Salts and crystal 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

The present invention discloses novel salt forms of a compound (I) represented by the following structural formula and corresponding pharmaceutical compositions, in particular, a single crystal form of the 1:1 compound (I) tartrate characterized by a variety of properties and physical measurements. The present invention also discloses a method for preparing a specific crystal form. The present disclosure also provides a method for treating cancer in a subject.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 022,867, filed on May 11, 2020. The entire content of the above application is incorporated herein by reference. Technical Field

[0003] Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted Ste20 serine / threonine kinase. HPK1 has been reported to be a new target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. December 2012; 54(1-3):262-5). Specifically, targeted disruption of the HPK1 allele confers elevated Th1 cytokine production in T cells in response to TCR engagement. HPK1 (- / -) T cells proliferate faster than haplotype-matched wild-type counterparts and are resistant to prostaglandin E2 (PGE(2))-mediated inhibition. Most strikingly, mice receiving adoptive transfer of HPK1 (- / -) T cells become resistant to lung tumor growth. In addition, loss of HPK1 from dendritic cells (DCs) confers superior antigen-presenting ability, such that HPK1 (- / -) DCs can elicit a more effective anti-tumor immune response when used as a cancer vaccine.

[0004] U.S. Patent No. 10,501,474 (the entire teachings of which are incorporated herein by reference) discloses potent inhibitors of HPK1. The structure of one of the inhibitors disclosed in U.S. Patent No. 10,501,474 (referred to herein as "Compound (I)") is shown below:

[0005]

[0006] 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.

[0007] The successful development of a pharmaceutically active agent (such as Compound (I)) typically requires identification of a solid form having the following properties: being readily separable and purifiable after synthesis, suitable for large-scale manufacture, storable for an extended period of time with minimal water absorption, decomposition, or conversion to other solid forms, being suitable for formulation and readily absorbable (e.g., soluble in water and gastric juice) upon administration to a subject. Summary of the Invention

[0008] The present disclosure relates to the tartrate salt of compound (I), wherein the molar ratio between compound (I) and 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 salt".

[0009] It has now been found that the 1:1 compound (I) tartrate salt 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 in simulated gastric fluid (see Examples 7 and Table 7), has an extended shelf life (see Example 8), and is suitable for large-scale synthesis (see Example 5).

[0010] Salt screening was carried out using thirteen different acids at different compound (I) / acid molar ratios (see Examples 1 to 3). Among 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 crystallinity of the mesylate and maleate was moderate (see Example 3). In addition, different polymorphic forms of the monohydrochloride, mesylate, and maleate were isolated when different solvent systems were used. Notably, the dihydrochloride did not have or had very low crystallinity, as shown in Examples 1 and 4.

[0011] Compared with the monohydrochloride, the 1:1 compound (I) tartrate salt has the additional advantage of being non-hygroscopic. In addition, as shown in Example 9 below, the crystalline 1:1 compound (I) tartrate salt produced improved plasma concentrations in dogs after oral administration compared to the free base and the monohydrochloride. This is a significant advantage since the novel solid form can be orally administered to produce an effective plasma level of the drug.

[0012] In one aspect, the present disclosure provides a tartrate salt of compound (I), wherein the molar ratio between compound (I) and tartaric acid is 1:1.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising the 1:1 compound (I) tartrate salt and a pharmaceutically acceptable carrier or diluent.

[0014] In yet another aspect, the present disclosure provides a method of treating a subject suffering from cancer, which comprises administering to the subject an effective amount of the 1:1 compound (I) tartrate salt or the corresponding pharmaceutical composition disclosed herein.

[0015] The present disclosure also provides a method of treating a subject having cancer, which comprises administering to the subject an effective amount of the 1:1 compound (I) tartrate disclosed herein or a corresponding pharmaceutical composition, 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 instance, the immunomodulator is an anti-PD-1 antibody.

[0016] In an alternative, the 1:1 compound (I) tartrate or a corresponding pharmaceutical composition is administered together with an effective amount of one or more other anti-cancer agents, and 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 a specific embodiment, the PD-1 inhibitor is nivolumab. In a specific embodiment, the PD-1 inhibitor is pembrolizumab.

[0017] The present disclosure also provides the use of the 1:1 compound (I) tartrate disclosed herein or a corresponding pharmaceutical composition comprising the same in any of the above methods. In one embodiment, there is provided a 1:1 compound (I) tartrate or a pharmaceutical composition comprising the same for use in any of the methods described herein. In another embodiment, there is provided the use of a 1:1 compound (I) tartrate or a pharmaceutical composition comprising the same in the preparation of a medicament for use in any of the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Shows X-ray powder diffraction (XRPD) patterns of the 1:1 compound (I) hydrochloride obtained from different examples. The bottom spectrum is for the hydrochloride (batch 1) obtained from Example 1. The middle spectrum is for the hydrochloride (batch 2) obtained from Example 3 using IPA:water. The top spectrum is for the hydrochloride (batch 3) obtained from Example 3 using acetone.

[0019] Figure 2 Shows X-ray powder diffraction (XRPD) patterns of the 1:1 compound (I) mesylate obtained from different examples. The bottom spectrum is for the mesylate (batch 1) obtained from Example 2. The middle spectrum is for the mesylate (batch 2) obtained from Example 3 using IPA:water. The top spectrum is for the mesylate (batch 3) obtained from Example 3 using acetone.

[0020] Figure 3Shows the X-ray powder diffraction (XRPD) patterns of the 1:1 compound (I) maleate obtained from different examples. The bottom spectrum is for the maleate obtained from Example 2 (Batch 1). The middle spectrum is for the maleate obtained from Example 3 using IPA:water (Batch 2). The top spectrum is for the maleate obtained from Example 3 using acetone (Batch 3).

[0021] Figure 4 Shows the X-ray powder diffraction (XRPD) pattern of the 1:2 compound (I) dihydrochloride.

[0022] Figure 5 Shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of the 1:1 compound (I) tartrate obtained from Example 5:

[0023] Figure 6 Shows the X-ray powder diffraction (XRPD) pattern of the 1:1 compound (I) tartrate obtained from Example 5. Detailed Description

[0024] The present disclosure relates to novel tartrates of compound (I) (i.e., 1:1 tartrates), and polymorphic forms thereof.

[0025] In one embodiment, the tartrate of compound (I) (i.e., 1:1 tartrate) is crystalline.

[0026] As used herein, "crystalline" refers to a solid having a crystal structure in which individual molecules have a highly uniform regular locked chemical configuration. The crystalline compound (I) salt can be a crystal of a single polymorphic form of the compound (I) salt, or a mixture of crystals of different polymorphic forms. A single polymorphic form refers to a compound (I) salt that is a single crystal or multiple crystals, where each crystal has the same crystal form.

[0027] For the polymorphic forms of compound (I) disclosed herein, at least a specific weight percentage of the 1:1 compound (I) tartrate is in a single polymorphic form. Specific weight percentages include 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 a weight percentage of 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 - 80 wt%, 80 - 90 wt%, 90 - 100 wt% of the compound (I) salt in a single polymorphic form. It is understood that all values and ranges between these values and ranges are intended to be covered by the present disclosure.

[0028] When defining a specified percentage of a crystalline compound (I) salt as a specific crystalline form of the compound (I) salt, the remainder consists of an amorphous form and / or crystalline forms other than the specified one or more specific forms. Examples of single crystalline forms include the 1:1 compound (I) tartrate salt, which is characterized by one or more properties as discussed herein.

[0029] The crystalline compound (I) salts disclosed herein exhibit strong, distinct XRPD patterns having sharp peaks corresponding to 2θ angular peak positions and a flat baseline, indicating a highly crystalline substance (e.g., Figure 6 ). The XRPD patterns disclosed in this application were obtained with a copper radiation source (Cu Kα1; ).

[0030] Characterization of the 1:1 compound (I) tartrate crystalline form

[0031] In one embodiment, the 1:1 compound (I) tartrate is characterized by an X-ray powder diffraction pattern comprising peaks at 11.9°, 15.4°, 16.9°, and 17.2° ± 0.2 2θ. In another embodiment, the 1:1 compound (I) tartrate 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 2θ. In another embodiment, the 1:1 compound (I) tartrate 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 2θ. In another embodiment, the 1:1 compound (I) tartrate 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 2θ. In yet another embodiment, the 1:1 compound (I) tartrate 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 2θ. In another embodiment, the 1:1 compound (I) tartrate is characterized by the X-ray powder diffraction pattern as identified above and further comprising peaks at 8.7° and 12.9° ± 0.2 2θ. In yet another embodiment, the 1:1 compound (I) tartrate is characterized by being substantially similar to Figure 6 the X-ray powder diffraction pattern.

[0032] As used herein, an X-ray powder diffraction pattern "is substantially similar to the X-ray powder diffraction pattern in [a specific] figure" when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in two diffraction patterns are the same at ±0.2 2θ. In determining "similarity", one of ordinary skill in the art will understand that even for the same crystal form, there may be variations in the intensity and / or signal position in the XRPD diffraction pattern. Thus, one of ordinary skill in the art will understand that the signal maximum in the XRPD diffraction pattern (in degrees 2θ (°2θ) as referred to herein) generally means ±0.2° 2θ of the reported value, as is the generally recognized difference in the art as discussed below.

[0033] It is well known in the field of crystallography that for any given crystal form, the angular peak position 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 variation in the angular peak position is ±0.2 2θ. Additionally, the relative peak intensities of a given crystal form may vary due to differences in microcrystal size and non-random microcrystal orientation in the sample preparation for XRPD analysis. It is well known in the art that this variability will account for the above factors without preventing the clear identification of the crystal form.

[0034] In another embodiment, the 1:1 compound (I) tartrate is characterized by a differential scanning calorimetry (DSC) peak phase transition temperature of 189 ± 2 °C.

[0035] In another embodiment, the 1:1 compound (I) tartrate is characterized by hygroscopicity measurements, where the moisture absorption is less than 4% (such as 2% or 1%) of the mass of the tartrate at 90% relative humidity (RH); or less than 2% (such as 1% or 0.5%) of the mass of the tartrate at 60% RH; or less than 1% (such as 0.5% or 0.1%) of the mass of the tartrate at 30% RH. The hygroscopicity at different relative humidities (RH) is measured under the following conditions:

[0036] i) drying 0.5 to 1.5 mg of the tartrate for 2 hours at 0% relative humidity under a nitrogen atmosphere;

[0037] ii) increasing or decreasing the relative humidity from 0% to 90% and then to 0% in 10% steps;

[0038] iii) maintaining the relative humidity at each step until the mass change is less than 0.01 (% / min) per minute compared to the original mass of the tartrate, provided that the minimum and maximum durations of each step are 10 minutes and 180 minutes, respectively; and

[0039] iv) Measure the mass of the tartrate at the desired relative humidity (e.g., 90%, 60% or 30%), and wherein steps i)-iv) are carried out at 25 °C.

[0040] Use standard methods, such as those described in G. Zografi and M. J. Kontny, “Sorption of water by solids” Physical Characterization of Pharmaceutical Solids, edited by H. G. Brittain, Marcel Dekker, New York, NY (1995), pages 385-418, or the methods described in Example 6 of the present disclosure, to measure hygroscopicity.

[0041] Characterization of the 1:1 compound (I) monohydrochloride crystal form

[0042] In one embodiment, the 1:1 compound (I) monohydrochloride is a single crystal form, characterized in that the X-ray powder diffraction pattern is substantially similar to Figure 1 the top spectrum.

[0043] Pharmaceutical composition

[0044] The pharmaceutical compositions of the present disclosure comprise the 1:1 compound (I) tartrate or a crystal form thereof 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, 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 injurious to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) gum tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as 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 glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0045] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional and intracranial injection or infusion techniques. In one embodiment, the compositions of the present disclosure are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present disclosure can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium.

[0046] For this purpose, any mild fixed oil can be used, which includes synthetic mono- or di-glycerides of fatty acids. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and / or other emulsifying agents or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.

[0047] The pharmaceutically acceptable compositions of the present disclosure can be administered orally in any orally acceptable dosage form, including (but not limited to) capsules, tablets, aqueous suspensions or solutions. In the case of using tablets for oral administration, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are usually also added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifying agent and a suspending agent. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0048] Alternatively, the pharmaceutically acceptable compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These 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 will thus melt in the rectum to release the drug. These materials include cocoa butter, beeswax, and polyethylene glycol.

[0049] The pharmaceutically acceptable compositions of the present disclosure can also be administered topically, especially when the treatment target includes areas or organs that are easily accessible by topical administration, including eye, skin, or lower intestinal diseases. For each of these areas or organs, suitable topical formulations are readily prepared. Topical administration to the lower intestine can be achieved in the form of rectal suppository formulations (see above) or in the form of suitable enema formulations. Topical transdermal patches can also be used.

[0050] For topical administration, the pharmaceutically acceptable compositions can 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 the present disclosure include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions can 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0051] The pharmaceutically acceptable compositions of the present disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be formulated as saline solutions, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0052] 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 on the host being treated, the particular mode of administration, and other factors determined by the person administering the single dosage form.

[0053] Dosage

[0054] The toxicity and therapeutic efficacy of the salts or crystalline forms of compound (I) described herein can be determined in cell cultures or experimental animals by standard pharmaceutical procedures. LD 50 is the dose that is lethal to 50% of the population. ED 50 is the dose that is therapeutically effective in 50% of the population. The dose ratio between toxicity and therapeutic effect (LD 50 / ED 50 ) is the therapeutic index. Salts or crystalline forms of compound (I) that exhibit a large therapeutic index are preferred. Although salts or crystalline forms of compound (I) described herein that exhibit toxic side effects can be used, care should be taken in designing a delivery system that targets such salts or crystalline forms to the site of the infected tissue so as to minimize potential damage to uninfected cells and thereby reduce side effects.

[0055] Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for humans. The dosage of such salts or crystal forms can be within the range of circulating concentrations including ED 50 with little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration employed. For any salt of compound (I) or its crystal form described herein, the therapeutically effective dosage can initially be estimated from cell culture assays. Dosages can be formulated in animal models to achieve a range of circulating plasma concentrations including IC 50 (i.e., the concentration of the test compound that achieves half-maximal inhibition of symptoms) as determined in cell culture. This information can be used to more accurately determine the useful dosage in humans. The levels in plasma can be measured, for example, by high performance liquid chromatography.

[0056] 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, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of the salt or crystal form of compound (I) of the present disclosure in the composition will also depend on the specific compound in the composition.

[0057] Methods of treatment

[0058] 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.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0059] As used herein, "treating a subject having cancer" includes partially or substantially achieving one or more of the following: inhibiting growth, reducing the extent of cancer (e.g., reducing the size of a tumor), inhibiting the growth rate of cancer, ameliorating or improving clinical symptoms or markers associated with cancer (e.g., tissue or serum components), or increasing the lifespan of the subject; and reducing the likelihood of cancer recurrence.

[0060] The term "effective amount" means an amount that produces a beneficial or desired result (including a clinical result) when administered to a subject, e.g., an amount that inhibits, suppresses, or reduces cancer in a subject as compared to a control (e.g., as measured by clinical symptoms or the amount of cancer cells).

[0061] Typically, the effective amount of the compounds taught herein varies depending on various factors such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, etc., but can still be routinely determined by those skilled 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.

[0062] In one embodiment, the effective amount of the compounds taught herein is 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 is from about 0.5 to about 5000 mg / m 2 , or from about 5 to about 2500 mg / m 2 , and in another alternative is from about 50 to about 1000 mg / m 2 . Those skilled in the art will understand that certain factors can affect 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, previous treatments, the general health and / or age of the subject, and the presence of other diseases.

[0063] A "treatment" regimen in which a subject utilizes an effective amount of the disclosed compounds can consist of a single administration, or alternatively can include a series of administrations. For example, the 1:1 compound (I) tartrate can be administered at least once a week. However, in another embodiment, for a given treatment, the compound can be administered to the subject from about once a week to once a day. 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 disclosed compounds or a combination thereof. It should also be understood that the effective dose of the compound for treatment or prevention can be increased or decreased during the course of a particular treatment or prevention regimen. Changes in dosage can be effected and made apparent by standard diagnostic tests known in the art. In some cases, long-term administration may be required.

[0064] The disclosed compound (I), its salts and polymorphs inhibit HPK1. Thus, generally, the compounds described herein can be used to treat diseases or disorders associated with such kinases.

[0065] In one embodiment, the present disclosure provides a method of inhibiting HPK1 activity in a subject in need of inhibiting HPK1 activity, comprising administering to the subject an effective amount of the compound (I) or tartrate (such as the 1:1 compound (I) tartrate), polymorph or pharmaceutical composition described herein.

[0066] Due to their activity against HPK1, the compounds (I) or tartrates (e.g., 1:1 compound (I) tartrate), polymorphs or pharmaceutical compositions described herein can be used to treat a subject suffering from a disorder associated with abnormal HPK1 activity.

[0067] In one embodiment, the disorder associated with abnormal HPK1 activity is cancer.

[0068] Cancers treatable (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, and ovarian cancer. In one embodiment, the cancer is selected from leukemia, acute myeloid leukemia, chronic myelogenous 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 another embodiment, the cancer is breast cancer, colon cancer, and lung cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is basal sub-type breast cancer or luminal B sub-type breast cancer. In another embodiment, the cancer is basal sub-type breast cancer. In another embodiment, the basal sub-type breast cancer is ER (estrogen receptor), HER2, and PR (progesterone receptor) negative breast cancer. In another embodiment, the cancer is soft tissue cancer. "Soft tissue cancer" is a term well known in the art and includes tumors derived from any soft tissue of the body. Such soft tissue connects, supports, or surrounds various structures and organs of the body, including but not limited to, smooth muscle, skeletal muscle, tendons, fibrous tissue, adipose tissue, blood and lymphatic vessels, perivascular tissue, nerves, interstitial cells, and synovial tissue. Thus, 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 referred to as sarcoma, or soft tissue sarcoma.There are various types of soft tissue tumors, including lipoma, lipoblastoma, hibernoma, liposarcoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, neurofibroma, schwannoma / neurilemoma, neuroma, malignant schwannoma, neurofibrosarcoma, neurogenic sarcoma, nodular tenosynovitis, synovial sarcoma, hemangioma, glomus tumor, hemangiopericytoma, hemangioendothelioma, angiosarcoma, Kaposi's sarcoma, lymphangioma, fibroma, elastofibroma, superficial fibromatosis, fibrous histiocytoma, fibrosarcoma, fibromatosis, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), myxoma, granular cell tumor, malignant stromal tumor, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell sarcoma, and desmoplastic small round cell tumor. In a specific embodiment, the soft tissue cancer is a sarcoma selected from fibrosarcoma, gastrointestinal sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma.

[0069] The present teachings also provide methods of treating an afflicted subject, which include administering to the subject a combination of an effective amount of a compound represented by structural formula (I) and an effective immunomodulatory treatment (also referred to as immunotherapy). Immunotherapy is a disease treatment that utilizes immunomodulators to induce, enhance, or inhibit an immune response. Immunotherapy designed to elicit or expand an immune response is classified as activating immunotherapy, while immunotherapy that reduces or inhibits an immune response is classified as inhibitory immunotherapy. The disease described herein is cancer.

[0070] Immunomodulatory therapies - applied alone or in combination - include i) immune checkpoint blockade inhibitors, including but not limited to, anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies (e.g., Ipilimumab); agents that disrupt PD-1 / PD-L1 and PD-L2 interactions, e.g., Nivolumab (Opdivo - Bristol Myers Squibb), Pembrolizumab (Keytruda, KM-3475, Merck), Pidilizumab (CT-011, CureTech), BMS 936559 (BMS), and MPDL328OA (Roche); and other immune response inhibitory receptors, e.g., anti-CD47; ii) cell-based therapies (including but not limited to, dendritic cell therapies (e.g., Sipuleucel T (Provenge) and adoptive T cell therapies; iii) vaccination strategies; iv) adoptive T cell therapies; 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; and vi) cytokine-based therapies, e.g., interferons (specifically, type I interferons) and interleukins (e.g., interleukin-2).

[0071] In one embodiment, the immunomodulator for immunomodulatory therapy is a PD-1 inhibitor, e.g., an anti-PD1 antibody.

[0072] 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 and is expressed on T cells and progenitor B cells. PD-1 binds two ligands, PD-L1 and PD-L2, both of which are members of the B7 family.

[0073] PD-1 and its ligands play an important role in downregulating the immune system by preventing T cell activation (thereby reducing autoimmunity and promoting self-tolerance). The inhibitory effect of PD-1 is achieved by a dual mechanism that promotes apoptosis (programmed cell death) of antigen-specific T cells in lymph nodes while reducing apoptosis of regulatory T cells (suppressor T cells).

[0074] The PD-1 inhibitors used in the present invention include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL3280A, MSB0010718C or MEDI4736. Among them, BMS 936559, MPDL3280A, MSB0010718C, and MEDI4736 bind to the ligand PD-L1, all of which are antibodies. Nivolumab and pembrolizumab have both been approved by the Food and Drug Administration for the treatment of unresectable or metastatic melanoma that is no longer responsive to other drugs.

[0075] Vaccination strategies include antimicrobial immunotherapy, which includes vaccination and involves activating the immune system in response to an infectious agent.

[0076] Adoptive T cell therapy utilizes T cell-based cytotoxic responses to attack cancer cells. T cells that are naturally or genetically engineered to be reactive to a patient's cancer are generated in vitro and then transferred back into the cancer patient. One study utilizing autologous tumor-infiltrating lymphocytes is an effective treatment for patients with metastatic melanoma. This can be achieved by collecting the T cells found with the patient's tumor and training them to attack cancer cells. Then, using high concentrations of IL-2, anti-CD3, and alloreactive feeder cells, these T cells - called tumor-infiltrating lymphocytes (TILs) - are induced to proliferate in vitro. These T cells are then transferred back into the patient along with exogenous administration of IL-2 (to further increase their anti-cancer activity).

[0077] The present teachings also provide methods of treating a subject having cancer, comprising administering to the subject an effective amount of a compound (I) or tartrate (e.g., 1:1 compound (I) tartrate), polymorph, or pharmaceutical composition described herein in combination with an effective anti-cancer treatment. In one embodiment, the cancer is metastatic cancer. "Metastatic cancer" is cancer that has spread from its primary site to other parts of the body.

[0078] The anti-cancer treatments described herein include co-administering an effective amount of a second anti-cancer agent and an HPK-1 inhibitor of the present disclosure. An "anti-cancer agent" is a compound that, when administered to a cancer-bearing subject in an effective amount, can partially or substantially achieve one or more of the following: arresting cancer growth, reducing the extent of cancer (e.g., reducing tumor size), inhibiting the cancer growth rate, and alleviating or improving cancer-related clinical symptoms or markers (such as tissue or serum components) or increasing the lifespan of the subject.

[0079] Anticancer agents suitable for the methods described herein include any anticancer agent that has been 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 anti-tumor agents, and other anti-tumor agents. In one embodiment, the anticancer agent is a PD-1 inhibitor, for example, an anti-PD1 antibody.

[0080] In one embodiment, the anticancer agents useful in the methods 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.

[0081] In one embodiment, the anticancer agent and compound (I) or the tartrate salt (e.g., 1:1 compound (I) tartrate salt), crystal form, or pharmaceutical composition described herein are administered simultaneously. When administered simultaneously, the anticancer agent and the compound may be administered in the same formulation or in different formulations. Alternatively, the compound and the additional anticancer agent may be administered separately at different times.

[0082] The following examples are intended to be illustrative and not intended to limit the scope of the disclosure in any way.

[0083] Embodiment

[0084] Abbreviations:

[0085] 1 H proton

[0086] aq. aqueous

[0087] br. broad

[0088] DCM dichloromethane

[0089] DVS Dynamic Vapor Sorption

[0090] Equiv Equivalent

[0091] h hour

[0092] HPLC High Performance Liquid Chromatography

[0093] IPA Isopropyl Alcohol

[0094] LC-MS Liquid Chromatography-Mass Spectrometry

[0095] MeOH Methanol

[0096] min minute

[0097] NMR Nuclear Magnetic Resonance

[0098] PLM Polarizing Light Microscopy

[0099] RH Relative Humidity

[0100] rt Room Temperature

[0101] TGA Thermogravimetric Analysis

[0102] THF Tetrahydrofuran

[0103] UPLC Ultra Performance Liquid Chromatography

[0104] XRPD X-Ray Powder Diffraction

[0105] Analysis Conditions

[0106] X-Ray Powder Diffraction (XRPD)

[0107] XRPD analysis was performed using a Bruker D8 Advance X-ray powder diffractometer. The parameters of XRPD are listed below.

[0108]

[0109] Thermogravimetric Analysis (TGA)

[0110] 2 - 5 mg of the material was weighed into an open platinum pan and loaded into a TA Q5000IR thermogravimetric analyzer. Then the sample was heated from 25 °C to 350 °C / 400 °C at a rate of 10 °C / min.

[0111] Differential Scanning Calorimetry (DSC)

[0112] Weigh 0.5 - 1 mg of the material into an aluminum DSC pan and seal it non - gastight with an aluminum lid. Then place the sample pan into a TA Instruments Q2000. Once a stable heat - flow response is obtained at 25 °C, heat the sample and the reference at a rate of 10 °C / min to 350 °C and monitor the resulting heat - flow response.

[0113] 1 H - nuclear magnetic resonance spectroscopy ( 1 H - NMR)

[0114] Record NMR measurements on a Bruker Avance DRX 400 instrument at 400 MHz and room temperature using DMSO - d6 or CD3OD as the solvent without an internal standard.

[0115] HPLC / UPLC methods

[0116] Representative methods for solubility measurement are summarized in Table 1. Representative methods for stability evaluation are summarized in Table 2.

[0117] Table 1. UPLC methods for solubility measurement

[0118]

[0119] Table 2. HPLC methods for stability evaluation

[0120]

[0121]

[0122] Example 1: Initial salt screening

[0123] Perform initial salt screening using 1 or 2 equivalents of HCl, H2SO4, and H3PO4 in a mixture of DCM and MeOH (2:1).

[0124] Dissolve 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) in a 2:1 mixture of DCM and MeOH at 50 °C. Add 1 or 2 equivalents of the acid and stir the resulting solution at room temperature for 3 days, and analyze the resulting salt samples by XRPD.

[0125] Salts with weak crystallinity 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 diffraction pattern of the single HCl salt (batch 1) is shown in Figure 1 in.

[0126] Example 2: Extended Salt Screening

[0127] An extended salt screening was carried out 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.

[0128] 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 the acid were added and the resulting solution was stirred overnight at room temperature. Samples that provided solids were centrifuged, and samples that did not show precipitation were allowed to dry at room temperature. All samples were characterized by 1 1H NMR, PLM, and XRPD.

[0129] The 16 salts isolated showed different birefringences. However, by XRPD, only the 1:1 methanesulfonate, 1:1 maleate, and 1:1 tartrate showed moderate to good crystallinity. The diffraction patterns of the 1:1 methanesulfonate (batch 1) and 1:1 maleate (batch 1) prepared using this method are shown in Figure 2 and Figure 3 respectively. Notably, as shown in Table 3 below, 0.5 equivalent of tartaric acid did not yield the desired hemitartrate (1:0.5) and was therefore not studied further.

[0130] Table 3. 16 salts prepared using 11 pharmaceutically acceptable acids in an extended salt screening

[0131]

[0132] Example 3: Preparation of Selected Salts

[0133] The hydrochloride, methanesulfonate, tartrate, and maleate were prepared using two different solvent systems (acetone and IPA / water (95:5)), respectively.

[0134] 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 suspended in acetone (2 mL) or IPA / water (95:5, 2 mL). The suspension was stirred at 50 °C. The acid (1 equivalent, 0.5 mol / L) was added and the mixture was stirred overnight. The salt was then isolated and dried in vacuo at 30 °C. The resulting salts were characterized by TGA, DSC, and XRPD.

[0135] Two solvent systems produced different polymorphs of hydrochloride (IPA: batch 2; acetone: batch 3), mesylate (IPA: batch 2; acetone: batch 3), and maleate (IPA: batch 2; acetone: batch 3). The diffraction patterns of the separated polymorphs of HCl, mesylate, and maleate are shown in Figure 1 , Figure 2 and Figure 3 respectively. As shown by the XRPD diffraction patterns, the crystallinity of the mesylate and maleate is moderate.

[0136] One polymorph of the 1:1 compound (I) tartrate was isolated using the two solvent systems described in Example 3.

[0137] 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

[0138] 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). A solution of 2 M HCl in Et2O (45 mL, 90.15 mmol) was added slowly at room temperature. The resulting mixture was stirred at room temperature for 60 minutes. Then the solvent was removed in vacuo, and the resulting solid was triturated with Et2O (120 mL) and filtered to give the di-HCl salt as a brown solid. The di-HCl salt was characterized by XRPD and NMR. The XRPD diffraction pattern is shown in Figure 4 which indicates that the crystallinity of the obtained di-HCl salt is very low.

[0139] 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

[0140] 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 of water, 1.78 kg of acetic acid) at 55 to 60 °C. The solution was stirred for 15 to 120 minutes. In a separate reactor, an aqueous solution of L-(+)-tartaric acid was prepared by adding an acid (1.98 kg) to water (14 - 18 kg) at 20 to 30 °C, and the solution was stirred for 15 to 60 minutes. Then the acetic acid solution containing compound (I) was slowly added to the aqueous solution of L-(+)-tartaric acid at 55 to 60 °C. Optionally, seeds were added. The resulting mixture was crystallized at 55 to 60 °C for 12 to 24 hours. Then the mixture was cooled to 20 to 25 °C and stirred for 8 to 16 hours. Then the precipitated product was collected, washed with ethanol, and dried under vacuum at 40 to 60 °C for 3 to 24 hours to obtain the desired product. The title compound was characterized by 1 HNMR, DSC, TGA, and XRPD. The DSC and TGA results are shown in Figure 5 In. The XRPD diffraction pattern is shown in Figure 6 And the results are listed in Table 4.

[0141] Table 4. List of the main peaks and their relative intensities in the XRPD diffraction pattern of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one tartrate (1:1 compound (I) tartrate)

[0142] Angle (2θ) Relative intensity (%) 8.7 7.2 11.9 49.9 12.9 3.0 14.0 33.6 15.4 64.2 16.9 100 17.2 49.6 22.1 28.7 25.6 41.2 26.3 26.9 30.7 29.1 34.0 28.7

[0143] 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).

[0144] Example 6: Hygroscopicity measurement 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

[0145] The hygroscopicity test of the compound to be tested was carried out by a DVS device. The test parameters are shown in Table 5. The hygroscopicity measurement results are shown in Table 6.

[0146] Table 5. Parameters Used in the DVS Device

[0147]

[0148] Table 6. Hygroscopicity Measurement Results

[0149]

[0150] 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

[0151] The test compound was prepared in 3 different media as described below.

[0152] Sample prepared in water: Weigh approximately 30 - 40 mg of the test material into a glass vial. Add 1 mL of water. Stir the sample at ambient temperature for 1 hour and analyze the sample by HPLC at 24 hours.

[0153] Sample prepared in simulated gastric fluid (SGF) buffer: Weigh approximately 40 mg of the test material into a glass vial. Add 4 mL of SGF buffer to a target concentration of 10 mg / mL. Stir the sample at 37 °C for 24 hours and analyze the sample by HPLC at 24 hours.

[0154] Sample prepared in fasting state simulated intestinal fluid (FaSSIF) buffer: Weigh approximately 8 mg of the test material into a glass vial. Add 4 mL of FaSSIF buffer to a target concentration of 2 mg / mL. Stir the sample at 37 °C for 24 hours and analyze the sample by HPLC at 24 hours.

[0155] Stir the sample at ambient temperature for 1 hour or at 37 °C for 24 hours. Then centrifuge the sample and analyze the resulting supernatant by HPLC to determine the solubility. The solubilities of compound (I) and its salts in different media are summarized in Table 7.

[0156] Table 7. Solubilities of Compound (I) and Its Salts in Different Media

[0157]

[0158] 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) Tartrate

[0159] 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) tartrate have been tested. Stability samples were prepared and stored under 3 different storage conditions: 2 - 8 °C / ambient RH, 25 °C / 60% RH, and 40 °C / 75% RH. The stability samples were taken out from the storage conditions in each drawer and the samples were equilibrated to the ambient conditions before analysis. The appearance was evaluated by visual inspection, the purity and total amount of impurities were analyzed by HPLC, and the crystal form was characterized by XRPD. The results are summarized in Table 8.

[0160] Table 8. Long-term stability data of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one tartrate (1:1 compound (I) tartrate)

[0161]

[0162]

[0163] 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

[0164] A single dose of compound (I) as powder in capsules, 1:1 compound (I) monohydrochloride (batch 3), dihydrochloride of compound (I), and 1:1 compound (I) tartrate was administered to male beagle dogs at 125 mg / kg or 150 mg / kg. Blood samples were collected for up to 24 hours and the plasma levels of compound (I) in plasma were analyzed by LC / MS. The results are shown in Table 9.

[0165] Table 9. Pharmacokinetic parameters after oral administration of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (compound (I)) and its salts to beagle dogs

[0166]

Claims

1. The tartrate salt of the compound (I) represented by the following structural formula: wherein the molar ratio between the compound (I) and tartaric acid is 1:

1.

2. The tartrate salt according to claim 1, wherein the 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 2θ.

3. The tartrate salt according to claim 1, wherein the 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 2θ.

4. The tartrate salt according to claim 1, wherein the 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 2θ.

5. The tartrate salt according to claim 2, wherein the tartrate salt is further characterized by an X-ray powder diffraction pattern comprising peaks at 8.7° and 12.9° ± 0.2 2θ.

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

7. The tartrate salt according to any one of claims 1-5, wherein the moisture absorption at 90% relative humidity (RH) measured under the following conditions is less than 4% of the mass of the tartrate salt: i) drying 0.5 to 1.5 mg of the tartrate salt for 2 hours at 0% relative humidity in a nitrogen atmosphere; ii) increasing or decreasing the relative humidity from 0% to 90% and then to 0% in 10% steps; iii) maintaining the relative humidity at each step until the mass change per minute is less than 0.01% / min compared to the original mass of the tartrate salt, provided that the minimum and maximum durations of each step are 10 minutes and 180 minutes, respectively; and iv) measuring the mass of the tartrate salt at 90% relative humidity, and wherein steps i)-iv) are carried out at 25 °C.

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

9. The tartrate salt according to any one of claims 1-5, wherein the moisture absorption at 30% relative humidity (RH) measured under the following conditions is less than 1% of the mass of the tartrate salt: i) drying 0.5 to 1.5 mg of the tartrate salt for 2 hours at 0% relative humidity in a nitrogen atmosphere; ii) increasing or decreasing the relative humidity from 0% to 90% and then to 0% in 10% steps; iii) maintaining the relative humidity at each step until the mass change per minute is less than 0.01% / min compared to the original mass of the tartrate salt, provided that the minimum and maximum durations of each step are 10 minutes and 180 minutes, respectively; and iv) Measure the mass of the tartrate at 30% relative humidity, and wherein steps i)-iv) are carried out at 25 °C.

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

11. The tartrate according to any one of claims 1-5, wherein at least 90% by weight of the tartrate is in single crystal form.

12. A pharmaceutical composition comprising the tartrate according to any one of claims 1-5 and a pharmaceutically acceptable carrier or diluent.

13. Use of the tartrate according to any one of claims 1-11 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating a subject suffering from cancer.

14. Use of the tartrate according to any one of claims 1-11 or the pharmaceutical composition according to claim 12, and an anti-cancer therapeutic agent selected from a chemotherapeutic agent or a targeted therapeutic agent in the preparation of a medicament for treating a subject suffering from cancer.

15. Use of the tartrate according to any one of claims 1-11 or the pharmaceutical composition according to claim 12, and an immunomodulator selected from a checkpoint inhibitor or a tryptophan oxidation inhibitor in the preparation of a medicament for treating a subject suffering from cancer.

16. The use according to claim 15, wherein the checkpoint inhibitor is an anti-PD-1 antibody, an anti-CTLA4 antibody or an anti-PD-L1 antibody.

17. The use according to claim 15, wherein the tryptophan oxidation inhibitor is an IDO1, IDO2 or TDO2 inhibitor.

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