Lyophilized formulations of CD73 compounds

Abstract

Provided herein are lyophilized formulations comprising a compound of formula (I) and one or more amino acids, wherein W, X, Y, Z, Ra, Rc and each Rg are as defined herein. Methods of preparation, methods of use, and dosage forms are also provided. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 380,357, filed Oct. 20, 2022, which is hereby incorporated by reference in its entirety. Background of the Invention

[0003] Ectonucleotides catalyze the conversion of ATP into adenosine, which is an endogenous regulator affecting multiple systems, including the immune system, cardiovascular system, central nervous system, and respiratory system. 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, and then hydrolyzes ADP to AMP. In the next step, AMP is converted to adenosine by 5'-nucleotidase ecto (NT5E or 5NT), also known as CD73 (cluster of differentiation 73).

[0004] The enzymatic activities of CD39 and CD73 play a strategic role in calibrating the duration, amplitude, and chemistry of purinergic signaling delivered to various cells (e.g., immune cells). Alterations in these enzymatic activities can change the course or determine the outcome of several pathophysiological events, including cancer, autoimmune diseases, infections, atherosclerosis, and ischemia - reperfusion injury, indicating that these extracellular enzymes represent novel therapeutic targets for managing multiple disorders.

[0005] CD73 inhibitors in clinical development have been antibodies because the development of small molecules has been hindered by, for example, undesirable metabolic and physical stability and the availability of a suitable formulation for effective delivery of the agent.

[0006] Given the role of CD73 in cancer and a 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 methods related thereto. Summary of the Invention

[0007] In one aspect, the present disclosure provides a lyophilized formulation comprising a compound of formula (I)

[0008]

[0009] 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 are as defined herein. Also provided are methods of preparation, methods of use, and dosage forms as described in the following detailed description.

[0010] In a specific aspect, the present disclosure provides a lyophilized formulation having a compound of formula (Ia):

[0011]

[0012] The present disclosure also provides an aqueous solution (e.g., before lyophilization or for reconstituting the lyophilized formulation) comprising a compound of formula (I) or (Ia), one or more amino acids, a pH regulator, and in some embodiments a filler. The present disclosure also relates to the use of the reconstituted lyophilized formulation for the treatment and / or prevention of a variety of diseases, disorders, and conditions that are wholly or partially mediated by CD73. CD73 inhibitors have been linked to the treatment of a variety of conditions, including cancer, fibrosis, neurological disorders and neurodegenerative disorders (e.g., depression and Parkinson's disease), cerebral and cardiac ischemic diseases, immune-related disorders, and disorders having 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 can inhibit the immunosuppressive activity and / or anti-inflammatory activity of CD73 and can be used as a therapeutic or prophylactic treatment when such inhibition is desired. Unless otherwise indicated, when used herein to refer 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.

[0013] In some embodiments, the present disclosure contemplates methods for treating or preventing cancer in a subject (e.g., a human), the methods 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 for treating or preventing cancer in a subject by administering to the subject an amount of a compound of formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation described herein) effective to reverse, halt, or slow the progression of CD73-mediated immunosuppression.

[0014] The present disclosure also contemplates the use of a compound of formula (I) or (Ia) as 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 act via different mechanisms of action. In some embodiments, such agents include radiation (e.g., local radiotherapy or total body radiotherapy) and / or other treatment modalities of non-pharmacological nature (e.g., surgical resection). In yet other embodiments, when using combination therapy, the reconstituted lyophilized formulation comprising a compound of formula (I) or (Ia) as described herein and one or more additional agents may be in the form of a single composition or multiple compositions, and the treatment modalities may be administered simultaneously, sequentially, or by some other regimen. For example, the present disclosure contemplates a treatment regimen where a radiotherapy period is followed by a chemotherapy period, or where treatment with a compound of formula (I) or (Ia) for a period of time allows for subsequent surgical resection. The combination therapy may have an additive or synergistic effect. Other benefits of combination therapy are described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is a flow chart depicting an exemplary method of bulk lyophilization of a formulation according to the present disclosure. WFI = water for injection; qs = add sufficient amount; raw materials refer to excipients.

[0016] Figure 2 Shows population PK simulations after doses of 50 mg QW (once weekly), 100 mg Q2W (once every 2 weeks), and 300 mg Q3W (once every 3 weeks). The solid line represents the population median; the shaded area represents the 5 th to 95 th percentiles of the inter-individual variability in the predicted concentration of the compound of formula (Ia); the dashed line represents the measured IC 90 of the compound of formula (Ia) for inhibition of plasma CD73 enzyme activity. DETAILED DESCRIPTION

[0017] Before further describing the present disclosure, it is to be understood that the present disclosure is not limited to the specific embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0018] As used herein, the term "about" has its original meaning of "approximate" and provides literal support for the exact number preceding it as well as numbers close to or approximating the number preceding the term. Generally, the term "about" refers to the common error range of the corresponding value that would be readily known to a person skilled in the art. If the degree of approximation is not otherwise specified by the context, "about" means within ±10% of the value provided, or rounded to the nearest significant figure, including the value provided in all cases. When ranges are provided, they include the boundary values.

[0019] Overview

[0020] The present disclosure relates to a lyophilized formulation of a CD73 inhibitor (e.g., a compound of formula (I) or other nucleoside or nucleotide compound) in combination with one or more amino acids. Surprisingly, the shown combination prevents aggregation of the CD73 inhibitor. The lyophilized formulations according to the present disclosure may have certain advantages such as reduced breakage, brittleness, and / or shrinkage. In some embodiments, the lyophilized formulations of the present disclosure are stable and can be stored up to 3 months at about 40 °C / 75% relative humidity (“RH”) or 25 °C / 60% RH and 2 °C - 8 °C until reconstitution. In some embodiments, the stored lyophiles reconstitute rapidly to produce a clear solution, and the impurity profile of the reconstituted solution is unchanged compared to the initial lyophiles. 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 quemliclustat or AB680), as shown in formula (Ia) below:

[0021]

[0022] Definition

[0023] Unless otherwise indicated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

[0024] Unless otherwise indicated, the term “alkyl” by itself or as part of another substituent means a saturated straight-chain or branched hydrocarbon group having the specified number of carbon atoms (i.e., C 1-8 means one to eight carbons). Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0025] The term “cycloalkyl” refers to a hydrocarbon ring having the specified number of ring atoms and being fully saturated or having no more than one double bond between ring vertices (e.g., C 3-6 cycloalkyl). “Cycloalkyl” also means bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0026] The term "heterocycloalkyl" refers to a cycloalkyl ring having a specified number of ring vertices (or members) and having one to five heteroatoms selected from N, O, and S, where these heteroatoms replace one to five carbon vertices, and where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. Heterocycloalkyl can be a monocyclic, bicyclic, or polycyclic system. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine - S - oxide, thiomorpholine - S,S - dioxide, piperazine, pyran, pyridone, 3 - pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. When chemically permissible, the heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon atom or a ring heteroatom.

[0027] As used herein, a wavy line " " intersecting a single bond, double bond, or triple bond in any chemical structure described herein indicates that the attachment point at which the single bond, double bond, or triple bond is bonded to the remainder of the molecule is through any one of the atoms constituting the single bond, double bond, or triple bond. Additionally, a bond extending to the center of a ring (e.g., a phenyl ring) is intended to represent attachment at any available ring vertex, i.e., such that attachment of the substituent to the ring results in a chemically stable arrangement.

[0028] As referred to herein, a divalent moiety includes either orientation (forward or reverse) of the moiety. For example, the group "-C(O)NH-" is intended to include either orientation of the linkage: -C(O)NH- or -NHC(O)-, and similarly, "-O-CH 2 CH 2 -" is intended to include -O-CH 2 CH 2 - and -CH 2 CH 2 -O- both.

[0029] The terms "alkoxy", "alkylamino", and "alkylthio" (or thioalkoxy) are used in their conventional meanings and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino, the alkyl moieties can be the same or different and can also combine with the nitrogen atom to which they are attached to form a 3 - 7 - membered ring. Thus, a group represented as dialkylamino or -NR a R b includes piperidino, pyrrolidino, morpholino, azetidinyl, etc.

[0030] The terms "arylalkyl" and "heteroarylalkyl" are used in their conventional meanings and refer to those in which an aryl group or a heteroaryl group is attached to the remainder of the molecule via a C 1 -C 4Those groups to which the alkylene linker is attached to the remainder of the molecule. Exemplary embodiments of "arylalkyl" are phenylmethyl (or benzyl). Similarly, an exemplary embodiment of "heteroarylalkyl" is, for example, 3-pyridylpropyl. When "optionally substituted" is used to describe either of the terms "arylalkyl" or "heteroarylalkyl", it means those groups in which the aryl or heteroaryl moiety is optionally substituted as defined below and the alkyl moiety is optionally substituted as defined below.

[0031] The terms "cycloalkylalkyl" and "heterocycloalkylalkyl" are used in their conventional meanings and refer to those in which the cycloalkyl group or heterocycloalkyl group is attached to the remainder of the molecule via a C 1 -C 4 Those groups to which the alkylene linker is attached to the remainder of the molecule. When "optionally substituted" is used to describe either of the terms "cycloalkylalkyl" or "heterocycloalkylalkyl", it means those groups in which the cycloalkyl or heterocycloalkyl moiety is optionally substituted as defined below and the alkyl moiety is optionally substituted as defined below.

[0032] The term "alkylene" refers to a straight-chain or branched-chain saturated hydrocarbon group having one to four (e.g., C 1-4 alkylene) carbon atoms and connecting at least two other groups, i.e., a divalent hydrocarbon group. When two moieties are attached to the alkylene, they can be attached to the same carbon atom (i.e., geminal), e.g., -(CH(CH 3 ))-, or different carbon atoms of the alkylene group. For example, a straight-chain alkylene can be the divalent group -(CH 2 ) n -, where n is 1, 2, 3, or 4 (i.e., C 1-4 alkylene). Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, etc.

[0033] Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include both mono-haloalkyl and poly-haloalkyl. For example, the term "C 1-4 haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0034] Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon group, which can be monocyclic or polycyclic (up to three rings) fused together or covalently linked. In some embodiments, aryl can have six to fourteen (i.e., C6-14 aryl), or six to ten (i.e., C6-10 aryl), or six (i.e., C6 aryl) carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

[0035] The term "heteroaryl" refers to an aryl group (or ring) containing one to five 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, "heteroaryl" can have 5 to 14 (i.e., 5- to 14-membered heteroaryl), or 5 to 10 (i.e., 5- to 10-membered heteroaryl), or 5 to 6 (i.e., 5- to 6-membered heteroaryl) members (i.e., ring vertices), and contains one to five, one to four, one to three, one to two, or one heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S). When chemically permissible, the heteroaryl group can be attached to the rest of the molecule through a ring carbon atom or a ring heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzpyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, etc. The substituents of the heteroaryl ring can be selected from the group consisting of the following acceptable substituents.

[0036] In some embodiments, the above terms (e.g., "alkyl", "aryl", and "heteroaryl") will be optionally substituted. The selected substituents for various types of groups are provided below.

[0037] The optional substituents of the alkyl group (including those groups commonly referred to as alkylene, alkenyl, alkynyl, and cycloalkyl) can be a variety of groups selected from the following: halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R",

[0038] -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O) 2 R', -NH-C(NH 2 )=NH,

[0039] -NR'C(NH 2 )=NH, -NH-C(NH 2 )=NR', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", -NR'S(O)2 R″, -CN, and -NO 2 , in a number range of zero to (2m′ + 1), where m′ is the total number of carbon atoms in the group. R′, R″, and R‴ each independently refer to hydrogen, unsubstituted C 1-8 alkyl, unsubstituted aryl, aryl substituted with 1 - 3 halogens, unsubstituted C 1-8 alkyl, C 1-8 alkoxy, or C 1-8 thioalkoxy group, or unsubstituted aryl - C 1-4 alkyl group. When R′ and R″ are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 3 - membered ring, 4 - membered ring, 5 - membered ring, 6 - membered ring, or 7 - membered ring. For example, -NR′R″ includes 1 - pyrrolidinyl and 4 - morpholinyl.

[0040] Similarly, the optional substituents of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are variable and are generally selected from: - halogen, -OR′, -OC(O)R′, -NR′R″, -SR′, -R′, -CN, -NO 2 , -CO 2 R′, -CONR′R″, -C(O)R′, -OC(O)NR′R″, -NR″C(O)R′, -NR″C(O) 2 R′, -NR′ - C(O)NR″R‴, -NH - C(NH 2 ) = NH, -NR′C(NH 2 ) = NH, -NH - C(NH 2 ) = NR′, -S(O)R′, -S(O) 2 R′, -S(O) 2 NR′R″, -NR′S(O) 2 R″, -N 3 , perfluoro(C 1 - C 4 )alkoxy, and perfluoro(C 1 - C 4 )alkyl, in a number range from zero to the total number of open valences on the aromatic ring system; and where R′, R″, and R‴ are independently selected from hydrogen, C 1-8 alkyl, 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 - mentioned aryl substituents attached to a ring atom through an alkylene chain of 1 - 4 carbon atoms.

[0041] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). In some embodiments, the heteroatom is O or N.

[0042] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively non-toxic acids or bases in accordance with the particular substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, 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, and the like. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid, and the like, as well as those 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (see, e.g., Berge, S.M. 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 to base addition salts or acid addition salts. Additionally, certain compounds containing both acidic and basic functional groups can exist as zwitterions (i.e., inner salts).

[0043] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents, but for the purposes of the present disclosure, the salt is equivalent to the parent form of the compound.

[0044] In addition to the salt forms, the present disclosure provides prodrug forms of the compounds. Prodrugs of the compounds described herein are those compounds that readily undergo chemical change to provide the compounds of the present disclosure. Generally, a prodrug contains a moiety that cleaves in vivo to produce the compound of the present disclosure.

[0045] Certain compounds of the present disclosure can exist as 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 can exist in polymorphic or amorphous forms (see, e.g., 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.

[0046] Certain compounds of the present disclosure have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereoisomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are all intended to be encompassed within the scope of the present disclosure. When a stereochemical description is shown (e.g., using a dashed line and / or a wedge ), it is intended to refer to a compound in which one isomer is present and substantially free of the other isomer. "Substantially free" of the other isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10 or 95 / 5 or higher. In some embodiments, one of the isomers will be present in an amount of at least 99%. A chemical bond to an asymmetric carbon represented by a solid line ( ) represents all possible stereoisomers (e.g., enantiomers, diastereoisomers, racemic mixtures, etc.) on that carbon atom.

[0047] "Hydrate" refers to a complex formed, for example, by combining a compound of formula (I) (a compound that inhibits CD73) with water. The term includes stoichiometric hydrates as well as non-stoichiometric hydrates.

[0048] "Solvate" refers to a complex formed by combining a compound of formula (I) and a solvent. Exemplary solvents for forming 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.

[0049] "Desolvation" refers to a compound of formula (I) that is a solvate as described herein and from which solvent molecules have been partially or completely removed. Desolvation techniques for generating the desolvated form include, but are not limited to, exposing the compound of formula (I) (solvate) to a vacuum, subjecting the solvate to elevated temperature, exposing the solvate to a gas stream (such as air or nitrogen), slurrying the solvate in a different solvent, or any combination thereof. Thus, the desolvated form of the compound of formula (I) may be completely free of solvent molecules or may be partially solvated, where the solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0050] "Alcohol" refers to a solvent having a hydroxyl group. Representative alcohols may have any suitable number of carbon atoms, such as C 1 -C 6 , and any suitable number of hydroxyl groups, such as 1 - 3. Exemplary alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, etc.

[0051] The terms "patient" or "subject" are used interchangeably to refer to a human or non-human animal (e.g., a mammal).

[0052] The term "treatment" etc. refers to a course of action (such as administering an inhibitor of CD73 or a pharmaceutical composition comprising the inhibitor) that is initiated after a disease, disorder, or condition or its symptoms etc. have been diagnosed, observed, etc. in order to temporarily or permanently eliminate, reduce, suppress, alleviate, or improve at least one of the underlying causes of the disease, disorder, or condition afflicting the subject, or at least one of the symptoms associated with the disease, disorder, or condition afflicting the subject. Thus, treatment includes inhibiting (e.g., preventing the development or further development of a disease, disorder, or condition or its associated clinical symptoms), active disease, improving quality of life, and / or prolonging the survival of the subject. Treatment also refers to a course of action that results in remission (whether partial or complete) of the disease, disorder, or condition.

[0053] As used herein, the term "in need of treatment" refers to a determination by a physician or other caregiver that a subject requires treatment or would benefit from treatment. Such determination is made based on a variety of factors within the physician's or caregiver's area of expertise.

[0054] The term "prevention", etc. refers to a process (such as before the onset of a disease, disorder, condition or its symptoms) that starts in such a way as to temporarily or permanently prevent, deter, inhibit or reduce the risk that a subject develops a disease, disorder, condition, etc. (as determined, for example, by the absence of clinical symptoms) or delay its onset (such as the administration of a CD73 inhibitor or a pharmaceutical composition comprising the inhibitor), which is typically in the case of a subject susceptible to a particular disease, disorder or condition. In certain cases, the term also refers to slowing the progression of a disease, disorder or condition or inhibiting its progression to a harmful or other undesirable state. Prevention also refers to a process that starts 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.

[0055] As used herein, the term "in need of prevention" refers to the determination by a physician or other caregiver that a subject requires treatment or would benefit from preventive care. This determination is made based on a variety of factors within the physician's or caregiver's area of expertise.

[0056] The phrase "therapeutically effective amount" means a dosage regimen (i.e., amount and interval) of a compound that provides a particular pharmacological effect, where the compound is administered to a subject in need of such treatment. For treatment, a therapeutically effective amount can effectively reduce, ameliorate or eliminate one or more signs or symptoms associated with a disease, delay disease progression, prolong survival, reduce the dosage of other medications required to treat the disease or a combination thereof. Specifically with respect to cancer, a therapeutically effective amount can, for example, cause the killing of cancer cells, reduce the cancer cell count, reduce the tumor burden, eliminate the tumor or metastasis, or reduce the spread of metastasis. A therapeutically effective amount can vary based on, for example, one or more of the following: the age and weight of the subject, the overall health of the subject, the stage of the subject's disease, the route of administration, and prior or concomitant treatments. The "effective amount" of a CD73 inhibitor of the present disclosure means an amount of the compound sufficient to engage a target (e.g., by inhibiting the target) at a level indicative of the potency of the compound. Target engagement can be determined by one or more biochemical or cellular assays that produce an EC50, ED50, EC90, IC50 or a similar value that can be used as an assessment of the potency of the compound.

[0057] The phrases "lyophilized preparation" and "lyophilizate" are used interchangeably and refer to a composition formed by lyophilization; these preparations are further described herein.

[0058] The phrases "reconstituted lyophilized preparation" and "reconstituted preparation" and "reconstitution solution" and "reconstituted aqueous solution" and "reconstituted pharmaceutical composition" are used interchangeably and refer to a composition formed when a lyophilized preparation according to the present disclosure is reconstituted with a diluent.

[0059] "Substantially pure" indicates that the component accounts for more than about 50% of the total content of the composition, and generally more than about 60% of the total content. More typically, "substantially pure" refers to a composition in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the component of interest will account for more than about 90%, or more than about 95% of the total content of the composition. In some embodiments, the compound of formula (I) or (Ia) as described herein is substantially pure, i.e., at least 75%, at least 85%, at least 90% or more, or more than about 90%, or more than about 95% of the provided material is the compound of formula (I) or (Ia).

[0060] For example, the term "response" for a cell, tissue, organ or organism encompasses changes in biochemical or physiological behavior, e.g., concentration, density, adhesion or migration, gene expression rate or differentiation state within a biological compartment, where such changes are related to activation, stimulation or treatment, or to internal mechanisms such as genetic programming. In certain cases, the terms "activation", "stimulation", etc. refer to cell activation regulated by internal mechanisms as well as external or environmental factors; while the terms "inhibition", "downregulation", etc. refer to the opposite effects.

[0061] I. Composition before lyophilization

[0062] In one aspect, the present invention provides an aqueous composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, an amino acid and a pH regulator sufficient to adjust the pH of the aqueous composition between about 6 and about 8, wherein the compound of formula (I) has the structure:

[0063]

[0064] wherein W, X, Y, Z, R a , R c and each R g are as defined herein. In some embodiments, the composition further comprises a filler as described elsewhere herein.

[0065] Ia, Compound of formula (I)

[0066] The compounds useful for preparing the pre-lyophilization compositions and lyophilized formulations described herein are represented by formula (I):

[0067]

[0068] or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0069] W is selected from the group consisting of CR e and N;

[0070] X is selected from the group consisting of O, CH 2 and S;

[0071] Y and Z are each independently selected from the group consisting of CH and N:

[0072] R g is H or two R g groups combine to form an acetone compound;

[0073] R a is selected from the group consisting of NH 2 , NHR 1 and NR 1 R 2 ;

[0074] R c is selected from the group consisting of H, halogen, haloalkyl, NH 2 , NHR 3 , NR 3 R 4 , R 3 , OH, OR 3 , SR 3 , SO 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 ;

[0075] R e is selected from the group consisting of H, halogen and optionally substituted C 1 , -C 6 alkyl; and

[0076] Each X 1 is C 1 , -C 4 alkylene; and

[0077] R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of: optionally substituted C 1 , -C 10Alkyl, 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 heteroalkyl, optionally substituted 4- to 7-membered heteroalkyl C 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 when 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.

[0078] In some embodiments, the compound of formula (I) is a compound wherein X is O.

[0079] In some embodiments, the compound of formula (I) is a compound wherein each R g is H.

[0080] In some embodiments, the compound of formula (I) is a compound of any of the above embodiments, wherein R a is NHR 1 and R 1 is selected from the group consisting of optionally substituted aryl C 1 -C 4 alkyl and optionally substituted heteroaryl C 1 -C 4 alkyl. In some embodiments, the optionally substituted aryl C 1 -C 4 alkyl or optionally substituted heteroaryl C 1 -C 4 alkyl is substituted with 1-3 halo groups.

[0081] In some embodiments, the compound of formula (I) is a compound of any of the above embodiments, wherein R a is NHR 1 and R 1 is optionally substituted aryl C 1 -C 4 alkyl. In some embodiments, the optionally substituted aryl C 1 -C 4 alkyl is substituted with 0-3 halo groups. In some embodiments, the optionally substituted aryl C 1 -C4 The alkyl group is substituted with 1 - 3 halogen groups. In some embodiments, the optionally substituted aryl C 1 -C 4 The alkyl group is substituted with 1 fluorine.

[0082] In some embodiments, the compound of formula (I) is a compound of any of the above embodiments, wherein R c is selected from the group consisting of H, halogen, and haloalkyl.

[0083] In some embodiments, the compound of formula (I) is a compound of any of the above embodiments, wherein R c is halogen.

[0084] In some embodiments, the compound of formula (I) is a compound wherein W is CR e of the compound.

[0085] In some embodiments, the compound of formula (I) is a compound of any of the above embodiments, wherein R e is H.

[0086] In some embodiments, the compound of formula (I) is a compound having a structure selected from the group consisting of:

[0087]

[0088] or a pharmaceutically acceptable salt thereof.

[0089] 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.

[0090] In some embodiments, the compound of formula (I) is a compound represented by formula (Ia):

[0091]

[0092] and is provided in the form of a free acid. In another embodiment, the compound of formula (Ia) is provided in the solution as a pharmaceutically acceptable salt.

[0093] In some embodiments, the compound of formula (I) has a structure according to formula (Ia) or a pharmaceutically acceptable salt thereof.

[0094] In one embodiment, the compound of formula (I) is a compound represented by formula (Ia) and is provided in crystalline form:

[0095]

[0096] Wherein the crystalline form is crystalline form I to VI as described in WO2021 / 257643, or any one of crystalline forms A - D as described in WO 2020 / 123772, each of which is incorporated herein by reference accordingly.

[0097] Generally, the 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.

[0098] Ib. Amino acid

[0099] The pre - freeze - drying compositions and freeze - dried formulations described herein also contain one or more amino acids. The presence of one or more amino acids in the compositions according to the present disclosure improves the physical stability of the reconstituted freeze - dried formulations. Without wishing to be bound by theory, the amphiphilic nature of the compounds described herein (i.e., compounds of formula (I) and formula (Ia)) leads to a tendency for the reconstituted solution to undergo physical changes attributable to molecular aggregation. Thus, the presence of one or more amino acids disrupts the aggregation, providing a reconstituted composition with improved physical stability compared to those lacking one or more amino acids. Amino acids are generally provided in the form of an aqueous solution. In some embodiments, the amino acid is a basic amino acid. In yet another embodiment, the amino acid is selected from arginine, histidine, lysine, tryptophan, cysteine, or a combination thereof. In some embodiments, one or more amino acids include 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.

[0100] Ic. pH regulator

[0101] The pre - freeze compositions and freeze - dried formulations described herein also use a pH adjuster. The pH adjuster can 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 in the form of an aqueous solution. Although the concentration of the aqueous solution is not critical, the pH adjuster is provided to a composition comprising a compound of formula (I) or (Ia) and one or more amino acids in an amount sufficient to bring the pH of the solution within the range of about 6 to about 8. In another embodiment, the pH adjuster is provided to a composition comprising a compound of formula (I) or (Ia) and one or more amino acids in an amount sufficient to bring the pH of the solution within the range of about 6.5 to about 7.5. In one embodiment, the pH adjuster is phosphoric acid and is provided to a composition comprising a compound of formula (I) or (Ia) and one or more amino acids in an amount sufficient to bring the pH of the solution within the range of 6.0 - 7.0. In one embodiment, the pH adjuster is phosphoric acid and is provided to a composition comprising a compound of formula (I) or (Ia) and one or more amino acids in an amount sufficient to bring the pH of the solution within the range of 7.0 - 7.5.

[0102] Id. Filler

[0103] In one or more embodiments, the pre - freeze compositions, freeze - dried formulations, and aqueous solutions described herein contain a bulking agent. The bulking agent forms the bulk of the freeze - dried formulation and provides sufficient structure to the freeze - dried cake. Bulking agents can be used for low - dose (or low - concentration) drugs that do not have the volume necessary to support their own structure. The structure of the freeze - dried cake is important because proper cake formation results in proper pore formation, which provides a means for the vapor to escape from the formulation during the drying cycle. Exemplary bulking agents include, but are not limited to, mannitol, glycine, hydroxypropyl - β - cyclodextrin (HPBCD) (i.e., kleptose), dextran, sucrose, lactose, trehalose, sorbitol, glucose, raffinose, etc., and are used in the pre - freeze composition to provide structure to the freeze - dried cake and prevent cake collapse. In some embodiments, the bulking agent in the compositions and formulations according to the present disclosure is mannitol, glycine, hydroxypropyl - β - cyclodextrin (HPBCD), or dextran. In one embodiment, the bulking agent in the compositions and formulations according to the present disclosure is glycine. In one embodiment, the bulking agent in the compositions and formulations according to the present disclosure is mannitol.

[0104] Ie. Vial selection

[0105] Some embodiments provide a vial containing a freeze - dried formulation as described herein or an aqueous formulation as described herein.

[0106] In one or more embodiments, the vials used for lyophilizing the pre-lyophilization formulation are clear glass vials (USP Type 1). In one or more embodiments, the vials used for lyophilizing the pre-lyophilization formulation are characterized by a hydrophobic coating on their inner surfaces. Thus, in some embodiments, the vial comprises an inner surface that contacts the hydrophobic coating. Exemplary vials include SCHOTT vials, or those vials described in U.S. Patent No. 8,592,015, which is hereby incorporated by reference. The presence of the hydrophobic coating reduces the adhesion of the compositions and / or formulations according to the present disclosure to the sides of the vial and facilitates the formation of a lyophilized cake that is free of cracking, brittleness, and / or shrinkage. The reduced adhesion of the compositions and / or formulations according to the present disclosure to the sides of the vial allows for easy reconstitution, which aids in the consistent and accurate administration of the compounds according to the present disclosure.

[0107] The hydrophobic coating can be applied to the inner surface of the vial using methods known to those skilled in the art, such as, for example, physical or chemical vapor deposition methods, including, for example, plasma-assisted chemical vapor deposition. In some embodiments, the hydrophobic coating on the inner 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 an oxygen-to-silicon ratio of 1.2 or less. In some embodiments, the O:Si ratio is less than or equal to 1.2. In some embodiments, the hydrophobic coating comprises a compound having the formula SiO x C y H z where x is between 0.0 and 1.2; y is between 0.0 and 6.0; and z is between 0.0 and 6.0. In some embodiments, the hydrophobic coating comprises a compound having the formula SiO x C y H z where x is between 0.6 and 0.9; y is between 1.2 and 3.3; and z is between 0.0 and 6.0. In some embodiments, the hydrophobic coating comprises a compound having the formula SiO x C y H z where x is between 0.7 and 0.8; y is between 1.5 and 2.5; and z is between 0.0 and 6.0. In some embodiments, the hydrophobic coating is substantially free of fluorine. 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).

[0108] The hydrophobicity of the 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 with respect to water that is greater than or equal to 90°. In some embodiments, the coated vial is characterized by a water contact angle between about 90° and 120°, such as a contact angle of 90°, 95°, 100°, 105°, 110°, 115°, or 120°.

[0109] II. Lyophilization procedure

[0110] The lyophilization method includes three main stages: (1) freezing, (2) primary drying, and (3) secondary drying.

[0111] The freezing step ensures that the composition is in the solid phase prior to lyophilization to form a frozen pre-lyophilization composition. Freezing is achieved by reducing the temperature and maintaining a predetermined amount of time. The material should be cooled to a temperature below the lowest melting point of all components present in the pre-lyophilization composition (including, for example, the eutectic melting point, which is lower than the melting point of any individual component) to freeze it and ensure that sublimation rather than melting will occur as the frozen material is subsequently heated under vacuum or low pressure. 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 subsequent step.

[0112] In some embodiments, the pre-lyophilization composition is cooled to a temperature below 0°C. In some embodiments, the pre-lyophilization composition is cooled to a temperature of -50°C or lower. In some embodiments, the pre-lyophilization composition is cooled to a temperature between -40°C and -50°C. In some embodiments, the pre-lyophilization composition is cooled to a temperature of about -45°C. In some embodiments, the pre-lyophilization composition is cooled for 10 hours or less. In some embodiments, the pre-lyophilization 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.

[0113] There are many suitable freezing methods, each of which is included within the present disclosure. Suitable freezing methods include, but are not limited to, refrigeration, placement in an ice bath (e.g., a mixture of ice or dry ice with salt or an organic solvent or a combination thereof, such as placement in a bath of dry ice and methanol or ethanol), and placement in a liquid nitrogen bath.

[0114] After freezing, the primary drying step includes reducing the pressure to induce sublimation of the frozen water in the frozen pre-lyophilization composition. Generally, most of the water is removed during this primary drying stage.

[0115] Typically, a vacuum pump is used to reduce the pressure. The desired pressure can vary based on the temperature of the primary drying step, as the vapor pressure over ice is a function of temperature. In some embodiments, the pressure in the primary drying step is reduced below 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 such embodiments, the pressure in the primary drying step is below 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 would be approximately 85.8 mTorr 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). Again referring to -26 °C as an exemplary temperature, 20% to 30% of the vapor pressure would be approximately 85.8 mTorr to 128 mTorr. The vapor pressure over ice is generally known and can be obtained by those skilled in the art. Exemplary vapor pressures at given temperatures 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.

[0116] The primary drying step can be carried out at ambient temperature, a temperature below ambient temperature, or a temperature above ambient temperature. For example, in some embodiments, the primary drying step is carried out at a temperature of 40 °C or lower, 30 °C or lower, 20 °C or lower, 10 °C or lower, or 0 °C or lower.

[0117] The primary drying stage lasts for any suitable amount of time. In some embodiments, the primary drying stage 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 longer. In some embodiments, the primary drying stage runs overnight. In some embodiments, the primary drying temperature is -25 °C and is raised to 25 °C for approximately 3 hours.

[0118] After the primary drying stage, further drying (secondary drying stage) is carried out by raising the temperature to a temperature higher than that used in the primary drying stage. Most of the free water is removed during the primary drying stage, leaving most of the water bound to the formulation components. Thus, the second drying stage removes additional moisture as well as water that condensed or migrated from its initial location during the primary drying stage. Since most of the free water has been removed, the temperature of the secondary drying stage can be increased without melting the composition.

[0119] In some embodiments, the secondary drying stage is carried out at a temperature in the range of -10°C to 50°C, 0°C to 40°C, 10°C to 30°C, or 20°C to 25°C.

[0120] Low pressure is also typically used during this stage. Typically, the reduced pressure from the primary drying stage is maintained, but a variety of lower pressures that facilitate sublimation are suitable during this step.

[0121] The rate of water removal during the secondary drying stage is a function of temperature, and lower pressures generally do not increase the drying rate. In some embodiments, the secondary drying stage 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 longer. In some embodiments, the secondary drying stage is run overnight.

[0122] In some embodiments, the secondary drying stage can include drying in the presence of an inert gas (e.g., nitrogen) or a combination of inert gases. For example, the lyophilization container and / or the vial storage container can be purged with an inert gas and capped to avoid exposure of the formulation to air.

[0123] The lyophilized compositions described herein can have a water content of, for example, less than 20% after one or more drying steps. In some examples, the water 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%.

[0124] III. Lyophilized preparation containing formula (I)

[0125] In one aspect, the present disclosure provides a lyophilized formulation having a compound of formula (I):

[0126]

[0127] wherein W, X, Y, Z, R a , R c and each R g are as defined herein, or a pharmaceutically acceptable salt thereof, as described above in part Ia, 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 regulator, a filler, or both.

[0128] 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 from 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 from 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 the amino acid is from 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 the amino acid is about 1:4.5.

[0129] The lyophilized formulation can also be characterized by percentage composition. In one embodiment, the lyophilized formulation comprises a compound of formula (I) (e.g., the compound of formula (Ia)), one or more amino acids, and a pH adjuster, and the compound of formula (I) accounts for about 35% to 45% by weight of the lyophilized formulation, the amino acids account for about 45% to about 60% by weight of the lyophilized formulation, and the pH adjuster accounts for about 5% to about 10% by weight of the lyophilized composition. In another embodiment, the lyophilized formulation comprises a compound of formula (I) (e.g., the compound of formula (Ia)), one or more amino acids, a pH adjuster, and a filler, and the compound of formula (I) or (Ia) accounts for about 15% to about 25% by weight of the lyophilized formulation, the amino acids account for about 20% to about 35% by weight of the lyophilized formulation, the pH adjuster accounts for about 1% to about 10% by weight of the lyophilized formulation, and the filler accounts for about 40% to about 50% by weight of the lyophilized formulation.

[0130] The lyophilized formulation according to the present disclosure can have certain advantages such as reduced cracking, brittleness, and / or shrinkage. These properties can be determined by methods known in the art.

[0131] 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, wherein the amount of these amino acids is greater than the stoichiometric amount of the compound of formula (Ia).

[0132] In some embodiments, provided herein is a lyophilized formulation comprising

[0133] about 15% to about 20% by weight of the compound of formula (Ia)

[0134]

[0135] or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0136] about 20% to about 35% by weight of one or more amino acids;

[0137] About 2 wt% to about 5 wt% phosphoric acid; and

[0138] About 40 wt% to about 60 wt% filler;

[0139] wherein the weight percentages (i.e., wt%) are based on the total weight of the lyophilized formulation.

[0140] In some embodiments, the filler is kleptose, dextran, mannitol, or glycine. In some embodiments, the filler is mannitol. In some embodiments, the filler is glycine.

[0141] In some embodiments, provided herein is a lyophilized formulation comprising

[0142] About 17.4 wt% of a compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0143] About 23.4 wt% arginine;

[0144] About 3.5 wt% phosphoric acid; and

[0145] About 55.6 wt% mannitol;

[0146] wherein the weight percentages are based on the total weight of the lyophilized formulation.

[0147] In some embodiments, provided herein is a lyophilized formulation comprising

[0148] About 22.6 wt% of a compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0149] About 30.6 wt% arginine;

[0150] About 4.6 wt% phosphoric acid; and

[0151] About 42.1 wt% glycine;

[0152] wherein the weight percentages are based on the total weight of the lyophilized formulation.

[0153] In some embodiments, provided herein is a lyophilized formulation comprising

[0154] About 35 wt% to about 45 wt% of a compound of formula (Ia)

[0155]

[0156] or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0157] About 45 wt% to about 55 wt% of one or more amino acids;

[0158] About 5 wt% to about 10 wt% phosphoric acid; and

[0159] wherein the weight percentages (wt%) are based on the total weight of the lyophilized formulation.

[0160] In some embodiments, provided herein is a lyophilized formulation comprising

[0161] About 39.2 wt% of a compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0162] About 52.9 wt% arginine; and

[0163] About 7.9 wt% phosphoric acid;

[0164] wherein the weight percentages are based on the total weight of the lyophilized formulation.

[0165] In some embodiments, the pH of the lyophilized formulation is adjusted by a pH adjuster. Those skilled 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 is determined in particular by the target pH range before lyophilization. In some embodiments, the target pH range is between about 6 and about 8 (e.g., pH 7.0 - 7.5 or pH 7.2 - 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 includes sodium hydroxide. In some embodiments, the amount of sodium hydroxide corresponds to the amount of sodium hydroxide added to the solution before lyophilization such that the pH of the solution before lyophilization is between about 6 and about 8; in some embodiments, between about 7.0 and about 7.5; and in some embodiments, between about 7.2 and about 7.4.

[0166] In some embodiments, provided herein is a lyophilized formulation in a vial comprising

[0167] About 107.5 mg of a compound of formula (Ia)

[0168]

[0169] or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0170] About 145.34 mg arginine;

[0171] About 21.8 mg phosphoric acid; and

[0172] About 344 mg mannitol.

[0173] In some embodiments, provided herein is a lyophilized formulation in a vial comprising about 107.5 mg of a compound of formula (Ia)

[0174]

[0175] or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0176] about 145.34 mg of arginine;

[0177] about 21.8 mg of phosphoric acid; and

[0178] about 200 mg of glycine.

[0179] In some embodiments, provided herein is a lyophilized formulation in a vial comprising about 27.5 mg of a compound of formula (Ia)

[0180]

[0181] or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0182] about 37.1 mg of arginine; and

[0183] about 5.6 mg of phosphoric acid.

[0184] In some embodiments, provided herein is a lyophilized formulation in a vial comprising

[0185] about 107.5 mg of a compound of formula (Ia)

[0186]

[0187] or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0188] about 145.1 mg of arginine; and

[0189] about 21.8 mg of phosphoric acid.

[0190] In some embodiments, the lyophilized formulation in the vial further comprises sodium hydroxide. In some embodiments, the amount of sodium hydroxide corresponds to the amount of sodium hydroxide added to the solution before lyophilization such that the pH of the solution before lyophilization is between about 6 and about 8; in some embodiments, between about 7.0 and about 7.5; and in some embodiments, between about 7.2 and about 7.4.

[0191] In some embodiments, the lyophilized formulation described herein is prepared by the following steps:

[0192] (i) Prepare a bulk solution by dissolving a compound of formula (Ia), an amino acid (e.g., arginine, e.g., L-arginine), phosphoric acid, and a filler in sterile water;

[0193] (ii) Optionally adjust the pH of the bulk solution by adding a pH regulator;

[0194] (iii) Filter the bulk solution into sterile vials in a clean room;

[0195] (iv) Load the vials into a freeze dryer;

[0196] (v) Subject the vials to freeze-thaw cycles; and

[0197] (vi) Subject the vials to primary drying and secondary drying under reduced pressure;

[0198] To obtain a freeze-dried preparation.

[0199] In some embodiments, the freeze-dried preparation described herein is prepared by the following steps:

[0200] (i) Prepare a bulk solution by dissolving a compound of formula (Ia), arginine, phosphoric acid, and a filler in sterile water;

[0201] (ii) Optionally adjust the pH of the bulk solution by adding a pH regulator;

[0202] (iii) Filter the bulk solution into sterile vials in a clean room;

[0203] (iv) Load the vials into a freeze dryer;

[0204] (v) Cool the vials to a temperature of about -45 °C at a rate of about 0.5 °C / minute, and hold the vials at a temperature of about -45 °C for about 3 hours;

[0205] (vi) Warm the vials to a temperature of about -10 °C in about 50 minutes, and hold the vials at a temperature of about -10 °C for about 4 hours;

[0206] (vii) Cool the vials to a temperature of about -45 °C in about 70 minutes, and hold the vials at a temperature of about -45 °C for about 2 hours;

[0207] (viii) Warm the vials to a temperature of about -15 °C, reduce the pressure and start primary drying;

[0208] (ix) Maintain the vials under reduced pressure for about 36 hours;

[0209] (x) Warm the vials to a temperature of about 30 °C, and conduct secondary drying for about 4 hours; and

[0210] (xi) Backfill the lyophilizer with dry nitrogen to a pressure of about 700 Torr and stopper the vials to provide a lyophilized formulation.

[0211] In some embodiments, the lyophilized formulations described herein are prepared by the following steps:

[0212] (i) Prepare 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;

[0213] (ii) Optionally adjust the pH of the bulk solution by adding a pH regulator;

[0214] (iii) Filter the bulk solution into sterile vials in a clean room;

[0215] (iv) Load the vials into a lyophilizer;

[0216] (v) Subject the vials to freeze-thaw cycles; and

[0217] (vi) Subject the vials to primary drying and secondary drying under reduced pressure to obtain a lyophilized formulation. In some embodiments, the lyophilized formulations described herein are prepared by the following steps:

[0218] (i) Prepare a bulk solution by dissolving a compound of formula (Ia), arginine, and phosphoric acid in sterile water;

[0219] (ii) Optionally adjust the pH of the bulk solution by adding a pH regulator;

[0220] (iii) Filter the bulk solution into sterile vials in a clean room;

[0221] (iv) Load the vials into a lyophilizer;

[0222] (v) Cool the vials to a temperature of about -45 °C at a rate of about 0.5 °C / minute and hold the vials at a temperature of about -45 °C for about 3 hours;

[0223] (vi) Warm the vials to a temperature of about -10 °C in about 50 minutes and hold the vials at a temperature of about -10 °C for about 4 hours;

[0224] (vii) Cool the vials to a temperature of about -45 °C in about 70 minutes and hold the vials at a temperature of about -45 °C for about 2 hours;

[0225] (viii) Warm the vials to a temperature of about -15 °C, reduce the pressure, and initiate primary drying;

[0226] (ix) Maintain the vials under reduced pressure for about 36 hours;

[0227] (x) Warm the vial to a temperature of about 30 °C and perform secondary drying for about 4 hours; and

[0228] (xi) Backfill the lyophilizer with dry nitrogen to a pressure of about 700 Torr and stopper the vial,

[0229] Thereby providing a lyophilized formulation.

[0230] In some embodiments, the pH adjuster is a base. In some embodiments, the pH adjuster is an acid. In some embodiments, the pH adjuster is added to the aqueous solution that is subsequently subjected to lyophilization such that the pH of the aqueous solution before lyophilization is between about 6 and about 8; in some embodiments, between about 7.0 and about 7.5; and in some embodiments, between about 7.2 and 7.4.

[0231] The above temperature, time, pressure, and / or weight percentage ranges are provided by way of example only, and those skilled in the art can envision other variations, and all such variations are expected to be within the scope of the embodiments presented herein.

[0232] IV. Reconstitution of lyophilized preparation containing formula (I)

[0233] In one aspect, the present disclosure provides a reconstituted lyophilized formulation (i.e., a reconstituted pharmaceutical composition or reconstituted formulation) that comprises 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 adjuster, a filler, or both. The reconstituted lyophilized formulation (i.e., the reconstituted pharmaceutical composition) according to the present disclosure can be used in a method for treating a disease, disorder, or condition that is at least partially mediated by CD73 as described elsewhere herein.

[0234] The lyophilized formulations described herein are reconstituted with an acceptable diluent prior to administration. As used herein, "reconstitute" refers to the process of wetting the lyophilized cake in such a way that the cake completely dissolves and the resulting liquid has achieved an acceptable clarity for administration to a patient. Diluents for reconstituting lyophilized formulations comprising a compound of formula (I) or (Ia) include sterile water for injection (SFWI), containing stabilizers, solubilizers, tonicity modifiers such as NaCl, MgCl 2 or CaCl 2SWFI, 0.9% saline solution (i.e., physiological saline), half - saline, lactated Ringer's solution, glucose - containing water, glucose - containing saline, or glucose - containing lactated Ringer's solution and their mixtures. In one embodiment, the diluent is SWFI. In another embodiment, the diluent is physiological saline. In some embodiments, for example, when the vial containing the lyophilized formulation has been stored under refrigeration, the vial should be allowed to equilibrate to room temperature before reconstitution.

[0235] The volume of diluent used to reconstitute the formulations 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 mL to 3.3 mL of diluent. Those skilled in the art will understand that as the vial size (and sample size) increases, the amount of diluent can also increase. Thus, in some embodiments, the composition in the vial is reconstituted with 2.2 mL to 20.2 mL of diluent, such as 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, 4.9 mL, 5.0 mL, 5.1 mL, 5.2 mL, 5.3 mL, 5.4 mL, 5.5 mL, 5.6 mL, 5.7 mL, 5.8 mL, 5.9 mL, 6.0 mL, 6.1 mL, 6.2 mL, 6.3 mL, 6.4 mL, 6.5 mL, 6.6 mL, 6.7 mL, 6.8 mL, 6.9 mL, 7.0 mL, 7.1 mL, 7.2 mL, 7.3 mL, 7.4 mL, 7.5 mL, 7.6 mL, 7.7 mL, 7.8 mL, 7.9 mL, 8.0 mL, 8.1 mL, 8.2 mL, 8.3 mL, 8.4 mL, 8.5 mL, 8.6 mL, 8.7 mL, 8.8 mL, 8.9 mL, 9.0 mL, 9.1 mL, 9.2 mL, 9.3 mL, 9.4 mL, 9.5 mL, 9.6 mL, 9.7 mL, 9.8 mL, 9.9 mL, 10.0 mL, 10.1 mL, 10.2 mL 10.3 mL, 10.4 mL, 10.5 mL, 10.6 mL, 10.7 mL, 10.8 mL, 10.9 mL, 11.0 mL, 11.1 mL, 11.2 mL, 11.3 mL, 11.4 mL, 11.5 mL, 11.6 mL, 11.7 mL, 11.8 mL, 11.9 mL, 12.0 mL, 12.1 mL, 12.2 mL, 12.3 mL, 12.4 mL, 12.5 mL, 12.6 mL, 12.7 mL, 12.8 mL, 12.9 mL, 13.0 mL, 13.1 mL, 13.2 mL, 13.3 mL, 13.4 mL, 13.5 mL, 13.6 mL, 13.7 mL, 13.8 mL, 13.9 mL, 14.0 mL, 14.1 mL, 14.2 mL, 14.3 mL, 14.4 mL, 14.5 mL, 14.6 mL, 14.7 mL, 14.8 mL, 14.9 mL, 15.0 mL, 15.1 mL, 15.2 mL, 15.Reconstituted with 3 mL, 15.4 mL, 15.5 mL, 15.6 mL, 15.7 mL, 15.8 mL, 15.9 mL, 16.0 mL, 16.1 mL, 16.2 mL, 16.3 mL, 16.4 mL, 16.5 mL, 16.6 mL, 16.7 mL, 16.8 mL, 16.9 mL, 17.0 mL, 17.1 mL, 17.2 mL, 17.3 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.

[0236] In some embodiments, the diluent is water and provides the aqueous formulations described herein.

[0237] The present invention provides an aqueous formulation comprising a compound of formula (I)

[0238]

[0239] or a pharmaceutically acceptable salt, hydrate or solvate thereof

[0240] wherein

[0241] W is selected from the group consisting of CR e and N

[0242] X is selected from the group consisting of O, CH 2 and S

[0243] Y and Z are each independently selected from the group consisting of CH and N

[0244] R g is H or two R g groups combine to form an acetone compound

[0245] R a is selected from the group consisting of NH 2 , NHR 1 and NR 1R 2 a group consisting of;

[0246] R c is selected from the group consisting of H, halogen, haloalkyl, NH 2 , NHR 3 , NR 3 R 4 R 3 , OH, OR 3 , SR 3 , SO 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 a group consisting of;

[0247] R e is selected from the group consisting of H, halogen and optionally substituted C 1 , -C 6 alkyl; and

[0248] each X 1 is C 1 , -C 4 alkylene; and

[0249] R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of: 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 heterocycloalkyl C 1 , -C 4 alkyl, optionally substituted aryl, optionally substituted aryl C 1 , -C 4 alkyl, optionally substituted heteroaryl and optionally substituted heteroaryl C1 -C 4 alkyl or when 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;

[0250] One or more amino acids and an optional pH regulator in an amount sufficient to adjust the pH of the solution to between about 6 and about 8; in some embodiments, between about 7.0 and about 7.5; and in some embodiments, between about 7.2 and about 7.4.

[0251] Provided herein is an aqueous formulation comprising

[0252] About 15 wt% to about 20 wt% of a compound of formula (Ia)

[0253]

[0254] or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0255] About 20 wt% to about 35 wt% of one or more amino acids;

[0256] About 2 wt% to about 5 wt% of phosphoric acid; and

[0257] About 40 wt% to about 60 wt% of a filler;

[0258] wherein the weight percentages (wt%) are based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation.

[0259] In some embodiments, the filler is kleptose, dextran, mannitol or glycine. In some embodiments, the filler is mannitol. In some embodiments, the filler is glycine.

[0260] In some embodiments, there is provided an aqueous formulation comprising

[0261] About 17.4 wt% of a compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0262] About 23.4 wt% of arginine;

[0263] About 3.5 wt% of phosphoric acid; and

[0264] About 55.6 wt% of mannitol.

[0265] wherein the weight percentages are based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation. In some embodiments, the lyophilized formulation is any of the lyophilized formulations described herein.

[0266] In some embodiments, an aqueous formulation is provided that comprises

[0267] about 22.6% by weight of a compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0268] about 30.6% by weight of arginine;

[0269] about 4.6% by weight of phosphoric acid; and

[0270] about 42.1% by weight of glycine;

[0271] wherein the percentages by weight are based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation.

[0272] In some embodiments, an aqueous formulation is provided herein that comprises

[0273] from about 35% to about 45% by weight of a compound of formula (Ia)

[0274]

[0275] or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0276] from about 45% to about 55% by weight of one or more amino acids;

[0277] from about 5% to about 10% by weight of phosphoric acid; and

[0278] wherein the percentages by weight are based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation.

[0279] In some embodiments, an aqueous formulation is provided herein that comprises

[0280] about 39.2% by weight of a compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate, or solvate thereof,

[0281] about 52.9% by weight of arginine; and

[0282] about 7.9% by weight of phosphoric acid;

[0283] wherein the % by weight is based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation.

[0284] In some embodiments, an aqueous formulation is provided that comprises

[0285] about 107.5 mg of a compound of formula (Ia)

[0286]

[0287] or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0288] about 145.34 mg of arginine;

[0289] about 21.8 mg of phosphoric acid; and

[0290] about 344 mg of mannitol.

[0291] In some embodiments, there is provided an aqueous formulation comprising

[0292] about 107.5 mg of the compound of formula (Ia)

[0293]

[0294] or a pharmaceutically acceptable salt, hydrate or solvate thereof,

[0295] about 145.34 mg of arginine;

[0296] about 21.8 mg of phosphoric acid; and

[0297] about 200 mg of glycine.

[0298] In some embodiments, there is provided herein an aqueous formulation comprising about 27.5 mg of the compound of formula (Ia)

[0299]

[0300] or a pharmaceutically acceptable salt, hydrate or solvate thereof, about 37.1 mg of arginine; and

[0301] about 5.6 mg of phosphoric acid.

[0302] In some embodiments, there is provided herein an aqueous formulation comprising about 107.5 mg of the compound of formula (Ia)

[0303]

[0304] or a pharmaceutically acceptable salt, hydrate or solvate thereof, about 145.1 mg of arginine; and

[0305] about 21.8 mg of phosphoric acid.

[0306] In some embodiments, the aqueous formulation further comprises a pH regulator, optionally wherein the pH regulator is sodium hydroxide. In some embodiments, the amount of sodium hydroxide corresponds to the amount of sodium hydroxide added to the aqueous solution such that the pH of the aqueous solution is between about 6 and about 8; in some embodiments, between about 7.0 and about 7.5; and in some embodiments, between about 7.2 and about 7.4.

[0307] V. Therapeutic and prophylactic uses

[0308] In one aspect, the present disclosure relates to a method of treating a disease, disorder, or condition that is at least partially mediated by CD73, the method comprising:

[0309] a) reconstituting a lyophilized formulation according to the present disclosure with a diluent to form a reconstituted solution; and

[0310] b) administering a therapeutically effective amount of the reconstituted solution to a subject in need thereof.

[0311] The lyophilized formulation can be reconstituted with an acceptable diluent. In some embodiments, the diluent is selected from the group consisting of normal saline, half-normal saline, Ringer's solution, lactated Ringer's solution, sterile water for injection, water containing glucose, saline containing glucose, and lactated Ringer's solution containing glucose. In one embodiment, the diluent is sterile water for injection. In another embodiment, the diluent is normal saline.

[0312] In some embodiments, the lyophilized formulation is reconstituted with 2 mL to 20 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 2.0 mL to 15.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 2.0 mL to 10.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 2.2 mL to 6.6 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 3.0 mL to 6.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 3.0 mL to 4.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 3.0 mL to 3.5 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 6.5 mL to 10.5 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 7.0 mL to 10.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 7.5 mL to 9.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 8.0 mL to 9.0 mL of diluent. In some embodiments, the lyophilized formulation is reconstituted with 8.3 mL to 8.8 mL of diluent.

[0313] In one or more embodiments, the pH of the reconstitution solution ranges from about 6 to about 8. In some embodiments, the pH of the reconstitution solution ranges from about 6.5 to about 7.5. In some embodiments, the pH of the reconstitution solution ranges from about 6.0 to about 7.0. In some embodiments, the pH of the reconstitution solution ranges from about 7.0 to about 7.5.

[0314] In some embodiments, the reconstitution solution is administered parenterally to a subject. In some embodiments, the parenteral administration is intravenous, intraperitoneal, subcutaneous, intradermal, or intramuscular. In some embodiments, the parenteral administration is intravenous.

[0315] In some embodiments, the method further comprises diluting the reconstitution solution with an acceptable vehicle prior to administration to the subject to form a diluted reconstitution solution. In some embodiments, the vehicle is selected from the group consisting of normal saline, half-normal saline, Ringer's solution, lactated Ringer's solution, sterile water for injection, glucose-containing water, glucose-containing saline, and glucose-containing lactated Ringer's solution. In some embodiments, the vehicle is normal saline.

[0316] In some embodiments, within 24 hours of dilution, such as within 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1.5 hours, 1.25 hours, 1 hour, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 14 minutes, 13 minutes, 12 minutes, 11 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, the diluted reconstitution solution is administered to the subject. In some embodiments, the diluted reconstitution solution is administered to the subject within 24 hours of dilution. In some embodiments, the diluted reconstitution solution is administered to the subject within 4 hours of dilution. In some embodiments, the diluted reconstitution solution is administered to the subject within 1 hour of dilution. In some embodiments, the diluted reconstitution solution is administered to the subject within 30 minutes of dilution.

[0317] In some embodiments, the method further comprises filtering the diluted reconstitution solution prior to administration to the subject. In one embodiment, the diluted reconstitution solution is filtered using an in-line filter.

[0318] The present disclosure contemplates the use of a compound of formula (I) or (Ia) (e.g., a reconstituted formulation, e.g., a reconstituted solution or a diluted reconstituted solution as described herein) in the treatment or prevention of a variety of diseases, disorders, and / or conditions, and / or their symptoms. The reconstituted formulation is suitable for administration by injection. Common types of injection include intravenous, subcutaneous, and intramuscular; infusions are typically administered intravenously. Other sites of parenteral administration include: epidural, intraspinal, intrathecal, intracerebral, intra-articular, intracardiac, intradermal, intraperitoneal, intravitreal, intra-arterial, intraorbital, and transtracheal. Although specific uses are described in detail below, it should be understood that the present disclosure is not limited thereto. Additionally, although general categories of specific diseases, disorders, and conditions are set forth below, some diseases, disorders, and conditions may be members of more than one category, and other diseases, disorders, and conditions may not be members of any of the disclosed categories. Oncology-related conditions. According to the present disclosure, a compound of formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation as described herein) can be used to treat or prevent proliferative conditions or disorders, including cancer, e.g., uterine cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, gastrointestinal cancer (e.g., esophageal cancer, oropharyngeal cancer, gastric cancer, small intestine cancer or colorectal cancer, colon cancer or rectal cancer), kidney cancer, renal cell carcinoma, bladder cancer, bone cancer, myeloid cancer, skin cancer, head and neck cancer, liver cancer, bladder cancer, heart cancer, lung cancer, pancreatic cancer, salivary gland cancer, adrenal cancer, thyroid cancer, brain cancer (e.g., glioma), ganglioneuroma, central nervous system (CNS) cancer, and peripheral nervous system (PNS) cancer, as well as cancers of the hematopoietic and immune systems (e.g., spleen or thymus). The present disclosure also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions, including, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratocarcinoma, chemically induced cancers, metastatic cancers, and angiogenesis. The present disclosure contemplates reducing tolerance to tumor cells or cancer cell antigens, e.g., 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 a specific embodiment, the tumor or cancer is pancreatic cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, gastroesophageal cancer, urothelial cancer, gastric cancer, melanoma, lung cancer, kidney 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 as described herein) is used to treat cancer in a first-line setting (e.g., in a setting where no prior treatment has been received).In some embodiments, a compound of formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation as described herein) is used to treat cancer in second-line or greater settings. The use of the terms cancer-related diseases, conditions, and disorders is intended to broadly refer to conditions directly or indirectly related to cancer and includes, for example, angiogenesis and pre-cancerous conditions such as dysplasia.

[0319] In some embodiments, the cancer is castration-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 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). 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 has not received prior treatment. In some embodiments, the cancer is non-small cell lung cancer and the subject has disease progression in a prior line of treatment. In some embodiments, the cancer is pancreatic cancer, optionally metastatic pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is metastatic pancreatic cancer and the subject has not received prior treatment. In some embodiments, the cancer is metastatic pancreatic cancer. In some embodiments, the prior line of treatment includes chemotherapy. In some embodiments, the subject has not received prior treatment. In some embodiments, the subject has disease progression in a prior line of treatment. In some embodiments, the prior line of treatment includes checkpoint inhibitors, optionally wherein the checkpoint inhibitor is a PD-L1 antagonist or a PD-1 antagonist. In some embodiments, the prior line of treatment includes chemotherapy and checkpoint inhibitors, optionally wherein the checkpoint inhibitor is a PD-L1 antagonist or a PD-1 antagonist.

[0320] In certain embodiments, the cancer can be metastatic or at risk of becoming metastatic, or can occur in diffuse tissues, including cancers of the blood or bone marrow (e.g., leukemia). In some further embodiments, the reconstituted lyophilized formulation described herein can be used to overcome T cell tolerance.

[0321] In some embodiments, the present disclosure provides methods for treating and / or preventing proliferative conditions, cancer, tumors, or pre-cancerous conditions with a compound of formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation as described herein) and at least one additional therapeutic or diagnostic agent, examples of which are set forth elsewhere herein.

[0322] In one embodiment, the cancer is a gastrointestinal malignancy, such as pancreatic cancer. In one embodiment, the cancer is metastatic pancreatic adenocarcinoma. In one embodiment, a patient's pancreatic cancer is treated with a reconstituted formulation and an anti-PD-1 antibody as described herein. In another embodiment, a patient's pancreatic cancer, optionally pancreatic adenocarcinoma, is treated with a combination of a reconstituted formulation as described herein and chemotherapy. In another embodiment, a patient's metastatic pancreatic cancer is treated with a combination of a reconstituted formulation as described herein, chemotherapy, and an optional anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, suitable chemotherapy regimens are described in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN 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 (leucovorin, sometimes referred to as calcium folinate or folinic acid, fluorouracil (5-FU), irinotecan, and oxaliplatin). In some embodiments, the chemotherapy comprises gemcitabine, capecitabine, or 5-fluorouracil (5-FU). In another embodiment, a patient's first-line metastatic pancreatic cancer is treated with a compound of formula (I) or (Ia), an anti-PD-1 antibody, and a standard of care agent for pancreatic cancer, such as those described herein. For example, in some embodiments, a patient's first-line metastatic pancreatic cancer can be treated with a compound of formula (I) or (Ia), an anti-PD-1 antibody, and a gemcitabine and nab-paclitaxel chemotherapy regimen. In some embodiments, a patient's first-line metastatic pancreatic cancer can be treated with a compound of formula (I) or (Ia), an anti-PD-1 antibody, and a FOLFIRINOX chemotherapy regimen. The patient can be treatment-naive or treatment-experienced.

[0323] In some embodiments, the methods described herein can be labeled as first-line, second-line, or third-line treatment. In some embodiments, the methods described herein are indicated as first-line treatment. In some embodiments, the methods described herein are indicated as second-line treatment. In some embodiments, the methods described herein are indicated as third-line treatment.

[0324] Immune-related disorders and disorders with an inflammatory component. As used herein, terms such as "immune disease", "immune condition", "immune disorder", "inflammatory disease", "inflammatory condition", "inflammatory disorder", etc. are intended to broadly encompass any immune-related condition (e.g., autoimmune disease) or disorder with an inflammatory component that can be treated and / or prevented with a compound of formula (I) or (Ia) (e.g., a reconstituted lyophilized formulation as described herein) in order to obtain some therapeutic benefit. Such conditions are often inevitably intertwined with other diseases, disorders, and conditions. For 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.

[0325] The compound of formula (I) or (Ia) (e.g., the reconstituted lyophilized formulation described herein) can be used to increase or enhance the immune response; boost immunity, including increasing vaccine efficacy; and increase inflammation. The compounds disclosed herein can be used to treat immune deficiencies associated with immune deficiency diseases, immunosuppressive medical treatments, acute and / or chronic infections, and aging. The reconstituted lyophilized formulations described herein can also be used to stimulate the immune system of patients suffering from iatrogenically induced immunosuppression, including those patients who have undergone bone marrow transplantation, chemotherapy, or radiotherapy.

[0326] In certain embodiments of the present disclosure, the compound of formula (I) or (Ia) (e.g., the reconstituted lyophilized formulation described herein) is used to increase or enhance the immune response to an antigen by providing adjuvant activity. In one particular embodiment, at least one antigen or vaccine is administered in combination with the reconstituted lyophilized formulation described herein to a subject to prolong the immune response to the antigen or vaccine. Also provided are therapeutic compositions that comprise at least one antigenic agent or vaccine component in combination with the reconstituted lyophilized formulation described herein, including but not limited to viruses, bacteria, and fungi or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines.

[0327] Patient selection. In some cases, the methods according to the present disclosure may be indicated in certain patients, e.g., based on CD73, high microsatellite instability, or high tumor mutational burden as biomarkers. In some cases, a subject is identified as having an oncogene-driven cancer or oncogene-addicted cancer with a mutation in at least one gene associated with CD73. Methods for testing for determining CD73 levels and the presence of CD73-related oncogenes are disclosed in WO 2020 / 185859 and WO 2020 / 205527.

[0328] Combination therapy

[0329] The present disclosure contemplates using the compound of formula (I) or (Ia) alone (e.g., as a reconstituted lyophilized formulation as described herein) or in combination with one or more additional therapies. Each additional therapy can be an active therapeutic agent or another therapeutic modality. In embodiments comprising one or more additional therapeutic agents, each agent can target different but complementary mechanisms of action. The additional therapeutic agent can be a small chemical molecule; a macromolecule, such as a protein, antibody, peptibody, peptide, DNA, RNA, or a fragment of such a macromolecule; or a cell therapy or gene therapy. Non-limiting examples of additional therapeutic modalities include surgical removal of a tumor, bone marrow transplantation, radiation therapy, and photodynamic therapy. The use of the compound of formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation as described herein) in combination with one or more additional therapies can have a synergistic therapeutic or prophylactic effect on a potential disease, disorder, or condition. Additionally or alternatively, the combination therapy can allow for a reduction in the dose of one or more agents, thereby improving, reducing, or eliminating side effects associated with one or more agents. The compound of formula (I) or (Ia) of the present disclosure can also be used to overcome adenosine-dependent immunosuppression, thereby resulting in enhanced therapeutic efficacy of other agents. Furthermore, such combination therapies can have a synergistic therapeutic or prophylactic effect on a potential disease, disorder, or condition.

[0330] In embodiments comprising one or more additional therapeutic modalities, the compound of formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation as described herein) can be administered before, after, or during the use of the additional therapeutic modality. In embodiments comprising one or more additional therapeutic agents, the therapeutic agents for such combination therapy can be formulated as a single composition or separate compositions. If administered separately, each therapeutic agent in the combination can be administered simultaneously or approximately simultaneously, or at different times. Additionally, even if the therapeutic agents have different forms of administration (e.g., an oral capsule and intravenous administration), they can be "combined" administered, with different dosing intervals, one therapeutic agent administered according to a constant dosing regimen while the other is titrated up, titrated down, or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased, or decreased in dose, or discontinued and / or resumed during the course of treatment of the patient. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0331] In some embodiments, 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., ); (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 transmembrane tyrosine kinases of the human epidermal growth factor (HER) family, such as HER-2 / neu receptor inhibitors (e.g., and HER-3 receptor inhibitors; (iv) vascular endothelial growth factor (VEGFR) inhibitors, including small molecule inhibitors (e.g., axitinib tablets, 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 the AKT family kinases or the AKT pathway (e.g., rapamycin); (vi) inhibitors of serine / threonine-protein kinase B-Raf (BRAF), such as vemurafenib, dabrafenib, and encorafenib; (vii) rearranged during transfection (RET) inhibitors, including, for example, selpercatinib and pralsetinib; (viii) tyrosine-protein kinase Met (MET) inhibitors (e.g., tepotinib, tivantinib, cabozantinib, and crizotinib); (ix) anaplastic lymphoma kinase (ALK) inhibitors (e.g., ensartinib, ceritinib, lorlatinib, crizotinib, and brigatinib); (x) inhibitors of the RAS signaling pathway as described elsewhere herein (e.g., KRAS, HRAS, RAF, MEK, ERK inhibitors); (xi) FLT-3 inhibitors (e.g., gilteritinib); (xii) Trop-2 inhibitors, such as the antibody-drug conjugate sacituzumab govitecan-hziy; (xiii) inhibitors of the JAK / STAT pathway, such as JAK inhibitors, including tofacitinib and ruxolitinib, or STAT inhibitors, such as napabucasin; (xiv) NF-κB inhibitors; (xv) cell cycle kinase inhibitors (e.g., flavoxate); (xvi) phosphatidylinositol kinase (PI3K) inhibitors;(xix) Protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib); (xx) Platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, repretinib, etc.); and (xxi) Insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, osimertinib, dacomitinib). Agents involved in immunomodulation can 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 agents include inhibitors of EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-κB, PI3K, AKT or any combination thereof. Agents involved in immunomodulation can also be used in combination with the compounds of formula (I) or (Ia) (e.g., as a reconstituted lyophilized formulation comprising the compounds of formula (I) or (Ia) described herein) to inhibit tumor growth in cancer patients.;

[0332] In some embodiments, one or more additional therapeutic agents are chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to: alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodepa, carboquone, meturedepa and uredepa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trophosphamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclarubicin, actinomycin, authramycin, azaserine, bleomycin, actinomycin C, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, pomalidomide, porfiromycin, puromycin, quelamycin, rodorubicin, streptozocin, streptothricin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dihydrofolic acid, 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 such as calusterone, dihydrotestosterone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as leucovorin; acetoglucuronide; aldophosphamide glycoside; aminolevulinic acid; amsacrine; busulfan; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenesterine; pirarubicin; podophyllinic acid; 2-ethylhydrazine; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2”-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa;Taxanes, such as albumin-bound 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; esperamicin; capecitabine; anthracyclines; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. In some embodiments, the chemotherapeutic agent comprises a taxane chemotherapeutic agent, 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 albumin-bound paclitaxel. In certain embodiments, the combination therapy comprises a chemotherapeutic regimen comprising one or more chemotherapeutic agents. In one embodiment, the combination therapy comprises a chemotherapeutic regimen that comprises one or more of FOLFOX (leucovorin, fluorouracil, and oxaliplatin), FOLFIRI (e.g., leucovorin, fluorouracil, and irinotecan), taxanes (e.g., docetaxel, paclitaxel, albumin-bound paclitaxel, etc.), and / or gemcitabine.;

[0333] In some embodiments, one or more of the additional therapeutic agents are hormone therapies. Hormone therapies modulate or inhibit the action of hormones on tumors. Examples of hormone therapies include, but are not limited to: selective estrogen receptor degraders such as fulvestrant, giredestrant GDC-9545, SAR439859, RG6171, AZD9833, rintodestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549; selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, toremifene; aromatase inhibitors such as anastrozole, exemestane, letrozole, and other aromatases that inhibit 4(5)-imidazole; gonadotropin-releasing hormone agonists such as nafarelin, triptorelin, goserelin; gonadotropin-releasing hormone antagonists such as degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, darolutamide, flutamide, nilutamide, bicalutamide, leuprolide; 5α-reductase inhibitors such as finasteride, dutasteride; and the like. In certain embodiments, the combination therapy includes a chemotherapy regimen containing one or more chemotherapeutic agents. In certain embodiments, the combination therapy includes the administration of a hormone or related hormonal agent. In one embodiment, the combination therapy includes the administration of enzalutamide.

[0334] In some embodiments, one or more of the additional therapeutic agents are radiopharmaceuticals. Radiopharmaceuticals are a form of internal radiotherapy in which a radiation source (i.e., one or more radionuclides) is placed inside a subject. Targeted radionuclides include radionuclides associated (e.g., by covalent or ionic interactions) with a molecule (“targeting agent”) that specifically binds to a target on a cell (usually a cancer cell or an immune cell). The targeting agent can be a small molecule, a carbohydrate (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 carbohydrate (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 (minimally expressed to not expressed in normal tissues), or a neoantigen (an antigen specific to the cancer cell genome generated by a non-synonymous 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 enriched but not specific to cancer cells), a tumor-specific antigen (i.e., an antigen minimally expressed to not expressed in normal tissues), or a neoantigen (i.e., an antigen specific to the cancer cell genome generated by a non-synonymous mutation in the tumor cell genome). Non-limiting examples of targeted radionuclides include radionuclides attached to 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 homologous ligand of a receptor, a peptide derived from the ligand, or a variant thereof (e.g., 188Re-labeled VEGF 125-136 or a variant thereof with higher affinity for the VEGF receptor, etc.); and antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131- obinutuzumab, etc.).

[0335] In some embodiments, one or more of the additional therapeutic agents are targeted therapies. In one aspect, a targeted therapy can comprise 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 carbohydrate (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 carbohydrate (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not cancer cell-specific), a tumor-specific antigen (minimally expressed to not expressed in normal tissue), or a neoantigen (an antigen specific to the cancer cell genome generated by a non-synonymous mutation 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 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. Other targeted therapies can inhibit or interfere with specific proteins that help tumors grow and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, oncogenic transcription factor inhibitors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, ATP-adenosine axis targeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF-2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. Signal transduction inhibitors are described above, and other agents are described in further detail below.

[0336] 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 a 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 with an adenosine receptor antagonist selected from the group consisting of etrumadenant, 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 A2 A R antagonist, an A2 B R antagonist, or an A2 A R and A2 B R antagonist combination. In some embodiments, the present disclosure contemplates a combination with an adenosine receptor antagonist described in WO / 2018 / 136700, WO 2018 / 204661, WO 2018 / 213377, or WO / 2020 / 023846. In some embodiments, at least one additional therapeutic agent comprises an adenosine pathway inhibitor that inhibits A 2A R, A 2B R, CD39, or a combination thereof. In some embodiments, the adenosine pathway inhibitor is etrumadenant, inupadenant, taminadenant, caffeine citrate, imaradenant, or ciforadenant. In one embodiment, the adenosine receptor antagonist (adenosine pathway inhibitor) is etrumadenant (AB928).

[0337] 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 phosphatidylinositol 3-kinase (PI3K), particularly the PI3Kγ isoform. In one embodiment, the PI3Kγ inhibitor is copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, or pictilisib. In another embodiment, the PI3K inhibitor is selected from those described in WO / 2020 / 247496.

[0338] 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 arginase inhibitor, which has been shown to be responsible for or involved in inflammatory-triggered immune dysfunction, tumor immune escape, immunosuppression, and the immunopathology of infectious diseases. Suitable arginase inhibitors include CB-1158 and OAT-1746, and those described in WO 2019 / 173188 and WO / 2020 / 102646.

[0339] 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 the hypoxia-inducible factor (HIF) transcription factor, particularly HIF-2α. In some embodiments, the compound of formula (I) or (Ia) is combined with an HIF-2α inhibitor selected from the group consisting of belzutifan, ARO-HIF2, PT-2385, AB521, and those described in WO 2021113436 and WO 2021188769. In some embodiments, at least one additional therapeutic agent comprises an HIF-2α inhibitor selected from the group consisting of belzutifan, ARO-HIF2, PT-2385, and AB521. In some embodiments, the HIF-2α inhibitor is AB521.

[0340] The present disclosure also contemplates combinations of a compound of formula (I) or (Ia) (e.g., a reformulated preparation as described herein) with one or more RAS signaling inhibitors. Oncogenic mutations in the RAS gene family (e.g., HRAS, KRAS, and NRAS) are associated with multiple cancers. For example, mutations such as G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S in the KRAS gene family have been observed in multiple tumor types. Direct and indirect inhibition strategies have been investigated for inhibiting mutant RAS signaling. Splice inhibitors target effectors other than RAS in the RAS signaling pathway and include, but are 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 in development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, BI1701963. Direct inhibitors of RAS mutants have also been explored and generally target the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors in development include, but are not limited to, sotorasib (AMG510), MRTX849, mRNA-5671, and ARS1620. In some embodiments, one or more RAS signaling inhibitors are selected from: RAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, SOS1 inhibitors, mTORC1 inhibitors, SHP2 inhibitors, and AKT inhibitors. In other embodiments, one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0341] In some embodiments, the present disclosure relates to a combination of a compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) with one or more anexelekto (i.e., AXL) inhibitors. A variety of AXL inhibitors are being developed, which also inhibit other kinases in 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 have also been developed, such as DS-1205, SGI-7079, TP-0903 (i.e., dubermatinib), BGB324 (i.e., bemcentinib), and DP3975; as well as anti-AXL antibodies such as ADCT-601; and antibody-drug conjugates (ADCs) such as BA3011. Another strategy for inhibiting AXL signaling involves targeting the ligand of AXL, GAS6 (e.g., AVB-500). In some embodiments, at least one additional therapeutic agent comprises a multi-tyrosine kinase inhibitor selected from gilteritinib, glembatumumab, merestinib, cabozantinib, flecainide, ribatinib, sitravatinib, XL092, BMS777607, LY2801653, S49076, GSK1363089, and RXDX-106. In some embodiments, at least one additional therapeutic agent is an AXL inhibitor described in PCT / US2022 / 030227 or PCT / US2022 / 030230.

[0342] The present disclosure also contemplates a combination of a compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) with one or more p21-activated kinase 4 (PAK4) inhibitors.

[0343] In some embodiments, one or more of the additional therapeutic agents are epigenetic regulators. Epigenetic regulators alter the epigenetic mechanisms that control gene expression and can be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic regulators 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 a 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, givinostat, abexinostat, panobinostat, belinostat, and trichostatin A.

[0344] In some embodiments, one or more of the additional therapeutic agents are inhibitors of oncogenic transcription factors or activators of oncogenic transcription factor repressors. Suitable agents can act at the expression level (e.g., RNAi, siRNA, etc.), by physical degradation, at the protein / protein level, at the protein / DNA level, or by binding in 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 the hypoxia-inducible factor (HIF) transcription factor, and the like.

[0345] In some embodiments, one or more of the additional therapeutic agents are (i) agents that inhibit poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, rucaparib, etc.); (ii) inhibitors of the Bcl-2 protein family (e.g., venetoclax, navitoclax, etc.); (iii) MCL-1 inhibitors; (iv) inhibitors of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies); or (v) isocitrate dehydrogenase (IDH) inhibitors, such as IDH-1 or IDH-2 inhibitors (e.g., ivosidenib, enasidenib, etc.).

[0346] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents. Immunotherapeutic agents treat diseases by stimulating or inhibiting the immune system. Immunotherapeutic agents that can be used to treat cancer typically initiate 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 were described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are further described below.

[0347] In some embodiments, one or more of the 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 the presentation of antigenic epitopes on major histocompatibility complex molecule agonists, including but not limited to Toll-like receptor (TLR) agonists, mevalonate pathway antagonists, STING agonists; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors; and immunostimulatory oligonucleotides, as well as other T cell adjuvants.

[0348] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents, more specifically cell therapies. Cell therapy is a form of treatment in which live 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 that can be used to treat cancer typically initiate or amplify an immune response. These 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, these cells can be “(re)programmed” allogeneic immune cells generated from immune precursor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell precursors, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells can be expanded cell subsets with different 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.), can be genetically modified to target specific antigens and / or 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.), can be engineered to express tumor-associated antigens or have increased expression of tumor-associated antigens, or can be 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 vicleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel, 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.

[0349] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents, more specifically gene therapies. Gene therapies include administering recombinant nucleic acids to a subject or to the subject's cells ex vivo to modify the expression of endogenous genes or to cause heterologous expression of proteins (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA (miRNA) agents, viral or bacterial gene delivery, etc.), and gene editing therapies that may or may not include nucleic acid components (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapies useful for cancer treatment include (rAd-p53), (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), quaratusugene ozeplasmid (Immunogene), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0350] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents, more specifically agents that modulate immune checkpoints. Immune checkpoints are a set of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). Immune checkpoints engage when proteins on the surface of immune cells recognize and bind their cognate ligands. 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 agonist of a stimulatory or costimulatory pathway and / or an antagonist of an inhibitory pathway. The agonists of the stimulatory or costimulatory pathways and the antagonists of the inhibitory pathways may have utility as agents to overcome different immune suppression pathways in the tumor microenvironment, inhibit regulatory T cells, reverse / prevent T cell anergy or exhaustion, trigger innate immune activation and / or inflammation at the tumor site, or combinations thereof.

[0351] In some embodiments, one or more of the additional therapeutic agents are immune checkpoint inhibitors. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist that inhibits or co-inhibits an immune checkpoint. The terms "immune checkpoint inhibitor", "checkpoint inhibitor", and "CPI" are used interchangeably herein. Immune checkpoint inhibitors can antagonize the inhibition or co-inhibition of immune checkpoints by interfering with receptor-ligand binding and / or altering receptor signaling. Examples of some of the immune checkpoints (ligands and receptors) that are selectively upregulated in various types of cancer cells that can be antagonized 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); 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, and killer inhibitory receptors, which can be classified into two categories based on their structural characteristics: i) killer cell immunoglobulin-like receptors (KIR), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints that have been described in the literature are also contemplated, including 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, 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, at least one additional therapeutic agent comprises an immune checkpoint inhibitor that targets PD-1 or PD-L1. In some embodiments, at least one additional therapeutic agent comprises an immune checkpoint inhibitor that targets TIGIT.

[0352] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonistic CTLA-4 antibody. Suitable antagonistic CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, and bispecific antibodies such as MEDI5752 and KN046.

[0353] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonistic PD-1 antibody small molecule or peptide. Suitable antagonistic PD-1 antibodies include, for example, monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarlimab, cemiplimab, ezabenlimab, MEDI-0680 (AMP-514; WO2012 / 145493), nivolumab, pembrolizumab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab; and bispecific antibodies such as LY3434172. In still further embodiments, the PD-1 antagonist is a recombinant protein (AMP-224) consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0354] In some embodiments, the immune checkpoint inhibitor is nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, cemiplimab, or zimberelimab. In certain embodiments, the immune checkpoint inhibitor is zimberelimab.

[0355] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist can be an antagonistic PD-L1 antibody. Suitable antagonistic PD-L1 antibodies include, for example, monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and envafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0356] In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist can be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, EOS-448, etigilimab, IBI-929, JS006, M6223, ociperlimab, SEA-TGT, tiragolumab, and vibostolimab; and bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is an antagonistic anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In some embodiments, the immune checkpoint inhibitor is domvanalimab, etigilimab, ociperlimab, AB308, tiragolumab, or vibostolimab. In certain embodiments, the immune checkpoint inhibitor is domvanalimab or AB308.

[0357] On the other hand, the immune checkpoint inhibitor is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0358] In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonistic B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, MGA271 (WO11 / 109400), omburtumab, enoblituzumab, DS-7300a, ABBV-155, and SHR-A1811.

[0359] In some embodiments, one or more of the additional therapeutic agents activate, stimulate, or costimulate an 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.

[0360] In some embodiments, the agent that activates or co-stimulates an immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433). In some embodiments, the agent that activates or co-stimulates an immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683). In some embodiments, the agent that activates or co-stimulates an immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be an agonistic 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 or co-stimulates an immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonistic CD40 antibody. In some embodiments, the agent that activates or co-stimulates an immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0361] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents, more specifically signal transduction inhibitors. Intracellular signaling molecules that affect the function of immune cells can also be suitable targets for improving anti-tumor immunity. For example, one or more of the additional therapeutic agents can be an inhibitor of hematopoietic progenitor kinase 1 (HPK1). HPK1 is a serine / threonine kinase that functions as a negative regulator of activation signals generated by the T cell antigen receptor.

[0362] In some embodiments, one or more of the additional therapeutic agents are agents that inhibit or deplete immunosuppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, such as a CSF-1R antagonistic antibody, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264).

[0363] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, radiopharmaceutical, hormonal therapy, epigenetic modulator, targeting agent, immunotherapeutic agent, cell therapy, or gene therapy. For example, in one embodiment, the present disclosure contemplates the use of the formulations 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, hormonal therapy, targeting agent, immunotherapeutic agent, cell therapy, or gene therapy. In another embodiment, the present disclosure contemplates the use of the formulations 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, immunotherapeutic agent, or cell therapy. In another embodiment, the present disclosure contemplates the use of the formulations 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, hormonal therapy, targeting agent, chemotherapeutic agent, cell therapy, or gene therapy. In another embodiment, the present disclosure contemplates the use of the formulations 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, hormonal therapy, targeting agent, immunotherapeutic agent, cell therapy, or gene therapy. In another embodiment, the present disclosure contemplates the use of the formulations 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, targeting agent, immunotherapeutic agent, or cell therapy. In a further embodiment of the foregoing, (a) the targeting agent can be a PI3K inhibitor, arginase inhibitor, HIF2α inhibitor, AXL inhibitor, or 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 A2 A R and / or A2 Ban R antagonist or a CD39 inhibitor; (d) the ATP-adenosine axis targeting agent is iterdan; (e) the immunotherapeutic agent is an anti-PD-1 antagonistic antibody or an anti-TIGIT antagonistic antibody; (f) the immunotherapeutic agent is zimberelimab, donafenib or AB308 or (g) any combination thereof. In a further embodiment of the foregoing, the present disclosure contemplates the use of the formulations described herein in combination with donafenib, iterdan, zimberelimab, AB308, AB521, AB610 or any combination thereof.

[0364] In some embodiments, the methods described herein include administering to a subject at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent comprises one or more agents selected from the group consisting of chemotherapeutic agents, immune checkpoint inhibitors, HIF-2α inhibitors, adenosine pathway inhibitors, radiation therapy and multi-tyrosine kinase inhibitors

[0365] 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 an anti-PD-1 antagonistic antibody and an anti-TIGIT antagonistic antibody, wherein the compound of formula (Ia) is administered in an amount in the range of 50 mg to 300 mg every two to three weeks, the anti-PD-1 antagonistic antibody is administered in an amount in the range of 300 mg to 600 mg every two to five weeks, and the anti-TIGIT antagonistic antibody is administered in an amount in the range of 1200 mg to about 1600 mg every two to four weeks.

[0366] In some embodiments, the compound of formula (Ia) is administered in an amount of about 300 mg every three weeks. In some embodiments, the anti-PD-1 antagonistic antibody is administered in an amount of about 300 mg every three weeks. In some embodiments, the anti-TIGIT antagonistic antibody is administered in an amount in the range of about 1200 mg to about 1600 mg every three weeks. In some embodiments, the anti-PD-1 antagonistic antibody is zimberelimab. In some embodiments, the anti-TIGIT antagonistic antibody is donafenib 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 antagonistic antibody and the anti-TIGIT antagonistic antibody are administered intravenously in a three-week cycle.

[0367] 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.

[0368] Some embodiments provide a method of treating cancer, the method comprising administering a combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof with chemotherapy, wherein the compound of formula (Ia) is administered in an amount in the range of 50 mg to 300 mg every two to three weeks.

[0369] Examples of therapeutic agents for combination therapy for immune- and inflammation-related diseases, disorders or conditions include, but are not limited to, the following: non-steroidal anti-inflammatory drugs (NSAIDs), steroids such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone or hydrocortisone, or cytokine-suppressive anti-inflammatory drugs (CSAIDs).

[0370] Administration

[0371] 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 objective of the administration (e.g., the desired degree of regression); the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, disorder, condition or its symptoms. The dosing regimen can also take into account the presence, nature and extent of any adverse effects associated with the agent being administered.

[0372] Generally, dosing parameters indicate a dose less than the amount that can be reversibly toxic to the subject (maximum tolerated dose (MTD)) and not less than the amount required to produce a measurable effect in the subject. This amount is determined by, for example, pharmacokinetic and pharmacodynamic parameters related to ADME, taking into account the route of administration and other factors.

[0373] In certain embodiments, a compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) can be administered once or more times a day at a dose level of from about 0.01 mg / kg of subject body weight to about 50 mg / kg of subject body weight per day or from about 1 mg / kg of subject body weight to about 25 mg / kg of subject body weight (e.g., parenterally) to obtain the desired therapeutic effect.

[0374] In some embodiments, the lyophilized formulation contains from 1 to 500 mg of the active ingredient (i.e., the compound of formula (I) or (Ia)), particularly 20, 25, 30, 100, 150, 200, 225, 250, 275, 300, 325, 400, and 500 mg of the 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 mg. In some embodiments, the compound of formula (I) or (Ia) is provided in an amount of from 25 mg to 350 mg. In some embodiments, the compound of formula (I) or (Ia) is provided in an amount of from 25 mg to 300 mg. In some embodiments, the compound of formula (I) or (Ia) is provided in an amount of from 25 mg to 250 mg. In some embodiments, the compound of formula (I) or (Ia) is provided in an amount of from 25 mg to 200 mg. In some embodiments, the compound of formula (I) or (Ia) is provided in an amount of from 25 mg to 150 mg. In some embodiments, the compound is provided in an amount of from 25 mg to 120 mg. In some embodiments, the compound is provided in an amount of from 25 mg to 110 mg. In some embodiments, the compound is provided in an amount of from 25 mg to 100 mg. In some embodiments, the compound is provided in an amount of from 25 mg to 75 mg. In some embodiments, the compound is provided in an amount of from 25 mg to 50 mg. In some embodiments, the compound is provided in an amount of from 75 mg to 100 mg. In some embodiments, the compound is provided in an amount of from 50 mg to 200 mg. In some embodiments, the compound is provided in an amount of from 75 mg to 150 mg. In some embodiments, the compound is provided in an amount of from 75 mg to 125 mg. In some embodiments, the compound is provided in an amount of from 75 mg to 110 mg. In some embodiments, the compound is provided in an amount of from 90 mg to 110 mg.

[0375] In some embodiments, the compound of formula (I) or (Ia) (e.g., the reconstituted formulation described herein) can be administered (e.g., parenterally) monthly, weekly, or daily. In some embodiments, the compound of formula (I) or (Ia) can be administered at least once monthly, such as twice monthly, three times monthly, four times monthly, once weekly, or once daily. In some embodiments, the compound of formula (I) or (Ia) can be administered once weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. In some embodiments, the compound of formula (I) or (Ia) can be administered (e.g., parenterally) 1, 2, 3, or 4 times monthly. In some embodiments, the compound of formula (I) or (Ia) can be administered (e.g., parenterally) once weekly, or once every two weeks, or once every three weeks.

[0376] In some embodiments, a lyophilized formulation according to the present disclosure is reconstituted to form a reconstituted solution and administered parenterally as a loading dose to a subject. The loading dose can be administered to achieve a suitable plasma concentration in the subject. Once a suitable plasma concentration is achieved, subsequent doses of the compound of formula (I) or (Ia) can be administered by other means (e.g., orally). In some embodiments, the loading dose is between about 20 mg and about 500 mg, such as 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, such as 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.

[0377] In some embodiments, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every two weeks (Q2W) at a dose of about 10 mg to 225 mg, such as, for example, 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, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg or 250 mg once every two weeks. In some embodiments, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every two weeks (Q2W) at a dose of about 10 mg to about 250 mg, such as, for example, 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 once every two weeks. In one embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) is administered (e.g., parenterally) at a dose of 25 mg once every two weeks. In another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) is administered (e.g., parenterally) at a dose of 50 mg once every two weeks. In one embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) is administered (e.g., parenterally) at a dose of 75 mg once every two weeks. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) at a dose of 100 mg once every two weeks. In another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) at a dose of 125 mg once every two weeks. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) at a dose of 150 mg once every two weeks. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) at a dose of 175 mg once every two weeks.In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every two weeks at a dose of 200 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every two weeks at a dose of 225 mg.

[0378] In some embodiments, a compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every three weeks (Q3W) at a dose of about 10 mg to about 350 mg, such as, for example, 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, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 250 mg, 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 once every three weeks. In some embodiments, a compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every three weeks (Q3W) at a dose of about 10 mg to 250 mg, such as, for example, 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 once every three weeks. In one embodiment, a compound of formula (I) or (Ia) (e.g., the reconstituted formulation described herein) is administered once every three weeks (e.g., parenterally) at a dose of 25 mg. In another embodiment, a compound of formula (I) or (Ia) (e.g., the reconstituted formulation described herein) is administered once every three weeks (e.g., parenterally) at a dose of 50 mg. In one embodiment, a compound of formula (I) or (Ia) (e.g., the reconstituted formulation described herein) is administered once every three weeks (e.g., parenterally) at a dose of 75 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., the reconstituted formulation described herein) can 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., the reconstituted formulation described herein) can 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 as described herein) can be administered (e.g., parenterally) once every three weeks at a dose of 150 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every three weeks at a dose of 175 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every three weeks at a dose of 200 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every three weeks at a dose of 225 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every three weeks at a dose of 300 mg.

[0379] In some embodiments, the compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every four weeks (Q4W) at a dose of about 10 mg to about 325 mg, such as, for example, 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, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 250 mg, 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 once every four weeks. In some embodiments, the compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every four weeks (Q4W) at a dose of about 10 mg to 250 mg, such as, for example, 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 once every four weeks. In one embodiment, the compound of formula (I) or (Ia) (e.g., a reconstituted formulation as 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 as described herein) is administered once every four 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 as described herein) is administered once every four 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 as described herein) can be administered once every four weeks (e.g., parenterally) at a dose of 100 mg. In another embodiment, the compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can 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 as described herein) can be administered (e.g., parenterally) once every four weeks at a dose of 150 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every four weeks at a dose of 175 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every four weeks at a dose of 200 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every four weeks at a dose of 225 mg. In yet another embodiment, a compound of formula (I) or (Ia) (e.g., as a reconstituted formulation as described herein) can be administered (e.g., parenterally) once every four weeks at a dose of 300 mg.

[0380] In certain embodiments, the dose of the compound of formula (I) or (Ia) is included in a "unit dosage form". The phrase "unit dosage form" refers to a physically discrete unit, each unit containing a predetermined amount of the compound of formula (I) or (Ia) alone or in combination with one or more additional agents sufficient to produce the desired effect. The unit dosage form can be provided as a pre-lyophilization composition, a lyophilized formulation, or a reconstituted lyophilized formulation.

[0381] In some embodiments, provided herein is a single dosage form of a compound having formula (Ia), wherein the compound is present in an amount between about 20 mg and about 300 mg.

[0382] 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 25 mg.

[0383] 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 50 mg.

[0384] 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 75 mg.

[0385] 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.

[0386] In another embodiment, the lyophilized formulation described herein contains an amount of a compound of formula (I) or formula (Ia) sufficient to achieve a desired dose upon reconstitution of the lyophilized formulation. In some embodiments, the lyophilized formulation contains an amount of a compound of formula (I) or formula (Ia) that ranges from the desired dose to the desired dose plus about 10% of the compound of formula (I) or formula (Ia). A greater amount of the compound may be provided to account for residual drug volume remaining in the vial when the reconstitution solution is withdrawn from the vial for administration and / or dilution.

[0387] In some embodiments, the compound is present in the lyophilized formulation in an amount from about 25 mg to about 330 mg. In some embodiments, the compound is present in an amount between about 25 mg and about 27.5 mg. In some embodiments, the compound is present in an amount between about 50 mg and about 55 mg. In some embodiments, the compound is present in an amount between about 75 mg and about 82.5 mg. In some embodiments, the compound is present in an amount from about 100 mg to about 110 mg. In some embodiments, the compound is present in an amount from about 200 mg to about 325 mg.

[0388] In one embodiment, the compound is present in the lyophilized formulation in an amount between about 25.0 mg and about 27.5 mg, such as 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 between about 25.0 mg and about 27.5 mg, such as 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.

[0389] In one embodiment, the compound is present in the lyophilized formulation in an amount between about 50.0 mg and about 55.0 mg, such as 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 mg or 55.0 mg. In one embodiment, the compound is present in the lyophilized formulation in an amount between about 50.0 mg and about 55.0 mg, such as 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.

[0390] In one embodiment, the compound is present in the lyophilized formulation in an amount between about 75.0 mg and about 82.5 mg, such as 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 between about 75.0 mg and about 82.5 mg, such as 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 mg or about 82.5 mg.

[0391] In one embodiment, the compound is present in the lyophilized formulation in an amount between about 100.0 mg and about 110.0 mg, such as 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 between about 100.0 mg and about 110.0 mg, such as 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.

[0392] In one embodiment, the compound is present in the lyophilized formulation in an amount between about 200.0 mg and about 220.0 mg, such as 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 between about 200.0 mg and about 220.0 mg, such as 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.

[0393] In one embodiment, the compound is present in the lyophilized formulation in an amount between about 300.0 mg and about 330.0 mg, such as 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 or 330.0 mg. In one embodiment, the compound is present in the lyophilized formulation in an amount between about 300.0 mg and about 330.0 mg, such as 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, 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.

[0394] Kit

[0395] The present disclosure also contemplates kits comprising the lyophilized formulation that contains a compound of formula (I) or (Ia) as described herein. The kits are generally in the form of a physical structure that houses the various components, as described below, and can be used, for example, to practice the methods described above. The kit can include, for example, a syringe and a diluent for reconstitution as described above. When combination therapy is contemplated, the kit can contain several medicaments individually, or they may already be combined in the kit. Each component of the kit can be enclosed in a separate container, and all of the individual containers can be in a single package. The kits of the present disclosure can be designed to maintain the conditions (e.g., refrigeration or freezing) required for proper maintenance of the components contained therein.

[0396] The kit may contain a label or package insert including identification information of its components and instructions for use of the components (e.g., dosing parameters, clinical pharmacology of the active ingredient including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or insert may include manufacturer information such as lot number and expiration date. The label or package insert may be integrated into the physical structure containing the components, separately contained within the physical structure, or attached to components of the kit (e.g., ampoules, tubes or vials), for example.

[0397] The label or insert may additionally include or be incorporated into a computer-readable medium. In some embodiments, there are no actual instructions in the kit, but means are provided for obtaining instructions from a remote source, e.g., via the Internet.

[0398] Experiment

[0399] The following examples are presented in order to provide a complete disclosure and description to those of ordinary skill in the art 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 represent that they are all of the experiments that can be performed. Although efforts have been made to ensure the accuracy of the numerical values used (e.g., amounts, temperatures, etc.), it should be noted that there are some experimental errors and deviations.

[0400] Example

[0401] Example 1: Preparation of formulation before lyophilization

[0402] 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 sterile containers. Each sterilized cup 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, a flip seal was placed on each vial and the seal was crimped. Visual defects of the vials were inspected.

[0403] Table 1: Example lyophilization cycle

[0404]

[0405]

[0406] Example 2: Comparative chemical and physical stability of formulations

[0407] The chemical and physical suitability and stability of the compound of formula (Ia) and various excipients were evaluated. 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 presented in Table 2. Evaluate the formulations:

[0408] · The clarity, content, and purity of the solution before lyophilization at 5 °C for up to 5 days.

[0409] · The clarity, content, and purity of the solution reconstituted with normal saline or sterile water for injection.

[0410] · The stability of the reconstituted solution at 5 °C and 40 °C for up to 5 days.

[0411] The results of these studies are presented in the following table. It was noted that the formulation containing amino acids exhibited better physical stability, as evidenced by the clarity scores of both the solution before lyophilization and the reconstituted solution.

[0412] Table 2: Composition of prototype formulations of lyophilized powders of compound of formula (Ia)

[0413] Ingredient Batch 1 mg / vial Batch 2 mg / vial Batch 3 mg / vial Formula (Ia), neutral 27.50 27.50 27.50 L-Arginine USP <![CDATA[37.13 b > <![CDATA[8.25 c > L-Histidine USP <![CDATA[22.04 c > Sodium hydroxide NF <![CDATA[4.17 a > Phosphoric acid NF <![CDATA[5.58 b > Sterile water for injection qs. to 1.1 ml qs. to 1.1 ml qs. to 1.1 mL

[0414] a 2.2 equivalents of sodium hydroxide

[0415] b 4.5 equivalents of L-arginine and 1.2 equivalents of phosphoric acid

[0416] c 1 equivalent of L-arginine and 3 equivalents of L-histidine

[0417] Table 3: Clarity scores of solutions before lyophilization and after reconstitution

[0418]

[0419]

[0420] PreLyo = Before lyophilization; Recon = Reconstituted; SWFI = Sterile water for injection.

[0421] Solution of formula (Ia), 25 mg / mL (41.3 mM).

[0422] Visual clarity score: 0 = Clear; 6 = Clearly turbid with particulate precipitation.

[0423] HPLC method:

[0424] Column: Agilent Zorbax Eclipse Plus C18; 4.6 mm × 100 mm, 3.5 μm; Lot #B17287

[0425] Detection wavelength: 254 nm

[0426] Column temperature: 30 ± 2 °C

[0427] Flow rate: 1.0 mL / min

[0428] Sample diluent: 20 mM potassium phosphate buffer pH 8.2, 25 μM EDTA

[0429] Sample temperature: 20 °C

[0430] Mobile phase A, MPA: 20 mM potassium phosphate buffer pH 8.2, 25 μM EDTA

[0431] Mobile phase B, MPB: 100% acetonitrile

[0432] Mobile phase gradient:

[0433] Time (minutes) % MPA % MPB 0.0 100 0 2.0 100 0 15.0 20 80 17.0 100 0 19.0 100 0

[0434] Table 4: Purity of solutions before lyophilization and after reconstitution: initial and after storage at 5 °C and 40 °C for 3 days and 5 days

[0435]

[0436] Recon = Reconstitution solution; SWFI = Sterile water for injection.

[0437] Reconstitute the sample to a theoretical concentration of 25 mg / mL.

[0438] Example 3: Lyophilization of formulations containing fillers

[0439] Evaluate the cake appearance, reconstitution parameters, and stability of the reconstitution solution of the lyophilized product of the formulation containing the compound of formula (Ia), arginine, phosphoric acid, and various co-solutes (i.e., excipients). The vial configuration of the formulation before lyophilization is summarized in Table 5 below.

[0440] Table 5: Configuration of vials of formulations containing cosolutes

[0441]

[0442] Lyophilize the formulation according to the lyophilization cycles of various co-solutes summarized in Table 6 below. Both the primary drying and secondary drying steps of the lyophilization cycle are carried out under reduced pressure. The typical drying times for the primary drying stage and the secondary drying stage are about 36 hours - 40 hours and 7 hours - 10 hours, respectively.

[0443] Table 6: Lyophilization cycles of various cosolutes

[0444]

[0445] Evaluate the reconstitution time and stability of the reconstitution solution. Table 7 below summarizes the reconstitution times, solution pH, and osmolality of various formulations.

[0446] Table 7: Reconstitution results of formulations containing cosolutes

[0447]

[0448]

[0449] The filled volume corresponds to the volume of solvent added before lyophilization; the added SWFI corresponds to the volume of SWFI added for reconstitution; Recon = reconstitution; SWFI = Sterile Water for Injection.

[0450] Compared with the lyophilized products without fillers, all the lyophilized products containing fillers showed less cracking, brittleness and shrinkage.

[0451] It was also observed that the type of vial used for the lyophilized formulation also played a role in the appearance of the resulting cake. When mannitol, kleptose and dextran 40 were used as fillers, the lyophilized products prepared using SCHOTT vials formed complete cakes without crumbling.

[0452] All the tested lyophilized products reconstituted rapidly to form clear solutions.

[0453] For solutions stored at 40 °C, 75% relative humidity (RH) for 2 weeks and 4 weeks and solutions stored at -20 °C for two weeks, the stability of the selected reconstituted solutions was evaluated by high performance liquid chromatography (HPLC). The results are summarized in Table 8 below.

[0454] HPLC method

[0455] 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 minutes; Sample diluent: 20 mM potassium phosphate buffer pH 10.0 ± 0.05; Retention time: approximately 13 minutes; 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

[0456] Mobile phase gradient:

[0457] Time (minutes) % MPA % MPB 0.0 100 0 2.0 100 0 10.0 70 30 14.0 70 30 30.0 0 100 39.0 0 100 40.0 100 0 50.0 100 0

[0458] Table 8: Purity of reconstituted solutions after storage at -20 °C for 2 weeks, at 40 °C for 2 weeks and at 40 °C for 4 weeks

[0459]

[0460] When stored at -20°C for 2 weeks and at 40°C at 75% RH for 4 weeks, all the formulations showed chemical stability and had a similar impurity profile as determined by HPLC. All the test solutions were also physically stable and remained clear during the study.

[0461] Example 4: Exemplary protocol for preparing a large quantity of lyophilized preparations according to the present disclosure

[0462] The components of the lyophilized formulation are summarized in Table 9 below. The process description for large-scale lyophilization is described in Figure 1 herein. The parameters of the lyophilization process are summarized in Table 10 below.

[0463] Table 9: Exemplary components of lyophilized preparations

[0464] Ingredient mg / vial Formula (Ia), neutral 107.5 Arginine USP 145.34 Phosphoric acid NF 21.84 Mannitol 344 0.1N NaOH / phosphoric acid qs to pH 7.2 to 7.4 SWFI qs 4.3 mL

[0465] Table 10: Lyophilization process parameters

[0466]

[0467] Example 5: Evaluation of a zepalizumab-based combination in participants with advanced non-small cell lung cancer in a Phase II study

[0468] The Phase II open-label platform study will be used to investigate the safety and efficacy of zimberelimab in combination with other investigational products in participants with non-small cell lung cancer. Sub-study A will enroll treatment-naive, PD-L1-high, metastatic NSCLC patients without actionable genomic aberrations. Sub-study B will enroll treatment-naive, metastatic NSCLC patients without actionable genomic aberrations, regardless of PD-L1 status. The PD-L1-high status can be evaluated by a tumor proportion score (TPS) ≥50% with PharmDx 22C3 (Dako) or tumor cells (TC) >50% with SP263 (Ventana). Sub-study C will enroll metastatic NSCLC patients with documented disease progression during prior anti-PD-L1 and platinum-based chemotherapy in first or second line and without known actionable genomic aberrations. Arm A1: zimberelimab 360 mg Q3W + donanemab 5 mg / kg Q3W; Arm A2: zimberelimab 360 mg Q3W + donanemab 15 mg / kg Q3W; Arm A3: zimberelimab 480 mg Q4W + donanemab 1600 mg Q4W + quilizumab 100 mg Q2W; Arm B1: zimberelimab 360 mg Q3W + quilizumab 50 mg QW + platinum doublet chemotherapy; Arm B2: zimberelimab 360 mg Q3W + donanemab 1200 mg Q3W + platinum doublet chemotherapy; Arm B3: zimberelimab 360 mg Q3W + donanemab 1200 mg Q3W + quilizumab 50 mg QW + platinum doublet chemotherapy; Arm C1: zimberelimab 360 mg Q3W + donanemab 1200 mg Q3W + docetaxel; Arm C2: zimberelimab 360 mg Q3W + quilizumab 300 mg Q3W + docetaxel. The primary endpoints to be evaluated include objective response rate, safety, and tolerability. Secondary endpoints include progression-free survival, duration of response, overall survival, and PK.

[0469] Example 5-1: Q3W administration of compound of formula (Ia)

[0470] In the above study, the formulation according to the present disclosure can be administered at 300 mg 3QW. Preliminary population PK / PD modeling indicates that significantly higher doses are required when extending the dosing interval in order to maintain a steady-state C trough (Ctrough) (C trough, ss) equivalent to that of 50 mg QW or 100 mg Q2W. The 300 mg Q3W dose level can produce a median steady-state C trough equivalent to that of 50 mg QW and 100 mg Q2W to achieve ≥90% inhibition of CD73 enzyme activity in most participants. Figure 2Shows predicted population PK / PD following administration of 50 mg QW, 100 mg Q2W, or 300 mg Q3W. Simulations were conducted based on a population pharmacokinetic / pharmacodynamic model developed using pharmacokinetic and pharmacodynamic data collected from multiple clinical trials.

[0471] This specification describes particular embodiments of the present disclosure. After reading the foregoing description, variations of the disclosed embodiments may become apparent to individuals working in the art, and it is contemplated that those skilled in the art may appropriately adopt such variations. Accordingly, the present disclosure is intended to be practiced in a manner different from that specifically described herein, and the present disclosure includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Additionally, any combination of the above elements in all possible variations is covered by the present disclosure, unless otherwise stated herein or clearly contradicted by the context.

[0472] All publications, patent applications, accession numbers, and other references cited in this specification are incorporated herein by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A lyophilized preparation containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is selected from the group consisting of CR e and N; X is selected from the group consisting of O, CH 2 and S; Y and Z are each independently selected from the group consisting of CH and N; R g is H or two Rs g group combination forms an acetone compound; R a selected from the group consisting of NH 2 , NHR 1 and NR 1 R 2 ; R c selected from the group consisting of H, halogen, haloalkyl, NH 2 、NHR 3 、NR 3 R 4 、R 3 、OH, OR 3 、SR 3 、SO 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 ; R e selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl groups; Each X 1 is C 1 -C 4 an alkylene; and R 1 、R 2 、R 3 and R 4 each independently is selected from the group consisting of: 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 heterocycloalkyl C 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 when R 1 and R 2 or R 3 and R 4 attached to the same nitrogen, they combine to form 4- to 7-membered heterocycles; and one or more amino acids.

2. The lyophilized preparation according to claim 1, wherein X is O.

3. The lyophilized preparation according to claim 1 or claim 2, wherein R g is H.

4. The lyophilized preparation according to any one of claims 1 to 3, wherein R a is NHR 1 and R 1 is selected from the group consisting of optionally substituted aryl C 1 -C 4 alkyl and optionally substituted heteroaryl C 1 -C 4 alkyl.

5. The lyophilized preparation according to claim 4, wherein R a is NHR 1 and R 1 is optionally substituted aryl C 1 -C 4 alkyl.

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

7. The lyophilized preparation according to claim 6, wherein R c is a halogen.

8. The lyophilized preparation according to any one of claims 1 to 7, wherein R e is H.

9. The lyophilized preparation according to any one of claims 1 to 8, wherein the compound of formula (I) has a structure selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

10. The lyophilized preparation according to any one of claims 1 to 8, wherein the compound of formula (I) has a structure according to formula (Ia): or a pharmaceutically acceptable salt thereof.

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

12. The lyophilized preparation according to any one of claims 1 to 11, further comprising a pH regulator.

13. The lyophilized preparation according to claim 12, wherein the pH regulator is phosphoric acid.

14. The lyophilized preparation according to any one of claims 1 to 13, further comprising a filler.

15. The lyophilized preparation according to claim 14, wherein the filler is mannitol, glycine, hydroxypropyl-β-cyclodextrin (HPBCD), or dextran.

16. The lyophilized preparation 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 about 1:2 to about 1:

7.

17. The lyophilized preparation 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 about 1:4 to about 1:

5.

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

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

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

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

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

23. A lyophilized preparation containing 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 a stoichiometric amount greater than the compound of formula (Ia).

24. A lyophilized preparation comprising about 15 wt% to about 20 wt% of a compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, about 20 wt% to about 35 wt% of one or more amino acids; about 2 wt% to about 5 wt% of phosphoric acid; and About 40% to about 60% by weight of a filler; where the percentages by weight (wt%) are based on the total weight of the lyophilized preparation.

25. The lyophilized preparation according to claim 24, wherein the filler is kleptose, dextran, mannitol or glycine.

26. The lyophilized preparation according to claim 24, the lyophilized preparation comprising about 17.4% by weight of the 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; and about 55.6% by weight of mannitol; where the percentages by weight are based on the total weight of the lyophilized preparation.

27. The lyophilized preparation according to claim 24, the lyophilized preparation comprising about 22.6% by weight of the compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof, about 30.6% by weight of arginine; about 4.6% by weight of phosphoric acid; and about 42.1% by weight of glycine; where the percentages by weight are based on the total weight of the lyophilized preparation.

28. A lyophilized preparation, the lyophilized preparation comprising about 35% to about 45% by weight of a compound of formula (Ia) 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; and where the percentages by weight (wt%) are based on the total weight of the lyophilized preparation.

29. The lyophilized preparation according to claim 28, the lyophilized preparation comprising 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 of arginine; and about 7.9% by weight of phosphoric acid; where the percentages by weight are based on the total weight of the lyophilized preparation.

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

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

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

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

34. An aqueous preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein W is selected from the group consisting of CR e and N; X is selected from the group consisting of O, CH 2 and S; Y and Z are each independently selected from the group consisting of CH and N: R g is H or the two R g groups combine to form an acetone compound; R a selected from the group consisting of NH 2 , NHR 1 and NR 1 R 2 ; R c selected from the group consisting of H, halogen, haloalkyl, NH 2 、NHR 3 、NR 3 R 4 、R 3 、OH, OR 3 、SR 3 、SO 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 ; R e selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl groups; Each X 1 is C 1 -C 4 alkylene; and R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of: 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 4-7 membered heterocycloalkyl, optionally substituted 4-7 membered heterocycloalkylC 1 -C 4 alkyl, optionally substituted aryl, optionally substituted arylC 1 -C 4 alkyl, optionally substituted heteroaryl and optionally substituted heteroarylC 1 -C 4 Alkyl or when R 1 and R 2 or R 3 and R 4 attached to the same nitrogen as described above, and they combine to form a 4-membered to 7-membered heterocycle; One or more amino acids and an optional pH regulator in an amount sufficient to adjust the pH of the solution to between about 6 and about 8.

35. An aqueous formulation comprising From about 15% to about 20% by weight of a compound of formula (Ia) Or a pharmaceutically acceptable salt, hydrate or solvate thereof, From about 20% to about 35% by weight of one or more amino acids; From about 2% to about 5% by weight of phosphoric acid; and From about 40% to about 60% by weight of a filler; Wherein the weight percentages (wt%) are based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation.

36. The aqueous formulation according to claim 35, wherein the filler is kleptose, dextran, mannitol or glycine.

37. The aqueous formulation according to claim 35, the aqueous formulation comprising About 17.4% by weight of the 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; and About 55.6% by weight of mannitol; Wherein the weight percentages are based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation.

38. The aqueous formulation according to claim 35, the aqueous formulation comprising About 22.6% by weight of the compound of formula (Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof, About 30.6% by weight of arginine; About 4.6% by weight of phosphoric acid; and About 42.1% by weight of glycine; Wherein the weight percentages are based on the total weight of the lyophilized formulation that is dissolved in water to form the aqueous formulation.

39. An aqueous formulation comprising About 107.5 mg of a compound of formula (Ia) Or a pharmaceutically acceptable salt, hydrate or solvate thereof, About 145.34 mg of arginine; About 21.8 mg of phosphoric acid; and About 344 mg of mannitol.

40. An aqueous formulation comprising About 107.5 mg of a compound of formula (Ia) Or a pharmaceutically acceptable salt, hydrate or solvate thereof, About 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 lyophilized formulation in the vial according to claim 41 or the vial according to any one of claims 30 to 33, wherein the vial comprises an inner surface in contact with a hydrophobic coating.

43. The vial according to claim 42, wherein the hydrophobic coating comprises a compound having the formula SiO x C y H z where x is between 0.6 and 0.9, y is between 1.2 and 3.3, and z is between 0.0 and 6.

0.

44. The vial according to claim 41 or 42, wherein the ratio of O to Si is less than or equal to 1.

2.

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

46. A method of treating a disease, disorder or condition that is at least partially mediated by CD73, the method Comprising: a) Reconstitute the lyophilized formulation according to any one of claims 1 to 31 with a diluent to form a reconstituted solution; and b) Administer a therapeutically effective amount of the reconstituted solution to a subject in need thereof.

47. The method according to claim 46, wherein the pH of the reconstituted solution is in the range of about 6.0 to about 7.

0.

48. The method according to claim 46, wherein the pH of the reconstituted solution is in the range of about 7.0 to about 7.

5.

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

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

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

52. The method according to claim 51, wherein the cancer is pancreatic cancer, colorectal cancer, ovarian cancer, uterine cancer, breast cancer, gastroesophageal cancer, urothelial cancer, gastric cancer, melanoma, lung cancer, kidney cancer, liver cancer, glioblastoma, head and neck cancer, or leukemia.

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

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

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

57. The method according to 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, B7 family members, or any combination thereof.

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

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

60. The method according to claim 59, wherein the immune checkpoint inhibitor is zepalizumab.

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

62. The method according to claim 61, wherein the immune checkpoint inhibitor is donalizumab, atezolizumab, ospetinib, AB308, tirzepatide or vibostolimab.

63. The method according to claim 62, wherein the immune checkpoint inhibitor is AB308 or donalizumab.

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

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

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

67. The method according to claim 66, wherein the adenosine pathway inhibitor is iterdan, inudodan, tamidan, caffeine citrate, imedan or cefedinan.

68. The method according to claim 67, wherein the adenosine pathway inhibitor is iterdan.

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

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

71. The method according to claim 70, wherein the chemotherapeutic agent comprises a taxane chemotherapeutic agent, a platinum-based chemotherapeutic agent or an anthracycline-based chemotherapeutic agent.

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

73. The method according to claim 72, wherein the chemotherapeutic agent is gemcitabine or albumin-bound paclitaxel.

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

75. A method for preparing a lyophilized preparation according to any one of claims 14 to 15 and 24 to 27, the method comprising (i) preparing a bulk solution by dissolving the compound of formula (Ia), arginine, phosphoric acid and a filler in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH regulator; (iii) filtering the bulk solution into a sterilized vial in a clean room; (iv) loading the vial into a freeze dryer; (v) subjecting the vial to freeze-thaw cycles; and (vi) subjecting the vial to primary drying and secondary drying under reduced pressure to obtain the lyophilized preparation.

76. The method according to claim 75, the method comprising (i) preparing a bulk solution by dissolving the compound of formula (Ia), arginine, phosphoric acid, and a filler in sterile water; (ii) optionally adjusting the pH of the bulk solution by adding a pH regulator; (iii) filtering the bulk solution into a sterilized vial in a clean room; (iv) loading the vial into a freeze dryer; (v) cooling the vial at a rate of about 0.5 °C / minute to a temperature of about -45 °C, and holding the vial at the temperature of about -45 °C for about 3 hours; (vi) warming the vial to a temperature of about -10 °C within about 50 minutes, and holding the vial at the temperature of about -10 °C for about 4 hours; (vii) cooling the vial to a temperature of about -45 °C within about 70 minutes, and holding the vial at the temperature of about -45 °C for about 2 hours; (viii) warming the vial to a temperature of about -15 °C, reducing the pressure and starting the 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; and (xi) backfilling the freeze dryer with dry nitrogen to a pressure of about 700 Torr, and stoppering the vial, thereby providing the lyophilized formulation.

77. A method of treating cancer, the method 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 in the range of 50 mg to 300 mg every two to three weeks, the anti-PD-1 antagonist antibody is administered in an amount in the range of 300 mg to 600 mg every two to five weeks, and the anti-TIGIT antagonist antibody is administered in an amount in the range of 1200 mg to about 1600 mg every two to four weeks.

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

79. The method according to claim 77, wherein the cancer is non-small cell lung cancer and the subject has not received prior treatment.

80. The method according to claim 77, wherein the cancer is non-small cell lung cancer and the subject has disease progression in a previous line of treatment.

81. The method according to claim 77, wherein the cancer is pancreatic cancer, optionally metastatic pancreatic cancer.

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

83. The method according to claim 81 or 82, wherein the subject has not received prior treatment.

84. The method according to claim 81 or 82, wherein the subject has disease progression in a previous line of treatment.

85. 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 in the range of 50 mg to 300 mg every two to three weeks.

86. The method according to claim 82, wherein the cancer is pancreatic cancer, optionally metastatic pancreatic cancer.

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

88. The method according to any one of claims 85 to 87, wherein the subject has not received prior treatment.

89. The method according to any one of claims 85 to 87, wherein the subject has disease progression in a previous line of treatment.

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

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

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

93. The method according to claim 80, wherein the previous line of treatment comprises a checkpoint inhibitor, optionally wherein the checkpoint inhibitor is a PD-L1 antagonist or a PD-1 antagonist.

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

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

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

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

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

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

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

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

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