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

Abstract

Novel salt forms of Compound (I) represented by the following structural formula and their corresponding pharmaceutical compositions are disclosed. 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 present disclosure also provides a method for treating cancer in a subject. TIFF2023526054000014.tif3164

Description

[Technical Field]

[0001] Cross-references 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 aforementioned application are incorporated herein by reference. [Background technology]

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

[0003] U.S. Patent No. 10,501,474 discloses a very potent inhibitor of HPK1, the entirety of which is incorporated herein by reference. One structure of the inhibitor disclosed in U.S. Patent No. 10,501,474 is referred herein to as “Compound (I)”:

[0004] [ka]

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

[0006] To successfully develop a pharmaceutically active agent like compound (I), it is usually necessary to identify a solid form that is ready for isolation and purification after synthesis, modifiable for large-scale production, can be stored for long periods with minimal water absorption, degradation, or conversion to other solid forms, is suitable for formulation, and is readily absorbed after administration to the target (e.g., soluble in water and gastric juice). [Overview of the Initiative] [Means for solving the problem]

[0007] This disclosure relates to a tartrate 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 stoichiometrys are possible. For example, compound (I) forms both a 1:1 tartrate and a 1:0.5 tartrate. The 1:1 tartrate of compound (I) is referred to herein as "1:1 compound (I) tartaric acid" or "1:1 compound (I) tartrate".

[0008] Furthermore, it was found that a 1:1 compound (I) tartrate could be crystallized under clearly defined conditions to provide a non-hygroscopic crystalline form (see Example 6). The tartrate also exhibits improved solubility in water and simulated gastric juice (see Example 7 and Table 7), has 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 showed 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 had moderate crystallinity (see Example 3). Furthermore, different polymorphs were isolated for the monohydrochloride, mesylate, and maleate when different solvent systems were used. Notably, the dihydrochloride was non-crystalline or had very low crystallinity, as demonstrated in Examples 1 and 4.

[0010] Compared to monohydrochloride, the 1:1 compound (I) tartrate has the additional advantage of being non-hygroscopic. Furthermore, as shown in Example 9 below, the crystalline 1:1 compound (I) tartrate results in improved plasma concentrations in dogs after oral administration compared to the free base and monoHCl salt. This is a significant advantage because it allows for the oral administration of a new solid form to achieve effective plasma drug levels.

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

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

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

[0014] In one alternative, a 1:1 ratio of compound (I) tartrate or the corresponding pharmaceutical composition is administered, preferably in combination with a PD-1 inhibitor, along with one or more other anticancer therapies in an effective dose. 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] This disclosure also provides the use of a 1:1 compound (I) tartrate, or a corresponding pharmaceutical composition comprising a 1:1 compound (I) tartrate, as disclosed herein, in any of the methods described above. In one embodiment, a 1:1 compound (I) tartrate or a pharmaceutical composition comprising a 1:1 compound (I) tartrate is provided for use in any of the methods described herein. In another embodiment, the use of a 1:1 compound (I) tartrate or a pharmaceutical composition comprising a 1:1 compound (I) tartrate is provided for the manufacture of a pharmacopoeia for any of the methods described herein. [Brief explanation of the drawing]

[0016] [Figure 1]It is a graph showing the X-ray powder diffraction (XRPD) pattern of the 1:1 compound (I) hydrochloride obtained from different examples. The following spectrum is for the hydrochloride obtained from Example 1 (Batch 1). The middle spectrum is for the hydrochloride obtained from Example 3 (Batch 2) using IPA: water. The upper spectrum is for the hydrochloride obtained from Example 3 (Batch 3) using acetone. [Figure 2] It is a graph showing the X-ray powder diffraction (XRPD) pattern of the 1:1 compound (I) mesylate obtained from different examples. The following spectrum is for the mesylate obtained from Example 2 (Batch 1). The middle spectrum is for the mesylate obtained from Example 3 (Batch 2) using IPA: water. The upper spectrum is for the mesylate obtained from Example 3 (Batch 3) using acetone. [Figure 3] It is a graph showing the X-ray powder diffraction (XRPD) pattern of the 1:1 compound (I) maleate obtained from different examples. The following spectrum is for the maleate obtained from Example 2 (Batch 1). The middle spectrum is for the maleate obtained from Example 3 (Batch 2) using IPA: water. The upper spectrum is for the maleate obtained from Example 3 (Batch 3) using acetone. [Figure 4] It is a graph showing the X-ray powder diffraction (XRPD) pattern of the 1:2 compound (I) dihydrochloride. [Figure 5] It is a graph showing the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of the 1:1 compound (I) tartrate obtained from Example 5. [Figure 6] It is a graph showing the X-ray powder diffraction (XRPD) pattern of the 1:1 compound (I) tartrate obtained from Example 5.

Modes for Carrying Out the Invention

[0017] The present disclosure is directed to novel tartrate salts of compound (I) (i.e., 1:1 tartrate salts), and to the polymorphic forms described above. In one embodiment, the tartrate salt of compound (I) (i.e., 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 very homogeneous and regular locked-in chemical stereostructure. The crystalline compound (I) salt may be a crystal of a single crystal form of the compound (I) salt or a mixture of crystals of different single crystal forms. A single crystal form means a single crystal of the compound (I) salt or a plurality of crystals in which each crystal has the same crystal form.

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

[0020] When a crystalline compound (I) salt is defined as a specified proportion of one particular crystal form of the compound (I) salt, the remainder is composed of an amorphous form and / or a crystal form other than the one or more specified particular forms. Examples of single crystal forms include the 1:1 compound (I) tartrate salt characterized by one or more of the properties discussed herein.

[0021] The crystalline compound (I) salts disclosed herein exhibit a strong and unique XRPD pattern with a sharp peak corresponding to the 2θ angular peak position and a flat baseline, indicating a highly crystalline material (e.g., Figure 6). The XRPD patterns disclosed herein are obtained from a copper source (Cu Kα1; λ=1.54179 Å). Characterization of the crystalline morphology of compound (I) tartrate in a 1:1 ratio. In one embodiment, a 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern containing peaks at 11.9°, 15.4°, 16.9°, and 17.2°±0.2 at 2θ. In another embodiment, a 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern containing at least three peaks selected from 11.9°, 15.4°, 16.9°, 17.2°, and 25.6°±0.2 at 2θ. In yet another embodiment, a 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern containing peaks at 11.9°, 15.4°, 16.9°, 17.2°, and 25.6°±0.2 at 2θ. In another embodiment, the 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern containing peaks at 11.9°, 14.0°, 15.4°, 16.9°, 17.2°, 25.6°, 26.3°, and 30.7°±0.2° at 2θ. In yet another embodiment, the 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern containing 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° at 2θ. In yet another embodiment, the 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern as identified above, further containing peaks at 8.7° and 12.9°±0.2° at 2θ. In yet another embodiment, a 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern substantially similar to that in Figure 6.

[0022] As used herein, an X-ray powder diffractogram is considered "substantially similar to that in a particular figure" if at least 90% of the signals in two diffractograms, e.g., at least 95%, at least 98%, or at least 99%, are equivalent at 2θ ± 0.2. In determining "similarity," a person skilled in the art will understand that even with the same crystalline form, there can be variations in the intensity and / or signal position of an XRPD diffractogram. Thus, a person skilled in the art will understand that the maximum signal value of an XRPD diffractogram (2-theta degrees (°2θ) as used herein) generally means the reported value ± 0.2 degrees2θ, which is a variation recognized in the art as discussed below.

[0023] In the field of crystallography, it is well known that for any given crystal form, the angular peak position can vary slightly due to factors such as temperature changes, sample displacement, and the presence or absence of an internal standard. In this disclosure, the variability of the angular peak position is ±0.2 at 2θ. Furthermore, the relative peak intensity of a particular crystal form can 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 can explain the above factors without hindering the clear identification of the crystal form.

[0024] In another embodiment, the 1:1 compound (I) tartrate is characterized by having a differential scanning calorimeter (DSC) peak phase transition temperature of 189 ± 2°C. In another embodiment, the 1:1 tartrate of compound (I) is characterized by a hygroscopicity measurement, where the water absorption is less than 4% of the mass of the tartrate at 90% relative humidity (RH) (e.g., 2% or 1%), or less than 2% of the mass of the tartrate at 60% RH (e.g., 1% or 0.5%), or less than 1% of the mass of the tartrate at 30% RH (e.g., 0.5% or 0.1%). The hygroscopicity at different relative humidity (RH) is measured under the following conditions: i) Dry 0.5-1.5 mg of tartrate under a nitrogen atmosphere at 0% relative humidity for 2 hours. ii) Increase or decrease the relative humidity in 10% increments from 0% to 90%, and then return it to 0%. iii) Maintain relative humidity in each process until the mass change compared to the original mass of tartrate per minute is less than 0.01 (% / min), under the condition that the minimum and maximum durations in each process are 10 minutes and 180 minutes, respectively, and iv) Measure the mass of tartrate at the desired relative humidity (e.g., 90%, 60%, or 30%), and steps i) to iv) shall be carried out at 25°C.

[0025] Hygroscopicity is measured using standard methods, for example, G. Zografi and MJ Kontny, "sorption of water by solids," in Physical Characterization of Pharmaceutical Solids, ed. HGBrittain, Marcel Dekker, New York, NY (1995), pp. 385-418, or the procedure described in Example 6 of this disclosure. Characterization of the crystalline morphology of compound (I) monohydrochloride in a 1:1 ratio. In one embodiment, the 1:1 compound (I) monohydrochloride salt is in a single-crystal form characterized by an X-ray powder diffraction pattern substantially similar to the spectrum shown in Figure 1. Pharmaceutical composition The pharmaceutical compositions of this disclosure comprise a 1:1 compound (I) tartrate or its crystalline form as described herein, and one or more pharmaceutically acceptable carriers or diluents. The term “pharmaceutically acceptable carrier” means any pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in supporting or transporting any subject composition or its components. Each carrier must be “acceptable” in the sense that it is compatible with the subject composition and its components and is 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 such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, and their derivatives; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. Oils like oil; (10) Glycols like propylene glycol; (11) Polyols like glycerin, sorbitol, mannitol and polyethylene glycol; (12) Esters like ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers like 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, suitable substances used in pharmaceutical formulations.

[0026] The compositions of this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, intraoral, vaginally, or via an implanted reservoir. The term “parenterally” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-articular bursa, intrasternal, subarachnoid, intrahepatic, intralesional, and intracranial injection or infusion techniques. In one embodiment, the compositions of this disclosure are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of this disclosure may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using appropriate dispersants or wetting and suspending agents. The sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils have conventionally been used as solvents or suspension media.

[0027] For this purpose, any brand of fixed oil containing synthetic monoglycerides or diglycerides may be used. Fatty acids such as oleic acid and its glyceride derivatives, particularly their polyoxyethylated versions, are useful in the preparation of injectable formulations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in formulations 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 solids, liquids, or other dosage forms, may also be used for formulation purposes.

[0028] The pharmaceutically acceptable compositions of this disclosure may be administered orally 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 corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, lactose and dried corn starch are useful diluents. Where aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorants may also be added, if desired.

[0029] Alternatively, the pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of this 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. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0030] The pharmaceutically acceptable compositions of this disclosure may also be administered topically, in particular, when the subject of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestines. Appropriate topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestines can be done with rectal suppositories (see above) or appropriate enema formulations. Topical transdermal patches may also be used.

[0031] For topical application, pharmaceutically acceptable compositions may be formulated into suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, pharmaceutically acceptable compositions may be formulated into suitable lotions or creams 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 this disclosure may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to well-known techniques in the art of pharmaceutical formulations and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0033] The amount of the compound of this disclosure that can be combined with a carrier to produce a composition in single-dose form varies depending on the host being treated, the specific mode of administration, and other factors determined by the person administering the single-dose form. Dosage The toxicity and therapeutic efficacy of compound (I) or its crystalline salt described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. 50 This is a lethal dose for 50% of the population. 50 This is a therapeutically effective dose in 50% of the population. (L) Toxicity and therapeutic effects (LD50) 50 / ED 50The dose ratio between (1) and (2) is the therapeutic index. A salt of compound (I) or its crystalline form exhibiting a large therapeutic index is preferred. While a salt or crystalline form of compound (I) described herein that exhibits toxic side effects may be used, care should be taken to design a delivery system that targets such salt or crystalline form to the site of the affected tissue in order to minimize potential damage to uninfected cells and thereby reduce side effects.

[0034] Data obtained from cell culture assays and animal studies can be used when formulating dosage ranges for human use. Dosages of such salt or crystalline forms are less or no toxic ED. 50 The circulating concentration may be within the range of the compound(I) used. The dosage may be varied within this range depending on the dosage form used and the route of administration utilized. For compound(I) described herein or any salt of its crystalline form, the therapeutically effective dose can be initially estimated from a cell culture assay. IC determined in cell culture 50 Doses 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 the inhibition of up to half of the 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] Furthermore, it should be understood that specific dosages and treatment regimens for any particular subject depend on a variety of factors, including but not limited to the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, elimination rate, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the salt of compound (I) in the composition, or the crystalline form of the present disclosure, also depends on the specific compound in the composition. Treatment method As used herein, the "subject" is a mammal, preferably a human, but can also be an animal that requires veterinary treatment, for example, a pet (e.g., dog, cat, etc.), a livestock (e.g., cow, sheep, pig, horse, etc.) and a laboratory animal (e.g., rat, mouse, guinea pig, etc.).

[0036] As used herein, "treating a subject having cancer" includes achieving one or more of partially or substantially preventing proliferation, reducing the degree of cancer (e.g., reducing the size of a tumor), inhibiting the cancer growth rate, improving or enhancing clinical symptoms or markers associated with cancer (such as tissue or serum components), or extending the lifespan of the subject, and reducing the likelihood of cancer recurrence.

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

[0038] Generally, the effective amount of the compounds taught herein will vary depending on various factors such as, for example, the particular drug or compound, pharmaceutical formulation, route of administration, type of disease or disorder, the identity of the subject or host being treated, etc., but can nonetheless be routinely determined by one of ordinary skill in the art. The effective amount of the compounds of the present teachings can be readily determined by one of ordinary skill in the art by conventional methods known in the art.

[0039] In one embodiment, the effective amount of the compounds taught herein ranges from about 0.1 to about 1000 mg / kg body weight, or from about 1 to about 500 mg / kg body weight. In another embodiment, the effective amount of the compounds taught herein ranges from about 0.5 to about 5000 mg / m 2 or from about 5 to about 2500 mg / m 2 and in another alternative embodiment from about 50 to about 1000 mg / m 2This is within the scope of the subject. Those skilled in the art will understand that certain factors may influence the dosage required to effectively treat a subject with cancer, or reduce the likelihood of cancer recurrence. These factors include, but are not limited to, the severity of the disease or disorder, treatment history, the subject's overall health and / or age, and other pre-existing conditions.

[0040] A “treatment” regime for a subject with an effective dose of the compound of this disclosure may consist of a single dose 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 the 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 this disclosure, or a combination thereof. It is also understood that the effective dose of the compound used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regime. Changes in dosage may be made and revealed by standard diagnostic assays known in the art. In some cases, chronic administration may be required.

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

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

[0043] Due to their activity against HPK1, compound (I), or its tartrate (e.g., 1:1 compound (I) tartrate), crystalline form, or the pharmaceutical compositions described herein can be used to treat subjects having conditions associated with abnormal HPK1 activity.

[0044] In one embodiment, the condition associated with abnormal HPK1 activity is cancer. Cancers that can be treated by the method described herein (including a reduction in the likelihood of recurrence) 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, kidney cancer, and soft tissue sarcoma. In one embodiment, the cancers are breast cancer, colon cancer, and ovarian cancer. In one embodiment, the cancers are 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 kidney cancer. In one embodiment, the cancers are 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 another 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, 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 a term recognized in the art 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 are not limited to, smooth muscle, skeletal muscle, tendons, fibrous tissue, adipose tissue, blood vessels and lymphatic vessels, perivascular tissue, nerves, mesenchymal cells, and synovial tissue. Therefore, soft tissue cancer can be of adipose tissue, muscle tissue, nerve tissue, joint tissue, blood vessels, lymphatic vessels, and fibrous tissue. Soft tissue cancer can be benign or malignant. Generally, malignant soft tissue cancer is called sarcoma or soft tissue sarcoma.There are many types of soft tissue tumors, including lipoma, lipoblastoma, hibernating adenoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyomyoma, rhabdomyomyoma, neurofibroma, Schwann cell tumor (schwannoma), neuroma, malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, periangiocarcinoma, hemangioendothelioma, angiosarcoma, Kaposi's sarcoma, lymphangioma, fibroma, elastic fibroma, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant mesenchymal tumor, hydatidiform soft tissue sarcoma, epithelioid sarcoma, clear cell sarcoma, and fibroplastic 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] This instruction also provides a method for treating a subject with a disease, comprising the step of administering an effective amount of a compound represented by structural formula (I) to the subject in combination with an effective immunomodulatory therapy (also called immunotherapy). Immunotherapy is the treatment of a disease by inducing, enhancing, or suppressing an immune response using an immunomodulator. Immunotherapy designed to induce or amplify an immune response is classified as activating immunotherapy, and immunotherapy designed to reduce or suppress an immune response is classified as suppressive immunotherapy. The disease described herein is cancer.

[0046] Immunomodulatory therapy is used alone or in combination and includes: 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, Cure Tech), and BMS. ii) immune checkpoint blockers, including but not limited to 936559 (BMS) and MPDL328OA (Roche) and other immune response inhibitory receptors, such as anti-CD47; iii) cell-based therapies (including but not limited to dendritic cell therapy (e.g., Sipruce Cell T (Provenge) and adoptive T cell therapy); iv) vaccination strategies; 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, including interferons (especially type I interferons) and interleukins (e.g., interleukin-2).

[0047] In one embodiment, the immunomodulator used in immunomodulatory therapy is a PD-1 inhibitor, such as an anti-PD1 antibody. Programmed cell death protein 1, also known as PD-1 and CD279 (differentiation cluster 279), is a protein encoded by the PDCD1 gene in humans. PD-1 is a cell surface receptor belonging to the immunoglobulin superfamily and is expressed on T cells 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 a crucial 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, while simultaneously reducing apoptosis of regulatory T cells (suppressor T cells).

[0049] Examples of PD-1 inhibitors used 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 become refractory to other drugs.

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

[0051] This instruction also provides a method for treating a subject having cancer, comprising administering to the subject an effective amount of compound (I), or tartrate (e.g., 1:1 compound (I) tartrate), crystalline form, or the pharmaceutical composition described herein, in combination with an effective anticancer therapy. In one embodiment, the cancer is metastatic cancer. "Metastatic cancer" means cancer that has spread from a primary site to other parts of the body.

[0052] The anticancer therapies described herein include the co-administration of an effective dose of a second anticancer agent together with the disclosed HPK-1 inhibitor. The “anticancer agent” is a compound that, when administered in an effective dose to a subject with cancer, can partially or substantially achieve one or more of the following: inhibit growth, reduce the extent of the cancer (e.g., reduce the size of the tumor), inhibit the rate of cancer growth, improve or enhance cancer-related clinical symptoms or indicators (such as tissue or serum components), or extend the lifespan of the subject.

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

[0054] In one embodiment, anticancer agents that can be used in the method described herein include, but are not limited to, paclitaxel, docetaxel, 5-fluorouracil, trastuzumab, 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 anticancer agent and compound (I), or tartrate (e.g., 1:1 compound (I) tartrate), crystalline form, or the pharmaceutical composition described herein are administered simultaneously. When administered simultaneously, the anticancer agent and compound may be administered in the same formulation or in different formulations. Alternatively, the compound and additional anticancer agents may be administered separately at different times.

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

[0057] Abbreviation: 1 H proton aq. Water-based Wide DCM Dichloromethane DVS Dynamic Water Vapor Adsorption Equiv h time HPLC (High-Performance Liquid Chromatography) IPA Isopropanol LC-MS (Liquid Chromatography-Mass Spectrometry) MeOH methanol min NMR nuclear magnetic resonance PLM Polarizing Microscope RH (Relative Humidity) rt room temperature TGA thermogravimetric analysis THF (Tetrahydrofuran) UPLC Ultra-High-Speed ​​Liquid Chromatography XRPD (X-ray Powder Diffraction) Analysis conditions X-ray powder diffraction (XRPD) XRPD analysis was performed 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 the material was weighted into an open platinum pan and placed in 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 the material was loaded into an aluminum DSC pan and sealed with an aluminum lid without sealing it completely. Next, the sample pan was placed in a TA Instruments Q2000. Once a stable heat flow response was obtained at 25°C, the sample and reference material 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 the solvent without internal standards. HPLC / UPLC method Table 1 summarizes the typical methods used for measuring solubility. Table 2 summarizes the typical methods used for evaluating stability.

[0060] [Table 2]

[0061] [Table 3]

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

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

[0064] Weakly crystalline salts were obtained using HCl (1 equivalent), H2SO4 (2 equivalents), and H3PO4 (1 equivalent). Amorphous salts were obtained using HCl (2 equivalents) and H2SO4 (1 equivalent). The diffractogram of the monoHCl salt (batch 1) is shown in Figure 1.

[0065] Example 2: Extended salt screen Extended salt screening was performed on a mixture of THF and MeOH (2:1) using H3PO4, methanesulfonic acid, p-toluenesulfonic acid, citric acid, malic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, benzoic acid, and maleic acid in amounts of 0.5, 1, and / or 2 equivalents. 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]-imidazole-2-yl)thieno[2,3-b]pyridine-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 obtained samples were centrifuged, and those that did not show precipitation were dried at room temperature. All samples were, 1 The samples were characterized by 1H 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 showed moderate to good crystallinity by XRPD. The diffractograms of the 1:1 mesylate (batch 1) and 1:1 maleate (batch 1) prepared using this method are shown in Figures 2 and 3, respectively. In particular, 0.5 equivalents of tartaric acid did not yield the desired hemi-tartrate (1:0.5), as shown in Table 3 below, and were therefore not pursued further.

[0068] [Table 4]

[0069] Example 3: Preparation of selected salts Hydrochloride, mesylate, tartrate, and maleate salts were prepared individually 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]-imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-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 resulting salt was characterized by TGA, DSC, and XRPD.

[0071] The two solvent systems yielded different polymorphs of hydrochloric acid (IPA: batch 2; acetone: batch 3), mesylate (IPA: batch 2; acetone: batch 3), and maleate (IPA: batch 2; acetone: batch 3). Difractograms of the isolated polymorphs of HCl, mesylate, and maleate are shown in Figures 1, 2, and 3, respectively. As demonstrated in the XRPD diffractograms, the crystallinity of the mesylate and maleate is moderate.

[0072] One polymorph of compound (I) tartrate in a 1:1 ratio 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]imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-one(I) dihydrochloride Approximately 15 g (40.95 mmol) of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-one (I) was suspended in a mixture of DCM (300 mL) and MeOH (450 mL). 2 M HCl (45 mL, 90.15 mmol) in Et2O was slowly added at room temperature. The resulting mixture was stirred at room temperature for 60 minutes. The solvent was then removed under vacuum, and the resulting solid was pulverized with Et2O (120 mL) and filtered to obtain the diHCl salt as a brown solid. The diHCl salt was characterized by XRPD and NMR. The XRPD diffractogram is shown in Figure 4, indicating that the crystallinity of the obtained diHCl salt was very low.

[0074] Example 5: Preparation of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[D]imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-one(I) tartrate 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole-2-yl)thieno[2,3-b]pyridine-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 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. Seed crystals were added if necessary. 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. Next, the precipitated product was 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 1H NMR, DSC, TGA, and XRPD. The results of DSC and TGA are shown in Figure 5. The XRPD diffractogram is shown in Figure 6, and the results are summarized 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]imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-one(I) and its salts. The compounds under test were subjected to hygroscopicity testing using a DVS (Dynamic Ventilation System) instrument. The test parameters are shown 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]imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-one(I) and its salts The compounds to be tested were prepared in three different culture media, as described below.

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

[0082] Sample prepared in simulated gastric juice (SGF) buffer: Approximately 40 mg of the test material was loaded into a glass vial. 4 mL of SGF buffer was added to achieve the target concentration of 10 mg / mL. The sample was stirred at 37°C for 24 hours and analyzed by HPLC for 24 hours.

[0083] Samples prepared with fasting-simulated intestinal fluid (FaSSIF) buffer: Approximately 8 mg of the test material was loaded into a glass vial. 4 mL of FassiF buffer was added to achieve the target concentration of 2 mg / mL. The samples were stirred at 37°C for 24 hours and analyzed by HPLC for 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 supernatant was analyzed by HPLC to determine its solubility. Table 7 summarizes the solubility of compound (I) and its salts in different culture media.

[0085] [Table 8]

[0086] Example 8: Stability of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-one(I)tartaric acid The purity and stability of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole-2-yl)thieno[2,3-b]pyridine-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 each storage condition within the pull window, and the samples were equilibrated to ambient conditions before analysis. Appearance was evaluated by visual inspection, purity and total impurity were analyzed by HPLC, and crystalline morphology 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]imidazole-2-yl)thieno[2,3-b]pyridine-6(7H)-one(I) and its salts Male beagle dogs were administered a single dose of either 125 mg / kg or 150 mg / kg as either a capsule of compound (I), a 1:1 mixture of compound (I) monoHCl (batch 3), a diHCl of compound (I), or a 1:1 mixture of compound (I) tartrate powder. Blood samples were collected for up to 24 hours, and plasma levels of compound (I) were analyzed by LC / MS. The results are shown in Table 9.

[0089] [Table 10] In some embodiments, the present invention may be described as follows. [Aspect 1] A tartrate salt of compound (I) represented by the following structural formula, [ka] A tartrate salt in which the molar ratio of compound (I) to tartaric acid is 1:1. [Aspect 2] The tartrate salt according to aspect 1, wherein it is crystalline. [Aspect 3] The tartrate salt according to aspect 1, wherein at least 90% by weight is in single crystalline form. [Aspect 4] The tartrate salt according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern containing peaks at 0.2 ± 11.9°, 15.4°, 16.9°, and 17.2° ± 0.2° in 2θ. [Aspect 5] The tartrate according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern including at least three peaks selected from 11.9°, 15.4°, 16.9°, 17.2°, and 25.6°±0.2 at 2θ. [Aspect 6] The tartrate salt according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern containing peaks at 11.9°, 14.0°, 15.4°, 16.9°, 17.2°, 25.6°, 26.3° and 30.7°±0.2° in 2θ. [Aspect 7] A tartrate salt according to any one of aspects 1 to 3, characterized by an X-ray powder diffraction pattern containing 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. [Aspect 8] The tartrate salt according to any one of aspects 4 to 7, characterized by an X-ray powder diffraction pattern further including peaks at 8.7° and 12.9°±0.2 in 2θ. [Aspect 9] A tartrate salt according to any one of aspects 1 to 8, characterized by a differential scanning calorimeter (DSC) peak phase transition temperature of 189 ± 2°C. [Aspect 10] The amount of water absorbed is under the following conditions: i) Dry 0.5-1.5 mg of tartrate under a nitrogen atmosphere at 0% relative humidity for 2 hours. ii) Increase or decrease the relative humidity in 10% increments from 0% to 90%, and then return it to 0%. iii) Maintain relative humidity in each process until the mass change compared to the original mass of tartrate per minute is less than 0.01 (% / min), under the condition that the minimum and maximum durations in each process are 10 minutes and 180 minutes, respectively, and iv) Measure the mass of tartrate at 90% relative humidity, and steps i) to iv) shall be carried out at 25°C. The tartrate according to any one of embodiments 1 to 9, wherein, when measured under conditions of 90% relative humidity (RH), it is less than 4% of the mass of the tartrate. [Aspect 11] The tartrate according to aspect 10, wherein the water absorption is less than 1% of the mass of the tartrate at a relative humidity (RH) of 90%. [Aspect 12] The amount of water absorbed is under the following conditions: i) Dry 0.5-1.5 mg of tartrate under a nitrogen atmosphere at 0% relative humidity for 2 hours. ii) Increase or decrease the relative humidity in 10% increments from 0% to 90%, and then return it to 0%. iii) Maintain relative humidity in each process until the mass change compared to the original mass of tartrate per minute is less than 0.01 (% / min), under the condition that the minimum and maximum durations in each process are 10 minutes and 180 minutes, respectively, and iv) Measure the mass of tartrate at 30% relative humidity, and steps i) to iv) shall be carried out at 25°C. The tartrate according to any one of embodiments 1 to 11, which, when measured under conditions of 30% relative humidity (RH), is less than 1% of the mass of the tartrate. [Aspect 13] The tartrate according to aspect 12, wherein the water absorption is less than 0.1% of the mass of the tartrate at a relative humidity (RH) of 30%. [Aspect 14] A pharmaceutical composition comprising a tartrate salt according to any one of aspects 1 to 13 and a pharmaceutically acceptable carrier or diluent. [Aspect 15] A method for treating a subject having cancer, comprising the step of administering an effective amount of a tartrate salt according to any one of aspects 1 to 13 or a pharmaceutical composition according to aspect 14. [Aspect 16] A method for treating a subject having cancer, comprising the step of administering an effective amount of a tartrate salt according to any one of aspects 1 to 13 or a pharmaceutical composition according to aspect 14, and an effective amount of a second anti-cancer treatment (e.g., a chemotherapeutic agent, a targeted therapy agent, radiation or surgery) to the subject. [Aspect 17] A method for treating a subject with cancer, comprising the step of administering an effective amount of a tartrate salt according to any one of aspects 1 to 13 or a pharmaceutical composition according to aspect 14, and an effective amount of an immunomodulatory agent such as a checkpoint inhibitor (e.g., anti-PD-1 antibody, anti-CTLA4 antibody, or anti-PD-L1 antibody) or a tryptophan oxidation inhibitor (e.g., IDO1, IDO2, or TDO2 inhibitor).

Claims

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

1. The tartrate is a single crystalline form characterized by an X-ray powder diffraction pattern containing peaks at 11.9°, 15.4°, 16.9°, and 17.2°±0.2° in 2θ.

2. The tartrate salt according to claim 1, wherein the crystalline morphology is characterized by an X-ray powder diffraction pattern having at least three peaks selected from 11.9°, 15.4°, 16.9°, 17.2°, and 25.6° ± 0.2 at 2θ.

3. The tartrate salt according to claim 1 or 2, characterized by a crystalline morphology characterized by an X-ray powder diffraction pattern containing peaks at 11.9°, 14.0°, 15.4°, 16.9°, 17.2°, 25.6°, 26.3°, and 30.7°±0.2 in 2θ.

4. The tartrate salt according to claim 1 or 2, wherein the crystalline morphology is characterized by an X-ray powder diffraction pattern containing 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.

5. The tartrate salt according to any one of claims 1 to 4, wherein the crystalline morphology is characterized by an X-ray powder diffraction pattern further including peaks at 8.7° and 12.9° ± 0.2° in 2θ.

6. The tartrate salt according to any one of claims 1 to 5, wherein the crystalline form is characterized by a differential scanning calorimeter (DSC) peak phase transition temperature of 189 ± 2°C.

7. The water absorption capacity of the crystalline form is determined under the following conditions: i) Dry 0.5 to 1.5 mg of tartrate in crystalline form under a nitrogen atmosphere and 0% relative humidity for 2 hours. ii) Increase or decrease the relative humidity from 0% to 90% in 10% increments, and then return it to 0%. iii) Maintain relative humidity in each step until the mass change per minute, compared to the mass of the original crystalline form of tartrate, is less than 0.01 (% / min), under the condition that the minimum and maximum durations in each step are 10 minutes and 180 minutes, respectively, and iv) Measure the mass of the crystalline form of tartrate at 90% relative humidity, and steps i) to iv) shall be carried out at 25°C. The tartrate according to any one of claims 1 to 6, wherein, when measured under conditions of 90% relative humidity (RH), it is less than 4% of the mass of the crystalline form of the tartrate.

8. The tartrate according to claim 7, wherein the water absorption of the crystalline form is less than 1% of the mass of the crystalline form of the tartrate at 90% relative humidity (RH).

9. The water absorption capacity of the crystalline form is determined under the following conditions: i) Dry 0.5 to 1.5 mg of tartrate in crystalline form under a nitrogen atmosphere and 0% relative humidity for 2 hours. ii) Increase or decrease the relative humidity from 0% to 90% in 10% increments, and then return it to 0%. iii) Maintain relative humidity in each step until the mass change per minute, compared to the mass of the original crystalline form of tartrate, is less than 0.01 (% / min), under the condition that the minimum and maximum durations in each step are 10 minutes and 180 minutes, respectively, and iv) Measure the mass of the crystalline form of tartrate at 30% relative humidity, and steps i) to iv) shall be carried out at 25°C. The tartrate according to any one of claims 1 to 8, wherein, when measured under conditions of 30% relative humidity (RH), it is less than 1% of the mass of the crystalline form of the tartrate.

10. The tartrate according to claim 9, wherein the water absorption of the crystalline form is less than 0.1% of the mass of the crystalline form of the tartrate at a relative humidity (RH) of 30%.

11. A pharmaceutical composition comprising a tartrate salt according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier or diluent.

12. A pharmaceutical composition for treating cancer, comprising a tartrate salt according to any one of claims 1 to 10.

13. The pharmaceutical composition according to claim 12, wherein the tartrate salt according to any one of claims 1 to 10 is administered together with a second anti-cancer treatment (e.g., a chemotherapy agent, a targeted therapy agent, radiation, or surgery).

14. A pharmaceutical composition for treating cancer, comprising a tartrate according to any one of claims 1 to 10, 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 a tryptophan oxidation inhibitor (e.g., an IDO1, IDO2, or TDO2 inhibitor).

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