts.

[0041] "Alcohol" refers to a solvent having a hydroxy group. Representative alcohols can have any suitable number of carbon atoms, such as C1-C6, and any suitable number of hydroxy groups, such as 1 to 3. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, i-propanol, and the like.

[0042] The terms "patient" and "subject" are used interchangeably to refer to a human or non-human animal (eg, a mammal).

[0043] The terms "treat," "treating," "treatment," and the like refer to a course of action (e.g., administering an inhibitor of CD73 or a pharmaceutical composition comprising same) initiated after a disease, disorder, or condition, or a symptom thereof, has been diagnosed, observed, etc., to eliminate, reduce, suppress, alleviate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of the disease, disorder, or condition from which the subject is afflicted, or at least one of the symptoms associated with the disease, disorder, or condition from which the subject is afflicted. Thus, treatment includes inhibiting active disease (e.g., preventing the onset or further development of the disease, disorder, or condition or its associated clinical symptoms), improving quality of life, and / or prolonging the survival of a subject. Treatment also refers to a course of action that results in the remission (partial or total) of a disease, disorder, or condition.

[0044] As used herein, the term "in need of treatment" refers to a judgment made by a physician or other caregiver that a subject needs or would benefit from treatment. This judgment is made based on a variety of factors that are within the expertise of the physician or caregiver.

[0045] The terms "prevent," "preventing," "prevention," and the like generally refer to a course of action (e.g., administering a CD73 inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of the disease, disorder, condition, or symptoms thereof) that prevents, suppresses, inhibits, or reduces, either temporarily or permanently, the risk (e.g., as determined by the absence of clinical symptoms) of a subject developing or delaying the onset of a disease, disorder, condition, or the like in situations where the subject is predisposed to having a particular disease, disorder, or condition. In certain instances, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition, or symptom, in order to prevent the recurrence of the disease, disorder, condition, or symptom.

[0046] As used herein, the term "in need of prophylaxis" refers to a judgment made by a physician or other caregiver that a subject needs or would benefit from prophylactic measures. This judgment is made based on a variety of factors within the physician's or caregiver's expertise.

[0047] The phrase "therapeutically effective amount" refers to a dosing regimen (i.e., amount and interval) of a compound that provides a particular pharmacological effect upon administration of the compound to a subject in need of such treatment. For treatment, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with the disease, delay progression of the disease, prolong survival, reduce the dose of other medications required to treat the disease, or a combination thereof. With particular reference to cancer, a therapeutically effective amount may, for example, result in cancer cell death, reduce cancer cell numbers, reduce tumor burden, eliminate tumors or metastases, or reduce metastatic spread. A therapeutically effective amount may vary based on, for example, one or more of the subject's age and weight, the subject's overall health, the stage of the subject's disease, the route of administration, and previous or concurrent treatments. With respect to CD73 inhibitors of the present disclosure, an "effective amount" refers to an amount of compound sufficient to bind to the target (e.g., by inhibiting the target) at a level that exhibits the compound's efficacy. Target engagement can be determined by one or more biochemical or cellular assays that yield an EC50, ED50, EC90, IC50 or similar value, which can be used as an estimate of a compound's potency.

[0048] The phrases "lyophilized formulation" and "lyophilisate" are used interchangeably and refer to compositions formed by lyophilization; such formulations are further described herein.

[0049] The phrases "reconstituted lyophilized formulation" and "reconstituted formulation" and "reconstituted solution" and "reconstituted aqueous solution" and "reconstituted pharmaceutical composition" are used interchangeably and refer to the composition formed when a lyophilized formulation according to the present disclosure is reconstituted with a diluent.

[0050] "Substantially pure" indicates that a component comprises greater than about 50% of the total content of the composition, typically greater than about 60% of the total content. More typically, "substantially pure" refers to a composition in which the component of interest comprises at least 75%, at least 85%, at least 90%, or more of the total composition. In some cases, the component of interest will comprise greater than about 90%, or greater than about 95% of the total content of the composition. In some embodiments, the compounds of Formula (I) or (Ia) described herein are substantially pure, i.e., at least 75%, at least 85%, at least 90%, or greater than about 90%, or greater than about 95% of the provided material is a compound of Formula (I) or (Ia).

[0051] For example, the term "response" of a cell, tissue, organ, or organism encompasses a change in biochemical or physiological behavior, e.g., concentration, density, adhesion, or migration within a biological compartment, rate of gene expression, or state of differentiation, where the change correlates with activation, stimulation, or treatment, or internal mechanisms such as genetic programming. In certain contexts, the terms "activation," "stimulation," and the like refer to cellular activation that is regulated not only by external or environmental factors but also by internal mechanisms, while the terms "inhibition," "downregulation," and the like refer to the opposite effect. I. Composition before lyophilization

[0052] In one aspect, provided herein is an aqueous composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, an amino acid, and a pH adjuster sufficient to provide the aqueous composition with a pH of about 6 to about 8, wherein the compound of formula (I) has the following structure: [ka] In the formula, W, X, Y, Z, R a , R c , and each R g is as defined herein. In some embodiments, the composition further comprises a bulking agent as described elsewhere herein. Ia. Compound of formula (I)

[0053] Compounds useful for preparing the pre-lyophilized compositions and lyophilized formulations described herein have the formula (I): [ka] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: W is CR e and N, X is selected from the group consisting of O, CH2, and S; each of Y and Z is independently selected from the group consisting of CH and N; R g is H or two R g groups bond to form an acetonide, R a However, NH2, NHR 1 , and NR 1 R 2 is selected from the group consisting of R c H, halogen, haloalkyl, NH2, NHR 3 , N.R. 3 R 4 , R 3 , OH, OR 3 , S.R. 3 , SO2R 3 , -X 1 -NH2, -X 1 -NHR 3 , -X 1 -NR 3 R 4 , -X 1 -OH, -X 1 -OR 3 , -X 1 -SR 3 , and -X 1 -SO2R 3 is selected from the group consisting of R e is selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl; each X 1is C1-C4 alkylene Each R 1 , R 2 , R 3 and R 4 are independently optionally substituted C-C 10 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkylC1-C4 alkyl, optionally substituted 4- to 7-membered heterocycloalkyl, optionally substituted 4- to 7-membered heterocycloalkylC1-C4 alkyl, optionally substituted aryl, optionally substituted arylC1-C4 alkyl, optionally substituted heteroaryl, and optionally substituted heteroarylC1-C4 alkyl, or R 1 and R 2 or R 3 and R 4 are attached to the same nitrogen, they combine to form a 4- to 7-membered heterocyclic ring.

[0054] In some embodiments, the compounds of formula (I) are those where X is O.

[0055] In some embodiments, the compound of Formula (I) is g is a compound where H.

[0056] In some embodiments, the compound of formula (I) is R a However, NHR 1 and R 1 is selected from the group consisting of optionally substituted aryl C1-C4 alkyl and optionally substituted heteroaryl C1-C4 alkyl. In some embodiments, the optionally substituted aryl C1-C4 alkyl or optionally substituted heteroaryl C1-C4 alkyl is substituted with 1 to 3 halo.

[0057] In some embodiments, the compound of formula (I) is R a However, NHR 1 and R1 is an optionally substituted aryl C1-C4 alkyl. In some embodiments, the optionally substituted aryl C1-C4 alkyl is substituted with 0-3 halo. In some embodiments, the optionally substituted aryl C1-C4 alkyl is substituted with 1-3 halo. In some embodiments, the optionally substituted aryl C1-C4 alkyl is substituted with 1 fluoro.

[0058] In some embodiments, the compound of formula (I) is R c is selected from the group consisting of H, halogen, and haloalkyl.

[0059] In some embodiments, the compound of formula (I) is R c is a halogen.

[0060] In some embodiments, compounds of Formula (I) are those wherein W is CR e is a compound.

[0061] In some embodiments, the compound of formula (I) is R e is H.

[0062] In some embodiments, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound of formula (I) is provided in a solution to form an aqueous composition as described herein. In one embodiment, the compound of formula (I) is provided in the solution as a free acid. In another embodiment, the compound of formula (I) is provided in the solution as a pharmaceutically acceptable salt.

[0064] In some embodiments, the compound of Formula (I) has the formula (Ia): [ka] and is provided as the free acid. In another embodiment, the compound of formula (Ia) is provided in solution as a pharmaceutically acceptable salt.

[0065] In some embodiments, the compound of Formula (I) has a structure according to Formula (Ia): or a pharmaceutically acceptable salt thereof.

[0066] In one embodiment, the compound of Formula (I) is a compound represented by Formula (Ia) and is provided in crystalline form: [ka] The crystalline form is any one of crystalline forms I to VI described in WO 2021 / 257643 or crystalline forms A to D described in WO 2020 / 123772, each of which is incorporated herein by reference.

[0067] In general, compounds of formula (I) are prepared using methods described, for example, in WO 2017 / 120508, Org. Process Res. Dev. 2023, 27, 5, 945-953, and Org. Process Res. Dev. 2021, 25, 1, 157-162. Ib. Amino acids

[0068] The pre-lyophilized compositions and lyophilized formulations described herein also contain one or more amino acids. The presence of one or more amino acids in compositions according to the present disclosure improves the physical stability of the reconstituted lyophilized formulation. Without wishing to be bound by theory, the amphipathic nature of the compounds described herein (i.e., compounds of Formula (I) and Formula (Ia)) results in a tendency for reconstituted solutions to undergo physical changes due to molecular aggregation. Thus, the presence of one or more amino acids disrupts aggregation and provides the reconstituted composition with improved physical stability compared to one lacking one or more amino acids. The amino acids are generally provided as an aqueous solution. In some embodiments, the amino acid is a basic amino acid. In yet other embodiments, the amino acid is selected from arginine, histidine, lysine, tryptophan, cysteine, or a combination thereof. In some embodiments, the one or more amino acids comprise arginine, lysine, histidine, tryptophan, cysteine, or a combination thereof. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is histidine. In some embodiments, the amino acid is lysine. In some embodiments, the amino acid is tryptophan. In some embodiments, the amino acid is cysteine. In some embodiments, the amino acid is arginine, histidine, or a combination thereof. In some embodiments, the amino acid is a combination of arginine and histidine. Ic. pH adjuster

[0069] The pre-lyophilized compositions and lyophilized formulations described herein also utilize a pH adjuster. The pH adjuster may be a weak acid, such as, by way of non-limiting example, acetic acid, citric acid, hydrochloric acid, propionic acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid, and malic acid. In one embodiment, the pH adjuster is phosphoric acid. Generally, the pH adjuster is provided as an aqueous solution. While the concentration of the aqueous solution is not critical, the pH adjuster is provided in a composition comprising a compound of Formula (I) or (Ia) and one or more amino acids in an amount sufficient to provide a pH of the solution in the range of about 6 to about 8. In another embodiment, the pH adjuster is provided in a composition comprising a compound of Formula (I) or (Ia) and one or more amino acids in an amount sufficient to provide a pH of the solution in the range of about 6.5 to about 7.5. In one embodiment, the pH adjuster is phosphoric acid and is provided in a composition comprising a compound of Formula (I) or (Ia) and one or more amino acids in an amount sufficient to provide a pH of the solution in the range of 6.0 to 7.0. In one embodiment, the pH adjuster is phosphoric acid and is provided in a composition comprising Formula (I) or (Ia) and one or more amino acids in an amount sufficient to give the solution a pH in the range of 7.0 to 7.5. Id. Bulking Agent

[0070] In one or more embodiments, the pre-lyophilization compositions, lyophilized formulations, and aqueous solutions described herein contain a bulking agent. Bulking agents form the majority of the lyophilized formulation and provide proper structure to the lyophilized cake. Bulking agents can be used for low-dose (or low-concentration) drugs that do not have the bulk necessary to support their own structure. The structure of the lyophilized cake is important because proper cake formation results in proper pore formation, which provides a means for vapor to escape from the formulation during the drying cycle. Exemplary bulking agents include, but are not limited to, mannitol, glycine, hydroxypropyl-beta-cyclodextrin (HPBCD) (i.e., kleptose), dextran, sucrose, lactose, trehalose, sorbitol, glucose, raffinose, and the like, and are utilized in the pre-lyophilization composition to provide structure to the lyophilized cake and prevent cake collapse. In some embodiments, the bulking agent in compositions and formulations according to the present disclosure is mannitol, glycine, hydroxypropyl-beta-cyclodextrin (HPBCD), or dextran. In one embodiment, the bulking agent in compositions and formulations according to the present disclosure is glycine. In one embodiment, the bulking agent in compositions and formulations according to the present disclosure is mannitol. 1e. Vial Selection

[0071] Some embodiments provide a vial containing a lyophilized formulation described herein or an aqueous formulation described herein.

[0072] In one or more embodiments, the vial used to lyophilize the pre-lyophilized formulation is a clear glass vial (USP Type 1). In one or more embodiments, the vial used to lyophilize the pre-lyophilized formulation is characterized by a hydrophobic coating on its inner surface. Thus, in some embodiments, the vial includes an inner surface in contact with a hydrophobic coating. Exemplary vials include SCHOTT TopLyo® vials or those described in U.S. Pat. No. 8,592,015, incorporated herein by reference. The presence of a hydrophobic coating reduces adhesion of compositions and / or formulations according to the present disclosure to the sides of the vial, contributing to the formation of a lyophilized cake that is free of cracks, brittleness, and / or shrinkage. Reduced adhesion of compositions and / or formulations according to the present disclosure to the sides of the vial allows for ease of reconstitution, contributing to consistent and accurate dosing of compounds according to the present disclosure.

[0073] The hydrophobic coating may be applied to the interior surface of the vial using methods known to those skilled in the art, for example, physical or chemical vapor deposition methods (including, for example, plasma-assisted chemical vapor deposition). In some embodiments, the hydrophobic coating on the interior surface of the vial comprises silicon (Si), oxygen (O), carbon (C), and hydrogen (H). In some embodiments, the hydrophobic coating is characterized by a low Si content. In some embodiments, the hydrophobic coating is characterized by a ratio of oxygen content to silicon content of 1.2 or less. In some embodiments, the ratio of O to Si is 1.2 or less. In some embodiments, the hydrophobic coating has the formula SiO x C y H z where x is 0.0 to 1.2, y is 0.0 to 6.0, and z is 0.0 to 6.0. In some embodiments, the hydrophobic coating comprises a compound having the formula SiO x C y H zwhere x is 0.6 to 0.9, y is 1.2 to 3.3, and z is 0.0 to 6.0. In some embodiments, the hydrophobic coating comprises a compound having the formula SiO x C y H z wherein x is 0.7 to 0.8, y is 1.5 to 2.5, and z is 0.0 to 6.0. In some embodiments, the hydrophobic coating is essentially fluorine-free. The composition of the hydrophobic coating can be determined using methods known to those skilled in the art, such as, for example, X-ray photoelectron spectroscopy (XPS).

[0074] The hydrophobicity of a coating can be determined, for example, by measuring the contact angle of a water droplet on the surface of the coating to determine the water contact angle. In some embodiments, the coated vial (i.e., the hydrophobic coating) is characterized by a water contact angle of 90° or greater. In some embodiments, the coated vial is characterized by a water contact angle of about 90° to 120°, e.g., a contact angle of 90°, 95°, 100°, 105°, 110°, 115°, or 120°. II. Freeze-Drying Procedure

[0075] The process of freeze-drying involves three major steps: (1) freezing, (2) primary drying, and (3) secondary drying.

[0076] The freezing step ensures that the pre-lyophilization composition reaches a solid phase, forming a frozen pre-lyophilization composition. Freezing is achieved by lowering the temperature and maintaining it for a predetermined period of time. The material must be frozen by cooling to a temperature below the lowest melting point of all components present in the pre-lyophilization composition (including, for example, a eutectic melting point that is lower than the melting point of any of the individual components) to ensure that subsequent heating of the frozen material under vacuum or low pressure will result in sublimation rather than melting. Cooling the mixture to a temperature below the lowest temperature at which the solid and liquid phases of the material can coexist (e.g., the eutectic point) ensures that sublimation rather than melting will occur in the next step.

[0077] In some embodiments, the pre-lyophilized composition is cooled to a temperature below 0° C. In some embodiments, the pre-lyophilized composition is cooled to a temperature of −50° C. or less. In some embodiments, the pre-lyophilized composition is cooled to a temperature of −40° C. to −50° C. In some embodiments, the pre-lyophilized composition is cooled to a temperature of about −45° C. In some embodiments, the pre-lyophilized composition is cooled for 10 hours or less. In some embodiments, the pre-lyophilized composition is cooled for 9 hours or less, 8 hours or less, 7 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.

[0078] There are many suitable methods for freezing, each of which is encompassed within this disclosure. Suitable freezing methods include, but are not limited to, refrigeration, placement in an ice bath (e.g., a bath of ice or dry ice with a salt or organic solvent, or a combination thereof, e.g., dry ice with methanol or ethanol), and placement in a liquid nitrogen bath.

[0079] After freezing, the primary drying step involves reducing the pressure to induce sublimation of the frozen water in the pre-lyophilized composition. Typically, most of the water is removed during this primary drying step.

[0080] Typically, a vacuum pump is used to reduce the pressure. Because vapor pressure on ice is a function of temperature, the desired pressure can vary based on the temperature of the primary drying step. In some embodiments, the pressure in the primary drying step is reduced to less than the vapor pressure of ice at the target temperature (i.e., the temperature of the primary drying step). For example, the vapor pressure of ice at -26°C is approximately 429 mTorr. In the described embodiment, the pressure in the primary drying step is less than 429 mTorr. In some embodiments, the pressure in the primary drying step is 20% to 70% of the vapor pressure of ice at the target temperature (i.e., the temperature of the primary drying step). Again using -26°C as an exemplary temperature, 20% to 30% of the vapor pressure is approximately 85.8 to 300 mTorr. In some embodiments, the pressure in the primary drying step is 20% to 30% of the vapor pressure of ice at the target temperature (i.e., the temperature of the primary drying step). Referring again to −26° C. as an exemplary temperature, 20% to 30% of the vapor pressure is approximately 85.8 to 128 mTorr. Vapor pressure over ice is commonly known and can be estimated by one of ordinary skill in the art. Exemplary vapor pressures at a given temperature include: 0° C., approximately 4,584 mTorr; −10° C., approximately 1,949 mTorr; −20° C., approximately 774 mTorr; −30° C., approximately 285 mTorr; −40° C., approximately 96 mTorr; or −50° C., approximately 30 mTorr.

[0081] The primary drying step can be carried out at ambient, sub-ambient, or super-ambient temperatures. For example, in some embodiments, the primary drying step is carried out at a temperature of 40° C. or less, 30° C. or less, 20° C. or less, 10° C. or less, or 0° C. or less.

[0082] The primary drying stage lasts for any suitable period of time. In some embodiments, the primary drying stage lasts for at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more. In some embodiments, the primary drying stage occurs overnight. In some embodiments, the primary drying temperature is -25°C and is warmed to 25°C over about 3 hours.

[0083] Following the primary drying step, further drying (secondary drying step) is performed by increasing the temperature above that used in the primary drying step. Most of the free water is removed during the primary drying step, leaving most of the water bound to the components of the formulation. Thus, the secondary drying step removes not only the water that condensed or migrated from its original location during the primary drying step, but also additional moisture. Because most of the free water has already been removed, the temperature of the secondary drying step can be increased without melting the composition.

[0084] In some embodiments, the secondary drying step is carried out at a temperature ranging from -10°C to 50°C, 0°C to 40°C, 10°C to 30°C, or 20°C to 25°C.

[0085] Typically, low pressure is also used in this stage. Typically, the reduced pressure from the primary drying stage is maintained, although various lower pressures are preferred during this process to promote sublimation.

[0086] The rate of moisture removal during the secondary drying step is a function of temperature, and lower pressures typically do not increase the drying rate. In some embodiments, the secondary drying step is at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more. In some embodiments, the secondary drying step is carried out overnight.

[0087] In some embodiments, the secondary drying step can include drying in the presence of an inert gas (e.g., nitrogen) or a combination of inert gases. For example, the lyophilization vessel and / or vial reservoir can be purged with an inert gas and capped to avoid exposure of the formulation to air.

[0088] The lyophilized compositions described herein can have a moisture content of, for example, less than 20% after one or more drying steps. In some examples, the moisture content of the lyophilized compositions described herein is less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.1%. III. Lyophilized formulation comprising formula (I)

[0089] In one aspect, the present disclosure provides a compound of formula (I) described in Section Ia above: [ka] (In the formula, W, X, Y, Z, R a , R c , and each R g (wherein R is as defined herein) or a pharmaceutically acceptable salt thereof, and one or more amino acids. In some embodiments, the one or more amino acids are L-amino acids (e.g., L-arginine, etc.). In some embodiments, the lyophilized formulation further comprises a pH adjuster, a bulking agent, or both.

[0090] In some embodiments, the lyophilized formulation has a molar ratio of the compound of Formula (I) (e.g., the compound of Formula (Ia)) to one or more amino acids of about 1:2 to about 1:7. In some embodiments, the lyophilized formulation has a molar ratio of the compound of Formula (I) (e.g., the compound of Formula (Ia)) to one or more amino acids of about 1:2 to about 1:5. In another embodiment, the molar ratio of the compound of Formula (I) (e.g., the compound of Formula (Ia)) to one or more amino acids is about 1:4 to about 1:5. In another embodiment, the molar ratio of the compound of Formula (I) (e.g., the compound of Formula (Ia)) to amino acids is about 1:4.5.

[0091] Lyophilized formulations can also be characterized by percent composition. In one embodiment, the lyophilized formulation comprises a compound of Formula (I) (e.g., a compound of Formula (Ia)), one or more amino acids, and a pH adjuster, wherein the compound of Formula (I) comprises about 35% to 45% by weight of the lyophilized formulation, the amino acid comprises about 45% to 60% by weight of the lyophilized formulation, and the pH adjuster comprises about 5% to 10% by weight of the lyophilized composition. In another embodiment, the lyophilized formulation comprises a compound of Formula (I) (e.g., a compound of Formula (Ia)), one or more amino acids, a pH adjuster, and a bulking agent, wherein the compound of Formula (I) or (Ia) comprises about 15% to 25% by weight of the lyophilized formulation, the amino acid comprises about 20% to 35% by weight of the lyophilized formulation, the pH adjuster comprises about 1% to 10% by weight of the lyophilized formulation, and the bulking agent comprises about 40% to 50% by weight of the lyophilized formulation.

[0092] Lyophilized formulations according to the present disclosure may have certain advantages, such as reduced cracking, brittleness and / or shrinkage. Such characteristics may be determined according to methods known in the art.

[0093] In some embodiments, provided herein is a lyophilized formulation comprising a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof and one or more amino acids selected from arginine, lysine, histidine, tryptophan, cysteine, and combinations thereof in an amount greater than the stoichiometric amount of the compound of Formula (Ia).

[0094] In some embodiments, provided herein is a lyophilized formulation comprising: about 15% to about 20% by weight of a compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 20% to about 35% by weight of one or more amino acids; about 2% by weight to about 5% by weight of phosphoric acid; about 40% to about 60% by weight of a bulking agent; The weight percentages (ie, wt %) are lyophilized formulations based on the total weight of the lyophilized formulation.

[0095] In some embodiments, the bulking agent is kleptose, dextran, mannitol, or glycine. In some embodiments, the bulking agent is mannitol. In some embodiments, the bulking agent is glycine.

[0096] In some embodiments, provided herein is a lyophilized formulation comprising: about 17.4% by weight of a compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 23.4% by weight of arginine; About 3.5% by weight of phosphoric acid about 55.6% by weight of mannitol; The weight percentages are lyophilized formulations based on the total weight of the lyophilized formulation.

[0097] In some embodiments, provided herein is a lyophilized formulation comprising: about 22.6% by weight of a compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 30.6% by weight of arginine; about 4.6% by weight of phosphoric acid; about 42.1% by weight of glycine; The weight percentages are lyophilized formulations based on the total weight of the lyophilized formulation.

[0098] In some embodiments, provided herein is a lyophilized formulation comprising: about 35% to about 45% by weight of a compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; About 45% to about 55% by weight of one or more amino acids; about 5% to about 10% by weight of phosphoric acid; Weight percentages (wt%) are lyophilized formulations based on the total weight of the lyophilized formulation.

[0099] In some embodiments, provided herein is a lyophilized formulation comprising: about 39.2% by weight of a compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 52.9% by weight arginine; about 7.9% by weight of phosphoric acid; The weight percentages are lyophilized formulations based on the total weight of the lyophilized formulation.

[0100] In some embodiments, the pH of the lyophilized formulation is adjusted with a pH adjuster. It is contemplated that one of skill in the art will understand that the amount of any pH adjuster (e.g., a base such as sodium hydroxide or an acid such as phosphoric acid) present in the lyophilized formulation will be determined, among other things, by the target pH range before lyophilization. In some embodiments, the target pH range is about 6 to about 8 (e.g., pH 7.0 to 7.5 or pH 7.2 to 7.4). In some embodiments, the lyophilized formulation has a pH of about 7.2 to about 7.4. In some embodiments, the pH adjuster comprises sodium hydroxide. In some embodiments, the amount of sodium hydroxide corresponds to the amount of sodium hydroxide added to the pre-lyophilization solution to achieve a pH of about 6 to about 8, in some embodiments, about 7.0 to about 7.5, and in some embodiments, about 7.2 to about 7.4.

[0101] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: Approximately 107.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine, Approximately 21.8 mg of phosphate, and about 344 mg of mannitol.

[0102] In some embodiments, provided herein is a method for treating a psoriasis-associated inflammatory disease, comprising: Approximately 107.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine, Approximately 21.8 mg of phosphate, and about 200 mg of glycine, and a lyophilized formulation in a vial.

[0103] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: Approximately 27.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 37.1 mg of arginine, and about 5.6 mg of phosphoric acid.

[0104] In some embodiments, provided herein is a method for treating a pulmonary arthritis, comprising: Approximately 107.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.1 mg of arginine, and about 21.8 mg of phosphoric acid.

[0105] In some embodiments, the lyophilized formulation in the vial further comprises sodium hydroxide, in some embodiments, the amount of sodium hydroxide corresponding to the amount of sodium hydroxide added to the pre-lyophilization solution such that the pH of the pre-lyophilization solution is about 6 to about 8, in some embodiments, about 7.0 to about 7.5, and in some embodiments, about 7.2 to about 7.4.

[0106] In some embodiments, the lyophilized formulations described herein comprise: (i) preparing a bulk solution by dissolving a compound of Formula (Ia), an amino acid (e.g., arginine, e.g., L-arginine), phosphate, and a bulking agent in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH adjuster; (iii) filtering the bulk solution into sterile vials in a clean room; (iv) loading the vials into a freeze-dryer; (v) subjecting the vial to a freeze-thaw cycle; (vi) primary and secondary drying of the vials under reduced pressure; obtaining a lyophilized formulation.

[0107] In some embodiments, the lyophilized formulations described herein (i) preparing a bulk solution by dissolving a compound of Formula (Ia), arginine, phosphate, and a bulking agent in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH adjuster; (iii) filtering the bulk solution into sterile vials in a clean room; (iv) loading the vials into a freeze-dryer; (v) cooling the vial to a temperature of about −45° C. at a rate of about 0.5° C. / minute and holding the vial at a temperature of about −45° C. for about 3 hours; (vi) warming the vial to a temperature of about −10° C. over about 50 minutes and maintaining the vial at a temperature of about −10° C. for about 4 hours; (vii) cooling the vial to a temperature of about −45° C. over about 70 minutes and maintaining the vial at a temperature of about −45° C. for about 2 hours; (viii) warming the vial to a temperature of about −15° C. and reducing the pressure to initiate primary drying; (ix) maintaining the vial under reduced pressure for about 36 hours; (x) warming the vials to a temperature of about 30°C and performing secondary drying for about 4 hours; (xi) filling the lyophilizer with dry nitrogen to a pressure of about 700 Torr and stoppering the vials, thereby providing a lyophilized formulation.

[0108] In some embodiments, the lyophilized formulations described herein (i) preparing a bulk solution by dissolving a compound of Formula (Ia), an amino acid (e.g., arginine, e.g., L-arginine), and phosphoric acid in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH adjuster; (iii) filtering the bulk solution into sterile vials in a clean room; (iv) loading the vials into a freeze-dryer; (v) subjecting the vial to a freeze-thaw cycle; (vi) subjecting the vials to primary and secondary drying under reduced pressure, thereby obtaining a lyophilized formulation.

[0109] In some embodiments, the lyophilized formulations described herein comprise: (i) preparing a bulk solution by dissolving a compound of formula (Ia), arginine, and phosphoric acid in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH adjuster; (iii) filtering the bulk solution into sterile vials in a clean room; (iv) loading the vials into a freeze-dryer; (v) cooling the vial to a temperature of about −45° C. at a rate of about 0.5° C. / minute and holding the vial at a temperature of about −45° C. for about 3 hours; (vi) warming the vial to a temperature of about −10° C. over about 50 minutes and maintaining the vial at a temperature of about −10° C. for about 4 hours; (vii) cooling the vial to a temperature of about −45° C. over about 70 minutes and maintaining the vial at a temperature of about −45° C. for about 2 hours; (viii) warming the vial to a temperature of about −15° C. and reducing the pressure to initiate primary drying; (ix) maintaining the vial under reduced pressure for about 36 hours; (x) warming the vials to a temperature of about 30°C and performing secondary drying for about 4 hours; (xi) filling the lyophilizer with dry nitrogen to a pressure of about 700 Torr and stoppering the vials, thereby providing a lyophilized formulation.

[0110] In some embodiments, the pH adjusting agent is a base. In some embodiments, the pH adjusting agent is an acid. In some embodiments, a pH adjusting agent is added to an aqueous solution that is subsequently subjected to lyophilization so that the aqueous solution prior to lyophilization has a pH of about 6 to about 8, in some embodiments, about 7.0 to about 7.5, and in some embodiments, about 7.2 to 7.4.

[0111] The above temperature, time, pressure, and / or weight percent ranges are provided by way of example only, and other variations may be envisioned by those skilled in the art, and all such variations are contemplated to be within the scope of the embodiments presented herein. IV. Reconstitution of a lyophilized formulation containing Formula (I)

[0112] In one aspect, the present disclosure provides a reconstituted lyophilized formulation (i.e., a reconstituted pharmaceutical composition or a reconstituted formulation) comprising a compound of Formula (I) or (Ia), one or more amino acids, and an acceptable diluent. In some embodiments, the acceptable diluent is a pharmaceutically acceptable diluent. In some embodiments, the pharmaceutically acceptable diluent is suitable for intravenous administration. In some embodiments, the reconstituted lyophilized formulation further comprises a pH adjusting agent, a bulking agent, or both. Reconstituted lyophilized formulations (i.e., a reconstituted pharmaceutical composition) according to the present disclosure are useful in methods of treating diseases, disorders, or conditions mediated at least in part by CD73, as described elsewhere herein.

[0113] The lyophilized formulations described herein are reconstituted with an acceptable diluent before administration. As used herein, "reconstitution" refers to the process of wetting the lyophilized cake in such a manner that the cake is completely dissolved and the resulting liquid reaches a clarity acceptable for administration to a patient. Diluents useful for reconstituting lyophilized formulations comprising Formula (I) or (Ia) include sterile water for injection (SFWI), SWFI containing stabilizers, solubilizers, tonicity adjusters such as NaCl, MgCl or CaCl, and mixtures thereof, 0.9% saline solution (i.e., normal saline), semi-normal saline, lactated Ringer's solution, dextrose in water, dextrose saline, or dextrose lactated Ringer's solution. In one embodiment, the diluent is SWFI. In another embodiment, the diluent is normal saline. In some embodiments, for example, if the vial containing the lyophilized formulation is stored under refrigeration, the vial should be equilibrated to room temperature before reconstitution.

[0114] The volume of diluent used to reconstitute a formulation of the present disclosure depends on the intended mode of administration and the desired final concentration (mg / mL) of the reconstituted formulation. In some embodiments, the composition in the vial is reconstituted with 1.1 to 3.3 mL of diluent. One of skill in the art will understand that as vial size (and sample size) increases, the amount of diluent may also increase. Thus, in some embodiments, the composition in the vial is reconstituted with 2.2 to 20.2 mL of diluent, e.g., 2.2 mL, 2.3 mL, 2.4 mL, 2.5 mL, 2.6 mL, 2.7 mL, 2.8 mL, 2.9 mL, 3.0 mL, 3.1 mL, 3.2 mL, 3.3 mL, 3.4 mL, 3.5 mL, 3.6 mL, 3.7 mL, 3.8 mL, 3.9 mL, 4.0 mL, 4.1 mL, 4.2 mL, 4.3 mL, 4.4 mL, 4.5 mL, 4.6 mL, 4.7 mL, 4.8 mL, etc. L, 4.9mL, 5.0mL, 5.1mL, 5.2mL, 5.3mL, 5.4mL, 5.5mL, 5.6mL, 5.7mL, 5.8mL, 5.9mL, 6.0mL, 6.1mL, 6.2mL, 6.3mL, 6.4mL, 6.5mL, 6.6mL, 6.7mL, 6.8mL, 6.9mL, 7.0mL, 7.1mL, 7.2mL, 7.3mL, 7.4mL, 7.5mL, 7.6mL, 7.7mL, 7.8mL, 7.9mL, 8.0mL, 8.1mL, 8.2mL, 8.3 mL, 8.4mL, 8.5mL, 8.6mL, 8.7mL, 8.8mL, 8.9mL, 9.0mL, 9.1mL, 9.2mL, 9.3mL, 9.4mL, 9.5mL, 9.6mL, 9.7mL, 9.8mL, 9.9mL, 10.0m L, 10.1mL, 10.2mL, 10.3mL, 10.4mL, 10.5mL, 10.6mL, 10.7mL, 10.8mL, 10.9mL, 11.0mL, 11.1mL, 11.2mL, 11.3mL, 11.4mL, 11.5 mL, 11.6mL, 11.7mL, 11.8mL, 11.9mL, 12.0mL, 12.1mL, 12.2mL, 12.3mL, 12.4mL, 12.5mL, 12.6mL, 12.7mL, 12.8mL, 12.9mL, 13. 0mL, 13.1mL, 13.2mL, 13.3mL, 13.4mL, 13.5mL, 13.6mL, 13.7mL, 13.8mL, 13.9mL, 14.0mL, 14.1mL, 14.2mL, 14.3mL, 14.4mL, 14.5mL, 14.6mL, 14.7mL, 14.8mL, 14.9mL, 15.0mL, 15.1mL, 15.2mL, 15.3mL, 15.4mL, 15.5mL, 15.6mL, 15.7mL, 15.8mL, 15. 9mL, 16.0mL, 16.1mL, 16.2mL, 16.3mL, 16.4mL, 16.5mL, 16.6mL, 16.7mL, 16.8mL, 16.9mL, 17.0mL, 17.1mL, 17.2mL, 17. Reconstituted with 3 mL, 17.4 mL, 17.5 mL, 17.6 mL, 17.7 mL, 17.8 mL, 17.9 mL, 18.0 mL, 18.1 mL, 18.2 mL, 18.3 mL, 18.4 mL, 18.5 mL, 18.6 mL, 18.7 mL, 18.8 mL, 18.9 mL, 19.0 mL, 19.1 mL, 19.2 mL, 19.3 mL, 19.4 mL, 19.5 mL, 19.6 mL, 19.7 mL, 19.8 mL, 19.9 mL, or 20.0 mL of diluent. In one embodiment, the lyophilized formulations described herein can be reconstituted in diluent in about 15 minutes or less. In other embodiments, the lyophilized formulations comprising Formula (I) or (Ia) can be reconstituted in 10 minutes or less, or 5 minutes or less, or 4 minutes or less, or 3 minutes or less, or 2 minutes or less, or 1 minute or less.

[0115] In some embodiments, the diluent is water, providing the aqueous formulations described herein.

[0116] Provided herein is an aqueous formulation comprising a compound of formula (I) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof (In the formula, W is CR e and N, X is selected from the group consisting of O, CH2, and S; each of Y and Z is independently selected from the group consisting of CH and N; R g is H or two R g groups bond to form an acetonide, Ra However, NH2, NHR 1 , and NR 1 R 2 is selected from the group consisting of R c H, halogen, haloalkyl, NH2, NHR 3 , N.R. 3 R 4 , R 3 , OH, OR 3 , S.R. 3 , SO2R 3 , -X 1 -NH2, -X 1 -NHR 3 , -X 1 -NR 3 R 4 , -X 1 -OH, -X 1 -OR 3 , -X 1 -SR 3 , and -X 1 -SO2R 3 is selected from the group consisting of R e is selected from the group consisting of H, halogen, and optionally substituted C1-C6 alkyl; each X 1 is C1-C4 alkylene Each R 1 , R 2 , R 3 and R 4 are independently optionally substituted C-C 10 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkylC1-C4 alkyl, optionally substituted 4- to 7-membered heterocycloalkyl, optionally substituted 4- to 7-membered heterocycloalkylC1-C4 alkyl, optionally substituted aryl, optionally substituted arylC1-C4 alkyl, optionally substituted heteroaryl, and optionally substituted heteroarylC1-C4 alkyl, or R 1 and R 2 or R 3 and R 4are attached to the same nitrogen, they combine to form a 4- to 7-membered heterocycle) and An aqueous formulation comprising one or more amino acids and, optionally, a pH adjusting agent in an amount sufficient to adjust the pH of the solution to about 6 to about 8, in some embodiments, about 7.0 to about 7.5, and in some embodiments, about 7.2 to about 7.4.

[0117] Provided herein is an aqueous formulation comprising: about 15% to about 20% by weight of a compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 20% to about 35% by weight of one or more amino acids; about 2% by weight to about 5% by weight of phosphoric acid; about 40% to about 60% by weight of a bulking agent; Weight percentages (wt%) are aqueous formulations based on the total weight of the lyophilized formulation dissolved in water to form the aqueous formulation.

[0118] In some embodiments, the bulking agent is kleptose, dextran, mannitol, or glycine. In some embodiments, the bulking agent is mannitol. In some embodiments, the bulking agent is glycine.

[0119] In some embodiments, provided is an aqueous formulation comprising: about 17.4% by weight of a compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 23.4% by weight of arginine; About 3.5% by weight of phosphoric acid about 55.6% by weight of mannitol; The weight percentage is based on the total weight of the lyophilized formulation dissolved in water to form the aqueous formulation. In some embodiments, the lyophilized formulation is any of the lyophilized formulations described herein.

[0120] In some embodiments, provided is an aqueous formulation comprising: about 22.6% by weight of a compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 30.6% by weight of arginine; about 4.6% by weight of phosphoric acid; about 42.1% by weight of glycine; The weight percentages are aqueous formulations based on the total weight of the lyophilized formulation dissolved in water to form the aqueous formulation.

[0121] In some embodiments, provided herein is an aqueous formulation comprising: about 35% to about 45% by weight of a compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; About 45% to about 55% by weight of one or more amino acids; about 5% to about 10% by weight of phosphoric acid; The weight percentages are aqueous formulations based on the total weight of the lyophilized formulation dissolved in water to form the aqueous formulation.

[0122] In some embodiments, provided herein is an aqueous formulation comprising: about 39.2% by weight of a compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 52.9% by weight arginine; about 7.9% by weight of phosphoric acid; The weight percentages are aqueous formulations based on the total weight of the lyophilized formulation dissolved in water to form the aqueous formulation.

[0123] In some embodiments, provided is an aqueous formulation comprising: Approximately 107.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine, Approximately 21.8 mg of phosphate, and about 344 mg of mannitol.

[0124] In some embodiments, provided is an aqueous formulation comprising: Approximately 107.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine, Approximately 21.8 mg of phosphate, and about 200 mg of glycine.

[0125] In some embodiments, provided herein is an aqueous formulation comprising: Approximately 27.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 37.1 mg of arginine, and about 5.6 mg of phosphoric acid.

[0126] In some embodiments, provided herein is an aqueous formulation comprising: Approximately 107.5 mg of the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.1 mg of arginine, and about 21.8 mg of phosphoric acid.

[0127] In some embodiments, the aqueous formulation further comprises a pH adjuster, optionally sodium hydroxide, in some embodiments, the amount of sodium hydroxide corresponds to the amount of sodium hydroxide added to the aqueous solution to achieve a pH of about 6 to about 8, in some embodiments, about 7.0 to about 7.5, and in some embodiments, about 7.2 to about 7.4. V. Therapeutic and Prophylactic Uses

[0128] In one aspect, the present disclosure is directed to a method of treating a disease, disorder, or condition mediated at least in part by CD73, the method comprising: a) reconstituting a lyophilized formulation according to the present disclosure with a diluent to form a reconstituted solution; b) administering a therapeutically effective amount of the reconstituted solution to a subject in need thereof.

[0129] The lyophilized formulation can be reconstituted with an acceptable diluent. In some embodiments, the diluent is selected from the group consisting of normal saline, semi-normal saline, Ringer's solution, lactated Ringer's solution, sterile water for injection, dextrose in water, dextrose in saline, and dextrose in lactated Ringer's solution. In one embodiment, the diluent is sterile water for injection. In another embodiment, the diluent is normal saline.

[0130] In some embodiments, the lyophilized formulation is reconstituted with 2 to 20 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 2.0 to 15.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 2.0 to 10.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 2.2 to 6.6 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 3.0 to 6.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 3.0 to 4.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 3.0 to 3.5 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 6.5 to 10.5 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 7.0 to 10.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 7.5 to 9.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 8.0 to 9.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 8.3 to 8.8 mL of diluent.

[0131] In one or more embodiments, the pH of the reconstituted solution ranges from about 6 to about 8. In some embodiments, the pH of the reconstituted solution ranges from about 6.5 to about 7.5. In some embodiments, the pH of the reconstituted solution ranges from about 6.0 to about 7.0. In some embodiments, the pH of the reconstituted solution ranges from about 7.0 to about 7.5.

[0132] In some embodiments, the reconstituted solution is administered to a subject parenterally. In some embodiments, the parenteral administration is intravenous, intraperitoneal, subcutaneous, intradermal, or intramuscular. In some embodiments, the parenteral administration is intravenous.

[0133] In some embodiments, the method further comprises diluting the reconstituted solution with an acceptable vehicle to form a diluted reconstituted solution prior to administration to the subject. In some embodiments, the vehicle is selected from the group consisting of normal saline, semi-normal saline, Ringer's solution, lactated Ringer's solution, sterile water for injection, dextrose in water, dextrose saline, and dextrose lactate Ringer's solution. In some embodiments, the vehicle is normal saline.

[0134] In some embodiments, the diluted reconstituted solution is administered to a subject within 24 hours of dilution, e.g., within 24 hours, e.g., 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1.5, 1.25, 1, 50, 45, 40, 35, 30, 25, 20, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute of dilution. In some embodiments, the diluted reconstituted solution is administered to a subject within 24 hours of dilution. In some embodiments, the diluted reconstituted solution is administered to a subject within 4 hours of dilution. In some embodiments, the diluted reconstituted solution is administered to the subject within 1 hour of dilution, hi some embodiments, the diluted reconstituted solution is administered to the subject within 30 minutes of dilution.

[0135] In some embodiments, the method further comprises filtering the diluted reconstituted solution prior to administration to the subject, hi one embodiment, the diluted reconstituted solution is filtered using an in-line filter.

[0136] The present disclosure contemplates the use of compounds of Formula (I) or (Ia) (e.g., reconstituted formulations, e.g., reconstituted solutions or diluted and reconstituted solutions described herein) in the treatment or prevention of a wide range of diseases, disorders, and / or conditions, and / or their symptoms. The reconstituted formulations are suitable for administration by injection. Common types of injection include intravenous, subcutaneous, and intramuscular, with infusions typically given intravenously. Other application sites for parenteral administration include epidural, intraspinal, intrathecal, intracerebral, intraarticular, intracardiac, intradermal, intraperitoneal, intravitreal, intraarterial, intraorbital, and transtracheal. Specific uses are described in detail below, but it should be understood that the disclosure is not limited thereto. Additionally, general classifications of certain diseases, disorders, and conditions are described below, although some of the diseases, disorders, and conditions may be members of more than one classification, or may not be members of any of the disclosed classifications. Oncology-related disorders. According to the present disclosure, compounds of Formula (I) or (Ia) (e.g., reconstituted lyophilized formulations described herein) can be used to treat or prevent proliferative conditions or disorders, including cancers, such as cancers of the uterus, cervix, breast, prostate, testis, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon, or rectum), kidney, renal cell, bladder, bone, bone marrow, skin, head or neck, liver, gallbladder, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., glioma), ganglion, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic and immune systems (e.g., spleen or thymus). The present disclosure also provides methods of treating or preventing other cancer-related diseases, disorders, or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virally-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratoma, chemically-induced cancer, metastasis, and angiogenesis.The present disclosure contemplates reducing tolerance to tumor cells or cancer cell antigens, for example, by modulating the activity of regulatory T cells and / or CD8+ T cells (see, e.g., Ramirez-Montagut, et al. (2003) Oncogene 22:3180-87, and Sawaya, et al. (2003) New Engl. J. Med. 349:1501-09). In certain embodiments, the tumor or cancer is pancreatic cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, gastroesophageal cancer, urothelial cancer, gastric cancer, melanoma, lung cancer, renal cancer, liver cancer, glioblastoma, head and neck cancer, or leukemia. In some embodiments, a compound of Formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation described herein) is used to treat cancer in a first-line setting (e.g., treatment-naive in that setting). In some embodiments, compounds of Formula (I) or (Ia) (e.g., reconstituted lyophilized formulations described herein) are used to treat cancer in second-line or higher settings. The use of the term cancer-related diseases, disorders, and conditions is meant to refer broadly to conditions directly or indirectly associated with cancer, including, for example, angiogenesis and precancerous conditions, such as dysplasia.

[0137] In some embodiments, the cancer is castrate-resistant prostate cancer (CRPC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer, renal cell carcinoma, or colorectal cancer. In some embodiments, the cancer is castrate-resistant prostate cancer (CRPC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), or colorectal cancer (CRC). In some embodiments, the cancer is metastatic. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer and the subject is treatment-naive. In some embodiments, the cancer is non-small cell lung cancer and the subject has disease progression on a previously selected therapy. In some embodiments, the cancer is pancreatic cancer, optionally metastatic pancreatic cancer. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is metastatic pancreatic cancer and the subject is treatment-naive. In some embodiments, the cancer is metastatic pancreatic cancer. In some embodiments, the prior therapy comprises chemotherapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has disease progression on prior therapy. In some embodiments, the prior therapy comprises a checkpoint inhibitor, optionally, the checkpoint inhibitor is a PD-L1 antagonist or a PD-1 antagonist. In some embodiments, the prior therapy comprises chemotherapy and a checkpoint inhibitor, optionally, the checkpoint inhibitor is a PD-L1 antagonist or a PD-1 antagonist.

[0138] In certain embodiments, the cancer is metastatic or at risk of becoming metastatic, or may arise in widespread tissues, including cancers of the blood or bone marrow (e.g., leukemia). In some further embodiments, the reconstituted lyophilized formulations described herein can be used to overcome T-cell tolerance.

[0139] In some embodiments, the present disclosure provides methods for treating and / or preventing a proliferative condition, cancer, tumor, or precancerous condition using a compound of Formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation described herein) and at least one additional therapeutic or diagnostic agent, examples of which are described elsewhere herein.

[0140] In one embodiment, the cancer is a gastrointestinal malignancy, e.g., pancreatic cancer. In one embodiment, the cancer is metastatic pancreatic adenocarcinoma. In one embodiment, the patient is treated for pancreatic cancer using a reconstituted formulation and an anti-PD-1 antibody described herein. In another embodiment, the patient is treated for pancreatic cancer, optionally pancreatic adenocarcinoma, using a reconstituted formulation described herein in combination with chemotherapy. In another embodiment, the patient is treated for metastatic pancreatic cancer using a reconstituted formulation described herein in combination with chemotherapy and optionally an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, suitable chemotherapy regimens are described in the National Cancer Comprehensive Network (NCCN) Clinical Practice Guidelines for Pancreatic Adenocarcinoma (Version 2.2023). In some embodiments, the chemotherapy comprises (a) paclitaxel or nab-paclitaxel and (b) gemcitabine. In some embodiments, the chemotherapy comprises FOLFIRINOX (folinic acid, sometimes called calcium folinate or leucovorin, fluorouracil (5FU), irinotecan, and oxaliplatin). In some embodiments, the chemotherapy comprises gemcitabine, capecitabine, or 5-fluorouracil (5-FU). In another embodiment, the patient is treated for first-line metastatic pancreatic cancer using a compound of Formula (I) or (Ia) and an anti-PD-1 antibody and a standard of care for pancreatic cancer, such as those described herein. For example, in some embodiments, the patient may be treated for first-line metastatic pancreatic cancer using a compound of Formula (I) or (Ia) and an anti-PD-1 antibody and a gemcitabine and nab-paclitaxel chemotherapy regimen. In some embodiments, patients may be treated for first-line metastatic pancreatic cancer using a compound of Formula (I) or (Ia) and an anti-PD-1 antibody and a Forfirinox chemotherapy regimen. Patients may be treatment-experienced or treatment-naive.

[0141] In some embodiments, the methods described herein may be indicated as first-line, second-line, or third-line treatments. In some embodiments, the methods described herein are indicated as first-line treatments. In some embodiments, the methods described herein are indicated as second-line treatments. In some embodiments, the methods described herein are indicated as third-line treatments.

[0142] Immune-Related Disorders and Disorders with an Inflammatory Component. As used herein, the terms "immune disease," "immune condition," "immune disorder," "inflammatory disease," "inflammatory condition," "inflammatory disorder," and the like are meant to broadly encompass any immune-related condition (e.g., autoimmune disease) or disorder with an inflammatory component that can be treated and / or prevented using a compound of Formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation described herein) and that provides some therapeutic benefit. Such conditions are often intimately intertwined with other diseases, disorders, and conditions. By way of example, "immune condition" can refer to proliferative conditions, such as cancer, tumors, and angiogenesis, including infections (acute and chronic), tumors, and cancers that resist eradication by the immune system.

[0143] Compounds of Formula (I) or (Ia) (e.g., the reconstituted lyophilized formulations described herein) can be used to increase or enhance immune responses, improve immunization, including increasing vaccine efficacy, and increase inflammation. Immune deficiencies associated with immunodeficiency diseases, immunosuppressive medical treatments, acute and / or chronic infections, and aging can be treated using the compounds disclosed herein. The reconstituted lyophilized formulations described herein can also be used to stimulate the immune system of patients suffering from iatrogenically induced immunosuppression, including patients who have undergone bone marrow transplantation, chemotherapy, or radiation therapy.

[0144] In certain embodiments of the present disclosure, a compound of Formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation described herein) is used to increase or enhance the immune response to an antigen by providing adjuvant activity. In certain embodiments, at least one antigen or vaccine is administered to a subject in combination with a reconstituted lyophilized formulation described herein to prolong the immune response to the antigen or vaccine. Therapeutic compositions comprising at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with a reconstituted lyophilized formulation described herein are also provided.

[0145] Patient Selection. In some cases, the methods disclosed herein may be indicated for certain patients based on, for example, CD73 as a biomarker, high microsatellite instability, or high tumor mutation burden. In some cases, the subject is identified as having an oncogene-driven or oncogene-dependent cancer with a mutation in at least one gene associated with CD73. Test methods for determining CD73 levels and the presence of CD73-related oncogenes are disclosed in WO 2020 / 185859 and WO 2020 / 205527. Combination therapy

[0146] The present disclosure contemplates the use of a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation described herein) alone or in combination with one or more additional therapies. Each additional therapy may be an active therapeutic agent or another treatment modality. In embodiments including one or more additional therapeutic agents, each agent may target a different but complementary mechanism of action. The additional therapeutic agent may be a small chemical molecule; a macromolecule, e.g., a protein, antibody, peptibody, peptide, DNA, RNA, or fragment of such a macromolecule; or cell therapy or gene therapy. Non-limiting examples of additional treatment modalities include surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. The use of a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation described herein) in combination with one or more additional therapies may have a synergistic therapeutic or prophylactic effect against the underlying disease, disorder, or condition. Additionally or alternatively, the combination therapy may allow for a dose reduction of one or more of the drugs, thereby ameliorating, reducing, or eliminating adverse effects associated with one or more of the drugs. The compounds of formula (I) or (Ia) of the present disclosure may also be useful in overcoming adenosine-dependent immunosuppression, leading to enhanced therapeutic efficacy of other drugs. Furthermore, such combination therapy may have synergistic therapeutic or preventive effects on the underlying disease, disorder, or condition.

[0147] In embodiments including one or more additional therapeutic modalities, a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation described herein) can be administered before, after, or during treatment with the additional therapeutic modality. In embodiments including one or more additional therapeutic agents, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination can be administered simultaneously or near simultaneously, or at different times. Furthermore, therapeutic agents are "administered in combination" even if they have different dosage forms (e.g., oral capsules and intravenous), are given at different dosing intervals, one therapeutic agent is given on a fixed dosing regimen while another is titrated, tapered, or discontinued, or each therapeutic agent in the combination is independently titrated, tapered, or dose-up or -down, or discontinued and / or resumed during the course of a patient's treatment. When the therapeutic agents in the combination are formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0148] In some embodiments, the one or more additional therapeutic agents are signal transduction inhibitors. As used herein, the term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include: (i) BCR-ABL kinase inhibitors (e.g., GLEEVEC®), (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), including small molecule inhibitors (e.g., gefitinib, erlotinib, afatinib, and osimertinib) and anti-EGFR antibodies, (iii) inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, such as HER-2 / neu receptor inhibitors (e.g., HERCEPTIN®) and HER-3 receptor inhibitors, and (iv) vascular endothelial growth factor receptor (VGR) inhibitors. receptor (VEGFR) inhibitors, for example, small molecule inhibitors (e.g., axitinib, regorafenib, sunitinib, and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, etc.), anti-VEGF antibodies (e.g., bevacizumab), and anti-VEGFR antibodies (e.g., ramucirumab), (v) inhibitors of AKT family kinases or AKT pathways (e.g., rapamycin), (vi) serine / threonine kinase inhibitors (e.g., threonine / threonine kinase inhibitors), (vii) inhibitors of rearrangement during transfection (RET), including, for example, selpacatinib and pralsetonib; (viii) inhibitors of tyrosine-protein kinase Met (MET) (e.g., tepotinib, tivantinib, cabozantinib, and crizotinib); (ix) inhibitors of anaplastic lymphoma kinase (ADL) (e.g., anaplastic lymphoma kinase (ALK)).kinase, ALK) inhibitors (e.g., ensartinib, ceritinib, loratinib, crizotinib, and brigatinib), (x) inhibitors of the RAS signaling pathway described elsewhere herein (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK), (xi) FLT-3 inhibitors (e.g., gilteritinib), (xii) inhibitors of Trop-2, such as the antibody-drug conjugate sacituzumab govitecan-hziy, (xiii) JAK / STA inhibitors T pathway inhibitors, for example, JAK inhibitors including tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin, (xiv) inhibitors of NF-kB, (xv) cell cycle kinase inhibitors (e.g., flavopiridol), (xvi) phosphatidylinositol kinase (PI3K) inhibitors, (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, milansertib), (xx) platelet-derived growth factor receptor (PDR) inhibitors (xxi) insulin-like growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, lepretinib, etc.), and (xxi) insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, osimertinib, dacomitinib). Agents involved in immune modulation may also be used in combination with the compounds and formulations described herein to inhibit tumor growth in cancer patients. In one or more embodiments, the additional therapeutic agent includes an inhibitor of EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-kB, PI3K, AKT, or any combination thereof. Agents involved in immune modulation may also be used in combination with compounds of Formula (I) or (Ia) (e.g., as reconstituted lyophilized formulations comprising compounds of Formula (I) or (Ia) described herein) for the suppression of tumor growth in cancer patients.

[0149] In some embodiments, the one or more additional therapeutic agents are chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metredopa, and uredopa; ethylenimines and methylameramines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, Chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, e.g., aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, camomicin Ruzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, pomalidomide, potfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubeni mexamex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pemetrexed, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU;Androgens, e.g., calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; erformitin; vinegar Elliptinium nitrate; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid, 2-ethylhydrazide; Procarbazine; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Manno Mustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, such as nab-paclitaxel, paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP -16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamycin; capecitabine; anthracyclines;and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In some embodiments, the chemotherapeutic agent comprises a taxoid, a platinum-based chemotherapeutic agent, or an anthracycline-based chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, paclitaxel, and docetaxel. In some embodiments, the chemotherapeutic agent is gemcitabine or nab-paclitaxel. In certain embodiments, the combination therapy comprises a chemotherapy regimen comprising one or more chemotherapeutic agents. In one embodiment, the combination therapy comprises a chemotherapy regimen comprising one or more of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), a taxoid (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), and / or gemcitabine.

[0150] In some embodiments, one or more of the additional therapeutic agents is a hormone therapy. Hormonal therapy acts to regulate or inhibit the action of hormones on tumors. Examples of hormone therapy include, but are not limited to, selective estrogen receptor degraders, such as fulvestrant, gildestrant GDC-9545, SAR439859, RG6171, AZD9833, lindestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, selective estrogen receptor modulators, such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, toremifene, aromatase inhibitors, such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, toremifene, and ... Examples include anastrozole, exemestane, letrozole, and other aromatase inhibiting 4(5)-imidazoles; gonadotropin-releasing hormone agonists such as nafarelin, triptorelin, and goserelin; gonadotropin-releasing hormone antagonists such as degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, dalotamide, flutamide, nilutamide, bicalutamide, and leuprolide; and 5α-reductase inhibitors such as finasteride and dutasteride. In certain embodiments, the combination therapy includes a chemotherapy regimen comprising one or more chemotherapeutic agents. In certain embodiments, the combination therapy includes the administration of a hormone or related hormone agent. In one embodiment, the combination therapy includes the administration of enzalutamide.

[0151] In some embodiments, one or more of the additional therapeutic agents is a radiopharmaceutical. A radiopharmaceutical is a form of internal radiation therapy in which a radiation source (i.e., one or more radionuclides) is placed inside a subject's body. Targeted radionuclides comprise a radionuclide associated (e.g., by a covalent bond or ionic interaction) with a molecule (a "targeting agent") that specifically binds to a target on a cell, typically a cancer cell or immune cell. The targeting agent may be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of a cancer cell generated by a nonsynonymous mutation in the tumor cell genome). In some embodiments, the targeting agent is an antibody and the target is a tumor-associated antigen (i.e., an antigen that is enriched but not specific to cancer cells), a tumor-specific antigen (i.e., an antigen with minimal or no expression in normal tissues), or a neoantigen (i.e., an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include somatostatin or a peptide analogue thereof (e.g., 177Lu-Dotatate, etc.); prostate-specific membrane antigen or a peptide analogue thereof (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); a receptor's cognate ligand, a peptide derived from the ligand, or a variant thereof (e.g., 188-relabeled VEGF 125-136 or variants thereof with higher affinity for the VEGF receptor; or antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.), including radionuclides bound to antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.).

[0152] In some embodiments, one or more of the additional therapeutic agents is a targeted therapy. In one aspect, the targeted therapy can include a targeting agent and a drug. The drug can be a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug attached to the targeting agent. The targeting agent can be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen, a tumor-specific antigen, or a neoantigen. In some embodiments, the targeted therapy is an antibody-drug conjugate comprising an antibody and a drug, wherein the antibody specifically binds to HER2, HER3, Nectin-4, or Trop-2. Specific examples of targeted therapies comprising an antibody and a drug include, but are not limited to, patritumab deruxtecan, sacituzumab govitecan-hziy, telisotuzumab vedotin, and trastuzumab deruxtecan. In other aspects, the targeted therapy may inhibit or interfere with specific proteins that aid in tumor growth and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, ATP-adenosine axis targeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, 2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. Signal transduction inhibitors are described above, while other agents are described in more detail below.

[0153] In certain embodiments, the present disclosure contemplates the use of a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation comprising a compound of Formula (I) or (Ia) described herein) in combination with other agents that modulate adenosine levels (e.g., ATP-adenosine axis targeting agents). In some embodiments, the present disclosure contemplates combination with an ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39) inhibitor. Exemplary anti-CD39 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, and AB598. In some embodiments, the present disclosure contemplates a combination of a compound of Formula (I) or (Ia) described herein with an adenosine receptor antagonist selected from the group consisting of etormadenant, inupadenant, taminadenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385, EVOEXS-21546, AZD-4635, imaradenant, RVU-330, ciforadenant, PBF-509, PBF-999, PBF-1129, and CS-3005. In some embodiments, the present disclosure contemplates a combination of a compound of Formula (I) or (Ia) described herein with an adenosine receptor antagonist selected from the group consisting of A2 A R antagonist, A2 B R antagonist, or A2 A R and A2 B In some embodiments, the present disclosure contemplates combination with an adenosine receptor antagonist described in WO 2018 / 136700, WO 2018 / 204661, WO 2018 / 213377, or WO 2020 / 023846. In some embodiments, the at least one additional therapeutic agent is an adenosine receptor antagonist. 2A R.A. 2B The adenosine receptor antagonists include adenosine pathway inhibitors that inhibit CD39, CD49, or a combination thereof. In some embodiments, the adenosine pathway inhibitor is etormadenant, inupadenant, taminadenant, caffeine citrate, imadenant, or ciphoradenant. In one embodiment, the adenosine receptor antagonist (adenosine pathway inhibitor) is etormadenant (AB928).

[0154] In certain embodiments, the present disclosure contemplates the use of a compound of Formula (I) or (Ia) in combination with an inhibitor of phosphatidylinositol 3-kinase (PI3K), particularly the PI3Kγ isoform (e.g., as a reconstituted lyophilized formulation comprising a compound of Formula (I) or (Ia) described herein). In one embodiment, the PI3Kγ inhibitor is copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In another embodiment, the PI3K inhibitor is selected from those described in WO 2020 / 247496.

[0155] In certain embodiments, the present disclosure contemplates the use of a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation comprising a compound of Formula (I) or (Ia) described herein) in combination with an inhibitor of arginase, which has been shown to cause or contribute to pro-inflammatory immune dysfunction, tumor immune escape, immunosuppression, and the immunopathology of infectious diseases. Suitable arginase inhibitors include CB-1158 and OAT-1746, as well as those described in WO 2019 / 173188 and WO 2020 / 102646.

[0156] In certain embodiments, the present disclosure contemplates the use of a compound of Formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation comprising a compound of Formula (I) or (Ia) described herein) together with an inhibitor of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α. In some embodiments, a compound of Formula (I) or (Ia) is combined with a HIF-2α inhibitor selected from the group consisting of velzutifan, ARO-HIF2, PT-2385, AB521, and those described in WO2021113436 and WO2021188769. In some embodiments, at least one additional therapeutic agent comprises a HIF-2α inhibitor selected from the group consisting of velzutifan, ARO-HIF2, PT-2385, and AB521. In some embodiments, the HIF-2α inhibitor is AB521.

[0157] The present disclosure also contemplates a combination of a compound of Formula (I) or (Ia) (e.g., as a reconstituted formulation described herein) with one or more RAS signaling inhibitors. Oncogenic mutations in RAS family genes, such as HRAS, KRAS, and NRAS, are associated with various cancers. For example, in KRAS family genes, mutations such as G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S, among others, have been observed in multiple tumor types. Direct and indirect inhibitory strategies have been investigated to inhibit mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, including, but not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, and BI1701963. Direct inhibitors of RAS mutants are also being explored, generally targeting the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib (AMG510), MRTX849, mRNA-5671, and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an SOS1 inhibitor, an mTORC1 inhibitor, a SHP2 inhibitor, and an AKT inhibitor. In other embodiments, the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0158] In some embodiments, the present disclosure is directed to a combination of a compound of Formula (I) or (Ia) (e.g., as a reconstituted formulation described herein) with one or more inhibitors of anexelekto (i.e., AXL). There are various AXL inhibitors in development that also inhibit other kinases within the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases, including MET, FLT3, RON, and AURORA, among others. AXL-specific inhibitors, such as DS-1205, SGI-7079, TP-0903 (i.e., duvelmatinib), BGB324 (i.e., bemcentinib), and DP3975, are also in development, as are anti-AXL antibodies, such as ADCT-601, and antibody drug conjugates (ADCs), such as BA3011. Another strategy for inhibiting AXL signaling involves targeting GAS6, a ligand for AXL (e.g., AVB-500). In some embodiments, the at least one additional therapeutic agent comprises a multi-tyrosine kinase inhibitor selected from gilteritinib, glesatinib, merestinib, cabozantinib, foretinib, revastinib, sitravatinib, XL092, BMS777607, LY2801653, S49076, GSK1363089, and RXDX-106. In some embodiments, the at least one additional therapeutic agent is an AXL inhibitor described in International Application No. US2022 / 030227 or International Application No. US2022 / 030230.

[0159] The present disclosure also contemplates combinations of compounds of Formula (I) or (Ia) (e.g., as reconstituted formulations described herein) with one or more p21-activated kinase 4 (PAK4) inhibitors.

[0160] In some embodiments, one or more of the additional therapeutic agents is an epigenetic modulator. Epigenetic modulators alter the epigenetic mechanisms that control gene expression and can be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, a compound of Formula (I) or (Ia) according to the present disclosure (e.g., a reconstituted formulation described herein) is combined with a DNA methyltransferase (DNMT) inhibitor or hypomethylating agent. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitadine. In one or more embodiments, a combination of a compound of Formula (I) or (Ia) according to the present disclosure (e.g., a reconstituted formulation described herein) with a histone deacetylase (HDAC) inhibitor is also contemplated. Exemplary HDAC inhibitors include vorinostat, gibinostat, abexinostat, panobinostat, belinstat, and trichostatin A.

[0161] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of an oncogenic transcription factor or an activator of an oncogenic transcription factor repressor. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), via physical degradation, at the protein / protein level, at the protein / DNA level, or by binding to an activation / inhibition pocket. Non-limiting examples include inhibitors of one or more subunits of the MLL complex (e.g., HDAC, DOT1L, BRD4, menin, LEDGF, WDR5, KDM4C (JMJD2C), and PRMT1), inhibitors of hypoxia-inducible factor (HIF) transcription factors, etc.

[0162] In some embodiments, one or more of the additional therapeutic agents is (i) an agent that inhibits the enzyme poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib, etc.); (ii) an inhibitor of the Bcl-2 family of proteins (e.g., venetoclax, navitoclax, etc.); (iii) an inhibitor of MCL-1; (iv) an inhibitor of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies, magrolimus, etc.); or (v) an isocitrate dehydrogenase (IDH) inhibitor, e.g., an IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enazidenib, etc.).

[0163] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents treat diseases by stimulating or suppressing the immune system. Immunotherapeutic agents useful in treating cancer typically induce or amplify an immune response against cancer cells. Non-limiting examples of suitable immunotherapeutic agents include immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis targeting agents; immune checkpoint modulators; and certain signal transduction inhibitors. ATP-adenosine axis targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are further described below.

[0164] In some embodiments, the one or more additional therapeutic agents are immunotherapeutic agents, more specifically cytokines or chemokines, such as IL1, IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); organic or inorganic adjuvants that activate antigen-presenting cells and promote presentation of antigen epitopes on major histocompatibility complex molecule agonists, including, but not limited to, Toll-like receptor (TLR) agonists, mevalonate pathway antagonists, and STING agonists; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors; and immunostimulatory oligonucleotides, as well as other T cell adjuvants.

[0165] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents, more specifically cell therapy. Cell therapy is a form of treatment in which viable cells are administered to a subject. In certain embodiments, one or more of the additional therapeutic agents are cellular immunotherapies that activate or suppress the immune system. Cellular immunotherapies useful for treating cancer typically induce or amplify an immune response. The cells can be autologous or allogeneic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subjects. Alternatively, the cells can be "(re)programmed" allogeneic immune cells produced from immune progenitor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell progenitor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be expanded subsets of cells with distinct effector functions and / or maturation markers (e.g., adaptive memory NK cells, tumor-infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), M1 macrophages, M2 macrophages, etc.), may be genetically modified to target the cells to specific antigens and / or to enhance the anti-tumor effect of the cells (e.g., engineered T cell receptor (TCR) cell therapy, chimeric antigen receptor (CAR) cell therapy, lymph node homing of antigen-loaded dendritic cells, etc.), may be engineered to express or increase the expression of tumor-associated antigens, or any combination thereof. Non-limiting types of cell therapy include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines.Exemplary cellular immunotherapies include sipuleucel-T, tisagenlecleucel, lisocabtagene maraleucel, idecabtagene biculeucel, brexcabtagene autolucel, and axicabtagene ciloreucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92 / 5.28.z.

[0166] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, a gene therapy. Gene therapy includes recombinant nucleic acids administered ex vivo to a subject or to a subject's cells to modify the expression of an endogenous gene or to effect heterologous expression of a protein (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA (miRNA) agents, viral or bacterial gene delivery, etc.), as well as gene editing therapies that may or may not include a nucleic acid component (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapies that may be useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0167] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, an agent that modulates an immune checkpoint. Immune checkpoints are a series of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). Immune checkpoints are engaged when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present disclosure contemplates the use of compounds of Formula (I) or (Ia) (e.g., as reconstituted lyophilized formulations comprising compounds of Formula (I) or (Ia) described herein) in combination with agonists of stimulatory or costimulatory pathways and / or antagonists of inhibitory pathways. Agonists of stimulatory or costimulatory pathways and antagonists of inhibitory pathways may have utility as agents for overcoming distinct immunosuppressive pathways within the tumor microenvironment, inhibiting regulatory T cells, reversing / preventing T cell anergy or exhaustion, inducing innate immune activation and / or inflammation at the tumor site, or any combination thereof.

[0168] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms "immune checkpoint inhibitor," "checkpoint inhibitor," and "checkpoint inhibitor (CPI)" may be used interchangeably herein. Immune checkpoint inhibitors may antagonize inhibitory or co-inhibitory immune checkpoints by interfering with receptor-ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated and can be blocked in various types of cancer cells, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T-lymphocyte associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain containing protein 3); LAG-3 (lymphocyte activation gene 3) (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7-H3), PD-L2, galectin-9, CEACAM-1, BTLA, CD69, galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, as well as killer inhibitory receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family).Other less well-defined immune checkpoints are also contemplated and have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands, such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)). In some embodiments, the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors that target PD-1, PD-L1, TIGIT, CTLA-4, TIM-3, LAG-3, a B7 family member, or any combination thereof. In some embodiments, the at least one additional therapeutic agent comprises an immune checkpoint inhibitor that targets PD-1 or PD-L1. In some embodiments, the at least one additional therapeutic agent comprises an immune checkpoint inhibitor that targets TIGIT.

[0169] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist may be an antagonist CTLA-4 antibody. Suitable antagonist CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, and bispecific antibodies such as MEDI5752 and KN046.

[0170] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonist PD-1 antibody small molecule or peptide. Suitable antagonist PD-1 antibodies include monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostallimab, cemiplimab, ezabenlimab, MEDI-0680 (AMP-514, WO 2012 / 145493), nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimvelerimab; and bispecific antibodies such as LY3434172. In yet a further embodiment, the PD-1 antagonist may be a recombinant protein (AMP-224) composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0171] In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiplimab, or zimblerimab. In particular embodiments, the immune checkpoint inhibitor is zimblerimab.

[0172] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist may be an antagonist PD-L1 antibody. Suitable antagonist PD-L1 antibodies include monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and embafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0173] In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist may be an antagonist TIGIT antibody. Suitable antagonist anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, osipellimab, SEA-TGT, tiragolumab, and vibostolimab; and bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is an antagonist anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In some embodiments, the immune checkpoint inhibitor is domvanalimab, etigilimab, osipellimab, AB308, tiragolumab, or vibostolimab. In particular embodiments, the immune checkpoint inhibitor is domvanalimab or AB308.

[0174] In another aspect, the immune checkpoint inhibitor is a LAG-3 antagonist, such as an antagonist LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO 10 / 19570, WO 14 / 08218), or IMP-731 or IMP-321 (WO 8 / 132601, WO 9 / 44273).

[0175] In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonist B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, MGA271 (WO 11 / 109400), omburtumab, enoblitutumab, DS-7300a, ABBV-155, and SHR-A1811.

[0176] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or costimulatory immune checkpoint. Examples of stimulatory or costimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2.

[0177] In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO 12 / 32433). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO 06 / 105021, WO 09 / 009116), and MK-4166 (WO 11 / 028683). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonist CD40 antibody. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0178] In some embodiments, one or more of the additional therapies are immunotherapeutic agents, more specifically signal transduction inhibitors. Intracellular signal transduction molecules that affect immune cell function can also be suitable targets for improving anti-tumor immunity. For example, one or more of the additional therapeutic agents can be inhibitors of hematopoietic progenitor kinase 1 (HPK1). HPK1 is a serine / threonine kinase that functions as a negative regulator of the activation signal generated by T cell antigen receptors.

[0179] In some embodiments, one or more of the additional therapeutic agents is an agent that inhibits or depletes immunosuppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, such as RG7155 (WO 11 / 70024, WO 11 / 107553, WO 11 / 131407, WO 13 / 87699, WO 13 / 119716, WO 13 / 132044) or a CSF-1R antagonist antibody listed in WO 11 / 140249, WO 13169264.

[0180] In some embodiments, each additional therapeutic agent may independently be a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic modulator, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates the use of a formulation described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a formulation described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeting agent, an immunotherapeutic agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of a formulation described herein in combination with one or more immunotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, a chemotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a formulation described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of a formulation described herein in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cell therapy. In further embodiments of the above, (a) the targeting agent can be a PI3K inhibitor, an arginase inhibitor, a HIF2α inhibitor, an AXL inhibitor, or a PAK4 inhibitor; (b) the immunotherapeutic agent is an ATP-adenosine axis targeting agent or an immune checkpoint inhibitor; (c) the ATP-adenosine axis targeting agent is an A2 A R and / or A2 B(d) the ATP-adenosine axis targeting agent is etormadenant, (e) the immunotherapeutic agent is an anti-PD-1 antagonist antibody or an anti-TIGIT antagonist antibody, (f) the immunotherapeutic agent is dimmerimab, domvanalimab, or AB308; or (g) any combination thereof. In still further embodiments of the above, the present disclosure contemplates the use of the formulations described herein in combination with domvanalimab, etormadenant, dimmerimab, AB308, AB521, AB610, or any combination thereof.

[0181] In some embodiments, the methods described herein include administering to the subject at least one or more additional therapeutic agents, in some embodiments, the at least one additional therapeutic agent comprises one or more agents selected from the group consisting of a chemotherapeutic agent, an immune checkpoint inhibitor, an inhibitor of HIF-2α, an adenosine pathway inhibitor, radiation therapy, and a multi-tyrosine kinase inhibitor.

[0182] Some embodiments provide a method of treating cancer, comprising administering a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antagonist antibody and an anti-TIGIT antagonist antibody, wherein the compound of Formula (Ia) is administered in an amount ranging from 50 mg to 300 mg every 2 to 3 weeks, the anti-PD-1 antagonist antibody is administered in an amount ranging from 300 mg to 600 mg every 2 to 5 weeks, and the anti-TIGIT antagonist antibody is administered in an amount ranging from 1200 mg to about 1600 mg every 2 to 4 weeks.

[0183] In some embodiments, the compound of Formula (Ia) is administered every three weeks in an amount of about 300 mg. In some embodiments, the anti-PD-1 antagonist antibody is administered every three weeks in an amount of about 300 mg. In some embodiments, the anti-TIGIT antagonist antibody is administered every three weeks in an amount ranging from about 1200 mg to about 1600 mg. In some embodiments, the anti-PD-1 antagonist antibody is dimverelimab. In some embodiments, the anti-TIGIT antagonist antibody is domvanalimab or AB308. In some embodiments, the compound of Formula (Ia) is a reconstituted aqueous solution as described herein. In some embodiments, the compound of Formula (Ia), the anti-PD-1 antagonist antibody, and the anti-TIGIT antagonist antibody are administered intravenously in a three-week cycle.

[0184] In some embodiments, the methods described herein further comprise one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprise chemotherapy.

[0185] Some embodiments provide a method of treating cancer, the method comprising administering a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof in combination with chemotherapy, wherein the compound of Formula (Ia) is administered in an amount ranging from 50 mg to 300 mg every 2 to 3 weeks.

[0186] Examples of therapeutic agents useful in combination therapy for immune and inflammation-related diseases, disorders, or conditions include, but are not limited to, a non-steroidal anti-inflammatory drug (NSAID), a steroid such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone, or a cytokine suppressive anti-inflammatory drug (CSAID).

[0187] dosage A lyophilized formulation comprising a compound of Formula (I) or (Ia) can be administered to a subject in an amount that depends, for example, on the purpose of administration (e.g., the desired degree of degradation); the age, weight, sex, and health and physical condition of the subject to whom the formulation is to be administered; the route of administration; and the nature of the disease, disorder, condition, or symptoms thereof. The dosing regimen can also take into account the existence, nature, and extent of any adverse effects associated with the agent being administered.

[0188] In general, dosing parameters indicate that the dosage is below that which would be irreversibly toxic to the subject (maximum tolerated dose (MTD)) and not less than that required to produce a measurable effect in the subject, as determined, for example, by pharmacokinetic and pharmacodynamic parameters relevant to ADME, taking into account the route of administration and other factors.

[0189] In certain embodiments, a compound of Formula (I) or (Ia) (e.g., as a reconstituted formulation described herein) may be administered (e.g., parenterally) at a dosage level of about 0.01 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day to achieve the desired therapeutic effect.

[0190] In some embodiments, the lyophilized formulation contains 1 to 500 milligrams of active ingredient (i.e., a compound of Formula (I) or (Ia)), particularly 20, 25, 30, 100, 150, 200, 225, 250, 275, 300, 325, 400, and 500 milligrams of active ingredient. In some embodiments, the compound of Formula (I) or (Ia) is provided in an amount of 25, 50, 75, 100, 150, 200, 250, 300, or 350 milligrams. In some embodiments, the compound of Formula (I) or (Ia) is provided in an amount of about 25 milligrams to 350 milligrams. In some embodiments, the compound of Formula (I) or (Ia) is provided in an amount of about 25 milligrams to 300 milligrams. In some embodiments, the compound of Formula (I) or (Ia) is provided in an amount of about 25 milligrams to 250 milligrams. In some embodiments, the compound of Formula (I) or (Ia) is provided in an amount of about 25 milligrams to 200 milligrams. In some embodiments, the compound of Formula (I) or (Ia) is provided in an amount of about 25 milligrams to 150 milligrams. In some embodiments, the compound is provided in an amount of 25 milligrams to 120 milligrams. In some embodiments, the compound is provided in an amount of 25 milligrams to 110 milligrams. In some embodiments, the compound is provided in an amount of 25 milligrams to 100 milligrams. In some embodiments, the compound is provided in an amount of 25 milligrams to 75 milligrams. In some embodiments, the compound is provided in an amount of 25 milligrams to 50 milligrams. In some embodiments, the compound is provided in an amount of 75 milligrams to 100 milligrams. In some embodiments, the compound is provided in an amount of 50 milligrams to 200 milligrams. In some embodiments, the compound is provided in an amount of 75 milligrams to 150 milligrams. In some embodiments, the compound is provided in an amount of 75 milligrams to 125 milligrams. In some embodiments, the compound is provided in an amount of 75 milligrams to 110 milligrams. In some embodiments, the compound is provided in an amount of 90 milligrams to 110 milligrams.

[0191] In some embodiments, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered (e.g., parenterally) on a monthly, weekly, or daily basis. In some embodiments, a compound of Formula (I) or (Ia) may be administered at least once a month, for example, twice a month, three times a month, four times a month, once a week, or daily. In some embodiments, a compound of Formula (I) or (Ia) may be administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, a compound of Formula (I) or (Ia) may be administered once, twice, three times, or four times a month (e.g., parenterally). In some embodiments, a compound of Formula (I) or (Ia) may be administered once a week, once every two weeks, or once every three weeks (e.g., parenterally).

[0192] In some embodiments, a lyophilized formulation according to the present disclosure is reconstituted to form a reconstituted solution and parenterally administered to a subject as a loading dose. The loading dose can be administered to achieve an appropriate plasma concentration in the subject. Once a suitable plasma concentration is achieved, subsequent doses of a compound of Formula (I) or (Ia) can be administered by other means (e.g., orally). In some embodiments, the loading dose is about 20 mg to about 500 mg, e.g., about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, the loading dose is between 20 mg and 500 mg, e.g., 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.

[0193] In some embodiments, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered at a dose of about 10 mg to 225 mg once every two weeks (Q2W), e.g., 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg g, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, or 250 mg, or the like. In some embodiments, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered biweekly (e.g., parenterally) at a dose of about 10 mg to about 250 mg, such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In one embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered biweekly (e.g., parenterally) at a dose of 25 mg. In another embodiment, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered once every two weeks (e.g., parenterally) at a dose of 50 mg. In one embodiment, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered once every two weeks (e.g., parenterally) at a dose of 75 mg. In yet another embodiment, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every two weeks (e.g., parenterally) at a dose of 100 mg.In another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every two weeks (e.g., parenterally) at a dose of 125 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every two weeks (e.g., parenterally) at a dose of 150 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every two weeks (e.g., parenterally) at a dose of 175 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every two weeks (e.g., parenterally) at a dose of 200 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every two weeks (e.g., parenterally) at a dose of 225 mg.

[0194] In some embodiments, the compound of Formula (I) or (Ia) (e.g., as a reconstituted formulation described herein) is administered at a dose of about 10 mg to about 350 mg once every three weeks (Q3W), e.g., 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 5 It may be administered (e.g., parenterally) once every three weeks at a dose such as 45 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 250, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, or 350 mg. In some embodiments, a compound of Formula (I) or (Ia) (e.g., in a reconstituted formulation described herein) may be administered once every three weeks (Q3W) (e.g., parenterally) at a dose of about 10 mg to 250 mg, such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In one embodiment, a compound of Formula (I) or (Ia) (e.g., in a reconstituted formulation described herein) is administered once every three weeks (e.g., parenterally) at a dose of 25 mg. In another embodiment, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered (e.g., parenterally) at a dose of 50 mg once every three weeks. In one embodiment, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered (e.g., parenterally) at a dose of 75 mg once every three weeks.In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every three weeks (e.g., parenterally) at a dose of 100 mg. In another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every three weeks (e.g., parenterally) at a dose of 125 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every three weeks (e.g., parenterally) at a dose of 150 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every three weeks (e.g., parenterally) at a dose of 175 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every three weeks (e.g., parenterally) at a dose of 200 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., in a reconstituted formulation described herein) may be administered (e.g., parenterally) at a dose of 225 mg once every three weeks. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., in a reconstituted formulation described herein) may be administered (e.g., parenterally) at a dose of 300 mg once every three weeks.

[0195] In some embodiments, the compound of Formula (I) or (Ia) (e.g., as a reconstituted formulation described herein) is administered at a dose of about 10 mg to about 325 mg once every four weeks (Q4W), e.g., 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg g, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 250, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, or 325 mg, or the like, administered once every four weeks (e.g., parenterally). In some embodiments, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every four weeks (Q4W) (e.g., parenterally) at a dose of about 10 mg to 250 mg, such as 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg. In one embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered once every four weeks (e.g., parenterally) at a dose of 25 mg. In another embodiment, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered (e.g., parenterally) at a dose of 50 mg once every four weeks. In one embodiment, the compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) is administered (e.g., parenterally) at a dose of 75 mg once every four weeks.In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every four weeks (e.g., parenterally) at a dose of 100 mg. In another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every four weeks (e.g., parenterally) at a dose of 125 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every four weeks (e.g., parenterally) at a dose of 150 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every four weeks (e.g., parenterally) at a dose of 175 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., a reconstituted formulation described herein) may be administered once every four weeks (e.g., parenterally) at a dose of 200 mg. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., in a reconstituted formulation described herein) may be administered (e.g., parenterally) at a dose of 225 mg once every four weeks. In yet another embodiment, a compound of Formula (I) or (Ia) (e.g., in a reconstituted formulation described herein) may be administered (e.g., parenterally) at a dose of 300 mg once every four weeks.

[0196] In certain embodiments, the dosage of the compound of Formula (I) or (Ia) is contained in a "unit dosage form." The phrase "unit dosage form" refers to a physically discrete unit, each unit containing a predetermined amount of a compound of Formula (I) or (Ia), alone or in combination with one or more additional agents, sufficient to produce a desired effect. The unit dosage form may be provided as a pre-lyophilized composition, a lyophilized formulation, or a reconstituted lyophilized formulation.

[0197] In some embodiments, provided herein is a single dosage form of a compound having Formula (Ia), wherein the compound is present in an amount of about 20 mg to about 300 mg.

[0198] In one embodiment, provided herein is a single dosage form of the compound having formula (Ia), wherein the compound is present in an amount of 25 mg.

[0199] In one embodiment, provided herein is a single dosage form of the compound having formula (Ia), wherein the compound is present in an amount of 50 mg.

[0200] In one embodiment, provided herein is a single dosage form of the compound having formula (Ia), wherein the compound is present in an amount of 75 mg.

[0201] In one embodiment, provided herein is a single dosage form of a compound having Formula (Ia), wherein the compound is present in an amount of 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, or 325 mg.

[0202] In another embodiment, the lyophilized formulations described herein contain an amount of the compound of Formula (I) or Formula (Ia) sufficient to achieve a desired dosage upon reconstitution of the lyophilized formulation. In some embodiments, the lyophilized formulation contains an amount of the compound of Formula (I) or Formula (Ia) ranging from the desired dosage to the desired dosage plus about 10% of the compound of Formula (I) or Formula (Ia). Larger amounts of compound may be provided to account for residual drug volume remaining in the vial when the reconstituted solution is withdrawn from the vial for administration and / or dilution.

[0203] In some embodiments, the compound is present in the lyophilized formulation in an amount of about 25 mg to about 330 mg. In some embodiments, the compound is present in an amount of about 25 mg to about 27.5 mg. In some embodiments, the compound is present in an amount of about 50 mg to about 55 mg. In some embodiments, the compound is present in an amount of about 75 mg to about 82.5 mg. In some embodiments, the compound is present in an amount of about 100 mg to about 110 mg. In some embodiments, the compound is present in an amount of about 200 mg to about 325 mg.

[0204] In one embodiment, the compound is present in the lyophilized formulation in an amount of about 25.0 mg to about 27.5 mg, e.g., 25.0 mg, 25.1 mg, 25.2 mg, 25.3 mg, 25.4 mg, 25.5 mg, 25.6 mg, 25.7 mg, 25.8 mg, 25.9 mg, 26.0 mg, 26.1 mg, 26.2 mg, 26.3 mg, 26.4 mg, 26.5 mg, 26.6 mg, 26.7 mg, 26.8 mg, 26.9 mg, 27.0 mg, 27.1 mg, 27.2 mg, 27.3 mg, 27.4 mg, or 27.5 mg. In one embodiment, the compound is present in the lyophilized formulation in an amount of about 25.0 mg to about 27.5 mg, e.g., about 25.0 mg, about 25.1 mg, about 25.2 mg, about 25.3 mg, about 25.4 mg, about 25.5 mg, about 25.6 mg, about 25.7 mg, about 25.8 mg, about 25.9 mg, about 26.0 mg, about 26.1 mg, about 26.2 mg, about 26.3 mg, about 26.4 mg, about 26.5 mg, about 26.6 mg, about 26.7 mg, about 26.8 mg, about 26.9 mg, about 27.0 mg, about 27.1 mg, about 27.2 mg, about 27.3 mg, about 27.4 mg, or about 27.5 mg.

[0205] In one embodiment, the compound is present in the lyophilized formulation in an amount of about 50.0 mg to about 55.0 mg, e.g., 50.0 mg, 50.5 mg, 51.0 mg, 51.5 mg, 52.0 mg, 52.5 mg, 53.0 mg, 53.5 mg, 54.0 mg, 54.5, or 55.0 mg. In one embodiment, the compound is present in the lyophilized formulation in an amount of about 50.0 mg to about 55.0 mg, e.g., about 50.0 mg, about 50.5 mg, about 51.0 mg, about 51.5 mg, about 52.0 mg, about 52.5 mg, about 53.0 mg, about 53.5 mg, about 54.0 mg, about 54.5, or about 55.0 mg.

[0206] In one embodiment, the compound is present in the lyophilized formulation in an amount of about 75.0 mg to about 82.5 mg, e.g., 75.0 mg, 75.5 mg, 76.0 mg, 76.5 mg, 77.0 mg, 77.5 mg, 78.0 mg, 78.5 mg, 79.0 mg, 79.5 mg, 80.0 mg, 80.5 mg, 81.0 mg, 81.5 mg, 82.0, or 82.5 mg. In one embodiment, the compound is present in the lyophilized formulation in an amount of about 75.0 mg to about 82.5 mg, e.g., about 75.0 mg, about 75.5 mg, about 76.0 mg, about 76.5 mg, about 77.0 mg, about 77.5 mg, about 78.0 mg, about 78.5 mg, about 79.0 mg, about 79.5 mg, about 80.0 mg, about 80.5 mg, about 81.0 mg, about 81.5 mg, about 82.0, or about 82.5 mg.

[0207] In one embodiment, the compound is present in the lyophilized formulation in an amount of about 100.0 mg to about 110.0 mg, e.g., 100.0 mg, 100.5 mg, 101.0 mg, 101.5 mg, 102.0 mg, 102.5 mg, 103.0 mg, 103.5 mg, 104.0 mg, 104.5 mg, 105.0 mg, 105.5 mg, 106.0 mg, 106.5 mg, 107.0 mg, 107.5 mg, 108.0 mg, 108.5 mg, 109.0 mg, 109.5 mg, or 110.0 mg. In one embodiment, the compound is present in the lyophilized formulation in an amount of about 100.0 mg to about 110.0 mg, e.g., about 100.0 mg, about 100.5 mg, about 101.0 mg, about 101.5 mg, about 102.0 mg, about 102.5 mg, about 103.0 mg, about 103.5 mg, about 104.0 mg, about 104.5 mg, about 105.0 mg, about 105.5 mg, about 106.0 mg, about 106.5 mg, about 107.0 mg, about 107.5 mg, about 108.0 mg, about 108.5 mg, about 109.0 mg, about 109.5 mg, or about 110.0 mg.

[0208] In one embodiment, the compound is present in the lyophilized formulation in an amount of about 200.0 mg to about 220.0 mg, e.g., 200.0 mg, 201.0 mg, 202.0 mg, 203.0 mg, 204.0 mg, 205.0 mg, 206.0 mg, 207.0 mg, 208.0 mg, 209.0 mg, 210.0 mg, 211.0 mg, 212.0 mg, 213.0 mg, 214.0 mg, 215.0 mg, 216.0 mg, 217.0 mg, 218.0 mg, 219.0 mg, or 220.0 mg. In one embodiment, the compound is present in the lyophilized formulation in an amount of about 200.0 mg to about 220.0 mg, e.g., about 200.0 mg, about 201.0 mg, about 202.0 mg, about 203.0 mg, about 204.0 mg, about 205.0 mg, about 206.0 mg, about 207.0 mg, about 208.0 mg, about 209.0 mg, about 210.0 mg, about 211.0 mg, about 212.0 mg, about 213.0 mg, about 214.0 mg, about 215.0 mg, about 216.0 mg, about 217.0 mg, about 218.0 mg, about 219.0 mg, or about 220.0 mg.

[0209] In one embodiment, the compound is present in the lyophilized formulation at a concentration of about 300.0 mg to about 330.0 mg, e.g., 300.0 mg, 301.0 mg, 302.0 mg, 303.0 mg, 304.0 mg, 305.0 mg, 306.0 mg, 307.0 mg, 308.0 mg, 309.0 mg, 310.0 mg, 311.0 mg, 312.0 mg, 313.0 mg, 314.0 mg, 315.0 mg, 316.0 mg, 317.0 mg, 318.0 mg, 319.0 mg, 320.0 mg, 321.0 mg, 322.0 mg, 323.0 mg, 324.0 mg, 325.0 mg, 326.0 mg, 327.0 mg, 328.0 mg, 329.0 mg, 330.0 mg, 331.0 mg, 332.0 mg, 333.0 mg, 334.0 mg, 335.0 mg, 336.0 mg, 337.0 mg, 338.0 mg, 339.0 mg, 340.0 mg, 341.0 mg, 342.0 mg, 343.0 mg, 344.0 mg, 345.0 mg, 346.0 mg, 347.0 mg, 348.0 mg, 349.0 mg, 350.0 mg, 351.0 mg, 352.0 mg, 353.0 mg, 354.0 mg, 355.0 mg, 356.0 mg, 357.0 mg, 358. 0 mg, 314.0 mg, 315.0 mg, 316.0 mg, 317.0 mg, 318.0 mg, 319.0 mg, 320.0 mg, 321.0 mg, 322.0 mg, 323.0 mg, 324.0 mg, 325.0 mg, 326.0 mg, 327.0 mg, 328.0 mg, 329.0 mg, or 330.0 mg. In one embodiment, the compound is present in the lyophilized formulation at about 300.0 mg to about 330.0 mg, e.g., about 300.0 mg, about 301.0 mg, about 302.0 mg, about 303.0 mg, about 304.0 mg, about 305.0 mg, about 306.0 mg, about 307.0 mg, about 308.0 mg, about 309.0 mg, about 310.0 mg, about 311.0 mg, about 312.0 mg, about 313.0 mg g, about 314.0 mg, about 315.0 mg, about 316.0 mg, about 317.0 mg, about 318.0 mg, about 319.0 mg, about 320.0 mg, about 321.0 mg, about 322.0 mg, about 323.0 mg, about 324.0 mg, about 325.0 mg, about 326.0 mg, about 327.0 mg, about 328.0 mg, about 329.0 mg, or about 330.0 mg. kit

[0210] The present disclosure also contemplates kits containing lyophilized formulations containing compounds of Formula (I) or (Ia) described herein. The kits are generally in the form of physical structures housing various components, as described below, and can be utilized, for example, in carrying out the methods described above. The kits can include, for example, syringes and diluents for reconstitution, as described above. When combination therapy is contemplated, the kits can contain several agents separately or already combined in the kit. Each component of the kit can be enclosed in an individual container, and all of the various containers can be in a single package. The kits of the present disclosure can be designed for the conditions (e.g., refrigeration or freezing) necessary to properly maintain the components contained therein.

[0211] The kit may include a label or package insert containing information identifying the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredients, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information such as lot number and expiration date. The label or package insert may, for example, be incorporated into the physical structure that houses the component, be included separately within the physical structure, or be attached to a component of the kit (e.g., an ampoule, tube, or vial).

[0212] The label or package insert may further comprise, or be incorporated into, a computer-readable medium. In some embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, for example, via the internet. experiment

[0213] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure, nor are they intended to be all that may be performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. [Example]

[0214] Example 1: Preparation of pre-lyophilized formulation The compound of formula (Ia), L-arginine, and phosphoric acid were added to sterile water and mixed until dissolved. The bulk solution was transferred to a clean room and sterile filtered through a 0.22 micron pore size filter into a sterile container. Each sterile glass vial was filled to the lyophilization depth. The vials were lyophilized according to the cycle in Table 1. The lyophilization chamber and vials were purged with nitrogen, and the vials were stoppered. The vials were removed from the lyophilization chamber, and a flip-off seal was placed on each vial and the seal was crimped. The vials were inspected for visual defects. [Table 1] Example 2: Comparison of chemical and physical stability of formulations

[0215] The compound of formula (Ia) and various excipients were evaluated for chemical and physical compatibility and stability. Based on the results of these studies, three prototype formulations were selected for further evaluation of manufacturability and stability. The compositions of these prototypes are shown in Table 2. The formulations were evaluated for: Clarity, content and purity of the solution before freeze-drying for up to 5 days at 5°C. · Clarity, content, and purity of solutions reconstituted with either normal saline or sterile water for injection. Stability of reconstituted solution at 5°C and 40°C for up to 5 days.

[0216] The results of these studies are shown in the table below. It was noted that the formulations containing amino acids exhibited better physical stability as evidenced by the clarity scores of both the pre-lyophilized and reconstituted solutions. [Table 2] a 2.2 equivalents of sodium hydroxide b 4.5 equivalents of L-arginine and 1.2 equivalents of phosphate c 1 equivalent of L-arginine and 3 equivalents of L-histidine [Table 3] PreLyo=pre-lyophilization, Recon=reconstitution, SWFI=sterile water for injection. 25 mg / mL (41.3 mM) solution of formula (Ia). Visual clarity score: 0 = clear, 6 = significantly cloudy with particulate precipitate. HPLC method: Column: Agilent Zorbax Eclipse Plus C18; 4.6 x 100 mm, 3.5 μm; Lot No. B17287 Detection wavelength: 254 nm Column temperature: 30±2℃ Flow rate: 1.0mL / min Sample diluent: 20 mM potassium phosphate buffer pH 8.2, 25 μM EDTA Sample temperature: 20℃ Mobile phase A, MPA: 20 mM potassium phosphate buffer pH 8.2, 25 μM EDTA Mobile phase B, MPB: 100% acetonitrile Mobile phase gradient: [Table 11] [Table 4] Recon = reconstituted solution, SWFI = sterile water for injection. The sample was reconstituted to a theoretical concentration of 25 mg / mL. Example 3: Lyophilization of formulations containing bulking agents

[0217] Formulations containing the compound of Formula (Ia), arginine, phosphate, and various cosolutes (i.e., bulking agents) were evaluated for lyophilized cake appearance, reconstitution parameters, and reconstituted solution stability. The vial configurations of the pre-lyophilized formulations are summarized in Table 5 below. [Table 5]

[0218] The formulations were lyophilized according to the lyophilization cycles summarized for various cosolutes in Table 6 below. Both the primary and secondary drying steps of the lyophilization cycle were performed under vacuum. Typical drying times for the primary and secondary drying stages were approximately 36-40 hours and 7-10 hours, respectively. [Table 6]

[0219] The reconstitution time and stability of the reconstituted solutions were evaluated. The reconstitution time, solution pH, and osmolality for the various formulations are summarized in Table 7 below. [Table 7] Fill volume corresponds to the volume of solvent added before lyophilization. SWFI load corresponds to the volume of SWFI added for reconstitution. Recon = reconstitution, SWFI = sterile water for injection.

[0220] Compared to the lyophilisates without bulking agents, all lyophilisates with bulking agents showed less cracking, brittleness and shrinkage.

[0221] The type of vial used to lyophilize the formulation was also observed to affect the appearance of the resulting cake: Lyophilizates made using SCHOTT TopLyo® vials produced intact cakes without fractures when mannitol, kleptose, and dextran 40 were used as bulking agents.

[0222] All lyophilizates tested were rapidly reconstituted to form clear solutions.

[0223] The stability of selected reconstituted solutions was assessed by high-performance liquid chromatography (HPLC) for solutions stored at 40° C. and 75% relative humidity (RH) for 2 and 4 weeks, and for solutions stored at −20° C. for 2 weeks. The results are summarized in Table 8 below. HPLC method

[0224] Column: Waters Xbridge Shield RP18; 4.6 × 150 mm, 3.5 μm, detection wavelength: 305 nm; column temperature: 30 ± 2 °C; injection volume: 5 μL; flow rate: 1.0 mL / min; run time: 50 min; sample diluent: 20 mM potassium phosphate buffer pH 10.0 ± 0.05; retention time: approximately 13 min; sample temperature: 5.0 ± 1 °C; needle wash: acetonitrile:water (50:50); mobile phase A (MPA): 10% acetonitrile: 90% 20 mM potassium phosphate buffer pH 10.0 ± 0.05; mobile phase B (MPB): 65% acetonitrile: 35% 20 mM potassium phosphate, pH 10.0 ± 0.05. Mobile phase gradient: [Table 12] [Table 8]

[0225] All formulations demonstrated chemical stability and had similar impurity profiles, as determined by HPLC, when stored at -20°C for 2 weeks and at 40°C and 75% RH for 4 weeks. All solutions tested were also physically stable and remained clear throughout the study. Example 4: Exemplary Protocol for Preparation of Bulk Quantities of Lyophilized Formulations According to the Present Disclosure

[0226] The components of the lyophilized formulation are summarized below in Table 9. The process for bulk lyophilization is described in Figure 1. The parameters of the lyophilization process are summarized below in Table 10. [Table 9] [Table 10] Example 5: Phase 2 study to evaluate a dimvelelimab-based combination in participants with advanced non-small cell lung cancer.

[0227] A phase 2, open-label platform trial will investigate the safety and efficacy of gimvelelimab compared with other investigational agents in participants with non-small cell lung cancer. Substudy A will enroll treatment-naïve patients with metastatic NSCLC who have high PD-L1 levels and no actionable genomic aberrations. Substudy B will enroll treatment-naïve patients with metastatic NSCLC who have no actionable genomic aberrations but are not limited by PD-L1 status. High PD-L1 status can be assessed by a tumor proportion score (TPS) of ≥ 50% by PharmDx 22C3 (Dako) or tumor cells (TC) of ≥ 50% by SP263 (Ventana). Substudy C will enroll patients with metastatic NSCLC who have documented disease progression on anti-PD-L1 and platinum-based chemotherapy in one or two prior lines of therapy and no known actionable genomic aberrations. Group A1: gimvelerimab 360 mg Q3W + domvanalimab 5 mg / kg Q3W, Group A2: gimvelerimab 360 mg Q3W + domvanalimab 15 mg / kg Q3W, Group A3: gimvelerimab 480 mg Q4W + domvanalimab 1600 mg Q4W + quemliclustat 100 mg Q2W, Group B1: gimvelerimab 360 mg Q3W + quemliclustat 50 mg QW + platinum-based chemotherapy, Group B2: gimvelerimab 360 mg Q3W + domvanalimab 1200 mg Q3W + platinum-based chemotherapy, Group B3: gimvelerimab 360 mg Q3W + domvanalimab 1200 mg Q3W + quemliclustat 50 mg QW + platinum-based chemotherapy, Arm C1: dimvelelimab 360mg Q3W + domvanalimab 1200mg Q3W + docetaxel, Arm C2: dimvelelimab 360mg Q3W + quemliclustat 300mg Q3W + docetaxel. Primary endpoints include objective response rate, safety, and tolerability. Secondary endpoints include progression-free survival, duration of response, overall survival, and PK. Example 5-1: Q3W administration of compound of formula (Ia)

[0228] In the above study, formulations according to the present disclosure may be administered at 300 mg 3QW. Preliminary population PK / PD modeling suggests that substantially higher doses are required when extending the dosing interval to maintain a steady-state Ctrough (Ctrough,ss) comparable to 50 mg QW or 100 mg Q2W. The 300 mg Q3W dose level may result in a median steady-state Ctrough comparable to 50 mg QW and 100 mg Q2W to achieve ≥ 90% inhibition of CD73 enzyme activity in the majority of participants. Figure 2 shows predicted population PK / PD following administration of 50 mg QW, 100 mg Q2W, or 300 mg Q3W. Simulations were based on a population pharmacokinetic / pharmacodynamic model developed using pharmacokinetic and pharmacodynamic data collected from multiple clinical trials.

[0229] Specific embodiments of the present disclosure are described herein. It is anticipated that variations of the disclosed embodiments may become apparent to those skilled in the art upon reading the foregoing description, and that such variations may be employed by those skilled in the art as appropriate. Accordingly, it is intended that the present disclosure be practiced otherwise than as specifically described herein, and that the present disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or clearly contradicted by context.

[0230] All publications, patent applications, accession numbers, and other references referred to in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. A lyophilized formulation comprising a compound of formula (I) 【Chemistry 27】 or a pharmaceutically acceptable salt thereof, and one or more amino acids, wherein: W is CR ｅ and N, X is O, CH ２ and S, each of Y and Z is independently selected from the group consisting of CH and N; R ｇ is H or two R ｇ groups bond to form an acetonide, R ａ But NH ２ , N.H.R. １ , and N.R. １ R ２ is selected from the group consisting of R ｃ is H, halogen, haloalkyl, NH ２ , N.H.R. ３ , N.R. ３ R ４ , R ３ , OH, OR ３ , S.R. ３ , S.O. ２ R ３ , -X １ -NH ２ , -X １ -NHR ３ , -X １ -NR ３ R ４ , -X １ -OH, -X １ -OR ３ , -X １ -SR ３ , and −X １ -SO ２ R ３ is selected from the group consisting of R ｅ is selected from H, halogen, and optionally substituted C １ -C ６ is selected from the group consisting of alkyl, each X １ But C １ -C ４ is alkylene Each R １ , R ２ , R ３ and R ４ independently represent optionally substituted C １ -C １０ Alkyl, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted C ３ -C ７ Cycloalkyl C １ -C ４ Alkyl, optionally substituted 4- to 7-membered heterocycloalkyl, optionally substituted 4- to 7-membered heterocycloalkylC １ -C ４ Alkyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl, and optionally substituted heteroaryl C １ -C ４ alkyl, or R １ and R ２ or R ３ and R ４ are attached to the same nitrogen, they combine to form a 4- to 7-membered heterocycle; Lyophilized formulation.

2. The lyophilized formulation of claim 1, wherein X is O.

3. R ｇ The freeze-dried formulation according to claim 1 or 2, wherein is H.

4. R ａ However, NHR １ and R １ is an optionally substituted aryl C １ -C ４ Alkyl and optionally substituted heteroaryl C １ -C ４ The freeze-dried formulation according to any one of claims 1 to 3, wherein the alkyl group is selected from the group consisting of alkyl.

5. R ａ However, NHR １ and R １ is an optionally substituted aryl C １ -C ４ The freeze-dried formulation of claim 4, wherein the alkyl group is alkyl.

6. R ｃ The lyophilized formulation of any one of claims 1 to 5, wherein is selected from the group consisting of H, halogen, and haloalkyl.

7. R ｃ The freeze-dried formulation of claim 6, wherein is a halogen.

8. R ｅ The freeze-dried preparation according to any one of claims 1 to 7, wherein H.

9. The compound of formula (I) 【Chemistry 28】 The freeze-dried formulation according to any one of claims 1 to 8, having a structure selected from the group consisting of:

10. The compound of formula (I) has a structure according to formula (Ia): 【Chemistry 29】 or a pharmaceutically acceptable salt thereof.

11. The lyophilized formulation of any one of claims 1 to 10, wherein the one or more amino acids comprise arginine, lysine, histidine, tryptophan, cysteine, or a combination thereof.

12. The freeze-dried formulation according to any one of claims 1 to 11, further comprising a pH adjuster.

13. The lyophilized formulation of claim 12, wherein the pH adjuster is phosphoric acid.

14. The lyophilized formulation according to any one of claims 1 to 13, further comprising a bulking agent.

15. 15. The lyophilized formulation of claim 14, wherein the bulking agent is mannitol, glycine, hydroxypropyl-beta-cyclodextrin (HPBCD), or dextran.

16. The lyophilized formulation according to any one of claims 1 to 15, wherein the molar ratio of the compound of formula (I) to the one or more amino acids is from about 1:2 to about 1:

7.

17. The lyophilized formulation according to any one of claims 1 to 16, wherein the molar ratio of the compound of formula (I) to the one or more amino acids is from about 1:4 to about 1:

5.

18. The lyophilized formulation of any one of claims 1 to 17, wherein the compound is present in an amount of about 25 mg to about 27.5 mg.

19. The lyophilized formulation of any one of claims 1 to 17, wherein the compound is present in an amount of about 50 mg to about 55 mg.

20. The lyophilized formulation of any one of claims 1 to 17, wherein the compound is present in an amount of about 75 mg to about 82.5 mg.

21. The lyophilized formulation of any one of claims 1 to 17, wherein the compound is present in an amount of about 100 mg to about 110 mg.

22. The lyophilized formulation of any one of claims 1 to 17, wherein the compound is present in an amount of about 200 mg to about 325 mg.

23. A lyophilized formulation comprising a compound of formula (Ia) 【Transformation 30】 or a pharmaceutically acceptable salt thereof, and one or more amino acids selected from arginine, lysine, histidine, tryptophan, cysteine, and combinations thereof, in an amount greater than the stoichiometric amount of the compound of formula (Ia).

24. A lyophilized formulation comprising: about 15% to about 20% by weight of a compound of formula (Ia) 【Chemistry 31】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 20% to about 35% by weight of one or more amino acids; about 2% to about 5% by weight of phosphoric acid; about 40% to about 60% by weight of a bulking agent; A lyophilized formulation, wherein the weight percentage (wt%) is based on the total weight of the lyophilized formulation.

25. 25. The lyophilized formulation of claim 24, wherein the bulking agent is kleptose, dextran, mannitol, or glycine.

26. about 17.4% by weight of the compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 23.4% by weight of arginine; About 3.5% by weight of phosphoric acid about 55.6% by weight of mannitol; 25. The lyophilized formulation of claim 24, wherein the weight percentage is based on the total weight of the lyophilized formulation.

27. about 22.6% by weight of the compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 30.6% by weight of arginine; about 4.6% by weight of phosphoric acid; about 42.1% by weight of glycine; 25. The lyophilized formulation of claim 24, wherein the weight percentage is based on the total weight of the lyophilized formulation.

28. A lyophilized formulation comprising: about 35% to about 45% by weight of a compound of formula (Ia) 【Chemistry 32】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 45% to about 55% by weight of one or more amino acids; about 5% to about 10% by weight of phosphoric acid; A lyophilized formulation, wherein the weight percentage (wt%) is based on the total weight of the lyophilized formulation.

29. about 39.2% by weight of the compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 52.9% by weight arginine; about 7.9% by weight of phosphoric acid; 29. The lyophilized formulation of claim 28, wherein the weight percentage is based on the total weight of the lyophilized formulation.

30. A lyophilized formulation in a vial, comprising: Approximately 107.5 mg of the compound of formula (Ia) 【Transformation 33】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine; about 21.8 mg of phosphoric acid; and about 344 mg of mannitol.

31. A lyophilized formulation in a vial, comprising: Approximately 107.5 mg of the compound of formula (Ia) 【Transformation 34】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine; about 21.8 mg of phosphoric acid; and about 200 mg of glycine.

32. A lyophilized formulation in a vial, comprising: Approximately 27.5 mg of the compound of formula (Ia) 【Chemistry 35】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 37.1 mg of arginine; and about 5.6 mg of phosphoric acid.

33. A lyophilized formulation in a vial, comprising: Approximately 107.5 mg of the compound of formula (Ia) 【Transformation 36】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.1 mg of arginine; and about 21.8 mg of phosphoric acid.

34. An aqueous formulation comprising a compound of formula (I) 【Chemistry 37】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, one or more amino acids, and optionally a pH adjusting agent in an amount sufficient to adjust the pH of the solution to about 6 to about 8, wherein: W is CR ｅ and N, X is O, CH ２ and S, each of Y and Z is independently selected from the group consisting of CH and N; R ｇ is H or two R ｇ groups bond to form an acetonide, R ａ But NH ２ , N.H.R. １ , and N.R. １ R ２ is selected from the group consisting of R ｃ is H, halogen, haloalkyl, NH ２ , N.H.R. ３ , N.R. ３ R ４ , R ３ , OH, OR ３ , S.R. ３ , S.O. ２ R ３ , -X １ -NH ２ , -X １ -NHR ３ , -X １ -NR ３ R ４ , -X １ -OH, -X １ -OR ３ , -X １ -SR ３ , and −X １ -SO ２ R ３ is selected from the group consisting of R ｅ is selected from H, halogen, and optionally substituted C １ -C ６ is selected from the group consisting of alkyl, Each X １ But C １ -C ４ is alkylene Each R １ , R ２ , R ３ and R ４ independently represent optionally substituted C １ -C １０ Alkyl, optionally substituted C ３ -C ７ Cycloalkyl, optionally substituted C ３ -C ７ Cycloalkyl C １ -C ４ Alkyl, optionally substituted 4- to 7-membered heterocycloalkyl, optionally substituted 4- to 7-membered heterocycloalkylC １ -C ４ Alkyl, optionally substituted aryl, optionally substituted aryl C １ -C ４ Alkyl, optionally substituted heteroaryl, and optionally substituted heteroaryl C １ -C ４ alkyl, or R １ and R ２ or R ３ and R ４ are attached to the same nitrogen, they combine to form a 4- to 7-membered heterocycle; Aqueous formulation.

35. 1. An aqueous formulation comprising: about 15% to about 20% by weight of a compound of formula (Ia) 【Transformation 38】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; about 20% to about 35% by weight of one or more amino acids; about 2% to about 5% by weight of phosphoric acid; about 40% to about 60% by weight of a bulking agent; Aqueous formulations, where the weight percentage (wt%) is based on the total weight of the lyophilized formulation dissolved in water to form said aqueous formulation.

36. 36. The aqueous formulation of claim 35, wherein the bulking agent is kleptose, dextran, mannitol, or glycine.

37. about 17.4% by weight of the compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 23.4% by weight of arginine; About 3.5% by weight of phosphoric acid about 55.6% by weight of mannitol; 36. The aqueous formulation of claim 35, wherein the weight percentage is based on the total weight of the lyophilized formulation dissolved in water to form the aqueous formulation.

38. about 22.6% by weight of the compound of formula (Ia), or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 30.6% by weight of arginine; about 4.6% by weight of phosphoric acid; about 42.1% by weight of glycine; 36. The aqueous formulation of claim 35, wherein the weight percentage is based on the total weight of the lyophilized formulation dissolved in water to form the aqueous formulation.

39. 1. An aqueous formulation comprising: Approximately 107.5 mg of the compound of formula (Ia) 【Chemistry 39】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine; about 21.8 mg of phosphoric acid; and about 344 mg of mannitol.

40. 1. An aqueous formulation comprising: Approximately 107.5 mg of the compound of formula (Ia) 【Chemistry 40】 or a pharmaceutically acceptable salt, hydrate, or solvate thereof; Approximately 145.34 mg of arginine; about 21.8 mg of phosphoric acid; and about 200 mg of glycine.

41. A vial containing the lyophilized formulation according to any one of claims 1 to 29 or the aqueous formulation according to any one of claims 34 to 40.

42. The vial of claim 41 or the lyophilized formulation in the vial of any one of claims 30 to 33, wherein the vial has an inner surface in contact with a hydrophobic coating.

43. The hydrophobic coating has the formula SiO ｘ C ｙ H ｚ 43. The vial of claim 42, comprising a compound having the formula: wherein x is from 0.6 to 0.9, y is from 1.2 to 3.3, and z is from 0.0 to 6.

0.

44. 43. The vial of claim 41 or 42, wherein the ratio of O to Si is 1.2 or less.

45. 45. The vial of any one of claims 41 to 44, wherein the hydrophobic coating is characterized by a water contact angle of 90° or greater.

46. 1. A method of treating a disease, disorder, or condition mediated at least in part by CD73, said method comprising: a) reconstituting the lyophilized formulation of any one of claims 1 to 31 with a diluent to form a reconstituted solution; b) administering a therapeutically effective amount of the reconstituted solution to a subject in need thereof.

47. 47. The method of claim 46, wherein the pH of the reconstituted solution ranges from about 6.0 to about 7.

0.

48. 47. The method of claim 46, wherein the pH of the reconstituted solution ranges from about 7.0 to about 7.

5.

49. 49. The method of any one of claims 46-48, wherein the reconstituted solution is administered parenterally to the subject.

50. 50. The method of any one of claims 46 to 49, wherein the diluent is normal saline, semi-normal saline, Ringer's solution, lactated Ringer's solution, sterile water for injection, dextrose in water, dextrose in saline, or dextrose in lactated Ringer's solution.

51. 51. The method of any one of claims 46 to 50, wherein the disease, disorder, or condition is cancer.

52. 52. The method of claim 51, wherein the cancer is pancreatic cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, gastroesophageal cancer, urothelial cancer, stomach cancer, melanoma, lung cancer, renal cancer, liver cancer, glioblastoma, head and neck cancer, or leukemia.

53. 52. The method of claim 51, wherein the cancer is castration-resistant prostate cancer (CRPC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), or colorectal cancer (CRC).

54. 54. The method of any one of claims 51 to 53, wherein the cancer is metastatic.

55. 55. The method of any one of claims 51 to 54, wherein the method further comprises administering at least one additional therapeutic agent to the subject.

56. 56. The method of claim 55, wherein the at least one additional therapeutic agent comprises one or more agents selected from the group consisting of a chemotherapeutic agent, an immune checkpoint inhibitor, an inhibitor of HIF-2α, an adenosine pathway inhibitor, radiation therapy, and a multi-tyrosine kinase inhibitor.

57. 57. The method of claim 55 or 56, wherein the at least one additional therapeutic agent comprises one or more immune checkpoint inhibitors targeting PD-1, PD-L1, TIGIT, CTLA-4, TIM-3, LAG-3, a B7 family member, or any combination thereof.

58. 58. The method of claim 57, wherein the at least one additional therapeutic agent comprises an immune checkpoint inhibitor that targets PD-1 or PD-L1.

59. 59. The method of claim 58, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiplimab, or zimvelerimab.

60. 60. The method of claim 59, wherein the immune checkpoint inhibitor is dimverelimab.

61. 61. The method of any one of claims 55-60, wherein the at least one additional therapeutic agent comprises an immune checkpoint inhibitor that targets TIGIT.

62. 62. The method of claim 61, wherein the immune checkpoint inhibitor is domvanalimab, etigilimab, osipellimab, AB308, tiragolumab, or vibostolimab.

63. 63. The method of claim 62, wherein the immune checkpoint inhibitor is AB308 or domvanalimab.

64. 64. The method of any one of claims 55-63, wherein the at least one additional therapeutic agent comprises a HIF-2α inhibitor selected from the group consisting of belzutifan, ARO-HIF2, PT-2385, and AB521.

65. 65. The method of claim 64, wherein the HIF-2α inhibitor is AB521.

66. The at least one additional therapeutic agent is ２Ａ R.A. ２Ｂ 66. The method of any one of claims 55 to 65, comprising an adenosine pathway inhibitor that inhibits R, CD39, or a combination thereof.

67. 67. The method of claim 66, wherein the adenosine pathway inhibitor is etrumadenant, inupadenant, taminadenant, caffeine citrate, imaladenant, or ciphoradenant.

68. 68. The method of claim 67, wherein the adenosine pathway inhibitor is etormadenant.

69. 69. The method of any one of claims 55-68, wherein the at least one additional therapeutic agent comprises a multi-tyrosine kinase inhibitor selected from the group consisting of gilteritinib, glesatinib, merestinib, cabozantinib, foretinib, rebastinib, sitravatinib, XL092, BMS777607, LY2801653, S49076, GSK1363089, and RXDX-106.

70. 70. The method of any one of claims 55 to 69, wherein the one or more additional therapeutic agents comprises a chemotherapeutic agent.

71. 71. The method of claim 70, wherein the chemotherapeutic agent comprises a taxoid, a platinum-based chemotherapeutic agent, or an anthracycline-based chemotherapeutic agent.

72. 72. The method of claim 71, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, paclitaxel, and docetaxel.

73. 73. The method of claim 72, wherein the chemotherapeutic agent is gemcitabine or nab-paclitaxel.

74. 74. The method of any one of claims 55 to 73, wherein the one or more additional therapeutic agents comprises radiation.

75. A process for preparing the lyophilized formulation of any one of claims 14-15 and 24-27, comprising: (i) preparing a bulk solution by dissolving the compound of formula (Ia), arginine, phosphate, and a bulking agent in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH adjuster; (iii) filtering the bulk solution into sterile vials in a clean room; (iv) loading the vials into a freeze-dryer; (v) subjecting the vial to freeze-thaw cycles; (vi) subjecting the vial to primary and secondary drying under reduced pressure, thereby obtaining the lyophilized formulation.

76. (i) preparing a bulk solution by dissolving the compound of formula (Ia), arginine, phosphate, and a bulking agent in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH adjuster; (iii) filtering the bulk solution into sterile vials in a clean room; (iv) loading the vials into a freeze-dryer; (v) cooling the vial to a temperature of about −45° C. at a rate of about 0.5° C. / min and holding the vial at said temperature of about −45° C. for about 3 hours; (vi) warming the vial to a temperature of about −10° C. over about 50 minutes and maintaining the vial at the temperature of about −10° C. for about 4 hours; (vii) cooling the vial to a temperature of about −45° C. over about 70 minutes and maintaining the vial at said temperature of about −45° C. for about 2 hours; (viii) warming the vial to a temperature of about −15° C. and reducing the pressure to initiate primary drying; (ix) maintaining the vial under reduced pressure for about 36 hours; (x) warming the vial to a temperature of about 30° C. and performing secondary drying for about 4 hours; 76. The process of claim 75, comprising: (xi) charging the lyophilizer with dry nitrogen to a pressure of about 700 Torr and stoppering the vials, thereby providing the lyophilized formulation.

77. 1. A method of treating cancer, said method comprising administering to a patient a compound of formula (Ia) 【Chemistry 41】 or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antagonist antibody and an anti-TIGIT antagonist antibody, wherein the compound of formula (Ia) is administered in an amount ranging from 50 mg to 300 mg every 2 to 3 weeks, the anti-PD-1 antagonist antibody is administered in an amount ranging from 300 mg to 600 mg every 2 to 5 weeks, and the anti-TIGIT antagonist antibody is administered in an amount ranging from 1200 mg to about 1600 mg every 2 to 4 weeks.

78. 78. The method of claim 77, wherein the cancer is non-small cell lung cancer.

79. 78. The method of claim 77, wherein the cancer is non-small cell lung cancer and the subject is treatment-naive.

80. 78. The method of claim 77, wherein the cancer is non-small cell lung cancer and the subject has disease progression on a previously selected therapy.

81. 78. The method of claim 77, wherein the cancer is pancreatic cancer, optionally metastatic pancreatic cancer.

82. 82. The method of claim 81, wherein the pancreatic cancer is pancreatic adenocarcinoma.

83. 83. The method of claim 81 or 82, wherein the subject is treatment naive.

84. 83. The method of claim 81 or 82, wherein the subject has disease progression on a previously selected therapy.

85. 1. A method of treating cancer, said method comprising administering to a patient a compound of formula (Ia) 【Chemistry 42】 or a pharmaceutically acceptable salt thereof in combination with chemotherapy, wherein the compound of formula (Ia) is administered in an amount ranging from 50 mg to 300 mg every 2 to 3 weeks.

86. 83. The method of claim 82, wherein the cancer is pancreatic cancer, optionally metastatic pancreatic cancer.

87. 87. The method of claim 86, wherein the pancreatic cancer is pancreatic adenocarcinoma.

88. 88. The method of any one of claims 85 to 87, wherein the subject is treatment naive.

89. 88. The method of any one of claims 85 to 87, wherein the subject has disease progression on a previously selected therapy.

90. 90. The method of any one of claims 85 to 89, wherein the chemotherapy comprises (a) paclitaxel or nab-paclitaxel, and (b) gemcitabine.

91. 90. The method of any one of claims 85 to 89, wherein the chemotherapy comprises Forfirinox.

92. 90. The method of any one of claims 85 to 89, wherein the chemotherapy comprises gemcitabine, capecitabine, or 5-fluorouracil (5-FU).

93. 81. The method of claim 80, wherein the preselected therapy comprises a checkpoint inhibitor, and optionally, the checkpoint inhibitor is a PD-L1 antagonist or a PD-1 antagonist.

94. 94. The method of any one of claims 77 to 93, wherein the compound of formula (Ia) is administered in an amount of about 300 mg every three weeks.

95. 85. The method of any one of claims 77-84, wherein the anti-PD-1 antagonist antibody is administered in an amount of about 300 mg every three weeks.

96. 96. The method of any one of claims 77-84 and 95, wherein the anti-TIGIT antagonist antibody is administered every three weeks in an amount ranging from about 1200 mg to about 1600 mg.

97. The method of any one of claims 77 to 84 and 95 to 96, wherein the anti-PD-1 antagonist antibody is gimverelimab.

98. The method of any one of claims 77 to 84 and 95 to 97, wherein the anti-TIGIT antagonist antibody is domvanalimab or AB308.

99. 99. The method of any one of claims 77 to 98, wherein the compound of formula (Ia) is a reconstituted aqueous formulation of any one of claims 34 to 40.

100. 100. The method of any one of claims 77-84 and 95-99, wherein the compound of Formula (Ia), the anti-PD-1 antagonist antibody, and the anti-TIGIT antagonist antibody are administered intravenously in a three-week cycle.

101. 101. The method of any one of claims 77 to 100, further comprising one or more additional therapeutic agents.

102. 102. The method of claim 101, wherein the one or more additional therapeutic agents comprise chemotherapy.

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