Salts and crystalline forms of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[D]imidazol-2-yl)thieno[2,3-B]pyridin-6(7H)-one

Abstract

Novel salt forms of Compound (I), which are potent inhibitors of HPK1, and their corresponding pharmaceutical compositions are provided. A specific single crystalline form of the 1:1 tartrate salt of Compound (I) is characterized by various properties and physical measurements. Methods for preparing the specific crystalline form are also disclosed. The disclosure also provides a method for treating cancer in a subject. TIFF2026041889000014.tif3164

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 022,867, filed May 11, 2020. The entire contents of the foregoing application are incorporated herein by reference. [Background technology]

[0002] Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted Ste20 serine / threonine kinase. It has been reported that HPK1 could be a novel target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. 2012 Dec;54(1-3):262-5). Specifically, targeted disruption of the HPK1 allele confers increased Th1 cytokine production to T cells in response to TCR engagement. HPK1(- / -) T cells proliferate more rapidly than their haplotype-matched wild-type counterparts and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1(- / -) T cells became resistant to lung tumor growth. Furthermore, loss of HPK1 from dendritic cells (DCs) confers superior antigen-presenting capacity to mice, and HPK1(- / -) DCs can elicit stronger antitumor immune responses when used as cancer vaccines.

[0003] U.S. Patent No. 10,501,474, the entire teachings of which are incorporated herein by reference, discloses highly potent inhibitors of HPK1. The structure of one of the inhibitors disclosed in U.S. Patent No. 10,501,474 is referred to herein as "Compound (I)" as shown below:

[0004] [ka]

[0005] The chemical name of compound (I) is 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one.

[0006] Successful development of a pharmaceutically active agent such as Compound (I) typically requires the identification of a solid form that has properties that are amenable to isolation and purification after synthesis, amenable to large-scale manufacture, capable of being stored for extended periods with minimal absorption of water, degradation, or conversion to other solid forms, suitable for formulation, and readily absorbable after administration to a subject (e.g., soluble in water and gastric fluids). Summary of the Invention [Means for solving the problem]

[0007] The present disclosure relates to a tartrate salt of Compound (I), in which the molar ratio of Compound (I) to tartaric acid is 1:1. Due to the two carboxylic acid groups on tartaric acid and the multiple basic nitrogen atoms in Compound (I), multiple possible stoichiometries are possible. For example, Compound (I) forms both a 1:1 tartrate salt and a 1:0.5 tartrate salt. The 1:1 tartrate salt of Compound (I) is referred to herein as "1:1 Compound (I) tartrate" or "1:1 Compound (I) tartrate."

[0008] It has also been found that the 1:1 tartrate salt of Compound (I) can be crystallized under well-defined conditions to provide a non-hygroscopic crystalline form (see Example 6). The tartrate salt also has improved solubility in water and simulated gastric fluid (see Example 7 and Table 7), a long shelf life (see Example 8), and is suitable for large-scale synthesis (see Example 5).

[0009] Salt screening was performed using 13 different acids with different Compound (I) / acid molar ratios (see Examples 1-3). Of the 20 salt forms obtained (Examples 1 and 2), only the monohydrochloride, mesylate, tartrate, and maleate salts exhibited moderate to good crystallinity by X-ray powder diffraction (XRPD). Further evaluation of these four salts in different solvent systems showed that the mesylate and maleate salts exhibited moderate crystallinity (see Example 3). Furthermore, different polymorphic forms were isolated for the monohydrochloride, mesylate, and maleate salts when different solvent systems were used. Notably, the dihydrochloride salt exhibited no or very low crystallinity, as demonstrated in Examples 1 and 4.

[0010] Compared to the monohydrochloride salt, the 1:1 Compound (I) tartrate salt has the additional advantage of being non-hygroscopic. Furthermore, as shown in Example 9 below, the crystalline form of the 1:1 Compound (I) tartrate salt provides improved plasma concentrations in dogs after oral administration compared to the free base and the monohydrochloride salt. This is an important advantage, as the new solid form can be orally administered to provide effective drug plasma levels.

[0011] In one aspect, the present disclosure provides a tartrate salt of Compound (I), wherein the molar ratio of Compound (I) to tartaric acid is 1:1. In another aspect, the present disclosure provides a pharmaceutical composition comprising a 1:1 ratio of Compound (I) tartrate salt and a pharmaceutically acceptable carrier or diluent.

[0012] In yet another aspect, the present disclosure provides a method of treating a subject having cancer, comprising administering to the subject an effective amount of the 1:1 Compound (I) tartrate salt or corresponding pharmaceutical composition disclosed herein.

[0013] The present disclosure also provides a method of treating a subject with cancer, comprising administering to the subject an effective amount of a 1:1 Compound (I) tartrate salt or a corresponding pharmaceutical composition disclosed herein, and an effective amount of an immunomodulatory agent, such as a checkpoint inhibitor (e.g., an anti-PD-1 antibody, an anti-CTLA-4 antibody, or an anti-PD-L1 antibody) or an inhibitor of tryptophan oxidation (e.g., an IDO1, IDO2, or TDO2 inhibitor). In one example, the immunomodulatory agent is an anti-PD-1 antibody.

[0014] In one alternative, 1:1 Compound (I) tartrate or a corresponding pharmaceutical composition is administered together with an effective amount of one or more other anticancer therapies, preferably in combination with a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL3280A, MSB0010718C, or MEDI4736. In one particular embodiment, the PD-1 inhibitor is nivolumab. In one particular embodiment, the PD-1 inhibitor is pembrolizumab.

[0015] The present disclosure provides a 1:1 tartrate of Compound (I) disclosed herein, or a 1:1 Compound Also provided is the use of a corresponding pharmaceutical composition comprising Compound (I) tartrate salt in any of the above methods. In one embodiment, there is provided a 1:1 ratio of Compound (I) tartrate salt or a pharmaceutical composition thereof comprising 1:1 ratio of Compound (I) tartrate salt for use in any of the methods described herein. In another embodiment, there is provided the use of a 1:1 ratio of Compound (I) tartrate salt or a pharmaceutical composition thereof comprising 1:1 ratio of Compound (I) tartrate salt for the manufacture of a medicament for any of the methods described herein. [Brief explanation of the drawings]

[0016] [Figure 1]1 is a graph showing X-ray powder diffraction (XRPD) patterns of 1:1 Compound (I) hydrochloride salts obtained from different examples. The bottom spectrum is for the hydrochloride salt obtained from Example 1 (Batch 1). The middle spectrum is for the hydrochloride salt obtained from Example 3 (Batch 2) using IPA:water. The top spectrum is for the hydrochloride salt obtained from Example 3 (Batch 3) using acetone. [Figure 2] 1 is a graph showing X-ray powder diffraction (XRPD) patterns of 1:1 Compound (I) mesylate salts obtained from different examples. The bottom spectrum is for the mesylate salt obtained from Example 2 (Batch 1). The middle spectrum is for the mesylate salt obtained from Example 3 (Batch 2) using IPA:water. The top spectrum is for the mesylate salt obtained from Example 3 (Batch 3) using acetone. [Figure 3] 1 is a graph showing X-ray powder diffraction (XRPD) patterns of 1:1 Compound (I) maleate salts obtained from different examples. The bottom spectrum is for the maleate salt obtained from Example 2 (Batch 1). The middle spectrum is for the maleate salt obtained from Example 3 (Batch 2) using IPA:water. The top spectrum is for the maleate salt obtained from Example 3 (Batch 3) using acetone. [Figure 4] 1 is a graph showing the X-ray powder diffraction (XRPD) pattern of Compound (I) dihydrochloride salt 1:2. [Figure 5] 1 is a graph showing thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of the 1:1 Compound (I) tartrate salt obtained from Example 5. [Figure 6] 1 is a graph showing the X-ray powder diffraction (XRPD) pattern of the 1:1 Compound (I) tartrate salt obtained from Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present disclosure is directed to novel tartrate salts (i.e., 1:1 tartrate salts) of Compound (I), as well as the aforementioned polymorphic forms. In one embodiment, the tartrate salt of Compound (I) (i.e., the 1:1 tartrate salt) is crystalline.

[0018] As used herein, "crystalline" refers to a solid having a crystal structure in which individual molecules have a highly uniform, regular, locked-in chemical conformation. A crystalline Compound (I) salt may be a single crystal of Compound (I) salt or a mixture of crystals of different single crystal forms. A single crystal form refers to a Compound (I) salt as a single crystal or multiple crystals each having the same crystal form.

[0019] With respect to the crystalline forms of Compound (I) disclosed herein, at least a certain weight percent of the 1:1 Compound (I) tartrate salt is in a single crystalline form. The certain weight percent may be 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, 70% to 80%, 80% to 90%. %, 90% to 100% by weight of Compound (I) salt in a single crystalline form. It is understood that all values ​​and ranges between these values ​​and ranges are meant to be encompassed by the present disclosure.

[0020] When a crystalline Compound (I) salt is defined as a specified percentage of one particular crystalline form of Compound (I) salt, the remainder is made up of amorphous and / or crystalline forms other than the one or more particular forms specified. An example of a single crystalline form is a 1:1 Compound (I) tartrate salt characterized by one or more properties discussed herein.

[0021] The crystalline Compound (I) salts disclosed herein exhibit strong and unique XRPD patterns with sharp peaks corresponding to the 2θ angular peak positions and flat baselines, indicative of highly crystalline material (e.g., FIG. 6). The XRPD patterns disclosed in this application are obtained from a copper radiation source (Cu Kα1; λ=1.54179 Å). Characterization of the 1:1 Compound (I) Tartrate Crystalline Forms In one embodiment, the 1:1 Compound (I) tartrate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 11.9, 15.4, 16.9, and 17.2°±0.2 in terms of two-theta. In another embodiment, the 1:1 Compound (I) tartrate salt is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 11.9, 15.4, 16.9, 17.2, and 25.6°±0.2 in terms of two-theta. In another embodiment, the 1:1 Compound (I) tartrate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 11.9, 15.4, 16.9, 17.2, and 25.6°±0.2 in terms of two-theta. In another embodiment, the 1:1 Compound (I) tartrate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 11.9, 14.0, 15.4, 16.9, 17.2, 25.6, 26.3, and 30.7°±0.2 in terms of two-theta. In yet another embodiment, the 1:1 Compound (I) tartrate salt is characterized by an X-ray powder diffraction pattern comprising peaks at 11.9, 14.0, 15.4, 16.9, 17.2, 22.1, 25.6, 26.3, 30.7, and 34.0°±0.2 in terms of two-theta. In another embodiment, the 1:1 Compound (I) tartrate salt is characterized by an X-ray powder diffraction pattern as identified above, further comprising peaks at 8.7 and 12.9°±0.2 in terms of two-theta. In yet another embodiment, the 1:1 Compound (I) tartrate salt is characterized by an X-ray powder diffraction pattern substantially similar to FIG.

[0022] As used herein, an X-ray powder diffractogram is "substantially similar to that in a [particular] figure" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms are the same ±0.2 degrees 2θ. In determining "similarity," one skilled in the art will understand that there may be variations in intensity and / or signal position in XRPD diffractograms even for the same crystalline form. Thus, one skilled in the art will understand that signal maxima (as referred to herein in degrees 2θ (°2θ)) in an XRPD diffractogram generally refer to the reported value ±0.2 degrees 2θ, an art-recognized variation as discussed below.

[0023] It is well known in the art of crystallography that for any given crystalline form, angular peak positions may vary slightly due to factors such as temperature changes, sample displacement, and the presence or absence of an internal standard. In the present disclosure, the variability in angular peak positions is ±0.2 in 2θ. Furthermore, the relative peak intensities of a particular crystalline form may vary due to differences in crystallite size and non-random crystallite orientation in sample preparation for XRPD analysis. It is well known in the art that this variability accounts for the above factors without interfering with the unambiguous identification of the crystalline form.

[0024] In another embodiment, the 1:1 ratio of Compound (I) tartrate salt exhibits a differential scanning calorimetry (DSC) peak It is characterized by a phase transition temperature of 189±2°C. In another embodiment, the 1:1 tartrate salt of Compound (I) is characterized by a hygroscopicity measurement, wherein the amount of water absorbed is less than 4% (e.g., 2% or 1%) of the weight of the tartrate salt at 90% relative humidity (RH), or less than 2% (e.g., 1% or 0.5%) of the weight of the tartrate salt at 60% RH, or less than 1% (e.g., 0.5% or 0.1%) of the weight of the tartrate salt at 30% RH. The hygroscopicity at different relative humidity (RH) is measured under the following conditions: i) drying 0.5-1.5 mg of the tartrate salt under nitrogen at 0% relative humidity for 2 hours; ii) increasing or decreasing the relative humidity from 0% to 90% in 10% increments, then to 0%; iii) maintaining the relative humidity at each step until the mass change per minute compared to the original tartrate mass is less than 0.01 (% / min), with a minimum and maximum duration of each step being 10 minutes and 180 minutes, respectively; and iv) measuring the mass of tartrate salt at the desired relative humidity (e.g., 90%, 60%, or 30%), and steps i) to iv) being carried out at 25°C;

[0025] Hygroscopicity is measured using standard methods, such as G. Zografi and M.J. Kontny, "Sorption of water by solids," in Physical Characterization of Pharmaceutical Solids, ed. H.G. Brittain, Marcel Dekker, New York, NY (1995), pp. 385-418, or the procedure described in Example 6 of the present disclosure. Characterization of the 1:1 Compound (I) Monohydrochloride Crystalline Form In one embodiment, the 1:1 Compound (I) monohydrochloride salt is in a single crystalline form characterized by an X-ray powder diffraction pattern substantially similar to the upper spectrum of FIG. Pharmaceutical Composition The pharmaceutical compositions of the present disclosure comprise the 1:1 tartrate salt of Compound (I) or a crystalline form thereof as described herein, and one or more pharmaceutically acceptable carriers or diluents. The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting any subject composition or its components. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components, and not harmful to the subject. Some examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; and (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0026] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In one embodiment, the compositions of the present disclosure are administered orally, intraperitoneally, or intravenously. The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The sterile injectable form of the composition may be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0027] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated versions, are useful in the preparation of injectables, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0028] The pharmaceutically acceptable composition of the present disclosure may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0029] Alternatively, the pharmaceutically acceptable composition of the present disclosure may be administered in the form of a suppository for rectal administration.The pharmaceutically acceptable composition of the present disclosure can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0030] The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches may also be used.

[0031] For topical application, the pharmaceutically acceptable composition may be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the pharmaceutically acceptable composition may be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0032] The pharmaceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0033] The amount of the compounds of the present disclosure that can be combined with the carriers to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors determined by the person administering the single dosage form. Dosage The toxicity and therapeutic efficacy of Compound (I) or a salt thereof in crystalline form as described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. 50 is the dose that is lethal to 50% of the population. 50 is the dose that is therapeutically effective in 50% of the population. 50 / ED 50 ) is the therapeutic index. Salts of Compound (I), or crystalline forms thereof, that exhibit large therapeutic indices are preferred. While salts or crystalline forms of Compound (I) described herein that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such salts or crystalline forms to the site of affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.

[0034] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for human use. The dosages of such salts or crystalline forms can be administered at doses that produce little or no toxicity. 50 The circulating concentration of Compound (I) may be within a range including the IC 2 . The dosage may vary within this range depending on the dosage form used and the route of administration utilized. For any salt of Compound (I) or a crystalline form thereof described herein, the therapeutically effective dose can be estimated initially from cell culture assays. The IC 2 , determined in cell culture, may be used to estimate the therapeutically effective dose. 50A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography.

[0035] It should also be understood that the specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including, but not limited to, the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a salt of Compound (I), or a crystalline form of the present disclosure, in the composition will also depend on the particular compound in the composition. Treatment method A "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0036] As used herein, "treating a subject with cancer" includes partially or substantially achieving one or more of arresting the growth, reducing the extent of the cancer (e.g., reducing the size of a tumor), inhibiting the rate of growth of the cancer, ameliorating or improving clinical symptoms or indicators (such as tissue or serum components) associated with the cancer, or extending the subject's lifespan, and reducing the likelihood of cancer recurrence.

[0037] The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, e.g., inhibiting, suppressing, or reducing cancer in the subject compared to a control (e.g., as determined by clinical symptoms or amount of cancer cells).

[0038] Generally, an effective amount of a compound taught herein will vary depending on a variety of factors, such as the given drug or compound, pharmaceutical formulation, route of administration, type of disease or disorder, identity of the subject or host being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art. An effective amount of a compound of the present teachings can be readily determined by one of ordinary skill in the art by routine methods known in the art.

[0039] In one embodiment, an effective amount of a compound taught herein ranges from about 0.1 to about 1000 mg / kg of body weight, or alternatively, from about 1 to about 500 mg / kg of body weight. In another embodiment, an effective amount of a compound taught herein ranges from about 0.5 to about 5000 mg / kg of body weight. 2 , or about 5 to about 2500 mg / m 2 and in another alternative, from about 50 to about 1000 mg / m 2 Those skilled in the art will appreciate that certain factors may affect the dosage required to effectively treat a subject suffering from cancer or reduce the likelihood of cancer recurrence. These factors include, but are not limited to, the severity of the disease or disorder, previous treatment, the general health and / or age of the subject, and other diseases present.

[0040] A "treatment" regime for a subject with an effective amount of a compound of the present disclosure may consist of a single administration or may include a series of applications. For example, a 1:1 dose of Compound (I) tartrate may be administered at least once a week. However, in another embodiment, the compound may be administered to a subject about once a week to once a day for a given treatment. The length of the treatment period depends on various factors, such as the severity of the disease, the age of the subject, the concentration and activity of the compound of the present disclosure, or a combination thereof. It is also understood that the effective dosage of a compound used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regime. Dosage changes may occur and be evident using standard diagnostic assays known in the art. In some cases, chronic administration may be necessary.

[0041] Compound (I), its salts and crystalline forms disclosed herein inhibit HPK1, and therefore, generally, the compounds described herein are useful for treating diseases or conditions associated with such kinases.

[0042] In one embodiment, the disclosure provides a method for inhibiting HPK1 activity in a subject in need thereof, comprising administering to the subject an effective amount of Compound (I), or a tartrate salt thereof (e.g., a 1:1 Compound (I) tartrate salt), a crystalline form, or a pharmaceutical composition described herein.

[0043] Due to their activity against HPK1, Compound (I), or a tartrate salt (e.g., a 1:1 Compound (I) tartrate salt), crystalline form, or pharmaceutical composition described herein can be used to treat a subject having a condition associated with aberrant HPK1 activity.

[0044] In one embodiment, the condition associated with aberrant HPK1 activity is cancer. Cancers that can be treated (including reducing the likelihood of recurrence) by the methods of the present teachings include breast cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, prostate cancer, leukemia, lymphoma, brain cancer (including glioblastoma multiforme and neuroblastoma), head and neck cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, renal cancer, and soft tissue sarcoma. In one embodiment, the cancer is breast cancer, colon cancer, or ovarian cancer. In one embodiment, the cancer is selected from leukemia, acute myeloid leukemia, chronic myeloid leukemia, breast cancer, brain cancer, colon cancer, colorectal cancer, head and neck cancer, hepatocellular carcinoma, lung adenocarcinoma, metastatic melanoma, pancreatic cancer, prostate cancer, ovarian cancer, and renal cancer. In one embodiment, the cancer is lung cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer. In another embodiment, the cancer is lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, or ovarian cancer. In yet another embodiment, the cancer is breast cancer, colon cancer, and lung cancer. In the embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is basal subtype breast cancer or luminal B subtype breast cancer. In yet another embodiment, the cancer is basal subtype breast cancer. In yet another embodiment, the basal subtype breast cancer is ER (estrogen receptor), HER2, and PR (progesterone receptor) negative breast cancer. In yet another embodiment, the cancer is soft tissue cancer. "Soft tissue cancer" is an art-recognized term that encompasses tumors originating from any soft tissue of the body. Such soft tissues connect, support, or surround various structures and organs of the body, including, but not limited to, smooth muscle, skeletal muscle, tendon, fibrous tissue, adipose tissue, blood and lymphatic vessels, perivascular tissue, nerves, mesenchymal cells, and synovial tissue. Thus, soft tissue cancers can be of adipose tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymphatic vessels, and fibrous tissue. Soft tissue cancers can be benign or malignant. Generally, malignant soft tissue cancers are referred to as sarcomas, or soft tissue sarcomas. There are many types of soft tissue tumors, including lipoma, lipoblastoma, hibernation adenoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma (neurilemmoma), neuroma, malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi's sarcoma, lymphangioma, fibroma, fibroelastomatous tumor, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, clear cell sarcoma, and desmoplastic small round cell tumor. In certain embodiments, the soft tissue cancer is a sarcoma selected from the group consisting of fibrosarcoma, gastrointestinal sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma.

[0045] The present teachings also provide methods for treating a subject having a disease, comprising administering to the subject an effective amount of a compound represented by structural formula (I) in combination with an effective immunomodulatory therapy (also called immunotherapy). Immunotherapy is the treatment of disease by inducing, enhancing, or suppressing the immune response using an immunomodulator. Immunotherapies designed to induce or amplify the immune response are classified as activating immunotherapies, while immunotherapies that reduce or suppress the immune response are classified as suppressing immunotherapies. The disease described herein is cancer.

[0046] Immunomodulatory therapies, used alone or in a combined approach, include: i) anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibodies (e.g., ipilimumab), drugs that disrupt PD-1 / PD-L1 and PD-L2 interactions, such as nivolumab (Opdi-Bristol Myers Squibb), pembrolizumab (Keytruda, KM-3475, Merck), pidilizumab (CT-011, CureTech), BMS 936559 (BMS) and MPDL328OA (Roche) and other immune response inhibitory receptors, such as anti-CD47, immune checkpoint blockade inhibitors, including but not limited to; ii) cell-based therapies, including but not limited to dendritic cell therapy (e.g., Sipuleucel-T (Provenge) and adoptive T cell therapy; iii) vaccination strategies; iv) adoptive T cell therapy; v) agents that prevent metabolic inhibition of the immune response, including inhibitors of indoleamine 2,3-dioxygenase (e.g., INCB024360 (Incyte), 1-methyl-D-tryptophan, indoximod (NewLink Genetics)) or arginase; vi) cytokine-based therapies, such as interferons (particularly type I interferons) and interleukins (e.g., interleukin-2).

[0047] In one embodiment, the immunomodulatory agent used in the immunomodulatory therapy is a PD-1 inhibitor, e.g., an anti-PD1 antibody. Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein encoded by the PDCD1 gene in humans. PD-1 is a cell surface receptor belonging to the immunoglobulin superfamily that mediates the proliferation and proliferation of T cells. PD-1 is expressed on B and pro-B cells. PD-1 binds to two ligands, PD-L1 and PD-L2, both of which are members of the B7 family.

[0048] PD-1 and its ligands play an important role in downregulating the immune system by preventing T cell activation, reducing autoimmunity, and subsequently promoting self-tolerance. The inhibitory effect of PD-1 is achieved through two mechanisms: promoting apoptosis (programmed cell death) of antigen-specific T cells in lymph nodes and simultaneously reducing apoptosis of regulatory T cells (suppressor T cells).

[0049] PD-1 inhibitors for use in the present invention include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL3280A, MSB0010718C, or MEDI4736. Of these, BMS 936559, MPDL3280A, MSB0010718C, and MEDI4736 bind to the ligand PD-L1, and are all antibodies. Both nivolumab and pembrolizumab are approved by the Food and Drug Administration for the treatment of unresectable or metastatic melanoma that has stopped responding to other medications.

[0050] Vaccination strategies include antimicrobial immunotherapy, which involves vaccination and activating the immune system to respond to infectious pathogens. Adoptive T cell therapy uses a T cell-based cytotoxic response to attack cancer cells. T cells with natural or genetically engineered reactivity against a patient's cancer are generated in vitro and then infused back into the patient. One study using autologous tumor-infiltrating lymphocytes was an effective treatment for a patient with metastatic melanoma. This can be achieved by harvesting T cells found with the patient's tumor that are trained to attack cancer cells. These T cells, called tumor-infiltrating lymphocytes (TILs), are expanded in vitro using high concentrations of IL-2, anti-CD3, and alloreactive feeder cells. These T cells are then infused back into the patient with exogenous IL-2 to further enhance their anticancer activity.

[0051] The present teachings also provide for treating a subject with cancer, comprising administering to the subject an effective amount of Compound (I), or a tartrate salt (e.g., a 1:1 Compound (I) tartrate salt), a crystalline form, or a pharmaceutical composition described herein, in combination with an effective anti-cancer therapy. In one embodiment, the cancer is metastatic cancer. A "metastatic cancer" is a cancer that has spread from its primary site to other parts of the body.

[0052] The anti-cancer therapies described herein include co-administration of an effective amount of a second anti-cancer agent with the disclosed HPK-1 inhibitors. An "anti-cancer agent" is a compound that, when administered in an effective amount to a subject with cancer, can partially or substantially achieve one or more of: preventing the growth of, reducing the extent of, or inhibiting the growth rate of, the cancer (e.g., reducing tumor size), inhibiting the rate of growth of, or improving clinical symptoms or indicators associated with the cancer (such as tissue or serum components), or extending the lifespan of the subject.

[0053] Anti-cancer agents suitable for use in the methods described herein include any anti-cancer agent approved for the treatment of cancer. In one embodiment, anti-cancer agents include, but are not limited to, targeted antibodies, angiogenesis inhibitors, alkylating agents, antimetabolites, vinca alkaloids, taxanes, podophyllotoxins, topoisomerase inhibitors, hormonal anti-tumor agents, and other anti-tumor agents. In one embodiment, the anti-cancer agent is a PD-1 inhibitor, e.g., an anti-PD1 antibody.

[0054] In one embodiment, anti-cancer drugs that can be used in the methods described herein include, but are not limited to, paclitaxel, docetaxel, 5-fluorouracil, tramadol, thiazolinone ... These include tuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine, melphalan, cytarabine, etoposide, daunorubicin, bleomycin, mitomycin, and adriamycin, and combinations thereof.

[0055] In one embodiment, the anti-cancer agent and Compound (I), or a tartrate salt (e.g., a 1:1 Compound (I) tartrate salt), crystalline form, or pharmaceutical composition described herein are administered simultaneously. When administered simultaneously, the anti-cancer agent and the compound can be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anti-cancer agent are administered separately at different times.

[0056] The following examples are intended to be illustrative and not to limit the scope of the present disclosure in any way. [Example]

[0057] Abbreviation: 1 H proton aq. Water-based br. Wide DCM dichloromethane DVS Dynamic Vapor Sorption Equiv h time HPLC High Performance Liquid Chromatography IPA Isopropanol LC-MS Liquid Chromatography Mass Spectrometry MeOH Methanol min NMR nuclear magnetic resonance PLM polarized light microscope RH Relative Humidity rt room temperature TGA thermogravimetric analysis THF tetrahydrofuran UPLC Ultra High Performance Liquid Chromatography XRPD X-ray powder diffraction Analysis conditions X-ray powder diffraction (XRPD) XRPD analysis was carried out using a Bruker D8 Advance X-ray powder diffractometer. The XRPD parameters are as follows:

[0058] [Table 1]

[0059] Thermogravimetric analysis (TGA) 2–5 mg of material was weighted into an open platinum pan and loaded into a TA Q5000IR thermogravimetric analyzer. The sample was then heated from 25 °C to 350 °C / 400 °C at a rate of 10 °C / min. Differential scanning calorimetry (DSC) 0.5–1 mg of material was weighted into an aluminum DSC pan and sealed loosely with an aluminum lid. The sample pan was then loaded into a TA Instruments Q2000. Once a stable heat flow response was obtained at 25 °C, the sample and reference were heated to 350 °C at a rate of 10 °C / min, and the resulting heat flow response was monitored. 1 H-nuclear magnetic resonance spectroscopy ( 1 H-NMR) Nuclear magnetic resonance measurements were recorded on a Bruker D8 Advance DRX 400 instrument at 400 MHz and room temperature using DMSO-d6 or CD3OD as solvent without an internal standard. HPLC / UPLC method Representative methods used to measure solubility are summarized in Table 1. Representative methods used to evaluate stability are summarized in Table 2.

[0060] [Table 2]

[0061] [Table 3]

[0062] Example 1: Initial Salt Screen An initial salt screen was performed using either 1 or 2 equivalents of HCl, H2SO4, and H3PO4 in a mixture of DCM and MeOH (2:1).

[0063] Approximately 100 mg of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]-imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) was dissolved in a 2:1 mixture of DCM and MeOH at 50° C. Either 1 or 2 equivalents of acid was added, the resulting solution was stirred at room temperature for 3 days, and a sample of the resulting salt was analyzed by XRPD.

[0064] A weakly crystalline salt was obtained using HCl (1 equiv.), H2SO4 (2 equiv.), and H3PO4 (1 equiv.). An amorphous salt was obtained using HCl (2 equiv.) and H2SO4 (1 equiv.). The diffractogram of the mono-HCl salt (batch 1) is shown in Figure 1.

[0065] Example 2: Expanded Salt Screen An extended salt screen was performed using H3PO4, methanesulfonic acid, p-toluenesulfonic acid, citric acid, malic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, benzoic acid, and maleic acid at 0.5, 1, and / or 2 equivalents in a mixture of THF and MeOH (2:1). A total of 16 salts were prepared, and the results are summarized in Table 3.

[0066] Approximately 100 mg of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]-imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) was dissolved in a 2:1 mixture of THF and MeOH at 50°C. 0.5, 1, or 2 equivalents of acid were added, and the resulting solution was stirred overnight at room temperature. The solid samples were centrifuged to obtain the solid. Samples that showed no precipitation were dried at room temperature. 1 It was characterized by 1 H NMR, PLM and XRPD.

[0067] All 16 isolated salts exhibited varying degrees of birefringence. However, only the 1:1 mesylate, 1:1 maleate, and 1:1 tartrate salts exhibited moderate to good crystallinity by XRPD. Diffractograms of the 1:1 mesylate (Batch 1) and 1:1 maleate (Batch 1) salts prepared using this method are shown in Figures 2 and 3, respectively. Notably, as shown in Table 3 below, 0.5 equivalents of tartaric acid did not yield the desired hemi-tartrate salt (1:0.5), and therefore was not pursued further.

[0068] [Table 4]

[0069] Example 3: Preparation of selected salts The hydrochloride, mesylate, tartrate and maleate salts were prepared separately using two different solvent systems: acetone and IPA / water (95:5).

[0070] Approximately 100 mg of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridine-6(7H The )-one (I) was suspended in acetone (2 mL) or IPA / water (95:5, 2 mL). The suspension was stirred at 50 °C. Acid (1 equivalent, 0.5 mol / L) was added and the mixture was stirred overnight. The salt was then isolated and dried under vacuum at 30 °C. The obtained salt was characterized by TGA, DSC and XRPD.

[0071] The two solvent systems resulted in different polymorphic forms of the HCl (IPA: Batch 2; Acetone: Batch 3), mesylate (IPA: Batch 2; Acetone: Batch 3), and maleate (IPA: Batch 2; Acetone: Batch 3) salts. Diffractograms of the isolated HCl, mesylate, and maleate polymorphic forms are shown in Figures 1, 2, and 3, respectively. As demonstrated by the XRPD diffractograms, the mesylate and maleate salts are moderately crystalline.

[0072] One polymorphic form of the 1:1 Compound (I) tartrate salt was isolated using the two solvent systems described in Example 3.

[0073] Example 4: Preparation of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[D]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) dihydrochloride Approximately 15 g (40.95 mmol) of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) was suspended in a mixture of DCM (300 mL) and MeOH (450 mL). 2 M HCl in EtO (45 mL, 90.15 mmol) was added slowly at room temperature. The resulting mixture was stirred at room temperature for 60 min. The solvent was then removed in vacuo, and the resulting solid was triturated with EtO (120 mL) and filtered to obtain the di-HCl salt as a brown solid. The di-HCl salt was characterized by XRPD and NMR. The XRPD diffractogram is shown in Figure 4 and indicates that the resulting di-HCl salt had very low crystallinity.

[0074] Example 5 Preparation of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[D]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) tartrate 4-Amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (4.5 kg) was dissolved in an aqueous acetic acid solution (44 kg water, 1.78 kg acetic acid) at 55-60°C. The solution was stirred for 15-120 minutes. In a separate reactor, an aqueous solution of L-(+)-tartaric acid was prepared by adding the acid (1.98 kg) to water (14-18 kg) at 20-30°C, and the solution was stirred for 15-60 minutes. The acetic acid solution containing Compound (I) was then slowly added to the aqueous L-(+)-tartaric acid solution at 55-60°C. Optionally, seed crystals were added. The resulting mixture was crystallized at 55-60°C for 12-24 hours. The mixture was then cooled to 20-25°C and stirred for 8-16 hours. The precipitated product was then collected, washed with ethanol, and dried under vacuum at 40-60 °C for 3-24 hours to obtain the desired product. The title compound was characterized by H NMR, DSC, TGA, and XRPD. The DSC and TGA results are shown in Figure 5. The XRPD diffractogram is shown in Figure 6, and the results are tabulated in Table 4.

[0075] [Table 5]

[0076] 1H NMR (400 MHz, DMSO-d8): 12.65 (br s, 1H), 10.65 (br s, 1H), 8.00 (br s, 1H), 7.68 (d, J = 5.6 Hz, 1H), 7.49 (br s, 1H), 7.20-7.17 (m, 2H), 6.92 (d, J = 2.5 Hz, 1H), 6.71 (br, s, 4H), 4.16 (s, 2H), 3.22 (br s, 4H), 2.88 (br s, 4H), 2.52 (s, 3H).

[0077] Example 6: Measurement of the hygroscopicity of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) and its salts The compounds to be tested were subjected to hygroscopicity testing by a DVS instrument. The test parameters are in Table 5. The hygroscopicity measurement results are shown in Table 6.

[0078] [Table 6]

[0079] [Table 7]

[0080] Example 7: Solubility of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) and its salts The compounds to be tested were prepared in three different media as described below.

[0081] Samples prepared in water: Approximately 30-40 mg of test material was weighed into a glass vial. 1 mL of water was added. The sample was stirred at ambient temperature for 1 hour, and the sample was analyzed by HPLC at 24 hours.

[0082] Samples prepared in simulated gastric fluid (SGF) buffer: Approximately 40 mg of test material was weighed into a glass vial. 4 mL of SGF buffer was added to achieve a target concentration of 10 mg / mL. Samples were stirred at 37°C for 24 hours, and samples were analyzed by HPLC at 24 hours.

[0083] Samples prepared in Fasted State Simulated Intestinal Fluid (FaSSIF) buffer: Approximately 8 mg of test material was weighed into a glass vial. 4 mL of FaSSIF buffer was added to achieve a target concentration of 2 mg / mL. Samples were stirred at 37°C for 24 hours, and samples were analyzed by HPLC at 24 hours.

[0084] The samples were stirred at ambient temperature for 1 hour or at 37°C for 24 hours. The samples were then centrifuged and the resulting supernatants were analyzed by HPLC to determine solubility. The solubility of Compound (I) and its salts in different media is summarized in Table 7.

[0085] [Table 8]

[0086] Example 8: Stability of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) tartaric acid The purity and stability of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) tartaric acid were tested. Stability samples were prepared and stored under three different storage conditions: 2-8 °C / ambient RH, 25 °C / 60% RH, and 40 °C / 75% RH. Stability samples were removed from the storage conditions within each pull window, and the samples were allowed to equilibrate to ambient conditions before analysis. Appearance was assessed by visual inspection, purity and total impurities were analyzed by HPLC, and crystalline form was characterized by XRPD. The results are summarized in Table 8.

[0087] [Table 9]

[0088] Example 9: Pharmacokinetic analysis of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (I) and its salts Male beagle dogs were administered a single dose of either 125 mg / kg or 150 mg / kg of Compound (I) capsules, 1:1 Compound (I) mono-HCl (Batch 3), Compound (I) di-HCl, and 1:1 Compound (I) tartrate powders. Blood samples were collected for up to 24 hours, and plasma was analyzed for Compound (I) plasma levels by LC / MS. The results are shown in Table 9.

[0089] [Table 10]

Claims

1. A tartrate salt of compound (I) represented by the following structural formula: 【Chemistry 1】 A tartrate salt in which the molar ratio of compound (I) to tartaric acid is 1:

1.

2. 2. The tartrate salt of claim 1, which is crystalline.

3. 10. The tartrate salt of claim 1, wherein at least 90% by weight is in a single crystalline form.

4. 4. The tartrate salt of any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising peaks at 0.2±11.9°, 15.4°, 16.9°, and 17.2°±0.2 in 2θ.

5. 4. The tartrate salt of any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 11.9°, 15.4°, 16.9°, 17.2° and 25.6°±0.2 in 2θ.

6. 4. The tartrate salt of any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising peaks at 11.9°, 14.0°, 15.4°, 16.9°, 17.2°, 25.6°, 26.3° and 30.7°±0.2 in 2θ.

7. 4. The tartrate salt of any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising peaks at 11.9°, 14.0°, 15.4°, 16.9°, 17.2°, 22.1°, 25.6°, 26.3°, 30.7° and 34.0°±0.2 in 2θ.

8. 8. The tartrate salt of any one of claims 4 to 7, characterized by an X-ray powder diffraction pattern further comprising peaks at 8.7° and 12.9°±0.2° 2θ.

9. 9. The tartrate salt of any one of claims 1 to 8, characterized by a differential scanning calorimetry (DSC) peak phase transition temperature of 189±2°C.

10. Water absorption is as follows: i) drying 0.5-1.5 mg of the tartrate salt under nitrogen at 0% relative humidity for 2 hours; ii) increasing or decreasing the relative humidity from 0% to 90% in 10% increments and then to 0%; iii) maintaining the relative humidity at each step until the mass change compared to the original tartrate mass per minute is less than 0.01 (% / min), with a minimum and maximum duration of each step being 10 and 180 minutes, respectively; and iv) measuring the mass of the tartrate salt at 90% relative humidity, and steps i) to iv) being carried out at 25°C; 10. The tartrate salt according to any one of claims 1 to 9, wherein the moisture content is less than 4% of the mass of the tartrate salt at 90% relative humidity (RH) when measured under

11. 11. The tartrate salt of claim 10, wherein the water absorption is less than 1% of the mass of the tartrate salt at 90% relative humidity (RH).

12. Water absorption is as follows: i) drying 0.5-1.5 mg of the tartrate salt under nitrogen at 0% relative humidity for 2 hours; ii) increasing or decreasing the relative humidity from 0% to 90% in 10% increments and then to 0%; iii) maintaining the relative humidity at each step until the mass change compared to the original tartrate mass per minute is less than 0.01 (% / min), with a minimum and maximum duration of each step being 10 and 180 minutes, respectively; and iv) the mass of the tartrate salt is measured at a relative humidity of 30% and steps i) to iv) are carried out at 25°C.

12. The tartrate salt according to any one of claims 1 to 11, wherein the moisture content is less than 1% of the mass of the tartrate salt at 30% relative humidity (RH) when measured under

13. 13. The tartrate salt of claim 12, having a water absorption of less than 0.1% of the mass of the tartrate salt at 30% relative humidity (RH).

14. A pharmaceutical composition comprising the tartrate salt of any one of claims 1 to 13 and a pharmaceutically acceptable carrier or diluent.

15. A method for treating a subject with cancer, comprising administering to the subject an effective amount of the tartrate salt of any one of claims 1 to 13 or the pharmaceutical composition of claim 14.

16. 15. A method of treating a subject having cancer, comprising administering to the subject an effective amount of the tartrate salt of any one of claims 1 to 13 or the pharmaceutical composition of claim 14, and an effective amount of a second anti-cancer treatment (e.g., a chemotherapeutic agent, a targeted therapy agent, radiation, or surgery).

17. 15. A method of treating a subject with cancer, comprising administering to the subject an effective amount of the tartrate salt of any one of claims 1 to 13 or the pharmaceutical composition of claim 14, and an effective amount of an immunomodulator, such as a checkpoint inhibitor (e.g., an anti-PD-1 antibody, an anti-CTLA4 antibody, or an anti-PD-L1 antibody) or an inhibitor of tryptophan oxidation (e.g., an IDO1, IDO2, or TDO2 inhibitor).

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