IRAK inhibitor free bases, salts and polymorphs thereof

Abstract

The present disclosure provides crystalline free bases of imidazo [1, 2-b] pyridazine compounds and salts thereof. In some embodiments, the crystalline imidazo [1, 2-b] pyridazine compound is a single crystal. The disclosure also provides methods of using the crystalline forms to treat certain diseases or conditions. Some embodiments include methods of treating hematopoietic cancer, myelodysplastic syndrome (MDS), or acute myelogenous leukemia (AML) using the crystalline forms. Other embodiments provide disease treatment using the crystalline forms in combination with other therapies, such as tumor therapy.

Description

Technical Field

[0001] This disclosure generally relates to crystal forms as kinase inhibitors and their use in the treatment of diseases and conditions, including cancer.

[0002] Cross-reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 499,042, filed April 28, 2023, and U.S. Provisional Patent Application No. 63 / 590,940, filed October 17, 2023, the entire contents of each of which are incorporated herein by reference. Background Technology

[0003] Myelodysplastic syndromes (MDS) are malignant, potentially fatal blood disorders caused by defects in hematopoietic stem cells / progenitor cells. They can induce acute myeloid leukemia (AML) (Corey et al., 2007; Nimer, 2008) and often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). Most MDS patients die from bone marrow failure, immune dysfunction, and / or transformation to overt leukemia.

[0004] MDS is a heterogeneous disease with limited treatment options, lacking effective drugs that provide a durable response. Current treatment options for MDS are limited, including allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapies (Ebert, 2010). While hematopoietic stem cell (HSC) transplantation can be considered a radical treatment for MDS, many elderly patients are ineligible for this option and instead receive supportive care and transfusions to manage disease complications. Unfortunately, even after HSC transplantation, the MDS clone persists in the bone marrow, and disease progression is inevitable (Tehranchi et al., 2010). For advanced or high-risk MDS, patients may also receive immunosuppressive therapy, epigenetic modifying agents, and / or chemotherapy (Greenberg, 2010). Despite recent advances, most MDS patients experience treatment-related toxicities or relapse (Sekeres, 2010a). Overall, the efficacy of these treatments is mixed, typically offering only a slight extension of life expectancy compared to supportive care. The complexity and heterogeneity of MDS, along with the lack of human xenotransplantation models, pose challenges to identifying and evaluating novel molecular targets for the disease.

[0005] Approximately 30% of MDS patients also develop aggressive AML due to additional mutations in defective hematopoietic stem cells / progenitor cells (HSPCs) (Greenberg et al., 1997). AML is a myeloid blood cell cancer characterized by the rapid proliferation and accumulation of abnormal white blood cells in the bone marrow, interfering with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is projected to rise with an aging population. Several risk factors and chromosomal abnormalities have been identified, but the specific etiology remains unclear. As an acute leukemia, AML progresses rapidly and is often fatal within weeks or months if left untreated. AML caused by MDS has a worse prognosis compared to other types of AML.

[0006] Many compounds are known to be used to treat blood disorders and cancers (such as MDS and AML), but their efficacy is often unsatisfactory. While compounds such as quezartinib, gipritinib, and kranab are known to be used to treat AML, some of these treatments fail to achieve complete or partial remission. For example, in some cases, treatment may lead to adaptive resistance or the selection of inhibitor-resistant mutations, such as quezartinib, especially with repeated administration, which may lead to desensitization to tumor cell proliferation inhibition (Melgar et al., 2019).

[0007] In treating MDS and / or AML, there is a need to develop therapies that can inhibit adaptive resistance mechanisms to improve survival associated with AML and MDS. Currently, there are unmet needs in AML, including the need for drugs that can improve overall survival, shorten hospital stays, reduce readmission rates, overcome acquired resistance to other treatments, and improve the success rate of hematopoietic stem cell transplantation. Simultaneously, there is a need for therapeutics that can slow the rate of transformation from MDS to AML and reduce transfusion dependence.

[0008] Therefore, it is necessary to develop effective treatments for MDS and / or AML and / or other conditions or symptoms characterized by IRAK (such as IRAK1 and / or 4) dysregulation (e.g., overactivation). Furthermore, in doing so, it is important to determine the patient's likely response to a particular treatment or therapy. Certain embodiments of this disclosure address one or more of the aforementioned problems. Summary of the Invention

[0009] On the one hand, this disclosure provides the crystal form of the free base of the compound of formula (1): Equation (1), The crystal form is characterized by an X-ray powder diffraction pattern containing one or more peaks at 8.5102±0.2°, 13.4583±0.2°, 16.3830±0.2°, 20.0082±0.2°, and 24.6817±0.2° 2θ. In one embodiment, the crystal form is further characterized by an X-ray powder diffraction pattern containing one or more peaks at 11.2514±0.2°, 16.8018±0.2°, 20.9239±0.2°, 22.2447±0.2°, and 28.6101±0.2° 2θ. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes one or more peaks at 10.2265±0.2°, 17.1029±0.2°, 18.3658±0.2°, 22.6040±0.2°, and 23.6583±0.2° 2θ. In another embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes peaks at 12.4152±0.2°, 15.6546±0.2°, 18.5476±0.2°, 19.1056±0.2°, 19.3265±0.2°, 20.4980±0.2°, 21.3232±0.2°, 23.2420±0.2°, 24.2705±0.2°, 25.8013±0.2°, and 26.1668±0.2°. One or more peaks at 2θ: 2°, 27.1774±0.2°, 27.5557±0.2°, 28.1259±0.2°, 30.1759±0.2°, 31.5240±0.2°, 31.8408±0.2°, 32.3075±0.2°, 32.8563±0.2°, 33.7388±0.2°, 36.0412±0.2°, 36.7705±0.2°, 37.7457±0.2°, and 39.0376±0.2°. In one embodiment, the crystal form comprises a single crystal characterized by one or more of the following: i) monoclinic space group P21; ii) lattice parameters a = 9.5817(11) Å, b = 20.916(2) Å, c = 10.8470(12) Å, α = 90°, β = 114.836(4)°, γ = 90°; iii) a volume of approximately 1972.8(4) Å. 3 ; and / or iv) Crystal density d c =1.348 g / cm 3 .

[0010] On the other hand, this disclosure provides crystal forms of salts of compounds of formula (1): Equation (1), The salt contains a p-toluenesulfonic acid counterion, and the crystal form is characterized by an X-ray powder diffraction pattern containing one or more peaks at 5.1743±0.2°, 8.1663±0.2°, 10.3704±0.2°, 14.4880±0.2°, and 16.8942±0.2° 2θ. In one embodiment, the crystal form is further characterized by an X-ray powder diffraction pattern also containing one or more peaks at 7.0186±0.2°, 11.7589±0.2°, 14.0747±0.2°, 14.2385±0.2°, and 21.1626±0.2° 2θ. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes one or more peaks at 12.5062±0.2°, 13.2636±0.2°, 17.6050±0.2°, 25.1678±0.2° and 26.2810±0.2° 2θ.

[0011] In another aspect, this disclosure provides crystal forms of salts of compounds of formula (1): Equation (1), The salt contains a tartaric acid counterion, and the crystal form is characterized by an X-ray powder diffraction pattern containing one or more peaks at 7.7633±0.2°, 8.2996±0.2°, 12.4661±0.2°, 15.5489±0.2°, and 24.7464±0.2° 2θ. In one embodiment, the crystal form is further characterized by an X-ray powder diffraction pattern also containing one or more peaks at 4.1463±0.2°, 11.3791±0.2°, 17.4289±0.2°, 20.4382±0.2°, and 25.1566±0.2° 2θ. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes one or more peaks at 14.1011±0.2°, 18.6536±0.2°, 19.1095±0.2°, 22.5011±0.2° and 25.4454±0.2° 2θ.

[0012] In another aspect, this disclosure provides crystal forms of salts of compounds of formula (1): Equation (1), The salt contains a methanesulfonic acid counterion, and the crystal form is characterized by an X-ray powder diffraction pattern containing one or more peaks at 13.8951±0.2°, 15.8697±0.2°, 18.4951±0.2°, 19.5773±0.2°, and 21.5492±0.2° 2θ. In one embodiment, the crystal form is further characterized by an X-ray powder diffraction pattern containing one or more peaks at 10.7336±0.2°, 16.2453±0.2°, 21.7550±0.2°, 22.5396±0.2°, and 23.8137±0.2° 2θ. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes one or more peaks at 9.4332±0.2°, 15.3077±0.2°, 25.6827±0.2°, 27.3636±0.2° and 28.4083±0.2° 2θ.

[0013] On the other hand, this disclosure provides crystal forms of salts of compounds of formula (1): Equation (1), The salt contains a benzenesulfonic acid counterion, and the crystal form is characterized by an X-ray powder diffraction pattern containing peaks at 13.3296±0.2°, 14.2875±0.2°, 14.6072±0.2°, 17.6593±0.2°, and 20.4010±0.2° 2θ. In one embodiment, the crystal form is further characterized by an X-ray powder diffraction pattern containing one or more peaks at 8.8966±0.2°, 11.2206±0.2°, 12.2073±0.2°, 25.5863±0.2°, and 27.1334±0.2° 2θ. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes one or more peaks at 6.0882±0.2°, 14.1225±0.2°, 16.6160±0.2°, 21.5845±0.2° and 21.9720±0.2° 2θ.

[0014] On the other hand, the crystal form of the salt of compound (1): Equation (1), The salt contains a monohydrochloric acid counterion, and the crystal form is characterized by an X-ray powder diffraction pattern containing peaks at 6.8619±0.2°, 11.3373±0.2°, 14.5399±0.2°, 17.1417±0.2°, and 23.6521±0.2° 2θ. In one embodiment, the crystal form is further characterized by an X-ray powder diffraction pattern containing one or more peaks at 14.7217±0.2°, 16.2725±0.2°, 22.4223±0.2°, 23.3316±0.2°, and 28.8331±0.2° 2θ. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes one or more peaks at 2.0916±0.2°, 11.1062±0.2°, 20.9023±0.2°, 21.9400±0.2° and 27.5840±0.2° 2θ. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes 11.6132 ± 0.2°, 13.7106 ± 0.2°, 14.3405 ± 0.2°, 15.3177 ± 0.2°, 17.5260 ± 0.2°, 17.6282 ± 0.2°, 18.8337 ± 0.2°, 20.0236 ± 0.2°, 20.8136 ± 0.2°, 21.0463 ± 0.2°, 22.9619 ± 0.2°, 24.4120 ± 0.2°, 24.9258 ± 0.2°, 26.0850 ± 0.2°, 26.7151 ± 0.2°, One or more peaks at 2θ: 26.9745 ± 0.2°, 27.2880 ± 0.2°, 27.8954 ± 0.2°, 28.1817 ± 0.2°, 28.3383 ± 0.2°, 29.2852 ± 0.2°, 29.8645 ± 0.2°, 32.2115 ± 0.2°, 33.1644 ± 0.2°, 33.5088 ± 0.2°, 33.8427 ± 0.2°, 34.6622 ± 0.2°, 35.6915 ± 0.2°, 36.3485 ± 0.2°, 37.3533 ± 0.2°, and 38.0511 ± 0.2°. In one embodiment, the crystal form has formula (2): Equation (2).

[0015] It contains dihydrochloric acid counterions and has the crystal form described herein.

[0016] In one embodiment, this disclosure provides the crystal form described herein, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4 and FLT3, and / or wherein the compound is an inhibitor of IRAK1 and IRAK4 and not an inhibitor of FLT3. In one embodiment, this disclosure provides a crystal form described herein, wherein: the water content of the crystal form is less than or equal to about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%; and the crystal form contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of formula (1). (R)-enantiomer; the crystal form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0% or about 0.5% of the (1) (S)-enantiomer; and / or the crystal form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5% or about 0.25% of impurities.In one embodiment, this disclosure provides that, after storage for 6 months at about 25°C and about 60% relative humidity, or for 6 months at about 40°C and about 75% relative humidity, the water content of the crystal form is less than or equal to about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%. %; the crystal form contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0% or about 99.5% of the enantiomer of formula (1) (R); the crystal form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0% or about 0.5% of the enantiomer of formula (1) (S); and / or the crystal form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5% or about 0.25% of impurities.

[0017] In another aspect, this disclosure provides a pharmaceutical composition comprising the crystal form described herein, as well as a formulation ingredient, adjuvant, or carrier. In one embodiment, the pharmaceutical composition comprises about 0.1 mg to 10,000 mg, about 1.0 mg to about 9,000 mg, about 1.0 mg to about 8,000 mg, about 1.0 mg to about 7,000 mg, about 1.0 mg to about 6,000 mg, about 1.0 mg to about 5,000 mg, about 1.0 mg to about 4,000 mg, about 1.0 mg to about 3,000 mg, about 1.0 mg to about 2,000 mg, about 1.0 mg to about 1,500 mg, about 1.0 mg to about 1,000 mg, about 1.0 mg to about 750 mg, about 1.0 mg to about 700 mg, about 1.0 mg to about 650 mg, about 1.0 mg to about 600 mg, about 1.0 mg to about 550 mg, about 1.0 mg to about 500 mg, about 1.0 mg to about 450 mg, about 1.0 mg to about 400 mg, about 1.0 mg to about 450 mg. The crystal form is described in mg to about 350 mg, about 1.0 mg to about 300 mg, about 1.0 mg to about 250 mg, about 1.0 mg to about 200 mg, about 1.0 mg to about 150 mg, or about 1.0 mg to about 100 mg. In one embodiment, the pharmaceutical composition comprises amounts equivalent to about 0.1 mg to 10,000 mg, about 1.0 mg to about 9,000 mg, about 1.0 mg to about 8,000 mg, about 1.0 mg to about 7,000 mg, about 1.0 mg to about 6,000 mg, about 1.0 mg to about 5,000 mg, about 1.0 mg to about 4,000 mg, about 1.0 mg to about 3,000 mg, about 1.0 mg to about 2,000 mg, about 1.0 mg to about 1,500 mg, about 1.0 mg to about 1,000 mg, about 1.0 mg to about 750 mg, about 1.0 mg to about 700 mg, about 1.0 mg to about 650 mg, about 1.0 mg to about 600 mg, about 1.0 mg to about 550 mg, about 1.0 mg to about 500 mg, about 1.0 mg to about 450 mg, about 1.0 mg to about 400 mg, and about 1.0 mg to about 400 mg. The amount of free base in crystalline form is approximately 350 mg to about 350 mg, about 1.0 mg to about 300 mg, about 1.0 mg to about 250 mg, about 1.0 mg to about 200 mg, about 1.0 mg to about 150 mg, or about 1.0 mg to about 100 mg. In one embodiment, the pharmaceutical composition is a solid dosage form. In one embodiment, the pharmaceutical composition is a capsule.In one embodiment, the water content of the pharmaceutical composition is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.0 wt.%, about 1.0 wt.%, about 0.5 wt.%, or about 0.25 wt.%; the pharmaceutical composition contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of formula (1). (R)-enantiomer crystal form; the pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0% or about 0.5% of formula (1) (S)-enantiomer crystal form; and / or the pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5% or about 0.25% of impurities. In one embodiment, after storage for 3 months at about 25°C and about 60% relative humidity, or after storage for 3 months at about 40°C and about 75% relative humidity: the water content of the pharmaceutical composition is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.0 wt.%, about 1.0 wt.%, about 0.5 wt.%, or about 0.25 wt.%; the pharmaceutical composition contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of formula (1). (R)-enantiomer crystal form; the pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0% or about 0.5% of formula (1) (S)-enantiomer crystal form; and / or the pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5% or about 0.25% of impurities.

[0018] In another aspect, this disclosure provides a method for treating a subject's disease or condition, the method comprising administering to the subject a crystalline form or a pharmaceutical composition described herein, comprising a therapeutically effective amount of the compound. In one embodiment, the administration includes parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In one embodiment, the therapeutically effective amount of the compound is from about 0.005 mg / kg of subject body weight to about 1,000 mg / kg of subject body weight. In one embodiment, the pharmaceutical composition disintegrates in the subject's gastrointestinal tract within about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute. In one embodiment, the disease or condition includes hematopoietic system cancer. In one embodiment, the disease or condition includes myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). In one embodiment, the MDS includes an MDS with splicing factor mutations, an MDS with isocitrate dehydrogenase 1 mutations, or an MDS with isocitrate dehydrogenase 2 mutations; the AML includes relapsed AML, refractory AML, relapsed / refractory AML, AML resistant to hypomethylators, AML resistant to venetoclax, AML resistant to both hypomethylators and venetoclax, monocyte AML, or monocyte-like AML; or the AML includes AML with splicing factor mutations, AML with enhanced IRAK4-long expression and / or activity relative to IRAK4-short, and / or wherein the AML is not driven by an FLT3 mutation but expresses IRAK4-long. In one embodiment, the MDS with splicing factor mutations includes an MDS with U2AF1, SRSF2, SF3B1, or ZRSR2 splicing factor mutations; or the AML splicing factor mutations include AML with U2AF1 or SF3B1 splicing factor mutations. In one embodiment, the disease or condition includes lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma. In one embodiment, the disease or condition includes at least one of the following cancers: glioblastoma multiforme, myelofibrosis, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, gastric cancer, and uterine cancer.In one embodiment, the disease or condition includes one or more inflammatory diseases or autoimmune diseases selected from: chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, Crohn's disease, colitis, and atopic dermatitis. In one embodiment, the disease or condition includes diffuse large B-cell lymphoma (DLBCL), wherein the DLBCL includes the L265P MYD88 mutant (ABC) subtype of DLBCL or the S219C MYD88 mutant (GCB) subtype of DLBCL. In one embodiment, the disease or condition is an FLT3 inhibitor-resistant disease or condition. In one embodiment, the disease or condition is FLT3 inhibitor-resistant acute myeloid leukemia (AML), FLT3 inhibitor-resistant refractory acute myeloid leukemia (AML), or FLT3 inhibitor-resistant relapsed acute myeloid leukemia (AML). In one embodiment, the method further includes administering to the subject one or more adjunctive therapies selected from: chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, and so on. Slipperyone receptor antagonists, ERK inhibitors (including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors), PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura A inhibitors, aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT 1, 2 and / or 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, and multi-kinase inhibitors.In one embodiment, the adjunctive therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, and a DNA methyltransferase inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, the BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof, the glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt thereof, the CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1, and / or the CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt thereof, or the DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof. In one implementation, the disease or condition is: a BCL2 inhibitor-resistant disease or condition, a venetoclax-resistant disease or condition, a BTK inhibitor-resistant disease or condition, an ibrutinib-resistant disease or condition, a disease or condition sensitive to anti-inflammatory glucocorticoids, dexamethasone, methylprednisolone, or prednisolone, a CDK inhibitor-resistant disease or condition, a palbociclib, THZ1, BAY 12511152, or atuveciclib-resistant disease or condition, a DNA methyltransferase inhibitor-resistant disease or condition, an azacitidine-resistant disease or condition, a BCL2 inhibitor and a DNA methyltransferase inhibitor-resistant disease or condition, or a venetoclax and azacitidine-resistant disease or condition. In one embodiment, the disease or condition is BCL2 inhibitor-resistant acute myeloid leukemia (AML), venetoclax-resistant AML, BCL2 inhibitor-resistant refractory AML, venetoclax-resistant refractory AML, BCL2 inhibitor-resistant relapsed AML, or venetoclax-resistant relapsed AML. In one embodiment, the crystal form or composition described herein is administered in a single dose or in a single composition with one or more adjunctive therapies. In one embodiment, the crystal form or composition described herein is administered separately in more than a single dose or in more than a single composition with one or more adjunctive therapies. In one embodiment, the disease or condition is relieved by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject. Attached Figure Description

[0019] Figure 1A-1H The results are for characterization of the raw materials. Figure 1A PLM image of raw material with a purity of approximately 82%. Figure 1B PLM image of raw material with a purity of approximately 98%. Figure 1C PXRD patterns of raw materials with a purity of approximately 98% (top image) and raw materials with a purity of approximately 82% (bottom image). Figure 1D TGA and DSC graphs of raw material with a purity of approximately 82%. Figure 1E TGA and DSC graphs of raw material with a purity of approximately 98%. Figure 1F Raw materials with a purity of approximately 82% 1 HNMR spectrum. Figure 1G Raw materials with a purity of approximately 98% 1 HNMR spectrum. Figure 1H HPLC-UV chromatograms of raw materials with a purity of approximately 82% (top image) and approximately 98% purity (bottom image).

[0020] Figures 2A-2E The characterization results are for free alkali (FB) obtained from raw materials with a purity of approximately 82%. Figure 2A FB in MeOD-6 before vacuum drying (VD) 1 HNMR. Figure 2B FB in DMSO-6 before vacuum drying 1 HNMR. Figure 2C FB in MeOD-6 after vacuum drying 1 HNMR. Figure 2D After vacuum drying (step 19 in Table 1), FB in DMSO-6 1 HNMR. Figure 2E HPLC of FB after vacuum drying (VD).

[0021] Figures 3A-3E The characterization results are for FB (batch 1011-59-1) after vacuum drying. Figure 3A :FB image. Figure 3B : FB's PLM image. Figure 3C PXRD pattern of FB. Figure 3D a) SM, b) FB before VD (batch 1011-59-1), and c) FB after VD (batch 1011-59-1) 1 HNMR overlay image. Figure 3E TGA-DSC thermal analysis diagram of FB (batch 1011-62-4) after VD.

[0022] Figure 4 The image shows the HPLC-UV chromatogram of the raw material (initial intermediate method, purity 81.6%).

[0023] Figures 5A-5C The results are based on the UV, TIC, and MS characterization of the raw material (developed method, purity 81.8%). Figure 5A UV & TIC chromatogram of the raw material. Figure 5B : UV spectrum of the raw material. Figure 5C MS image of the raw material.

[0024] Figures 6A-6CThe UV, TIC, and MS characterization results are for FB (batch 1011-62-4). Figure 6A UV and TIC chromatograms of FB (batch 1011-62-4). Figure 6B UV spectrum of FB (batch 1011-62-4). Figure 6C MS of FB (batch 1011-62-4).

[0025] Figures 7A-7F The results are LCMS and MS characterizations of the raw materials. Figures 7A-7B LCMS spectrum of the raw material. Figures 7C-7D MS of raw materials at different retention times. Figure 7E-7F MS of the two main LCMS raw material peaks.

[0026] Figures 8A-8F The results are LCMS and MS characterizations of FB (batch 1011-62-4). Figures 8A-8B : LCMS spectrum of FB. Figure 8C-8D MS of FB under different retention times. Figure 8E-8F MS of the two main LCMS FB peaks.

[0027] Figure 9 The HPLC calibration curve is based on FB (batch 1011-74-1) as the reference standard.

[0028] Figures 10A-10C Characterization of FB (batch 1011-70-2) after vacuum drying and results of an attempt to purify FB using TLC. Figure 10A Image of FB recovered after vacuum drying. Figure 10B TLC results (Experiment 1011-65-6) image. Figure 10C : Recycle FB's TGA-DSC overlay image.

[0029] Figure 11A-11C Characterization results for recovering FB (batch 1011-70-2). Figure 11A Recovery of FB in deuterated dichloromethane before vacuum drying 1 HNMR spectrum. Figure 11B FB is recovered after vacuum drying. 1 HNMR spectrum. Figure 11C HPLC-UV chromatogram of FB recovered after vacuum drying.

[0030] Figures 12A-12C Characterization results of FB (batch 1011-74-1) obtained by salt decomposition of TSA-1. Figure 12A : FB's 1 HNMR spectrum. Figure 12B : HPLC chromatogram of FB. Figure 12C : FB's TGA-DSC overlay image.

[0031] Figures 13A-13F Table 6 shows the HPLC-UV chromatograms related to the stability experiment. Figure 13A HPLC-UV chromatogram of raw material (top) and HPLC-UV chromatogram of FB (batch 1011-62-4) (bottom). Figure 13B HPLC-UV chromatogram of FB (batch 1011-63-4) (top) and HPLC-UV chromatogram of FB (batch 1011-63-1) (bottom). Figure 13C : FB (batch 1011-63-2) HPLC-UV chromatogram. Figure 13D HPLC-UV chromatogram of buffer solution with initial pH 3.0 (pH 7.83 after weekend). Figure 13E : FB (batch 1011-63-3) HPLC-UV chromatogram. Figure 13F HPLC-UV chromatogram of buffer solution with initial pH 4.0 (pH 7.88 after weekend).

[0032] Figure 14 Table 7 shows the PXRD overlay images of the solids obtained from the experiment.

[0033] Figures 15A-15B Characterization results for FB (batch 1011-84-1) obtained from raw materials with a purity of approximately 98%. Figure 15A FB after vacuum drying 1 HNMR. Figure 15B TGA-DSC overlay image of FB after vacuum drying.

[0034] Figure 16 PXRD overlay images of a) amorphous FB (batch 1011-84-1), b) product after TGA, and c) product in experiment 1011-85-5.

[0035] Figure 17A-17G Characterization results for FB-1 (batch 1011-85-5). Figure 17A : FB-1's PLM. Figure 17B PXRD pattern of FB-1. Figure 17C : FB-1 after TGA 1 HNMR spectrum. Figure 17D HPLC-UV chromatogram of FB-1 (purity 98.88%). Figure 17E TGA-DSC of FB-1. TGA: 0.334% weight loss up to 100℃, decomposition at 200℃. DSC: First endothermic peak at 157.54℃. Figure 17FFB-1's DVS (weight gain of 2.238% at 80% relative humidity (RH), hygroscopic). Figure 17G PXRD pattern of FB-1 after DVS.

[0036] Figure 18 PXRD overlay plots for a) FB-1, b) 1011-94-1, c) 1011-94-2, d) 1011-94-3, e) 1011-94-4, f) 1011-94-5, g) 1011-94-6, h) 1011-94-7, i) 1011-94-8, j) 1011-94-9, k) 1011-94-10, l) 1011-94-11, m) 1011-94-12, n) 1011-94-13, o) 1011-94-14 and p) ACE-1:1011-94-15 (Experiments in Table 10).

[0037] Figures 19A-19C Characterization results for ACE-1 (batch 1011-94-15). Figure 19A ACE-1 after overnight vacuum drying 1 HNMR spectrum. Figure 19B PXRD pattern of ACE-1. Figure 19C TGA-DSC superimposed plot of ACE-1. TGA: Weight loss of 0.864% to 100℃, decomposition at 100℃. DSC: First endothermic peak at 110.70℃, second endothermic peak at 146.29℃.

[0038] Figures 20A-20C Characterization results for ACE-2 (batch 1011-99-16). Figure 20A PXRD pattern of ACE-2. Figure 20B ACE-2 1 HNMR. Figure 20C TGA-DSC overlay plot of ACE-2. TGA: Weight loss of 0.746% to 100℃, decomposition at 100℃. DSC: First endothermic peak at 143.16℃.

[0039] Figure 21 PXRD overlay plots for a) FB-1, b) 1011-91-1, c) 1011-91-2, d) 1011-91-3 and d) 1011-91-4 (Experiments in Table 13).

[0040] Figures 22A-22F The results are the stability assessment results of the FB-1 reference standard at time point t0. Figure 22A FB-1 reference standard stored open at 25℃ / 60% RH. Figure 22BFB-1 reference standard stored open at 40℃ / 75% RH. Figure 22C FB-1 reference standard stored at 60°C (open plate). Figure 22D FB-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 22E FB-1 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 22F FB-1 reference standard stored in a closed dish at 60°C.

[0041] Figures 23A-23F The results show the stability assessment of the FB-1 control at a 1-week time point. Figure 23A FB-1 reference standard stored open at 25℃ / 60% RH. Figure 23B FB-1 reference standard stored open at 40℃ / 75% RH. Figure 23C FB-1 reference standard stored at 60°C (open plate). Figure 23D FB-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 23E FB-1 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 23F FB-1 reference standard stored in a closed dish at 60°C.

[0042] Figures 24A-24F The results are the stability assessment results of the FB-1 control at a 2-week time point. Figure 24A FB-1 reference standard stored open at 25℃ / 60% RH. Figure 24B FB-1 reference standard stored open at 40℃ / 75% RH. Figure 24C FB-1 reference standard stored at 60°C (open plate). Figure 24D FB-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 24E FB-1 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 24F FB-1 reference standard stored in a closed dish at 60°C.

[0043] Figure 25A-25F The results show the stability assessment of FB-1 at a 1-week time point. Figure 25A Store in FB-1 at 25°C / 60% RH. Figure 25B Store in FB-1 at 40℃ / 75% RH. Figure 25C Store in FB-1 at 60°C after opening. Figure 25D Store in sealed dish at 25°C / 60% RH in FB-1. Figure 25E Store in sealed dish at 40°C / 75% RH in FB-1. Figure 25F Store in a sealed dish at 60°C in FB-1.

[0044] Figures 26A-26F The results show the stability assessment of FB-1 at a 2-week time point. Figure 26A Store in FB-1 at 25°C / 60% RH. Figure 26B Store in FB-1 at 40℃ / 75% RH. Figure 26C Store in FB-1 at 60°C after opening. Figure 26D Store in sealed dish at 25°C / 60% RH in FB-1. Figure 26E Store in sealed dish at 40°C / 75% RH in FB-1. Figure 26F Store in a sealed dish at 60°C in FB-1.

[0045] Figures 27A-27B This is a PXRD overlay plot of FB-1 used in stability assessment. Figure 27A PXRD patterns of FB-1 and samples taken at week 1: (a) FB-1, (b) 1011-90-1A-1w, (c) 1011-90-1B-1w, (d) 1011-90-1C-1w, (e) 1011-90-1D-1w, (f) 1011-90-1E-1w, (g) 1011-90-1F-1w. Figure 27B PXRD patterns of FB-1 and samples taken 2 weeks ago: (a) FB-1, (b) 1011-90-1A-2w, (c) 1011-90-1B-2w, (d) 1011-90-1C-2w, (e) 1011-90-1D-2w, (f) 1011-90-1E-2w, (g) 1011-90-1F-2w.

[0046] Figure 28 : 106 atomic labeling diagram of compounds used for pKa prediction.

[0047] Figures 29A-29B PLM images for salt screening #1 (Experiment 16 in Table 16). Figure 29A PLM images of the first 18 slurries after overnight mixing. Figure 29B Images of four other slurries after the weekend mixing.

[0048] Figures 30A-30D Table 16 shows the PXRD patterns of the four salts used in the experiment. Figure 30A a) PXRD overlay images of fumaric acid and b) residual fumaric acid (1011-66-6B_wc) obtained from MeCN. Figure 30B :a) PXRD overlay of citric acid and b) residual citric acid (1011-66-7B_wc) obtained from MeCN. Figure 30Ca) pTSA, b) pTSA salt obtained from EtOAc (TSA-1:1011-66-3D_wc), c) PXRD overlay of pTSA salt obtained from 9:1 acetone:water (TSA-1:1011-66-3E_wc). Figure 30D PXRD overlays of tartaric acid and tartrate obtained from 9:1 acetone:water (TAR-1:1011-66-5E_wc).

[0049] Figures 31A-31F Characterization results for TSA-1 (batch 1011-89-1). Figure 31A : TSA-1 PLM. Figure 31B DVS of TSA-1 (3.954% weight gain at 80% RH, non-hygroscopic). Figure 31C PXRD pattern of TSA-1. Figure 31D TGA-DSC overlay plot of TSA-1. TGA: Weight loss of 3.165% to 100℃, decomposition at 250℃. DSC: First endothermic peak at 64.14℃, second endothermic peak (melting point) at 122.17℃. Figure 31E TSA-1 1 HNMR spectrum. Figure 31F HPLC-UV chromatogram of TSA-1.

[0050] Figures 32A-32E Characterization results for TAR-1 (batch 1011-89-2). Figure 32A : TAR-1's PLM. Figure 32B DVS of TAR-1 (8.046% weight gain at 80% RH). Figure 32C PXRD pattern of TAR-1. Figure 32D TGA-DSC overlay plot of TAR-1. TGA: Weight loss of 5.426% to 100℃, decomposition at 200℃. DSC: First endothermic peak at 60.69℃, second endothermic peak at 125.62℃, third endothermic peak at 177.08℃. Figure 32E TAR-1 1 HNMR spectrum.

[0051] Figure 33 PXRD overlay images of experiments 1011-71-3 to 1011-71-10 (Table 20).

[0052] Figure 34A-34I The HPLC-UV chromatograms of the TSA-1 polymorph screening described in Table 20 are shown. Figure 34A HPLC-UV chromatogram of TSA-1 (batch 1011-68-1). Figure 34BHPLC-UV chromatogram of TSA-1 polymorph obtained from iPAc. Figure 34C HPLC-UV chromatogram of the TSA-1 polymorph obtained from EtOAc. Figure 34D HPLC-UV chromatogram of TSA-1 polymorph obtained from MeCN. Figure 34E HPLC-UV chromatogram of TSA-1 polymorph obtained from MEK. Figure 34F HPLC-UV chromatogram of TSA-1 polymorph obtained from MTBE. Figure 34G HPLC-UV chromatogram of TSA-1 polymorph obtained from THF. Figure 34H HPLC-UV chromatogram of the TSA-1 polymorph obtained from water. Figure 34I HPLC-UV chromatogram of the TSA-1 polymorph obtained from acetone.

[0053] Figures 35A-35F Characterization results for TSA-2 (batch 1011-75-2). Figure 35A : TSA-2 PLM. Figure 35B DVS of TSA-2 (3.193% weight gain at 80% RH, hydrate). Figure 35C PXRD pattern of TSA-2. Figure 35D TGA-DSC overlay plot of TSA-2. TGA: Weight loss 3.334% (room temperature to 100℃), decomposes at 250℃. DSC: First endothermic peak 54.27℃, second endothermic peak (TSA-1 melting point) 124.83℃, third endothermic peak (TSA-2 melting point) 175.23℃. Figure 35E TSA-2 1 HNMR spectrum. Figure 35F HPLC-UV chromatogram of TSA-2.

[0054] Figures 36A-36B The PXRD pattern of TSA salt. Figure 36A PXRD overlay images of TSA-1 and TSA-2. Figure 36B a) PXRD overlay plots of TSA-1, b) TSA-2, c) 1011-91-5, d) 1011-91-6, e) 1011-91-7, f) 1011-91-8, g) FB-1, h) pTSA (Experiment 23).

[0055] Figures 37A-37B Characterization results for TSA-3 (batch 1011-91-8). Figure 37A PXRD pattern of TSA-3. Figure 37B TSA-3 1HNMR spectrum.

[0056] Figures 38A-38C Two-week stability study data for TSA-2 (lot 1011-88-3) and TAR-1 (lot 1011-88-5). Figure 38A Summary of stability assessments for TSA-2 and TAR-1. Figure 38B PXRD overlay images of TSA-2 and samples taken at week 1: (a) TSA-2, (b) 1011-90-2A-1w, (c) 1011-90-2B-1w, (d) 1011-90-2C-1w, (e) 1011-90-2D-1w, (f) 1011-90-2E-1w, (g) 1011-90-2F-1w. Figure 38C PXRD overlay images of TSA-2 and samples taken 2 weeks ago: (a) TSA-2, (b) 1011-90-2A-2w, (c) 1011-90-2B-2w, (d) 1011-90-2C-2w, (e) 1011-90-2D-2w, (f) 1011-90-2E-2w, (g) 1011-90-2F-2w.

[0057] Figures 39A-39F The results show the stability assessment of the TSA-2 reference standard at time point t0. Figure 39A TSA-2 reference standard stored open at 25℃ / 60% RH. Figure 39B TSA-2 reference standard stored open at 40℃ / 75% RH. Figure 39C : TSA-2 reference standard stored open at 60℃. Figure 39D TSA-2 reference standard stored in closed dishes at 25°C / 60% RH. Figure 39E TSA-2 reference standard stored in closed dishes at 40°C / 75% RH. Figure 39F TSA-2 reference standard stored in a closed dish at 60°C.

[0058] Figure 40A-40F The results show the stability assessment of the TSA-2 reference standard at a 1-week time point. Figure 40A TSA-2 reference standard stored open at 25℃ / 60% RH. Figure 40B TSA-2 reference standard stored open at 40℃ / 75% RH. Figure 40C : TSA-2 reference standard stored open at 60℃. Figure 40D TSA-2 reference standard stored in closed dishes at 25°C / 60% RH. Figure 40E TSA-2 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 40F TSA-2 reference standard stored in a closed dish at 60°C.

[0059] Figure 41A-41F The results show the stability assessment of the TSA-2 reference standard at a 2-week time point. Figure 41A TSA-2 reference standard stored open at 25℃ / 60% RH. Figure 41B TSA-2 reference standard stored open at 40℃ / 75% RH. Figure 41C : TSA-2 reference standard stored open at 60℃. Figure 41D TSA-2 reference standard stored in closed dishes at 25°C / 60% RH. Figure 41E TSA-2 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 41F TSA-2 reference standard stored in a closed dish at 60°C.

[0060] Figures 42A-42F The results of the stability assessment of TSA-2 (batch 1011-88-3) at the 1-week time point. Figure 42A Store in TSA-2 at 25°C / 60% RH. Figure 42B Store in TSA-2 at 40°C / 75% RH. Figure 42C Store in TSA-2 at 60°C after opening. Figure 42D Store in a closed dish at 25°C / 60% RH in TSA-2. Figure 42E Store in a closed dish at 40°C / 75% RH in TSA-2. Figure 42F Store in a sealed dish at 60°C in TSA-2.

[0061] Figures 43A-43F The results are the stability assessment results for TSA-2 (batch 1011-88-3) at a 2-week time point. Figure 43A Store in TSA-2 at 25°C / 60% RH. Figure 43B Store in TSA-2 at 40°C / 75% RH. Figure 43C Store in TSA-2 at 60°C after opening. Figure 43D Store in a closed dish at 25°C / 60% RH in TSA-2. Figure 43E Store in a closed dish at 40°C / 75% RH in TSA-2. Figure 43F Store in a sealed dish at 60°C in TSA-2.

[0062] Figures 44A-44B PXRD overlay plot for TAR-1 stability assessment. Figure 44APXRD overlay images of TAR-1 and samples taken at week 1: (a) TAR-1, (b) 1011-90-3A-1w, (c) 1011-90-3B-1w, (d) 1011-90-3C-1w, (e) 1011-90-3D-1w, (f) 1011-90-3E-1w, (g) 1011-90-3F-1w. Figure 44B PXRD overlay images of TAR-1 and samples taken at 2 weeks: (a) TAR-1, (b) 1011-90-3A-2w, (c) 1011-90-3B-2w, (d) 1011-90-3C-2w, (e) 1011-90-3D-2w, (f) 1011-90-3E-2w, (g) 1011-90-3F-2w.

[0063] Figure 45A-45F The results are the stability assessment results of the TAR-1 reference standard at time point t0. Figure 45A TAR-1 reference standard stored open at 25℃ / 60% RH. Figure 45B TAR-1 reference standard stored open at 40℃ / 75% RH. Figure 45C TAR-1 reference standard stored at 60℃ (open plate). Figure 45D TAR-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 45E TAR-1 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 45F TAR-1 reference standard stored in closed dishes at 60°C.

[0064] Figures 46A-46F The results show the stability assessment of the TAR-1 reference standard at a 1-week time point. Figure 46A TAR-1 reference standard stored open at 25℃ / 60% RH. Figure 46B TAR-1 reference standard stored open at 40℃ / 75% RH. Figure 46C TAR-1 reference standard stored at 60℃ (open plate). Figure 46D TAR-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 46E TAR-1 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 46F TAR-1 reference standard stored in closed dishes at 60°C.

[0065] Figures 47A-47F The results are the stability assessment results of the TAR-1 reference standard at a 2-week time point. Figure 47A TAR-1 reference standard stored open at 25℃ / 60% RH. Figure 47B TAR-1 reference standard stored open at 40℃ / 75% RH. Figure 47CTAR-1 reference standard stored at 60℃ (open plate). Figure 47D TAR-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 47E TAR-1 reference standard stored in closed dishes at 40℃ / 75% RH. Figure 47F TAR-1 reference standard stored in closed dishes at 60°C.

[0066] Figures 48A-48F The results are the stability assessment results for TAR-1 (batch 1011-88-5) at the 1-week time point. Figure 48A Store in TAR-1 at 25°C / 60% RH. Figure 48B Store in TAR-1 at 40℃ / 75% RH. Figure 48C Store in TAR-1 at 60°C. Figure 48D Store in a closed dish at 25°C / 60% RH in TAR-1. Figure 48E Store in a closed dish at 40°C / 75% RH in TAR-1. Figure 48F Store in a sealed dish at 60°C in TAR-1.

[0067] Figures 49A-49F The results are the stability assessment results for TAR-1 (batch 1011-88-5) at a 2-week time point. Figure 49A Store in TAR-1 at 25°C / 60% RH. Figure 49B Store in TAR-1 at 40℃ / 75% RH. Figure 49C Store in TAR-1 at 60°C. Figure 49D Store in a closed dish at 25°C / 60% RH in TAR-1. Figure 49E Store in a closed dish at 40°C / 75% RH in TAR-1. Figure 49F Store in a sealed dish at 60°C in TAR-1.

[0068] Figure 50 PLM images of the slurry obtained from the experiment are provided in Table 27.

[0069] Figures 51A-51E The image shows the PXRD pattern and DSC-TGA overlay of BSA-1 (batch 1011-79-1). Figure 51APXRD overlay images of BSA, BSA salt obtained from THF (wet cake, 1011-79-1C_wc), BSA salt obtained from THF after vacuum drying (1011-79-1C_pw), BSA salt obtained from EtOAc (wet cake, 1011-79-1D_wc), BSA salt obtained from EtOAc after vacuum drying (1011-79-1C_pw), BSA salt obtained from MeCN (wet cake, 1011-79-1B_wc), and BSA salt obtained from MeCN after vacuum drying (1011-79-1B_pw). Figure 51B PXRD pattern of BSA-1. Figure 51C : DSC-TGA overlay image of BSA-1 obtained from MeCN. Figure 51D : DSC-TGA overlay image of BSA-1 obtained from THF. Figure 51E : DSC-TGA overlay image of BSA-1 obtained from EtOAc.

[0070] Figures 52A-52B Table 27 shows the PXRD patterns of the ESA salts obtained from the experiment. Figure 52A a) PXRD overlay images of ESA salt obtained from EtOAc (wet cake, ESA-1, batch 1101-79-2, 1011-79-2D_wc) and b) ESA salt obtained from EtOAc after vacuum drying (1011-79-2D_pw). Figure 52B PXRD pattern of ESA-1.

[0071] Figure 53 PXRD overlay images of a) L-aspartic acid, b) FB-1, c) a mixture of L-aspartic acid salt and FB-1 obtained from MeCN (wet cake, 1011-79-4B_wc), d) a mixture of L-aspartic acid salt and FB-1 obtained from MeCN after vacuum drying (1011-79-4B_pw), e) residual L-aspartic acid obtained from EtOH (1011-79-4A_wc), f) residual L-aspartic acid obtained from THF (1011-79-4C_wc), and g) residual L-aspartic acid obtained from EtOAc (1011-79-4D_wc).

[0072] Figure 54PXRD overlay images of the solid glutamic acid collected in Table 27: a) glutamic acid, b) residual glutamic acid obtained from MeCN (1011-79-6B), c) residual glutamic acid obtained from EtOAc (1011-79-6D), d) residual glutamic acid obtained from EtOH (1011-79-6A), e) residual glutamic acid obtained from THF (1011-79-6C).

[0073] Figure 55 PXRD overlay images of the glycolic acid solids collected in Table 27: a) glycolic acid, b) FB-1, c) a mixture of glycolic acid and FB-1 obtained from EtOAc (wet cake, 1011-79-7D_wc), d) a mixture of glycolic acid and FB-1 obtained from EtOAc after vacuum drying (1011-79-7D_pw), e) a mixture of glycolic acid and FB-1 obtained from MeCN (wet cake, 1011-79-7B_wc), f) a mixture of glycolic acid and FB-1 obtained from MeCN after vacuum drying (1011-79-7B_pw).

[0074] Figures 56A-56C Table 27 shows the PXRD and DSC-TGA overlays of maleate obtained in the experiment. Figure 56A a) Maleic acid, b) Maleate (wet cake) obtained from MeCN, c) PXRD overlay of maleate obtained from MeCN after vacuum drying (1011-79-5B_pw). Figure 56B PXRD pattern of MAL-1. Figure 56C : DSC-TGA overlay image of MAL-1 obtained from MeCN.

[0075] Figures 57A-57D Table 27 shows the PXRD and DSC-TGA overlays of the methanesulfonate obtained in the experiment. Figure 57A PXRD overlays of MSA-1 salts: (a) Methanesulfonate obtained from MeCN (wet cake, 1011-79-3B_wc), (b) Methanesulfonate obtained from MeCN after vacuum drying (1011-79-3B_pw), (c) Methanesulfonate obtained from THF (wet cake, 1011-79-3C_wc), (d) Methanesulfonate obtained from THF after vacuum drying (1011-79-3C_pw), (e) Methanesulfonate obtained from EtOAc (wet cake, 1011-79-3D_wc), (f) Methanesulfonate obtained from EtOAc after vacuum drying (1011-79-3D_pw) Figure 57B : DSC-TGA overlay image of MSA-1 obtained from MeCN. Figure 57C: DSC-TGA overlay image of MSA-1 obtained from THF. Figure 57D : DSC-TGA overlay image of MSA-1 obtained from EtOAc.

[0076] Figures 58A-58E Characterization results for MSA-1 (batch 1011-85-3). Figure 58A PLM for MSA-1. Figure 58B DVS of MSA-1 (9.53% weight gain at 80% RH, hygroscopic). Figure 58C PXRD pattern of MSA-1. Figure 58D TGA-DSC of MSA-1. TGA: 0.805% weight loss to 100℃, decomposition at 250℃. DSC: First endothermic peak at 207.94℃. Figure 58E MSA-1 1 HNMR spectrum.

[0077] Figures 59A-59C The results of a two-week solid-state stability study of MSA-1 (batch 1011-88-6) are presented. Figure 59A Stability assessment summary. Figure 59B PXRD overlay images of MSA-1 and samples taken at week 1: (a) MSA-1, (b) 1011-90-4A-1w, (c) 1011-90-4B-1w, (d) 1011-90-4C-1w, (e) 1011-90-4D-1w, (f) 1011-90-4E-1w, (g) 1011-90-4F-1w. Figure 59C PXRD overlay images of MSA-1 and samples taken 2 weeks ago: (a) MSA-1, (b) 1011-90-4A-2w, (c) 1011-90-4B-2w, (d) 1011-90-4C-2w, (e) 1011-90-4D-2w, (f) 1011-90-4E-2w, (g) 1011-90-4F-2w.

[0078] Figures 60A-60F The results show the stability assessment of the MSA-1 reference standard at time point t0. Figure 60A MSA-1 reference standard stored open at 25℃ / 60% RH. Figure 60B MSA-1 reference standard stored open at 40℃ / 75% RH. Figure 60C MSA-1 reference standard stored open at 60°C. Figure 60D MSA-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 60E MSA-1 reference standard stored in closed dishes at 40°C / 75% RH. Figure 60FMSA-1 reference standard stored in a closed dish at 60°C.

[0079] Figures 61A-61F The results show the stability assessment of the MSA-1 reference standard at a 1-week time point. Figure 61A MSA-1 reference standard stored open at 25℃ / 60% RH. Figure 61B MSA-1 reference standard stored open at 40℃ / 75% RH. Figure 61C MSA-1 reference standard stored open at 60°C. Figure 61D MSA-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 61E MSA-1 reference standard stored in closed dishes at 40°C / 75% RH. Figure 61F MSA-1 reference standard stored in a closed dish at 60°C.

[0080] Figures 62A-62F The results show the stability assessment of the MSA-1 reference standard at a 2-week time point. Figure 62A MSA-1 reference standard stored open at 25℃ / 60% RH. Figure 62B MSA-1 reference standard stored open at 40℃ / 75% RH. Figure 62C MSA-1 reference standard stored open at 60°C. Figure 62D MSA-1 reference standard stored in closed dishes at 25°C / 60% RH. Figure 62E MSA-1 reference standard stored in closed dishes at 40°C / 75% RH. Figure 62F MSA-1 reference standard stored in a closed dish at 60°C.

[0081] Figures 63A-63F The results show the stability assessment of MSA-1 (batch 1011-88-6) at the 1-week time point. Figure 63A MSA-1 stored open at 25°C / 60% RH. Figure 63B Store in MSA-1 at 40°C / 75% RH. Figure 63C Store in MSA-1 at 60°C after opening. Figure 63D Store in a closed dish at 25°C / 60% RH in MSA-1. Figure 63E Store in a closed dish at 40°C / 75% RH in MSA-1. Figure 63F Store in a sealed dish at 60°C in MSA-1.

[0082] Figures 64A-64F The results are the stability assessment results for MSA-1 (batch 1011-88-6) at the 2-week time point. Figure 64A MSA-1 stored open at 25°C / 60% RH. Figure 64BStore in MSA-1 at 40°C / 75% RH. Figure 64C Store in MSA-1 at 60°C after opening. Figure 64D Store in a closed dish at 25°C / 60% RH in MSA-1. Figure 64E Store in a closed dish at 40°C / 75% RH in MSA-1. Figure 64F Store in a sealed dish at 60°C in MSA-1.

[0083] Figure 65 PXRD overlay plots of a) L-ascorbic acid and b) residual L-ascorbic acid (1011-79-9D_wc) obtained from EtOAc.

[0084] Figures 66A-66E DVS analysis of TSA-2 (batch 1011-75-2) and characterization results of TSA-2 after DVS. Figure 66A DVS of TSA-2. TSA-2 is non-hygroscopic, with a moisture gain of 3.193% at 80% RH. The isotherm indicates that it is a monohydrate when RH>10%. Figure 66B a) PXRD patterns of TSA-2 and b) after DVS. Figure 66C DVS after TSA-2 1 HNMR spectrum. Figure 66D : a) TSA-2, b) TSA-2 and c) TSA-1 after DVS 1 HNMR overlay image. Figure 66E HPLC-UV chromatogram of TSA-2 after DVS.

[0085] Figure 67A-67G The results of TGA-PXRD-DSC analysis are for TSA-2 (batch 1011-75-2). Figure 67A HPLC-UV chromatogram of TSA-2 after TGA. Figure 67B TGA thermal analysis diagram of TSA-2. Figure 67C a) PXRD overlay images of TSA-2 and b) TGA-2. Figure 67D TGA after TSA-2 1 HNMR spectrum. Figure 67E : a) TSA-2 after TGA, b) TSA-2 and c) TSA-1 1 HNMR overlay image. Figure 67F DSC thermal analysis diagram of TSA-2 after TGA. Figure 67G : DSC heating-cooling-heating data for TSA-2.

[0086] Figures 68A-68BThe results of DVS analysis of TAR-1 and characterization of TAR-1 after DVS are presented. Figure 68A The DVS of TAR-1 (batch 1011-76-5) was 8.046% at 80% RH. TAR-1 was not definitively identified as hygroscopic. Figure 68B a) PXRD overlay images of TAR-1 and b) TAR-1 after DVS.

[0087] Figures 69A-69B Table 27 shows the PXRD and DSC-TGA characterization results of L-aspartate obtained from the experiment. Figure 69A PXRD overlay images of L-aspartic acid, L-aspartic acid obtained from MeCN (wet cake, 1011-79-4B_WC), L-aspartic acid obtained from MeCN after vacuum drying (1011-79-4B_PW), L-aspartic acid obtained from EtOH (wet cake, 1011-79-4A_WC), L-aspartic acid obtained from THF (wet cake, 1011-79-4C_WC), and L-aspartic acid obtained from EtOAc (wet cake, 1011-79-4D_WC). Figure 69B : DSC-TGA overlay image of ASP-1 obtained from MeCN.

[0088] Figures 70A-70C Table 27 shows the PXRD and DSC-TGA characterization results of the glycolate obtained in the experiment. Figure 70A PXRD overlay images of: a) glycolic acid, b) glycolate obtained from EtOAc (wet cake, GLY-1, 1011-79-7D_WC), c) glycolate obtained from EtOAc after vacuum drying (1011-79-7D_PW), d) glycolate obtained from MeCN (wet cake, 1011-79-7B_WC), and e) glycolate obtained from MeCN after vacuum drying (GLY-2, 1011-79-7B_PW). Figure 70B : DSC-TGA overlay image of GLY-1 obtained from EtOAc. Figure 70C : DSC-TGA overlay image of GLY-2 obtained from MeCN.

[0089] Figure 71A-71J The HPLC-UV chromatogram of the salts obtained in the experiment is shown in Table 27. Figure 71A HPLC-UV chromatogram of BSA salt obtained from THF. Figure 71B HPLC-UV chromatogram of BSA salt obtained from EtOAc. Figure 71C HPLC-UV chromatogram of BSA salt obtained from MeCN. Figure 71DHPLC-UV chromatogram of ESA salt obtained from EtOAc. Figure 71E HPLC-UV chromatogram of MSA salt obtained from MeCN. Figure 71F HPLC-UV chromatogram of MSA salt obtained from THF. Figure 71G HPLC-UV chromatogram of L-aspartate obtained from MeCN. Figure 71H HPLC-UV chromatogram of maleate obtained from MeCN. Figure 71I HPLC-UV chromatogram of glycolate obtained from MeCN. Figure 71J HPLC-UV chromatogram of glycolate obtained from EtOAc.

[0090] Figure 72A-72K The salts obtained from the experiment in Table 27 1 HNMR spectrum. Figure 72A BSA salts obtained from MeCN 1 HNMR spectrum. Figure 72B BSA salts obtained from THF 1 HNMR spectrum. Figure 72C BSA salts obtained from EtOAc 1 HNMR spectrum. Figure 72D ESA salts obtained from EtOAc 1 HNMR spectrum. Figure 72E MSA salt obtained from MeCN 1 HNMR spectrum. Figure 72F MSA salts obtained from THF 1 HNMR spectrum. Figure 72G MSA salt obtained from EtOAc 1 HNMR spectrum. Figure 72H L-Aspartate obtained from MeCN 1 HNMR spectrum. Figure 72I Maleate obtained from MeCN 1 HNMR spectrum. Figure 72J glycolate obtained from MeCN 1 HNMR spectrum. Figure 72K glycolate obtained from EtOAc 1 HNMR spectrum.

[0091] Figures 73A-73B The image shows the PXRD pattern of SM, the mono-HCl salt of compound 106.

[0092] Figures 74A-74D Characterization results for compound 106 mono-HCl salt SM (batch 1050-19-2). Figure 74A : 1 HNMR spectrum. Figure 74B HPLC chromatogram. Figure 74C PLM characterization results. Figure 74D : DSC-TGA characterization results.

[0093] Figures 75A-75D Characterization results for compound 106 mono-HCl salt SM (batch 1036-84-8). Figure 75A : 1 HNMR spectrum. Figure 75B HPLC chromatogram. Figure 75C PLM characterization results. Figure 75D : DSC-TGA characterization results.

[0094] Figure 76 For two batches of compound 106 mono-HCl salt SM (batch 1036-84-8 (bottom image) and batch 1050-19-2 (top image)) 1 HNMR overlay image.

[0095] Figure 77 DVS results for compound 106 mono-HCl salt SM (batch 1050-19-2).

[0096] Figure 78 PXRD overlay images of compound 106 mono-HCl salt SM (ID: 1050-19-2) a) before DVS and b) after DVS.

[0097] Figure 79 PLM images of the raw material (left: batch 966-195) and the crystals obtained by recrystallization of the raw material in THF / methyl tert-butyl ether (MTBE) (right: ZW-1109-07-A6).

[0098] Figure 80 The unit cell of compound 106 in its free base pure form contains four molecules (Z' = 2).

[0099] Figure 81 This is an ORTEP diagram of two crystallographically independent molecules (i.e., two conformational isomers) in the pure base form of compound 106. Non-hydrogen atoms are represented by ellipsoids with a 45% probability, and hydrogen atoms are represented by small circles. Carbon and hydrogen atoms are not labeled.

[0100] Figure 82 The crystal packing diagram of compound 106 in its free base form shows infinite hydrogen bonding interactions along the crystallographic a-axis, involving three amines (N2_1-H...N4_1, N2_2-H...N4_2, N1_1-H...N1_2).

[0101] Figure 83 PXRD overlays of compound 106 FB-1 reference (top), bulk solid from batch ZW-1109-07-A6 (middle), and compound 106 simulated based on crystal structure (bottom).

[0102] Figure 84 This is an XRPD overlay image of free form SM (ID: ZW-1109-01-A) of compound 106 in Example 2 and FB-1 in an earlier project (Q3864).

[0103] Figure 85 PLM image of compound 106 free form SM (ID: ZW-1109-01-A).

[0104] Figure 86 The DSC-TGA spectrum of compound 106 free form SM (ID: ZW-1109-01-A) is shown.

[0105] Figure 87 For the free form of compound 106 SM (ID: ZW-1109-01-A) 1 HNMR spectrum.

[0106] Figure 88 XRPD overlay plots of simulated spectra of compounds 106 FB-1 (ZW-1109-01-A), FB-2 (ZW-1109-07-A4), FB-3 (ZW-1109-09-A7), and FB-1.

[0107] Figure 89 This is a diagram showing the interconversion of the free crystalline form of compound 106.

[0108] Figure 90 Compound 106 FB-3 (ZW-1109-09-A7) in DMSO-6 1 HNMR spectrum.

[0109] Figure 91 The image shows the DSC-TGA spectrum of compound 106FB-2.

[0110] Figure 92 The image shows the DSC-TGA spectrum of compound 106FB-3.

[0111] Figure 93 PLM image of compound 106FB-3.

[0112] Figure 94 DSC heating-cooling-heating curves of compound 106 free form SM (ZW-1109-01-A) are provided.

[0113] Figure 95 XRPD spectra of compound 106 FB-1 reference (ZW-1109-01-A), FB-2 reference (ZW-1109-07-A4), and reconstituted FB-2 (ZW-1109-07-A6 and ZW-1109-17-A7) are overlaid.

[0114] Figure 96 XRPD overlay plots of compound 106 FB-1 reference (ZW-1109-01-A), reconstituted FB-3 (ZW-1109-09-A7), and a mixture of FB-1 and FB-3 obtained from polymorph screening (ZW-1109-09-A5).

[0115] Figure 97 XRPD overlay plots of compound 106 HCl salt: a) 1036-072-FS-MP (reference), b) simulated spectrum of pure form of hydrochloric acid, c) SM (ID: 1050-19-2).

[0116] Figure 98 PLM images of compound 106 mono-HCl salt SM (ID: 1050-19-2) are provided.

[0117] Figure 99 The image shows the DSC-TGA spectrum of compound 106 HCl salt SM (ID: 1050-19-2).

[0118] Figure 100 The salt of compound 106 mono-HCl, SM (above, ID: 1050-19-2). 1 HNMR spectrum.

[0119] Figure 101 The compounds 106 mono-HCl salt SM (top image) and FB #966-195 (bottom image) are... 1 The HNMR spectrum overlay diagram shows changes in chemical shifts.

[0120] Figure 102 XRPD overlay plots of compound 106 HCl salt: a) 1036-072-FS-MP (reference), b) simulated spectrum of pure form of hydrochloric acid, c) SM (ID: 1036-84-FS).

[0121] Figure 103 PLM images of compound 106 mono-HCl salt SM (ID: 1036-84-FS) are provided.

[0122] Figure 104The image shows the DSC-TGA spectrum of compound 106 HCl salt SM (ID: 1036-84-FS).

[0123] Figure 105 The salt of compound 106 HCl, SM (ID: 1036-84-FS). 1 HNMR spectrum.

[0124] Figure 106 For batch 1036-84-FS (see image below) 1 The HNMR spectrum is the same as that of batch 1050-19-2 (above). 1 A superimposed image of HNMR spectra.

[0125] Figure 107 The HPLC chromatogram is for FB (batch 966-195) with a concentration of 99.9% A.

[0126] Figure 108 This is a superimposed graph of compound 106 mono-HCl #1036-84-FS w / blank (A%<0.05 rejection criterion).

[0127] Figure 109 The HPLC calibration curve for FB (batch 966-195).

[0128] Figure 110 The HPLC chromatogram of compound 106 FB (#966-195) is shown.

[0129] Figure 111 The HPLC chromatogram of compound 106 mono-HCl (#1036-84-FS) is shown.

[0130] Figure 112 Dynamic vapor adsorption (DVS) data for compound 106 HCl salt SM (ID: 1050-19-2) are provided, showing a weight gain of 0.24% at 80% RH and slight hygroscopicity.

[0131] Figure 113 XRPD overlay images of compound 106 SM (ID: 1050-19-2): a) before DVS, b) after DVS.

[0132] Figure 114 XRPD overlay plots for polymorphism screening of HCl-1 (compound 106 #1036-84-FS) at room temperature / 1 day: a) HCl-1 reference, b) chloroform, c) EtOH, d) nPA, e) DMF, f) DMSO.

[0133] Figure 115XRPD overlay plots of polymorphism screening for HCl-1 (compound 106 #1036-84-FS) at 50°C for 3 days: a) HCl-1 reference, b) slurry in solvent.

[0134] Figure 116 XRPD overlay for polymorphism screening of HCl-1 (compound 106 #1036-84-FS) at 50℃ / 3 days: a) HCl-1 reference, bp) slurry in solvent.

[0135] Figure 117 XRPD overlay plots for polymorphism screening of HCl-1 (compound 106 #1036-84-FS) at 50 °C / 3 days: a) HCl-1 reference, b) Compound 106 HCl w / extra peak in isopropanol (IPA).

[0136] Figure 118 XRPD overlay plots of polymorphism screening for HCl-1 (compound 106 #1036-84-FS) at 50℃ / 3 days: a) HCl-1 reference, b) Compound 106 HCl w / extra peak in 2-butanol.

[0137] Figure 119 Repeated attempts for polymorph screening at 50°C / 2 days: a) HCl-1 reference, b) IPA, c) 2-butanol.

[0138] Figure 120 Repeated experiments for polymorph screening at 50°C: a) HCl-1 reference, b) initial IPA polymorph screening, c) repeated attempts in IPA at 50°C for 5 days.

[0139] Figure 121 Repeated experiments for polymorph screening at 50°C: a) HCl-1 reference, b) 2-butanol at 50°C for 5 days.

[0140] Figure 122 Repeated experiments for polymorph screening at 50°C: a) HCl-1 reference, b) IPA at 50°C for 5 days, c) IPA at 50°C for 10 days, d) 2-butanol at 50°C for 5 days, e) 2-butanol at 50°C for 10 days.

[0141] Figure 123 Repeated experiments for polymorph screening at 50°C: a) HCl-1 reference, b) IPA at 50°C for 13 days, c) 2-butanol at 50°C for 13 days.

[0142] Figure 124Polymorphism screening of compound 106 mono-HCl (batch 1036-84-FS) in an organic solvent containing 2 vol% water at 50 °C / 1 day: a) HCl-1 reference, b)-l) organic solvent containing 2 vol% water.

[0143] Figure 125 Polymorphism screening of compound 106 mono-HCl (batch 1036-84-FS) in organic solvents containing 2 vol% water at 50°C for 4 days: a) HCl-1 reference, b)-j) organic solvents containing 2 vol% water.

[0144] Figure 126 Polymorphism screening for compound 106 mono-HCl (batch 1036-84-FS) by liquid-phase assisted milling at room temperature: a) HCl-1 reference, b) -k) organic solvent.

[0145] Figure 127 Polymorphism screening for solid-phase vapor diffusion at room temperature for compound 106 mono-HCl (batch 1036-84-FS): a) HCl-1 reference, b) -i) organic solvents.

[0146] Figure 128 Polymorphism screening for liquid-phase vapor diffusion at room temperature for compound 106 mono-HCl (batch 1036-84-FS): a) HCl-1 reference, b)-c) organic solvents.

[0147] Figure 129 Solubility curves of compound 106 mono-HCl (#1036-84-FS) in 2-butanol-water systems with three compositions (1, 2, and 3 vol% water) measured at four temperatures (50 °C, 40 °C, 30 °C, and 20 °C).

[0148] Figure 130 This is an example of a solvent overlay diagram showing the removal of impurities from SM #1036-84-FS and 2-butanol containing 3% H2O at 30°C.

[0149] Figure 131A-131B The purity of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 50°C for 18 hours in 2-butanol containing 1 vol% H2O was studied. Figure 131A PLM image. Figure 131B HPLC chromatogram.

[0150] Figure 132A-132B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 50°C for 18 hours in 2-butanol containing 2 vol% H2O. Figure 132A PLM image. Figure 132BHPLC chromatogram.

[0151] Figure 133A-133B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 50°C for 18 hours in 2-butanol containing 3 vol% H2O. Figure 133A PLM image. Figure 133B HPLC chromatogram.

[0152] Figure 134A-134B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 40°C for 2 hours in 2-butanol containing 1 vol% H2O. Figure 134A PLM image. Figure 134B HPLC chromatogram.

[0153] Figure 135A-135B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 40°C for 2 hours in 2-butanol containing 2 vol% H2O. Figure 135A PLM image. Figure 135B HPLC chromatogram.

[0154] Figures 136A-136B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 40°C for 2 hours in 2-butanol containing 3 vol% H2O. Figure 136A PLM image. Figure 136B HPLC chromatogram.

[0155] Figure 137A-137B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 30°C for 2 hours in 2-butanol containing 1 vol% H2O. Figure 137A PLM image. Figure 137B HPLC chromatogram.

[0156] Figure 138A-138B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 30°C for 2 hours in 2-butanol containing 2 vol% H2O. Figure 138A PLM image. Figure 138B HPLC chromatogram.

[0157] Figures 139A-139B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 30°C for 2 hours in 2-butanol containing 3 vol% H2O. Figure 139A PLM image. Figure 139B HPLC chromatogram.

[0158] Figure 140A-140B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in 2-butanol containing 1 vol% H2O at 20°C for 18 hours. Figure 140A PLM image. Figure 140B HPLC chromatogram.

[0159] Figures 141A-141B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in 2-butanol containing 2 vol% H2O at 20°C for 18 hours. Figure 141A PLM image. Figure 141B HPLC chromatogram.

[0160] Figures 142A-142B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in 2-butanol containing 3 vol% H2O at 20°C for 18 hours. Figure 142A PLM image. Figure 142B HPLC chromatogram.

[0161] Figure 143 XRPD analysis of the solubility of the terminal solid of compound 106 mono-HCl (#1036-84-FS) at 50 °C: a) HCl-1 reference, b) 2-butanol containing 1 vol% water, c) 2-butanol containing 2 vol% water, d) 2-butanol containing 3 vol% water.

[0162] Figure 144 XRPD analysis of the solubility of the terminal solid of compound 106 mono-HCl (#1036-84-FS) at 40 °C: a) HCl-1 reference, b) 2-butanol containing 1 vol% water, c) 2-butanol containing 2 vol% water, d) 2-butanol containing 3 vol% water.

[0163] Figure 145 XRPD analysis of the solubility of the terminal solid of compound 106 mono-HCl (#1036-84-FS) at 30 °C: a) HCl-1 reference, b) 2-butanol containing 1 vol% water, c) 2-butanol containing 2 vol% water, d) 2-butanol containing 3 vol% water.

[0164] Figure 146XRPD analysis of the solubility of the terminal solid of compound 106 mono-HCl (#1036-84-FS) at 20 °C: a) HCl-1 reference, b) 2-butanol containing 1 vol% water, c) 2-butanol containing 2 vol% water, d) 2-butanol containing 3 vol% water.

[0165] Figures 147A-147B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in acetone containing 1 vol% H2O at 20°C for 1-3 days. Figure 147A PLM image. Figure 147B HPLC chromatogram.

[0166] Figures 148A-148B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in acetone containing 1 vol% H2O at 35°C for 1-3 days. Figure 148A PLM image. Figure 148B HPLC chromatogram.

[0167] Figures 149A-149B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in acetone containing 1 vol% H2O at 40°C for 1-3 days. Figure 149A PLM image. Figure 149B HPLC chromatogram.

[0168] Figure 150A-150B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 50°C for 1-3 days in acetone containing 1 vol% H2O. Figure 150A PLM image. Figure 150B HPLC chromatogram.

[0169] Figure 151A-151B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in IPA containing 1 vol% H2O at 25°C for 1-3 days. Figure 151A PLM image. Figure 151B HPLC chromatogram.

[0170] Figure 152A-152B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in IPA containing 1 vol% H2O at 35°C for 1-3 days. Figure 152A PLM image. Figure 152B HPLC chromatogram.

[0171] Figures 153A-153BProvide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in IPA containing 1 vol% H2O at 40°C for 1-3 days. Figure 153A PLM image. Figure 153B HPLC chromatogram.

[0172] Figures 154A-154B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in IPA containing 1 vol% H2O at 50°C for 1-3 days. Figure 154A PLM image. Figure 154B HPLC chromatogram.

[0173] Figure 155A-155B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in IPA containing 1 vol% H2O at 60°C for 1-3 days. Figure 155A PLM image. Figure 155B HPLC chromatogram.

[0174] Figures 156A-156B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in IPA containing 1 vol% H2O at 70°C for 1-3 days. Figure 156A PLM image. Figure 156B HPLC chromatogram.

[0175] Figure 157A-157B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in acetonitrile (ACN) containing 1 vol% H2O at 20°C for 1-3 days. Figure 157A PLM image. Figure 157B HPLC chromatogram.

[0176] Figures 158A-158B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in ACN containing 1 vol% H2O at 35°C for 1-3 days. Figure 158A PLM image. Figure 158B HPLC chromatogram.

[0177] Figures 159A-159B Provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring in ACN containing 1 vol% H2O at 40°C for 1-3 days. Figure 159A PLM image. Figure 159B HPLC chromatogram.

[0178] Figure 160A-160BProvide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 50°C for 1-3 days in ACN containing 1 vol% H2O. Figure 160A PLM image. Figure 160B HPLC chromatogram.

[0179] Figure 161 The solubility curves of compound 106 mono-HCl (#1036-84-FS) in organic solvent systems containing 1 vol% water were tested at different temperatures.

[0180] Figure 162 XRPD plots of compound 106 mono-HCl (#1036-84-FS) in acetone containing 1 vol% water are overlaid: a) HCl-1 reference, b) 20℃, c) 35℃, d) 40℃, e) 50℃.

[0181] Figure 163 XRPD plots of compound 106 mono-HCl (#1036-84-FS) in IPA containing 1 vol% water are overlaid: a) HCl-1 reference, b) 25℃, c) 35℃, d) 40℃, e) 50℃, f) 60℃, g) 70℃.

[0182] Figure 164 XRPD plots of compound 106 mono-HCl (#1036-84-FS) in ACN containing 1 vol% water are overlaid: a) HCl-1 reference, b) 20℃, c) 35℃, d) 40℃, e) 50℃.

[0183] Figure 165 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 vol% water at 25 °C.

[0184] Figure 166 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 vol% water at 42 °C.

[0185] Figure 167 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 vol% water at 60 °C.

[0186] Figure 168 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 vol% water at 70 °C.

[0187] Figure 169 The solubility curves of compound 106 mono-HCl (#1036-84-FS) in IPA containing 8 vol% water were tested at different temperatures.

[0188] Figure 170 XRPD plots of the solubility of compound 106 mono-HCl (#1036-84-FS) in IPA containing 8 vol% water are overlaid: a) HCl-1 reference, b) 25℃, c) 42℃, d) 60℃, e) 70℃.

[0189] Figure 171 Solubility curves of compound 106 mono-HCl (#1036-84-FS) in pure IPA at different temperatures (5-80℃).

[0190] Figure 172 Solubility measurements of compound 106 mono-HCl (#1036-84-FS) in pure IPA, IPA containing 1 vol% water, and IPA containing 8 vol% water are provided at different temperatures.

[0191] Figure 173 XRPD plots of the solubility of compound 106 mono-HCl (#1036-84-FS) in IPA are superimposed: a) HCl-1 reference, b) 5℃, c) 25℃, d) 50℃, e) 65℃, f) 80℃.

[0192] Figure 174 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 20 wt.% acetone as a countersolvent at 25 °C.

[0193] Figure 175 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 40 wt.% acetone as a countersolvent at 25 °C.

[0194] Figure 176 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 60 wt.% acetone as a countersolvent at 25 °C.

[0195] Figure 177 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 80 wt.% acetone as a countersolvent at 25 °C.

[0196] Figure 178 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 20 wt.% MTBE as an antisolvent at 25 °C.

[0197] Figure 179 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 40 wt.% MTBE as an antisolvent at 25 °C.

[0198] Figure 180 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 60 wt.% MTBE as an antisolvent at 25 °C.

[0199] Figure 181 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 80 wt.% MTBE as an antisolvent at 25 °C.

[0200] Figure 182 The solubility curves of compound 106 mono-HCl (#1036-84-FS) in IPA containing 8 wt.% water and antisolvents (acetone and MTBE) at 25 °C are shown.

[0201] Figure 183 XRPD plots of compound 106 mono-HCl (#1036-84-FS) at 25°C with IPA containing 8 wt.% water and acetone are superimposed: a) HCl-1 reference, b) 20 wt.% acetone, c) 40 wt.% acetone, d) 60 wt.% acetone, e) 80 wt.% acetone.

[0202] Figure 184 XRPD spectra of compound 106 mono-HCl (#1036-84-FS) at 25 °C for IPA and MTBE containing 8 wt.% water are overlaid: a) HCl-1 reference, b) 20 wt.% MTBE, c) 40 wt.% MTBE, d) 60 wt.% MTBE, e) 80 wt.% MTBE.

[0203] Figure 185 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in DCM for impurity removal studies.

[0204] Figure 186 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in MTBE for impurity removal studies.

[0205] Figure 187 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in acetone for impurity removal studies.

[0206] Figure 188 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in THF for impurity removal studies.

[0207] Figure 189 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in hexane for impurity removal studies.

[0208] Figure 190 The HPLC chromatogram is for the study of impurity removal of compound 106 mono-HCl (batch 1036-84-FS) in diisopropyl ether (DIPE).

[0209] Figure 191 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in EtOAc.

[0210] Figure 192 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in EtOH for impurity removal studies.

[0211] Figure 193 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in MEK for impurity removal studies.

[0212] Figure 194 The HPLC chromatogram is for the study of impurity removal of compound 106 mono-HCl (batch 1036-84-FS) in 2-MeTHF.

[0213] Figure 195 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in cyclohexane.

[0214] Figure 196 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in ACN for impurity removal studies.

[0215] Figure 197This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in an IPA impurity removal study.

[0216] Figure 198 The HPLC chromatogram is for the study of impurity removal of compound 106 mono-HCl (batch 1036-84-FS) in 1,2-dimethoxyethane (DME).

[0217] Figure 199 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in isopropyl acetate (iPAc) for impurity removal studies.

[0218] Figure 200 HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in n-propanol (nPA) for impurity removal study.

[0219] Figure 201 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in heptane for impurity removal studies.

[0220] Figure 202 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in 2-butanol.

[0221] Figure 203 The HPLC chromatogram is the result of an investigation into the removal of impurities from 1,4-dioxane in compound 106 mono-HCl (batch 1036-84-FS).

[0222] Figure 204 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in CPME for impurity removal studies.

[0223] Figure 205 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in toluene for impurity removal studies.

[0224] Figure 206 The HPLC chromatogram is the result of an impurity removal study of compound 106 mono-HCl (batch 1036-84-FS) in methyl isobutyl ketone (MIBK).

[0225] Figure 207 This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in n-butanol for impurity removal studies.

[0226] Figure 208This is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in DMSO for impurity removal studies.

[0227] Figure 209 For compound 106 1 HNMR spectrum.

[0228] Figure 210 The gradient COSY spectrum of compound 106 is shown.

[0229] Figure 211 The image shows the ROESY 2D spectrum of compound 106.

[0230] Figure 212 For compound 106 19 FNMR spectrum.

[0231] Figure 213 For compound 106 13 CNMR spectrum.

[0232] Figure 214 The image shows the HSQC spectrum of compound 106.

[0233] Figure 215 The gradient HMBC spectrum of compound 106 is shown.

[0234] Figure 216 For the salt of compound 106 HCl 1 HNMR spectrum.

[0235] Figure 217 For the salt of compound 106 HCl 13 CNMR spectrum.

[0236] Figure 218 The gradient COSY spectrum of compound 106 HCl salt is shown.

[0237] Figure 219 The image shows the ROESY 2D spectrum of the salt of compound 106 HCl.

[0238] Figure 220 The HSQC spectrum of compound 106 HCl salt is shown.

[0239] Figure 221 The gradient HMBC spectrum of compound 106 HCl salt is shown.

[0240] Figure 222 For the salt of compound 106 HCl 19 FNMR spectrum.

[0241] Figure 223 This is a typical working standard chromatogram for the UPLC assay of compound 106 capsules.

[0242] Figure 224 This is a typical working standard chromatogram for HPLC determination of the S-enantiomer content level in compound 106 capsules.

[0243] Figure 225 The graph shows the stability results of the API after 6 months of storage at 25℃±2℃ and 60%±5% room temperature and humidity.

[0244] Figure 226 The graph shows the stability results of the API after 6 months of storage at 40℃±2℃ and 75%±5% room temperature and humidity.

[0245] Figure 227 The graph shows the DP stability results of a 10 mg dose after 3 months of storage at 25℃±2℃ and 60%±5% room temperature and humidity. ND = Not detected or <0.10%, CFU = Colony forming units, RRT = Relative retention time, NT = Not tested, TGA = Thermogravimetric analysis, PXRD = Powder X-ray diffraction. 1 Refer to COA-1585-001.0, 2 The listed RRTs reflect the current point in time; previous RRTs may have differed. 3 Testing outsourcing.

[0246] Figure 228 The graph shows the DP stability results of a 10 mg dose after 3 months of storage at 40℃±2℃ and 75%±5% room temperature and humidity. ND = Not detected or <0.10%, CFU = Colony forming units, RRT = Relative retention time, NT = Not tested, TGA = Thermogravimetric analysis, PXRD = Powder X-ray diffraction. 1 Refer to COA-1585-001.0, 2 The listed RRTs reflect the current point in time; previous RRTs may have differed. 3 Testing outsourcing.

[0247] Figure 229 The graph shows the DP stability results of a 50 mg dose after 3 months of storage at 25℃±2℃ and 60%±5% room temperature and humidity. ND = Not detected or <0.10%, CFU = Colony forming units, RRT = Relative retention time, NT = Not tested, TGA = Thermogravimetric analysis, PXRD = Powder X-ray diffraction. 1 Refer to COA-1585-001.0, 2 The listed RRTs reflect the current point in time; previous RRTs may have differed. 3 Testing outsourcing. Detailed Implementation

[0248] The following related applications are incorporated herein by reference in their entirety and are used for all purposes: International Publication No. WO2018081738, Treatment of Disses Assaulted with Actualized Irk, filed October 30, 2017; U.S. Publication No. 2021 / 0292843, Treatment of Disses Assaulted with Actualized Irk, filed April 4, 2019; International Publication No. WO 2014190163, Combination Therapy for MDS, filed May 22, 2014; U.S. Patent No. 9,168,257, Combination Therapy for MDS, granted October 27, 2015; U.S. Patent No. 9,504,706, Combination Therapy for MDS, granted November 29, 2016; U.S. Patent No. 9,855,273, Combination Therapy for MDS, authorized January 2, 2018; International Publication No. WO 2018038988, Compounds, Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017; US Patent No. 11,254,667, Substituted imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors, authorized February 2, 2022; US Publication No. 2022 / 0213094, Substituted Imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 Inhibitors, filed January 4, 2022; US Publication No. 2020 / 0199123, Substitutedimidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 Inhibitors, submitted February 28, 2020; US Publication No. 2022 / 0235042, Substituted Imidazo[l,2-a]-pyridines as IRAK 1 / 4 and FLT3 Inhibitors, submitted January 28, 2022;International Publication No. WO 2020252487, Rationaltherapeutic targeting of oncogenic immune signaling states in myeloid malignancies via the ubiquitin conjugating enzyme UBE2N, submitted June 15, 2020; International Publication No. WO 2022026935, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, submitted July 31, 2021; International Publication No. WO 2022140647, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, submitted December 23, 2021; International Publication No. WO2023009833, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 29, 2022; International Patent Application No. PCT / US2023 / 068520, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses; Thereof, filed June 15, 2023; International Patent Application No. PCT / US2023 / 068897, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses; Thereof, filed June 22, 2023; International Patent Application No. PCT / US2023 / 071435, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses; Thereof, filed August 1, 2023; International Patent Application No. PCT / US2023 / 034438, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed October 4, 2023; U.S. Patent Application No. 18 / 293,109, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed January 29, 2024;And international patent application number PCT / US2024 / 014038, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed February 1, 2024.

[0249] While embodiments incorporating the inventive concept may take many forms, various embodiments will be described herein, and it is understood that this disclosure should be considered exemplary only, and the inventive concept is not intended to be limited to the disclosed embodiments.

[0250] Some embodiments of the present invention include crystalline forms of compound 106 and / or polymorphs of compound 106. Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the crystalline form of compound 106 described herein. Still other embodiments of the present invention include compositions for treating, for example, certain diseases using the crystalline form of compound 106 described herein. Some embodiments include methods of administering and treating using the crystalline form of compound 106 described herein (e.g., in a composition or pharmaceutical composition). Further embodiments include methods for preparing the crystalline form disclosed herein. Still other embodiments include methods for determining whether a particular patient is likely to respond to such treatment with the compounds and compositions of the present invention.

[0251] Unless otherwise stated, the terminology should be understood as it is understood by a person skilled in the art based on its conventional usage.

[0252] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas listed in this article are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0253] In a numerical context, the term "about" means a range of ±10% of the value, unless otherwise explicitly stated.

[0254] Some compounds of this invention may have one or more chiral centers, and for any one or more chiral centers, they may exist and be separated in optically active and racemic forms. Some compounds may exhibit polymorphism. The compounds of this invention cover any optically active form, racemic form, stereoisomer form, polymorph, or mixture thereof. If the configuration of the chiral center in the chemical structure is not specified (i.e., R or S), it should be considered to represent R, S, or a racemic form.

[0255] The term "evaluation" as used herein includes any form of measurement and includes determining the presence of an element. The terms "determine," "measure," "evaluate," "assess," "analyze," and "detect" are used interchangeably and may include qualitative and / or quantitative measurements.

[0256] As used herein, the term "monitoring," when referring to cancer type, means the methods or processes for determining the severity or grade of that cancer type, or for stratifying that cancer type based on the risk and / or probability of death. In some implementations, monitoring involves methods or processes for determining the therapeutic effect of treatments being received by a patient.

[0257] As used in this article, "outcome" may refer to the results of the study. In some implementations, "outcome" may refer to survival / death within a specific time frame. For example, "outcome" may refer to survival / death at 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer. In some implementations, an increased risk of adverse outcome indicates poor treatment efficacy, while a decreased risk of adverse outcome indicates good treatment efficacy.

[0258] As used herein, "high-risk clinical trial" refers to a trial in which the test reagent has "above the minimum risk" (as defined by the Institutional Review Board or IRB). In some implementation schemes, a high-risk clinical trial is a drug trial.

[0259] As used herein, the term "low-risk clinical trial" refers to a trial in which the test reagent has "minimal risk" (as defined in the IRB terminology). In some implementations, a low-risk clinical trial is a non-pharmaceutical trial. In some implementations, a low-risk clinical trial involves the use of monitors or clinical practice procedures. In some implementations, a low-risk clinical trial is an observational clinical trial.

[0260] As used herein, the terms “regulation” or “modulation” and “differential regulation” can refer to upregulation (activation or stimulation, e.g., by arousal or enhancement) and downregulation (inhibition or suppression, e.g., by antagonism, reduction or suppression) unless otherwise stated or clearly indicated from the specific context of use.

[0261] As used herein, the term "subject" refers to any suitable (e.g., treatable) member of the animal kingdom. In the method, the subject is preferably a mammal. In the method, the subject is preferably a human patient. In the method, the subject may be a mammalian pediatric patient. In the method, a pediatric patient is a mammalian patient (e.g., preferably a human) under the age of 18, and an adult patient is 18 years of age or older.

[0262] As used herein, the term "treatment" (and its variations, such as "treatment," "manipulation," etc.) should be considered in its broadest context, unless otherwise stated, to refer to achieving the desired pharmacological and / or physiological effect. Specifically, for example, "treatment" does not necessarily imply or require that an animal be treated until fully recovered. Therefore, "treatment" includes improving symptoms, alleviating symptoms or effects associated with the condition, reducing the severity of the condition, or preventing, preventively improving symptoms, or otherwise reducing the risk of developing a particular condition. In some respects, "treatment" may not require or include prevention. Animals referred to herein as "treated" include, but are not limited to, preventative and therapeutic treatment. The effect may be preventative, i.e., complete or partial prevention of the disease or its symptoms, and / or therapeutic, i.e., partial or complete cure of the disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses any treatment of a disease in a subject (preferably a mammal, such as a human), and may include one or more of the following: (a) preventing the development of the disease in a subject who may be susceptible but has not yet been diagnosed with the disease; (b) inhibiting the disease, i.e., preventing its development; and (c) alleviating the disease, i.e., causing the remission or elimination of the disease and / or reducing one or more disease symptoms. In a particular aspect of the methods, such as a symptom or disease characterized by dysregulation of IRAK expression or dysregulation (e.g., hyperactivity) of IRAK-mediated signaling pathways, treatment may be or may include reducing such expression or signaling. "Treatment" may also include the delivery of a medicament or administration of a therapy to provide a pharmacological effect, even in the absence of a disease or symptom. Any composition described herein (e.g., a pharmaceutical composition) may be used to treat a suitable subject.

[0263] "Therapeutic effective amount" refers to the effective amount that achieves the desired and / or beneficial effect. The effective amount may be administered once or multiple times. In the described method, the therapeutic effective amount is the amount appropriate for the therapeutic indication. The therapeutic indication refers to achieving any desired effect, such as remission, improvement, stabilization, reversal, slowing or delaying disease progression, improving quality of life, or prolonging life, or one or more of these. This achievement may be measured by any suitable method, such as tumor size or blood cell count measurements, or any other suitable measurement method.

[0264] As used in this article, the term "marker" or "biomarker" refers to a biomolecule (such as nucleic acids, peptides, proteins, hormones, etc.) whose presence or concentration can be detected and associated with a known condition (such as a disease state). The term may also refer to differentially expressed genes whose expression patterns can be used in the prediction, prognosis, or diagnostic process of health or disease states, or as a method for identifying effective treatments or preventative therapies.

[0265] The term "mRNA isotype" as used in this article refers to an alternative transcript of a specific mRNA or gene. This term includes premRNA, immature mRNA, mature mRNA, cleaved or otherwise shortened, shortened or aberrant mRNA, modified mRNA (e.g., containing any residue modification, capping variants, polyadenylation variants, etc.), etc.

[0266] "Antibody" or "antibody peptide" refers to an intact antibody or a binding fragment that competes with it for specific binding; this definition also includes monoclonal and polyclonal antibodies. Binding fragments are produced through recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab′, F(ab′)2, Fv, and single-chain antibodies. Except for "bispecific" or "bifunctional" antibodies, antibodies are understood to have the same binding site for each antibody. For example, when an excess of antibody reduces the amount of binding between the receptor and its corresponding receptor by at least about 20%, 40%, 60%, or 80% (typically greater than about 85%, as measured by an in vitro competitive binding assay), the antibody substantially inhibits receptor-corresponder adhesion.

[0267] The compositions of the present invention also include crystal forms of compound 106, including polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), and conformational polymorphs and mixtures thereof. The terms "crystal form" and "polymorph" are intended to include all crystal forms of the compound, including polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), and conformational polymorphs and mixtures thereof, unless a specific crystal form is specifically indicated.

[0268] A "solvent" is a crystalline phase in which a compound is physically bonded to one or more solvent molecules. A crystalline phase in which a compound is physically bonded to one or more water molecules is called a "hydrate".

[0269] "Amorphous" refers to the form in which a compound, its salt, or a molecular complex lacks long-range crystalline order.

[0270] The embodiments of the invention described herein include crystalline forms of compound 106 and / or polymorphs of compound 106 described herein. Other embodiments include compositions comprising crystalline forms and / or polymorphs of compound 106 (e.g., pharmaceutical compositions). Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using crystalline forms and / or polymorphs of compound 106. Some embodiments include methods of administering and treating (e.g., diseases such as cancer or blood disorders) using crystalline forms and / or polymorphs of compound 106 (e.g., in a composition or pharmaceutical composition). Some embodiments include methods for determining whether a patient is suitable for a particular treatment or is likely to produce a good response. Further embodiments include methods for preparing the compounds of the invention. Other embodiments of the invention are also discussed herein.

[0271] Compounds and compositions, including pharmaceutical compositions On the one hand, this disclosure relates to compound 106: Salts, esters, solvates, optical isomers, geometric isomers, or salts of isomers thereof, or salts thereof. In one embodiment, this disclosure relates to crystal forms and / or polymorphs of compound 106. In one embodiment, this disclosure relates to a single crystal form of compound 106. In one embodiment, this disclosure provides a single crystal of a salt of compound 106. In one embodiment, this disclosure provides a crystalline solid form of a free base of compound 106. In one embodiment, this disclosure provides a crystalline solid form of a salt of compound 106. This disclosure provides polymorphs, such as the crystal form of compound 106. In some embodiments, the polymorph comprises a free base of compound 106. In some embodiments, the polymorph comprises a salt of compound 106 whose counterion corresponds to an acid selected from benzenesulfonic acid, ethanesulfonic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, L-aspartic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, glutamic acid, glycolic acid, and L-ascorbic acid. In some embodiments, this disclosure provides an acetate salt of compound 106. In one embodiment, this disclosure provides a single crystal of the free base of compound 106.

[0272] In one embodiment, the compound disclosed herein (i.e., compound 106 or its salts, esters, solvates, optical isomers, geometric isomers, isomer salts, crystal forms and / or polymorphs) is an IRAK1, IRAK4, IRAK1 / 4 and / or FLT3 inhibitor. In one embodiment, the compound disclosed herein is an IRAK1 / 4, a pan-FLT3 inhibitor.

[0273] In some embodiments, the compound may be in the form of a salt, an optical and geometric isomer, or an isomeric salt. In other embodiments, the compound may be in a variety of forms, such as an uncharged molecule, a component of a molecular complex, or a non-irritating, pharmaceutically acceptable salt, including but not limited to hydrochloride, dihydrochloride (bis-HCl), hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some cases, for acidic compounds, the salt may contain a metal, amine, or organic cation (e.g., a quaternary ammonium salt). In other embodiments, simple derivatives of the compound (e.g., ethers, esters, or amides) may be used, which have desirable retention and release properties but are readily hydrolyzed in vivo by pH, enzymes, or other suitable mechanisms.

[0274] In some embodiments, the compounds of this disclosure have a chiral center and can exist and be separated in optically active and racemic forms. In other embodiments, the compounds may exhibit polymorphism. Some embodiments of this disclosure cover any racemic, optically active, polymorphic, or stereoisomeric forms or mixtures thereof of the compounds described herein, including isotopically labeled and radiolabeled compounds. See, for example, Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be separated by standard resolution techniques, including, for example, stepwise crystallization, chiral chromatography, etc. See, for example, Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of the optically active form can be accomplished by any suitable method, including but not limited to resolution of the racemic form by recrystallization, synthesis from optically active raw materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.

[0275] In some embodiments, the compounds disclosed herein have one or more asymmetric centers and can exist as racemates, racemic mixtures, and single enantiomers or diastereomers, all of which are considered for use in the compounds and methods described herein. The compounds considered herein do not include those known in the art to be too unstable to synthesize and / or isolate.

[0276] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may contain radioactive isotopes (such as tritium). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling. All isotopic variants of the compounds disclosed herein, whether or not radioactive, are included in this consideration.

[0277] In some embodiments, metabolites of the compounds disclosed herein can be used in the methods disclosed herein.

[0278] In some embodiments, the compounds considered herein may be provided in prodrug form. The term "prodrug" refers to a compound that can be converted in vivo into the compound described herein (e.g., a bioactive compound). Prodrugs may be used for a variety of reasons known in the art, including, for example, ease of administration due to increased bioavailability from oral administration. Prodrugs may also have better solubility in pharmaceutical compositions than bioactive compounds. Examples (not limiting) of prodrugs are compounds administered in ester form (i.e., "prodrugs") to facilitate transmembrane transport (where water solubility is unfavorable for migration), but which, once inside the cell (where water solubility is favorable), are metabolized and hydrolyzed into carboxylic acids (the active entity). Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing procedures and preparation of suitable prodrug derivatives.

[0279] Some of the compounds disclosed herein may exist in both solvated and solvated forms (including hydrated forms). Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the compounds considered herein. Some of the compounds disclosed herein may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods considered herein and are intended to fall within the scope of this disclosure.

[0280] In some embodiments, one or more compounds of this disclosure (e.g., compound 106, a crystal form of compound 106, and / or a polymorph of compound 106) may be part of the composition, and the amount thereof (by weight of the total composition) may be at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, not more than about 75%, not more than about 90%, not more than about 95%, not more than about 99%, or not more than about 99.99%, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%.

[0281] In some embodiments, one or more compounds of this disclosure (e.g., compound 106, a crystal form of compound 106, and / or a polymorph of compound 106) may be purified or isolated in amounts of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, not exceeding about 75%, not exceeding about 90%, not exceeding about 95%, not exceeding about 99%, not exceeding about 99.99%, about 0.0001% to about 99%, about 0.0001% to about 50%, about 0.01% to about 95%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75% (by weight of the total composition).

[0282] Crystal form In one embodiment, this disclosure provides a crystalline solid form of compound 106, or a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt thereof. In one embodiment, this disclosure provides a single crystal of compound 106. In one embodiment, this disclosure provides a single crystal of a salt of compound 106. In one embodiment, this disclosure provides a crystalline solid form of a free base of compound 106. In one embodiment, this disclosure provides a crystalline solid form of a salt of compound 106. This disclosure provides polymorphs, such as those of compound 106. In some embodiments, the polymorph comprises a free base of compound 106. In some embodiments, the polymorph comprises a salt of compound 106 whose counterion corresponds to an acid selected from benzenesulfonic acid, ethanesulfonic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, L-aspartic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, glutamic acid, glycolic acid, and L-ascorbic acid. In some embodiments, this disclosure provides an acetate salt of compound 106. In one embodiment, this disclosure provides a single crystal of a free base of compound 106.

[0283] Any crystal form described herein can be characterized by X-ray diffraction. In some embodiments, X-ray diffraction refers to X-ray powder diffraction. In some embodiments, X-ray diffraction can be measured using either transmission or reflection modes. In one embodiment, the X-ray diffraction pattern of any embodiment herein is measured in transmission mode. In one embodiment, the X-ray diffraction pattern of any embodiment herein is measured in reflection mode. It is known in the art that the obtained X-ray powder diffraction pattern may contain one or more measurement errors, depending on the measurement conditions (such as equipment, sample preparation, or instrument used). In particular, it is generally known that the intensity in an X-ray powder diffraction pattern can vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of X-ray powder diffraction will recognize that the relative intensity of peaks can vary depending on the orientation of the sample being tested and the type and settings of the instrument used. Those skilled in the art will also recognize that the position of the reflection peaks can be affected by the precise height of the sample in the diffractometer, the smoothness of the sample surface, and the zero-point calibration of the diffractometer. Therefore, those skilled in the art will understand that the diffraction pattern data provided herein should not be interpreted as absolute data, and any crystal form that provides a powder diffraction pattern substantially identical to that disclosed herein falls within the scope of this disclosure. For more information, see Jenkins and Snyder's... Introduction to X-Ray Powder Diffractometry John Wiley & Sons, 1996.

[0284] Compared to amorphous forms, different crystalline forms may offer unexpected advantages, including improved thermodynamic stability, faster dissolution rates, improved performance in the stomach and gastric environment (including avoiding or reducing precipitation from solution at elevated pH), improved exposure in mammals, and superior processability when formulating drugs into end products suitable for patients.

[0285] In one aspect, this disclosure provides crystal forms of the free base of compound 106 and / or polymorphs (FB-1) of the free base of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 8.5102 4175.51 2 10.2265 343.56 3 11.2514 587.62 4 12.4152 103.90 5 13.4583 786.44 6 15.6546 319.77 7 16.3830 842.71 8 16.8018 759.98 9 17.1029 362.63 10 18.3658 373.30 11 18.5476 156.86 12 19.1056 86.49 13 19.3265 194.07 14 20.0082 1520.77 15 20.4980 300.57 16 20.9239 462.17 17 21.3232 66.57 18 22.2447 691.96 19 22.6040 423.51 20 23.2420 163.36 21 23.6583 400.98 22 24.2705 182.67 23 24.6817 865.27 24 25.8013 208.32 25 26.1668 41.27 26 27.1774 180.52 27 27.5557 281.22 28 28.1259 76.69 29 28.6101 657.64 30 30.1759 42.68 31 31.5240 26.66 32 31.8408 100.33 33 32.3075 95.39 34 32.8563 59.47 35 33.7388 43.46 36 36.0412 38.62 37 36.7705 21.37 38 37.7457 28.92 39 39.0376 39.92 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0286] In another aspect, this disclosure provides an acetate crystal form of compound 106 and / or an acetate polymorph (ACE-1) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 6.5000 1154.68 2 6.7290 917.03 3 7.5260 202.55 4 10.5847 37.87 5 11.0130 113.10 6 12.4889 661.63 7 13.0149 198.69 8 16.3929 398.48 9 16.8800 94.31 10 17.1858 73.11 11 18.4708 375.26 12 18.8843 52.20 13 19.5304 103.52 14 20.0616 60.88 15 21.3454 540.29 16 21.7009 489.67 17 22.3172 889.46 18 22.5705 290.98 19 22.9289 45.35 20 23.9165 31.34 21 24.7744 192.32 22 25.0876 154.15 23 25.5671 43.35 24 26.1732 94.53 25 26.5912 32.96 26 27.0355 154.95 27 27.2423 192.90 28 27.6728 48.26 29 28.3256 44.74 30 29.0800 35.43 31 31.1977 18.89 32 32.9851 39.40 33 34.0111 32.94 34 34.7003 34.40 35 35.6768 13.92 36 38.0226 14.57 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0287] In another aspect, this disclosure provides an acetate crystal form of compound 106 and / or an acetate polymorph (ACE-2) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 6.2182 62.34 2 9.4463 54.67 3 10.3025 14.22 4 12.4148 55.30 5 14.3135 30.30 6 14.9697 15.88 7 16.2453 8.02 8 16.8470 19.53 9 17.9204 13.52 10 18.9193 25.24 11 19.4893 8.36 12 20.0171 5.44 13 21.6036 65.69 14 22.4177 25.49 15 23.5670 21.64 16 24.4393 10.16 17 25.0411 12.24 18 26.0228 3.98 19 26.6839 6.28 20 27.3926 9.84 21 33.2748 5.89 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0288] In another aspect, this disclosure provides a p-toluenesulfonate crystal form of compound 106 and / or a p-toluenesulfonate polymorph (TSA-1) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 5.1743 1879.49 2 7.0186 311.18 3 8.1663 650.05 4 9.1859 33.81 5 10.3704 2647.23 6 11.7589 324.75 7 12.5062 216.10 8 13.2636 216.11 9 14.0747 319.79 10 14.2385 342.43 11 14.4880 357.43 12 14.7418 31.98 13 15.1588 40.38 14 15.6231 82.37 15 16.2702 95.28 16 16.8942 804.11 17 17.6050 228.95 18 17.9401 92.34 19 19.0641 21.67 20 19.8933 94.30 21 20.5140 132.26 22 21.1626 260.87 23 21.7948 20.72 24 22.4148 148.24 25 23.0891 90.56 26 23.8417 103.35 27 24.6896 102.50 28 24.8272 82.73 29 25.1678 220.17 30 26.2810 219.64 31 26.7775 90.05 32 27.4170 71.84 33 28.1822 19.68 34 29.0287 29.21 35 29.9521 23.93 36 31.4883 83.78 37 33.1844 11.02 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0289] In another aspect, this disclosure provides a p-toluenesulfonate crystal form of compound 106 and / or a p-toluenesulfonate polymorph (TSA-2) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 5.9392 967.34 2 7.0763 86.43 3 8.7637 1121.04 4 10.9989 459.04 5 11.8931 2025.27 6 12.8975 147.98 7 13.2326 521.18 8 13.5257 360.74 9 14.0442 247.16 10 14.2012 175.56 11 14.3568 170.85 12 15.2718 43.05 13 15.6918 175.46 14 16.2197 454.00 15 16.6651 31.26 16 17.2545 663.39 17 17.5695 166.74 18 17.8762 248.65 19 18.4091 23.61 20 19.0089 318.58 21 19.7271 125.92 22 20.0891 345.47 23 20.2884 194.99 24 21.3708 257.20 25 21.6008 191.44 26 21.8351 49.25 27 22.0956 205.46 28 22.8019 271.10 29 23.3518 95.63 30 24.5049 29.46 31 25.0766 184.11 32 25.2479 84.04 33 25.4378 45.25 34 26.1134 204.58 35 26.6147 132.69 36 27.2503 20.35 37 27.4629 28.54 38 27.7389 83.16 39 28.6339 36.87 40 30.0194 26.25 41 30.7184 168.09 42 31.6744 28.93 43 32.6249 37.03 44 33.1826 22.68 45 33.7315 41.41 46 35.6161 27.48 47 36.1791 57.48 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0290] In another aspect, this disclosure provides a p-toluenesulfonate crystal form of compound 106 and / or a p-toluenesulfonate polymorph (TSA-3) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 7.7311 878.06 2 8.6730 470.34 3 9.1020 977.26 4 10.0547 74.39 5 10.4519 1356.37 6 11.4067 145.21 7 11.7315 762.23 8 12.4876 303.53 9 13.5800 462.40 10 14.7963 622.61 11 15.4790 1090.75 12 16.5562 407.19 13 16.7117 1023.68 14 17.2255 2039.71 15 17.9216 116.71 16 18.2518 247.53 17 18.7057 351.41 18 18.9171 1849.03 19 19.7204 56.83 20 20.1315 1032.30 21 21.0767 264.60 22 21.5198 2088.86 23 22.0848 370.74 24 22.3841 699.21 25 22.7469 127.55 26 22.9067 524.27 27 23.0532 76.50 28 23.3139 101.20 29 23.5901 292.16 30 24.0642 1564.97 31 24.4832 414.00 32 25.1100 415.26 33 25.4147 391.55 34 26.2214 141.52 35 26.4958 375.32 36 26.8376 251.00 37 27.2203 292.07 38 27.5068 223.31 39 27.9358 200.46 40 28.3874 357.80 41 29.5122 156.62 42 29.9189 45.62 43 30.2906 314.12 44 30.8246 22.17 45 31.3301 70.90 46 31.7008 105.42 47 32.9084 248.96 48 32.9880 221.96 49 33.7702 60.26 50 34.0199 61.49 51 34.3192 21.75 52 34.7098 54.42 53 35.4529 47.72 54 35.6577 35.98 55 36.2798 71.10 56 36.7875 21.11 57 37.2640 73.98 58 37.8389 65.65 59 38.7782 49.19 60 39.4366 18.96 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0291] In another aspect, this disclosure provides tartrate crystal forms of compound 106 and / or tartrate polymorphs of compound 106 (TAR-1), characterized in that the X-ray powder diffraction patterns contain one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 4.1463 292.13 2 7.7633 1129.20 3 8.2996 818.64 4 10.1216 35.79 5 11.3791 401.36 6 12.4661 1527.44 7 13.7867 122.80 8 14.1011 242.59 9 15.5489 513.64 10 16.6578 106.23 11 17.4289 360.73 12 18.6536 226.83 13 19.1095 175.66 14 19.3112 45.50 15 19.6662 27.08 16 20.4382 242.82 17 20.8586 33.34 18 21.3540 20.43 19 22.5011 118.52 20 22.8792 81.04 21 23.4372 113.35 22 23.7287 64.62 23 24.7464 432.12 24 25.1566 337.24 25 25.4454 230.87 26 25.9362 72.47 27 26.4885 84.41 28 26.7874 88.49 29 27.7072 85.98 30 28.1883 75.69 31 29.5023 29.96 32 31.4659 41.01 33 33.1605 19.26 34 35.2961 29.98 35 36.2252 37.30 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0292] In another aspect, this disclosure provides a benzenesulfonate crystal form of compound 106 and / or a benzenesulfonate polymorph (BSA-1) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 6.0882 171.45 2 7.1501 35.44 3 8.8966 363.67 4 11.2206 257.48 5 12.2073 272.12 6 12.9781 63.71 7 13.3296 563.57 8 14.1225 148.72 9 14.2875 435.42 10 14.6072 395.92 11 15.5340 30.58 12 15.8947 89.33 13 16.6160 143.37 14 16.9428 24.92 15 17.6593 848.14 16 17.8182 132.03 17 18.1970 39.34 18 19.2161 74.26 19 19.4884 88.64 20 19.9886 15.67 21 20.1070 21.37 22 20.4010 600.80 23 20.9762 45.76 24 21.5845 222.25 25 21.9720 194.81 26 22.5384 120.35 27 23.3474 101.39 28 23.5613 106.08 29 23.8492 95.22 30 24.8742 30.64 31 25.1031 21.26 32 25.5863 387.01 33 25.9489 103.05 34 26.2968 93.67 35 26.5983 91.95 36 27.1334 269.76 37 28.4875 44.12 38 29.1808 29.84 39 29.8640 17.93 40 30.6238 38.71 41 31.5579 43.71 42 32.7200 26.30 43 33.4281 19.61 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0293] In another aspect, this disclosure provides an isosulfonate crystal form of compound 106 and / or an isosulfonate polymorph (ESA-1) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 2.1456 362.07 2 9.4378 185.71 3 10.5830 85.72 4 13.5242 270.47 5 15.6498 598.76 6 16.1666 217.70 7 18.2082 285.59 8 19.1561 487.55 9 19.5803 169.46 10 21.4651 392.70 11 22.5054 135.53 12 23.1563 207.57 13 24.4272 177.24 14 24.9066 189.20 15 26.2932 149.38 16 26.6850 96.34 17 27.1646 71.63 18 27.6300 56.59 19 28.0821 75.84 20 29.1008 34.27 21 29.7364 41.39 22 30.1128 36.73 23 31.0951 31.89 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0294] In another aspect, this disclosure provides maleate crystal form of compound 106 and / or maleate polymorph (MAL-1) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 7.6183 153.33 2 8.8782 695.70 3 10.1164 72.58 4 10.4550 130.97 5 11.3945 70.78 6 12.6363 33.01 7 14.9782 87.25 8 16.0301 177.32 9 16.5998 133.91 10 17.8112 151.49 11 19.2988 44.76 12 20.7943 308.46 13 22.5892 64.85 14 24.0658 36.07 15 25.1163 38.37 16 25.8815 61.95 17 27.5537 24.26 18 30.8678 11.45 19 15.28 0.8187 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0295] In another aspect, this disclosure provides a methanesulfonate crystal form of compound 106 and / or a methanesulfonate polymorph (MSA-1) of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 9.4332 240.48 2 10.7336 341.26 3 13.1847 51.98 4 13.8951 1057.01 5 15.3077 178.32 6 15.8697 1156.30 7 16.2453 367.02 8 18.4951 565.77 9 19.5773 1743.95 10 20.4125 68.22 11 21.5492 647.01 12 21.7550 365.96 13 22.5396 516.70 14 23.1636 117.85 15 23.8137 490.21 16 24.4222 113.58 17 24.9633 153.21 18 25.6827 244.09 19 26.2564 93.79 20 26.5213 120.22 21 26.7162 77.32 22 27.3636 155.00 23 28.0011 115.34 24 28.4083 171.21 25 30.0138 81.85 26 30.6070 95.30 27 32.0467 62.42 28 33.2600 77.65 29 34.7889 49.67 30 36.4246 42.47 31 37.0117 22.05 32 37.5445 23.80 33 38.3512 34.52 34 39.4875 28.64 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0296] In another aspect, this disclosure provides a monohydrochloric acid crystal form and / or a monohydrochloric acid polymorph of compound 106, characterized in that the X-ray powder diffraction pattern contains one or more peaks selected from the following: peak# Position [°2θ] Altitude [cts] 1 2.0916 351.93 2 6.8619 1456.89 3 11.1062 405.49 4 11.3373 730.14 5 11.6132 222.45 6 13.7106 147.47 7 14.3405 115.61 8 14.5399 1071.38 9 14.7217 552.01 10 15.3177 261.07 11 16.2725 461.28 12 17.1417 1100.83 13 17.5260 178.40 14 17.6282 72.44 15 18.8337 80.88 16 20.0236 25.40 17 20.8136 202.24 18 20.9023 341.03 19 21.0463 278.93 20 21.9400 355.15 21 22.4223 496.19 22 22.9619 90.59 23 23.3316 439.10 24 23.6521 761.75 25 24.4120 91.91 26 24.9258 67.24 27 26.0850 25.56 28 26.4484 99.46 29 26.7151 125.93 30 26.9745 107.91 31 27.2880 149.19 32 27.5840 398.95 33 27.8954 41.50 34 28.1817 281.51 35 28.3383 92.72 36 28.8331 509.42 37 29.2852 77.84 38 29.8645 24.14 39 32.2115 22.04 40 33.1644 22.35 41 33.5088 54.17 42 33.8427 69.37 43 34.6622 102.68 44 35.6915 24.48 45 36.3485 50.26 46 37.3533 38.93 47 38.0511 25.62 In some implementations, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0297] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 8.5102±0.2°, 10.2265±0.2°, 11.2514±0.2°, 12.4152±0.2°, 13.4583±0.2°, 15.6546±0.2°, 16.3830±0.2°, 16.8 0.18±0.2°, 17.1029±0.2°, 18.3658±0.2°, 18.5476±0.2°, 19.1056±0.2°, 19.3265±0.2°, 20.0082±0.2°, 20.4980±0.2°, 20.9239±0.2°, 21.3232±0.2°, 22.2447±0.2 °, 22.6040±0.2°, 23.2420±0.2°, 23.6583±0.2°, 24.2705±0.2°, 24.6817±0.2°, 25.8013±0.2°, 26.1668±0.2°, 27.1774±0.2°, 27.5557±0.2°, 28.1259±0.2°, 28.61 The X-ray diffraction pattern comprises one or more peaks of 2θ selected from the above peak groups: 01±0.2°, 30.1759±0.2°, 31.5240±0.2°, 31.8408±0.2°, 32.3075±0.2°, 32.8563±0.2°, 33.7388±0.2°, 36.0412±0.2°, 36.7705±0.2°, 37.7457±0.2°, and 39.0376±0.2°. In some embodiments, the X-ray diffraction pattern comprises at least one, at least two, at least three, at least four, at least five, etc., peaks selected from the above peak groups. In some embodiments, the crystal form comprises the free base of compound 106. In some embodiments, the crystal form comprises the pure free base form of compound 106.

[0298] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 6.5000±0.2°, 6.7290±0.2°, 7.5260±0.2°, 10.5847±0.2°, 11.0130±0.2°, 12.4889±0.2°, 13.0149±0.2°, 16.3929±0.2°, 16.8800±0.2°, 17.1858±0.2°, 18.4708±0.2°, 18.8843±0.2°, 19.5304±0.2°, 20.0616±0.2°, 21.3454±0.2°, 21.7009±0.2°, 22.317 2±0.2°, 22.5705±0.2°, 22.9289±0.2°, 23.9165±0.2°, 24.7744±0.2°, 25.0876±0.2°, 25.5671±0.2°, 26.1732±0.2°, 26.5912±0.2°, 27.0355±0.2°, 27 The X-ray diffraction pattern comprises one or more peaks of 2θ selected from the above peak groups: 0.2423±0.2°, 27.6728±0.2°, 28.3256±0.2°, 29.0800±0.2°, 31.1977±0.2°, 32.9851±0.2°, 34.0111±0.2°, 34.7003±0.2°, 35.6768±0.2°, and 38.0226±0.2°. In some embodiments, the X-ray diffraction pattern includes at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises an acetate of compound 106. In some embodiments, the crystal form comprises a solvated acetate of compound 106.

[0299] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 6.2182±0.2°, 9.4463±0.2°, 10.3025±0.2°, 12.4148±0.2°, 14.3135±0.2°, 14.9697±0.2°, 16.2453±0.2°, 16.8470±0.2°, 17.9204±0.2°, 18.9 One or more peaks of 193±0.2°, 19.4893±0.2°, 20.0171±0.2°, 21.6036±0.2°, 22.4177±0.2°, 23.5670±0.2°, 24.4393±0.2°, 25.0411±0.2°, 26.0228±0.2°, 26.6839±0.2°, 27.3926±0.2°, and 33.2748±0.2°2θ. In some embodiments, the X-ray diffraction pattern includes at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises an acetate of compound 106. In some embodiments, the crystal form comprises a desolvated acetate of compound 106.

[0300] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 5.1743±0.2°, 7.0186±0.2°, 8.1663±0.2°, 9.1859±0.2°, 10.3704±0.2°, 11.7589±0.2°, 12.5062±0.2°, 13.2636±0.2°, 14.0747±0.2°, 14.2385±0.2°, 14.4880±0.2°, 14.7418±0.2°, 15.1588±0.2°, 15.6231±0.2°, 16.2702±0.2°, 16.8942±0.2°, 17.6050±0.2°. 17.9401±0.2°, 19.0641±0.2°, 19.8933±0.2°, 20.5140±0.2°, 21.1626±0.2°, 21.7948±0.2°, 22.4148±0.2°, 23.0891±0.2°, 23.8417±0.2°, 24.6896±0.2° The X-ray diffraction pattern comprises one or more peaks of 2θ, including 24.8272±0.2°, 25.1678±0.2°, 26.2810±0.2°, 26.7775±0.2°, 27.4170±0.2°, 28.1822±0.2°, 29.0287±0.2°, 29.9521±0.2°, 31.4883±0.2°, and 33.1844±0.2°. In some embodiments, the X-ray diffraction pattern includes at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises hydrated p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises p-toluenesulfonic acid monohydrate salt of compound 106.

[0301] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 5.9392±0.2°, 7.0763±0.2°, 8.7637±0.2°, 10.9989±0.2°, 11.8931±0.2°, 12.8975±0.2°, 13.2326±0.2°, 13.5257±0.2°, 14.0442±0.2°, 14.2012. ±0.2°, 14.3568±0.2°, ±0.2°, 15.2718±0.2°, 15.6918±0.2°, 16.2197±0.2°, 16.6651±0.2°, 17.2545±0.2°, 17.5695±0.2°, 17.8762±0.2°, 18.4091±0.2°, 19.0089±0.2°, 19.7271±0.2°, 20.0891±0 0.2°, 20.2884±0.2°, 21.3708±0.2°, 21.6008±0.2°, 21.8351±0.2°, 22.0956±0.2°, 22.8019±0.2°, 23.3518±0.2°, 24.5049±0.2°, 25.0766±0.2°, 25.2479±0.2°, 25.4378±0.2°, 26.1134±0.2°, 26.6 One or more peaks of 2θ are selected from the above peak groups: 147±0.2°, 27.2503±0.2°, 27.4629±0.2°, 27.7389±0.2°, 28.6339±0.2°, 30.0194±0.2°, 30.7184±0.2°, 31.6744±0.2°, 32.6249±0.2°, 33.1826±0.2°, 33.7315±0.2°, 35.6161±0.2°, and 36.1791±0.2°. In some embodiments, the X-ray diffraction pattern includes at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises hydrated p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises a p-toluenesulfonic acid monohydrate salt of compound 106.

[0302] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 7.7311±0.2°, 8.6730±0.2°, 9.1020±0.2°, 10.0547±0.2°, 10.4519±0.2°, 11.4067±0.2°, 11.7315±0.2°, 12.4876±0.2°, 13.5800±0.2°, 14.7963±0.2°, 15.4790±0.2°, 16.5562±0.2°, and 16.7117±0.2°. 17.2255±0.2°, 17.9216±0.2°, 18.2518±0.2°, 18.7057±0.2°, 18.9171±0.2°, 19.7204±0.2°, 20.1315±0.2°, 21.0767±0.2°, 21.5198±0.2°, 22.0848±0.2°, 22.3841±0.2°, 22.7469±0.2°, 22.9067±0.2°, 23.0532±0.2°, 23.3139±0.2°, 23.5901±0.2° °, 24.0642±0.2°, 24.4832±0.2°, 25.1100±0.2°, 25.4147±0.2°, 26.2214±0.2°, 26.4958±0.2°, 26.8376±0.2°, 27.2203±0.2°, 27.5068±0.2°, 27.9358±0.2°, 28.3874±0.2°, 29.5122±0.2°, 29.9189±0.2°, 30.2906±0.2°, 30.8246±0.2°, 31.3301±0. One or more peaks of 2°, 31.7008±0.2°, 32.9084±0.2°, 32.9880±0.2°, 33.7702±0.2°, 34.0199±0.2°, 34.3192±0.2°, 34.7098±0.2°, 35.4529±0.2°, 35.6577±0.2°, 36.2798±0.2°, 36.7875±0.2°, 37.2640±0.2°, 37.8389±0.2°, 38.7782±0.2°, and 39.4366±0.2°2θ. In some embodiments, the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, etc., selected from the above peak groups. In some embodiments, the crystal form comprises p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises hydrated p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises anhydrous p-toluenesulfonate of compound 106.In some embodiments, the crystal form comprises a solvated p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises a desolvated p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises an amorphous p-toluenesulfonate of compound 106.

[0303] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 4.1463±0.2°, 7.7633±0.2°, 8.2996±0.2°, 10.1216±0.2°, 11.3791±0.2°, 12.4661±0.2°, 13.7867±0.2°, 14.1011±0.2°, 15.5489±0.2°, 16.6578±0.2°, 17.4289±0.2°, 18.6536±0.2°, 19.1095±0.2°, 19.3112±0.2°, 19.6662±0.2°, and 20.4382±0.2°. 20.8586±0.2°, 21.3540±0.2°, 22.5011±0.2°, 22.8792±0.2°, 23.4372±0.2°, 23.7287±0.2°, 24.7464±0.2°, 25.1566±0.2°, 25.4454±0.2°, 25.93 One or more peaks of 2θ are selected from the above peak groups: 62±0.2°, 26.4885±0.2°, 26.7874±0.2°, 27.7072±0.2°, 28.1883±0.2°, 29.5023±0.2°, 31.4659±0.2°, 33.1605±0.2°, 35.2961±0.2°, and 36.2252±0.2°. In some embodiments, the X-ray diffraction pattern contains at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises (+)-L-tartrate of compound 106. In some embodiments, the crystal form comprises (+)-L-tartrate hydrate salt of compound 106.

[0304] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 6.0882±0.2°, 7.1501±0.2°, 8.8966±0.2°, 11.2206±0.2°, 12.2073±0.2°, 12.9781±0.2°, 13.3296±0.2°, 14.1225±0.2°, 14.287 5±0.2°, 14.6072±0.2°, 15.5340±0.2°, 15.8947±0.2°, 16.6160±0.2°, 16.9428±0.2°, 17.6593±0.2°, 17.8182±0.2°, 18.1970±0.2°, 19.2161±0.2°, 19.4884±0.2°, 19.9886±0.2° 20.1070±0.2°, 20.4010±0.2°, 20.9762±0.2°, 21.5845±0.2°, 21.9720±0.2°, 22.5384±0.2°, 23.3474±0.2°, 23.5613±0.2°, 23.8492±0.2°, 24.8742±0.2°, 25.1031±0.2°, 25.58 One or more peaks of 2θ are selected from the above peak groups: 63±0.2°, 25.9489±0.2°, 26.2968±0.2°, 26.5983±0.2°, 27.1334±0.2°, 28.4875±0.2°, 29.1808±0.2°, 29.8640±0.2°, 30.6238±0.2°, 31.5579±0.2°, 32.7200±0.2°, and 33.4281±0.2°. In some embodiments, the X-ray diffraction pattern contains at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises a benzenesulfonate of compound 106. In some embodiments, the crystal form comprises a hydrated benzenesulfonate of compound 106. In some embodiments, the crystalline form comprises an anhydrous benzenesulfonate of compound 106. In some embodiments, the crystalline form comprises a solvated benzenesulfonate of compound 106. In some embodiments, the crystalline form comprises a desolvated benzenesulfonate of compound 106. In some embodiments, the crystalline form comprises an amorphous benzenesulfonate of compound 106.

[0305] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 2.1456±0.2°, 9.4378±0.2°, 10.5830±0.2°, 13.5242±0.2°, 15.6498±0.2°, 16.1666±0.2°, 18.2082±0.2°, 19.1561±0.2°, 19.5803±0.2°, and 21.4651±0.2°. The X-ray diffraction pattern comprises one or more peaks of 2θ, including 22.5054±0.2°, 23.1563±0.2°, 24.4272±0.2°, 24.9066±0.2°, 26.2932±0.2°, 26.6850±0.2°, 27.1646±0.2°, 27.6300±0.2°, 28.0821±0.2°, 29.1008±0.2°, 29.7364±0.2°, 30.1128±0.2°, and 31.0951±0.2°. In some embodiments, the X-ray diffraction pattern includes at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises the ethanesulfonate of compound 106. In some embodiments, the crystalline form comprises hydrated ethanesulfonate of compound 106. In some embodiments, the crystalline form comprises anhydrous benzenesulfonate of compound 106. In some embodiments, the crystalline form comprises solvated benzenesulfonate of compound 106. In some embodiments, the crystalline form comprises desolvated benzenesulfonate of compound 106. In some embodiments, the crystalline form comprises amorphous benzenesulfonate of compound 106.

[0306] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 7.6183±0.2°, 8.8782±0.2°, 10.1164±0.2°, 10.4550±0.2°, 11.3945±0.2°, 12.6363±0.2°, 14.9782±0.2°, and 16.03°. The X-ray diffraction pattern comprises one or more peaks of 2θ selected from the above peak groups: 01±0.2°, 16.5998±0.2°, 17.8112±0.2°, 19.2988±0.2°, 20.7943±0.2°, 22.5892±0.2°, 24.0658±0.2°, 25.1163±0.2°, 25.8815±0.2°, 27.5537±0.2°, and 30.8678±0.2°. In some embodiments, the X-ray diffraction pattern includes at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises the maleate salt of compound 106. In some embodiments, the crystal form comprises the hydrated maleate salt of compound 106. In some embodiments, the crystal form comprises the anhydrous maleate salt of compound 106. In some embodiments, the crystal form comprises a solvated maleate of compound 106. In some embodiments, the crystal form comprises a desolvated maleate of compound 106. In some embodiments, the crystal form comprises an amorphous maleate of compound 106.

[0307] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises a region selected from 9.4332±0.2°, 10.7336±0.2°, 13.1847±0.2°, 13.8951±0.2°, 15.3077±0.2°, 15.8697±0.2°, 16.2453±0.2°, 18.4951±0.2°, 19.5773±0.2°, 20.4125±0.2°, 21.5492±0.2°, 21.7550±0.2°, 22.5396±0.2°, 23.1636±0.2°, 23.8137±0.2°, 24.42 22±0.2°, 24.9633±0.2°, 25.6827±0.2°, 26.2564±0.2°, 26.5213±0.2°, 26.7162±0.2°, 27.3636±0.2°, 28.0011±0.2°, 28.4083±0.2°, 30.0138±0.2°, 30.6070±0.2°, 32.0467±0.2°, 33.2600±0.2°, 34.7889±0.2°, 36.4246±0.2°, 37.0117±0.2°, 37.5445±0.2°, 38.3512±0.2°, and 39.4875±0.2° One or more peaks at 2θ. In some embodiments, the X-ray diffraction pattern includes at least one peak, at least two peaks, at least three peaks, at least four peaks, at least five peaks, etc., selected from the above peak groups. In some embodiments, the crystal form comprises the methanesulfonate of compound 106. In some embodiments, the crystal form comprises pure methanesulfonate of compound 106.

[0308] In one embodiment, this disclosure provides a crystal form of compound 106, characterized in that its X-ray powder diffraction pattern comprises 2.0916, 6.8619, 11.1062, 11.3373, 11.6132, 13.7106, 14.3405, 14.5399, 14.7217, 15.3177, 16.2725, 17.1417, 17.5260, 17.6282, 18.8337, 20.0236, 20.8136, 20.9023, 21.0463, 21.9400, 22.4223, 22. One or more peaks from the groups 9619, 23.3316, 23.6521, 24.4120, 24.9258, 26.0850, 26.4484, 26.7151, 26.9745, 27.2880, 27.5840, 27.8954, 28.1817, 28.3383, 28.8331, 29.2852, 29.8645, 32.2115, 33.1644, 33.5088, 33.8427, 34.6622, 35.6915, 36.3485, 37.3533, and 38.0511. In some embodiments, the X-ray diffraction pattern includes at least one, at least two, at least three, at least four, or at least five peaks selected from the above peak groups. In some embodiments, the crystal form comprises a monohydrochloride salt of compound 106. In some embodiments, the crystal form comprises a hydrated monohydrochloride salt of compound 106. In some embodiments, the crystal form comprises an anhydrous monohydrochloride salt of compound 106. In some embodiments, the crystal form comprises a solvated monohydrochloride salt of compound 106. In some embodiments, the crystal form comprises a desolvated monohydrochloride salt of compound 106. In some embodiments, the crystal form comprises an amorphous monohydrochloride salt of compound 106.

[0309] In one embodiment, the water content of the crystal form during formation is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%. In one embodiment, the water content of the crystal form is measured by Karl Fischer titration. In one embodiment, the crystal form comprises a free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0310] In one embodiment, the crystalline form, when formed, comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomer of formula (1) (R). In one embodiment, the crystalline form, when formed, comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the enantiomer of formula (1) (S). In one embodiment, the crystalline form comprises the free base of compound 106. In one embodiment, the crystalline form comprises a monohydrochloride salt of compound 106.

[0311] In one embodiment, the crystal form, when formed, contains less than or equal to about 10%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% impurities. In one embodiment, the impurities include soluble impurities. In one embodiment, the crystal form contains a free base of compound 106. In one embodiment, the crystal form contains a monohydrochloride salt of compound 106.

[0312] In one embodiment, after storage at about 25°C and about 60% relative humidity for 6 months, the water content of the crystal form is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%. In one embodiment, the crystal form comprises a free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0313] In one embodiment, after being stored at about 25°C and about 60% relative humidity for 6 months, the crystalline form contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomer of formula (1) (R). In one embodiment, after being stored at about 25°C and about 60% relative humidity for 6 months, the crystalline form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the enantiomer of formula (1) (S). In one embodiment, the crystalline form contains the free base of compound 106. In one embodiment, the crystalline form contains a monohydrochloride salt of compound 106.

[0314] In one embodiment, after being stored at about 25°C and about 60% relative humidity for 6 months, the crystalline form contains less than or equal to about 10%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% impurities. In one embodiment, the impurities include soluble impurities. In one embodiment, the crystalline form contains the free base of compound 106. In one embodiment, the crystalline form contains a monohydrochloride salt of compound 106.

[0315] In one embodiment, after storage at about 40°C and about 75% relative humidity for 6 months, the water content of the crystal form is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%. In one embodiment, the crystal form comprises a free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0316] In one embodiment, after being stored at about 40°C and about 75% relative humidity for 6 months, the crystalline form contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomer of formula (1) (R). In one embodiment, after being stored at about 40°C and about 75% relative humidity for 6 months, the crystalline form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the enantiomer of formula (1) (S). In one embodiment, the crystalline form contains the free base of compound 106. In one embodiment, the crystalline form contains a monohydrochloride salt of compound 106.

[0317] In one embodiment, after being stored at about 40°C and about 75% relative humidity for 6 months, the crystalline form contains less than or equal to about 10%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% impurities. In one embodiment, the impurities include soluble impurities. In one embodiment, the crystalline form contains the free base of compound 106. In one embodiment, the crystalline form contains a monohydrochloride salt of compound 106.

[0318] In one embodiment, the water content of the crystal form during formation is measured by Karl Fischer titration. In one embodiment, the water content of the crystal form is measured by Karl Fischer titration after storage for 6 months at about 25°C and about 60% relative humidity. In one embodiment, the water content of the crystal form is measured by Karl Fischer titration after storage for 6 months at about 40°C and about 75% relative humidity.

[0319] In one embodiment, the chiral purity of the crystal form at formation is measured by high-performance liquid chromatography (HPLC). In one embodiment, the chiral purity of the crystal form after storage for 6 months at about 25°C and about 60% relative humidity is measured by HPLC. In one embodiment, the chiral purity of the crystal form after storage for 6 months at about 40°C and about 75% relative humidity is measured by HPLC. In one embodiment, the percentage of each enantiomer in the crystal form at formation and after storage is measured as the area percentage of the HPLC chromatogram. In one embodiment, the chiral purity of the crystal form at formation and after storage is measured by HPLC, as described in the "Chiral Purity Obtained by High-Performance Liquid Chromatography" section of Example 6 of this disclosure.

[0320] In one embodiment, impurities present in the crystal form at formation are measured by ultra-high performance liquid chromatography (UPLC). In one embodiment, impurities present in the crystal form after storage for 6 months at about 25°C and about 60% relative humidity are measured by UPLC. In one embodiment, impurities present in the crystal form after storage for 6 months at about 40°C and about 75% relative humidity are measured by UPLC. In one embodiment, the percentage of each impurity in the crystal form at formation and after storage is measured as the area percentage of the UPLC chromatogram. In one embodiment, the impurity content present in the crystal form at formation and after storage is measured by UPLC, as described in the "Identification, Measurement and Related Substances by Ultra-High Performance Liquid Chromatography" section of Embodiment 6 of this disclosure.

[0321] In one embodiment, this disclosure provides a single crystal of a free base of compound 106. In one embodiment, the single crystal of the free base of compound 106 comprises a lattice parameter a of about 9.0 Å to about 10.0 Å, about 9.1 Å to about 9.9 Å, about 9.2 Å to about 9.8 Å, about 9.3 Å to about 9.7 Å, about 9.4 Å to about 9.7 Å, about 9.5 Å to about 9.7 Å, or about 9.58 Å. In one embodiment, the single crystal of the free base of compound 106 comprises a lattice parameter b of about 15.0 Å to about 25.0 Å, about 16.0 Å to about 24.0 Å, about 17.0 Å to about 23.0 Å, about 18.0 Å to about 22.0 Å, about 19.0 Å to about 22.0 Å, about 20.0 Å to about 22.0 Å, or about 20.9 Å. In one embodiment, the single crystal of the free base of compound 106 comprises a lattice parameter c of about 5.0 Å to about 15.0 Å, about 6.0 Å to about 14.0 Å, about 7.0 Å to about 13.0 Å, about 8.0 Å to about 12.0 Å, about 9.0 Å to about 12.0 Å, about 10.0 Å to about 12.0 Å, or about 10.8 Å. In one embodiment, the single crystal of the free base of compound 106 comprises an α of about 85° to about 95°, about 86° to about 94°, about 87° to about 93°, about 88° to about 92°, about 89° to about 91°, or about 90°. In one embodiment, the single crystal of the free base of compound 106 comprises β at about 110° to about 120°, about 111° to about 119°, about 112° to about 118°, about 113° to about 117°, about 114° to about 116°, or about 114.8°. In one embodiment, the single crystal of the free base of compound 106 comprises γ at about 85° to about 95°, about 86° to about 94°, about 87° to about 93°, about 88° to about 92°, about 89° to about 91°, or about 90°. In one embodiment, the single crystal of the free base of compound 106 comprises about 1950 Å. 3 Approximately 2000 Å 3 Approximately 1955 Å 3 approximately 1995 Å 3 Approximately 1960 Å 3 approximately 1990Å 3 Approximately 1965 Å 3 approximately 1985 Å 3 Approximately 1965 Å 3 approximately 1980 Å 3 Approximately 1970 Å 3 approximately 1975 Å 3 Or approximately 1972 Å 3The volume. In one embodiment, a single crystal of the free base of compound 106 contains about 0.9 g / cm³. 3 Approximately 1.9 g / cm 3 Approximately 0.9 g / cm 3 Approximately 1.8 g / cm 3 Approximately 0.9 g / cm 3 Approximately 1.7 g / cm 3 Approximately 0.9 g / cm 3 Approximately 1.6 g / cm 3 Approximately 1.0 g / cm³ 3 To approximately 1.5 g / cm 3 Approximately 1.1 g / cm³ 3 Approximately 1.4 g / cm 3 Approximately 1.2 g / cm³ 3 Approximately 1.4 g / cm 3 Or approximately 1.35 g / cm 3 Crystal density d c .

[0322] In another aspect, this disclosure provides pharmaceutical compositions comprising a crystal form of compound 106 and a formulation ingredient, adjuvant, or carrier. In one embodiment, the crystal form of said compound 106 is as described elsewhere herein. In one embodiment, said crystal form comprises a free base of compound 106. In one embodiment, said crystal form comprises a monohydrochloride salt of compound 106. In one embodiment, the pharmaceutical composition comprises about 1 mg to about 100 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, or about 50 mg of the crystal form of compound 106. In another embodiment, the pharmaceutical composition comprises about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, about 5 mg to about 15 mg, or about 10 mg of compound 106 crystal form.

[0323] In one embodiment, the water content of the pharmaceutical composition during formation is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%. In one embodiment, the water content of the pharmaceutical composition is measured by Karl Fischer titration. In one embodiment, the crystal form comprises the free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0324] In one embodiment, the pharmaceutical composition, when formed, comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomer of formula (1) (R). In one embodiment, the pharmaceutical composition, when formed, comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the enantiomer of formula (1) (S). In one embodiment, the crystal form comprises the free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0325] In one embodiment, the pharmaceutical composition, when formed, contains less than or equal to about 10%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% impurities. In one embodiment, the impurities include soluble impurities. In one embodiment, the crystal form comprises the free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0326] In one embodiment, after storage at about 25°C and about 60% relative humidity for 1 month or 3 months, the water content of the pharmaceutical composition is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%. In one embodiment, the crystalline form comprises the free base of compound 106. In one embodiment, the crystalline form comprises a monohydrochloride salt of compound 106.

[0327] In one embodiment, after storage at about 25°C and about 60% relative humidity for 1 month or 3 months, the pharmaceutical composition comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomer of formula (1) (R). In one embodiment, after storage at about 25°C and about 60% relative humidity for 1 month or 3 months, the pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the enantiomer of formula (1) (S). In one embodiment, the crystal form comprises the free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0328] In one embodiment, after storage at about 25°C and about 60% relative humidity for 1 month or 3 months, the pharmaceutical composition contains less than or equal to about 10%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% impurities. In one embodiment, the impurities comprise soluble impurities. In one embodiment, the crystal form comprises the free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0329] In one embodiment, after storage at about 40°C and about 75% relative humidity for 1 month or 3 months, the water content of the pharmaceutical composition is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%. In one embodiment, the crystalline form comprises the free base of compound 106. In one embodiment, the crystalline form comprises a monohydrochloride salt of compound 106.

[0330] In one embodiment, after storage at about 40°C and about 75% relative humidity for 1 month or 3 months, the pharmaceutical composition comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomer of formula (1) (R). In one embodiment, after storage at about 40°C and about 75% relative humidity for 1 month or 3 months, the pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the enantiomer of formula (1) (S). In one embodiment, the crystal form comprises the free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0331] In one embodiment, after storage at about 40°C and about 75% relative humidity for 1 month or 3 months, the pharmaceutical composition contains less than or equal to about 10%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% impurities. In one embodiment, the impurities comprise soluble impurities. In one embodiment, the crystal form comprises the free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0332] In one embodiment, the water content of the pharmaceutical composition at formation is measured by thermogravimetric analysis (TGA). In one embodiment, the water content of the pharmaceutical composition is measured by TGA after storage at about 25°C and about 60% relative humidity for 1 month or 3 months. In one embodiment, the water content of the pharmaceutical composition is measured by TGA after storage at about 40°C and about 75% relative humidity for 1 month or 3 months.

[0333] In one embodiment, the chiral purity of the crystal form in the pharmaceutical composition at formation is measured by high-performance liquid chromatography (HPLC). In one embodiment, the chiral purity of the crystal form in the pharmaceutical composition after storage at about 25°C and about 60% relative humidity for 1 month or 3 months is measured by HPLC. In one embodiment, the chiral purity of the crystal form in the pharmaceutical composition after storage at about 40°C and about 75% relative humidity for 1 month or 3 months is measured by HPLC. In one embodiment, the percentage of each enantiomer in the crystal form at formation and after storage is measured as the area percentage of the HPLC chromatogram. In one embodiment, the chiral purity of the crystal form in the pharmaceutical composition at formation and after storage is measured by HPLC, as described in the "Chiral Purity Obtained by High-Performance Liquid Chromatography" section of Example 6 of this disclosure.

[0334] In one embodiment, impurities present in the pharmaceutical composition at the time of formation are measured by ultra-high performance liquid chromatography (UPLC). In one embodiment, impurities present in the pharmaceutical composition after storage at about 25°C and about 60% relative humidity for 1 month or 3 months are measured by UPLC. In one embodiment, impurities present in the pharmaceutical composition after storage at about 40°C and about 75% relative humidity for 1 month or 3 months are measured by UPLC. In one embodiment, the percentage of each impurity in the pharmaceutical composition at the time of formation and after storage is measured as the area percentage of the UPLC chromatogram. In one embodiment, the content of impurities present in the pharmaceutical composition at the time of formation and after storage is measured by UPLC, as described in the "Identification, Measurement and Related Substances by Ultra-High Performance Liquid Chromatography" section of Example 6 of this disclosure.

[0335] In one embodiment, the pharmaceutical composition is a solid dosage form. In one embodiment, the solid dosage form is a capsule or tablet. In one embodiment, the solid dosage form comprises a cellulose capsule containing compound 106 or a salt, ester, solvate, optical isomer, geometric isomer, or isomer salt thereof. In one embodiment, the cellulose capsule comprises a hydroxypropyl methylcellulose capsule. In one embodiment, the hydroxypropyl methylcellulose capsule is a hard hydroxypropyl methylcellulose capsule. In one embodiment, the capsule is filled with compound 106 in mono-HCl form as described elsewhere herein. In one embodiment, the solid dosage form is orally administered to a subject in need. In one embodiment, after oral administration of the solid dosage form, the solid dosage form disintegrates in the gastrointestinal tract of the subject within about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute. In one embodiment, after oral administration of the solid dosage form, the solid dosage form disintegrates in the stomach of the subject within about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute.

[0336] combination therapy In one embodiment, the crystalline form of the free base of compound 106 is administered with one or more therapeutic agents. In another embodiment, the crystalline form of the salt of compound 106 is administered with one or more therapeutic agents. Exemplary therapeutic agents include, but are not limited to: CDK inhibitors, BCL2 inhibitors, PTEFb inhibitors, DNA polymerase inhibitors, cytidine deaminase inhibitors, DNA methyltransferase (DNMT) inhibitors, immunomodulatory imides, cereblon modulators, purine nucleoside antimetabolites, type II topoisomerase inhibitors, DNA intercalators, hedgehog antagonists, IDH2 inhibitors, IDH1 inhibitors, ribonucleotide reductase inhibitors, adenosine deaminase inhibitors, Mek 1 / 2 inhibitors, ERK 1 / 2 inhibitors, AKT inhibitors, PTPN11 inhibitors, SHP2 inhibitors, glucocorticoids, menin inhibitors, MDM2 inhibitors, BTK inhibitors, and mutant / inactivated p53 reactivators.

[0337] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax or a salt thereof. In one embodiment, the therapeutic agent comprises a DNA polymerase inhibitor. In one embodiment, the DNA polymerase inhibitor is cytidine. In one embodiment, the therapeutic agent comprises a cytidine deaminase inhibitor. In one embodiment, the cytidine deaminase inhibitor is zabralline. In one embodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, the DNMT inhibitor is zabralline, decitabine, or azacitidine. In one embodiment, the therapeutic agent comprises an immunomodulatory imide (cereblon modulator). In one embodiment, the immunomodulatory imide (cereblon modulator) is lenalidomide. In one embodiment, the therapeutic agent comprises a purine nucleoside antimetabolite. In one embodiment, the purine nucleoside antimetabolite is clofarabine. In one embodiment, the therapeutic agent comprises a type II topoisomerase inhibitor / DNA intercalator. In one embodiment, the type II topoisomerase inhibitor / DNA intercalator is vorxarosine. In one embodiment, the therapeutic agent comprises a hedgehog antagonist. In one embodiment, the hedgehog antagonist is glasgibrazolidinone. In one embodiment, the therapeutic agent comprises an IDH1 inhibitor. In one embodiment, the IDH1 inhibitor is iverosidinib. In one embodiment, the therapeutic agent comprises an IDH2 inhibitor. In one embodiment, the IDH2 inhibitor is ensidipin. In one embodiment, the therapeutic agent comprises a ribonucleotide reductase inhibitor. In one embodiment, the ribonucleotide reductase inhibitor is gemcitabine. In one embodiment, the therapeutic agent comprises an adenosine deaminase inhibitor. In one embodiment, the adenosine deaminase inhibitor is cladribine. In one embodiment, the therapeutic agent comprises a Mek 1 / 2 inhibitor. In one embodiment, the Mek 1 / 2 inhibitor is trametinib. In one embodiment, the therapeutic agent comprises an ERK 1 / 2 inhibitor. In one embodiment, the ERK 1 / 2 inhibitor is ulilistatinib. In one embodiment, the therapeutic agent comprises an AKT inhibitor. In one embodiment, the AKT inhibitor is carpicovacetinib (AZD5363). In one embodiment, the therapeutic agent comprises a PTPN11 / SHP2 inhibitor. In one embodiment, the PTPN11 / SHP2 inhibitor is TNO-155. In one embodiment, the therapeutic agent comprises a glucocorticoid. In one embodiment, the glucocorticoid is prednisolone. In one embodiment, the therapeutic agent comprises a menin inhibitor. In one embodiment, the menin inhibitor is SNDX-5613.In one embodiment, the therapeutic agent comprises an MDM2 inhibitor. In one embodiment, the MDM2 inhibitor is naftemaline (AMG 232, KRT-232). In one embodiment, the therapeutic agent comprises a BTK inhibitor. In one embodiment, the BTK inhibitor is selected from ibrutinib, acalabrutinib, and zanubrutinib. In one embodiment, the therapeutic agent comprises a mutant / inactivated p53 reactivator. In one embodiment, the mutant / inactivated p53 reactivator is Eprenetapopt (APR-246).

[0338] In one embodiment, the therapeutic agent comprises a CDK inhibitor. The CDK inhibitor may be any CDK inhibitor known to those skilled in the art. In one embodiment, the CDK inhibitor is a CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 inhibitor, or a combination thereof.

[0339] In one embodiment, the CDK inhibitor comprises an inhibitor described in one of the following patents or patent applications: US 20210332071, US 20210330653, WO 2021214253, WO 2021178595, WO2021207632, US 8685660, US 20200361906, US 10695346, US 11142507, WO2021198439, WO 2021201170, US 8153632, US 11013743, US 11135198, US20210299111, WO 2021190637, WO 2021188855, WO 2021188849. 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US6632820, US 6620818, US 20030166016, US 6596694, US 6586203, US 20030119816,US 20030113897, US 20030114504, US 6579903, US 6576647, US 6573044, US6043030, US 20030049602, US 20030100477, US 20030032177, WO 2003030909, US6319918, WO 2003027299, US 20030060397, US 6504034, WO 2002074742, WO2002053096, US 20030018005, US 6500846, WO 2002100401, US 6486166, WO2002072085, US 6462069, US 6451618, US 6420345, WO 2002051849, US 6413974, US6414013, US 6407103, WO 2001083716, US 5672508, US 6291504, WO 2001038532, WO2001027080, US 6303618, US 6290951, WO 2001055148, WO 2001053293, US 6001868,US 6197804, WO 1999066055, US 6013646, WO 1999043676, US 5767258,The entire contents of US 5733920 and any INPADOC family members of the foregoing references are incorporated herein by reference. In another embodiment, the CDK inhibitor comprises the inhibitors described below: Alsfouk, A., Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36(1):693-706; Goel, B. et al., Curr.Top. Med. Chem., 2020, 20(17):1535-1563; Heptinstall, AB et al., Future Med. Chem., 2018, 10(11):1369-1388; Sánchez-Martínez, C. et al., Bioorganic & Medicinal Chemistry Letters, 2019, 29:126637; Di Sante, G. et al., Expert Review of Anticancer Therapy, 2019, 19(7): 569-587; Whittaker, SR et al., Pharmacology & Therapeutics, 2017, 173:83-105; Chou, J. et al., Cancer Discovery, 2020, 10:351-370; Galbraith, MD et al., Transcription, 2019, 10(2):118-136; Goel, B. et al., Current Topics in Medicinal Chemistry, 2020, 20:1535-1563; Heptinstall, AB et al., Future Medicinal Chemistry, 2018, 10(11): 1369-1388; The entire contents of these publications are incorporated herein by reference.

[0340] In one embodiment, the CDK inhibitor is a CDK9 inhibitor. In one embodiment, the CDK9 inhibitor is Atuveciclib (BAY-1143572) or BAY-1251152 (VIP152). In one embodiment, BAY-1251152 (VIP152) is a selective CDK9 inhibitor, while Atuveciclib (BAY-1143572) is a CDK9 / PTEFb inhibitor. In one embodiment, the CDK inhibitor is a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is palbociclib. In one embodiment, the CDK inhibitor is a CDK7 inhibitor. In one embodiment, the CDK7 inhibitor is THZ1.

[0341] Exemplary CDK inhibitors include, but are not limited to: compound 21 (PMID 27326333), CYC065, YKL-1-116, i-CDK9, JH-VII-49, JH-XI-10-02, SEL120-34A, MM-D37K, PF-06873600, BEY-1007, BEY-1107, birocilib (XZP-3297), FCN-437, TP-1287, BEBT-209, TQB-3616, AMG-925 (FLX-925), CS3002, HS-10342, terameprocol (EM-1421), NU-6102, CGP-60474, BMS-265246, NU-6027, Purvalanol A, Purvalanol B, RGB-286147, Indirubin, 7-Hydroxystaurosporine, BS-194, PHA-690509, CDK4 / 6 inhibitor IV, FCN437c; Dinaciclib (SCH 727965); CDKI-73(LS-007); flavopiridol (alvocidib); dinaciclib; SNS-032 (BMS-387032); (RGB286638); (zortiraciclib, TG02, SB1317); (atuveciclib,BAY-1143572); (AZD4573); abemaciclib(LY2835219, Verzenio); Palbocicini (PD-0332991, Ibrance); Kisqali (LEE-011); PF-06873600; trilaciclib (G1T28); lerociclib(G1T38); SHR-6390; milciclib (PHA-848125); FN-1501; inditinib (AGM-130); (+)-BPI-16350; AT-7519; AZD-4573; voruciclib (P-1446A-05); BCD-115; CT7001 (ICEC 0942); CYC-065; seliciclib (R-roscovitine, CY-202); SY-1365; roniciclib (BAY-1000394); THZ1; THZ2; THZ531; E9; FMF-04-159-2; YKL-5-124; NU6300; SY-314; SY-351; dabrafenib; rebastinib; K03861; MC180295; BRD6989; SR-3029; Nordihydroguaiacol (NDGA); protaglandin E1; adapalene; fluspirilene; candesartan cilexil; indocyanine green; rafoxanide; HSD922; 20 - 223(CP668863); roxyl - zhc - 84; abemaciclib; vorinostat; cabozantinib; corticostatin A; MSC2530818; CCT251545; CCT251921; ZK - 304709; riviciclib (P276 - 00); R547; AZD5438; AG - 024322; LDC3140; LDC4297; wogonin; CMPD14; LDC000067; CMPD 93; sorafenib; senexin A; senexin B; CMPD 20; CMPD 32; SEL120; PHA - 793887; IIIM - 290; olomoucine; rohitukine; Fascaplysin; hymenialdisine; variolin B; konbu’acidin A; staurosporine; LY2857785; BS - 181; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; BS-181; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Where Ar is or ; ; ; ; ; Where X is N, Y is –C(=O)H and Ar are X is N, Y is -CH2OH and Ar is Or X is CH, Y is -CH2OH and Ar is ; Where X is NH or O; Where X is NH or O; Where R1 is or ; Where R is H or -CH3; Where R is -CH3 and X is F, R is H and X is F, or R is -CH3 and X is Cl; Where R is tetrahydro-pyran-4-yl and R' is H, R is -CH2CH3 and R' is -OCH 3， R is isopropyl and R' is H, or R is -CH2CH3 and R' is F; Where R is t-butylcarboxyl and n is 1 or R is H and n is 2; Where X is NH or O; Where R is H and R' is F, R is F and R' is F, or R is H and R' is H; Where R is -OCH3 and R' is F, R is F and R' is SF5, or R is -OCH3 and R' is -SF5; Where R is F and R' is -CH3 or R is -SF5 and R' is H; Where R is -CF3 and R' is -CH3 or R is H and R' is cyclopropyl; Where R is 3-fluoroaniline-1-yl and R' is F or R is phenyl and R' is -CH3; Where R is H or F and Alkyl is -CH3 or -CH2CH3; Where R is 3-fluorophenyl or morpholino-4-yl; Where R is cyclopropan-1-ol-1-yl, X is Cl and n is 1, or R is tetrahydrofuran-3-yl, X is Cl and n is 1, or R is -CH3, X is F and n is 2, or R is cyclopropan-1-1-yl, X is F and n is 1, or oxacyclobutan-3-yl, X is -CH3 and n is 1; Where R is 1,2-oxazol-3-yl or 3,4-difluorophenyl-1-yl; Where R is H, C(=O)NHCH3, -SO2NH2, SO2CH3, or 2,3-dihydroxypropyl-1-yl; Where R is H, CH3, 2-aminoethyl-1-yl, 3-aminopropyl-1-yl, or 2,3-dihydroxypropyl-1-yl; Where R is H or -CH3; Where R is H, C(=O)NHCH3, or -SO2CH3; Where R is 3-fluorobenzyl or 3-fluoropyridin-3-yl; Aryl is 4-fluorophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 4-methylphenyl, 2-ethylphenyl, or 3-pyridyl and R is H, cyclopropyl, cyclopentyl, or cycloheptyl; Where R is 2-phenylethyl-1-yl or (furan-2-yl)methyl; Where R is H or -C(=O)CH2OH; Where R is -NHC(=O)CH3 or -NHSO2CH3; Where R is H or isobutyl; Where R is H and R' is -CH3 or R is -CN and R' is H; Where R is 3,4-dimethyl-1H-pyrazol-4-yl and R' is -CH3 or R is piperazine-1-yl and R' is H; Where R is 2,6-dichlorophenyl, 2,3,4,5,6-tetrafluorophenyl, or 3-fluorophenyl; Where R is -CH2NCH3 or H; Where R is -CH2N(CH3)2 or H; Where R is H, -SO2CH3, -CH2C(=O)N(CH3)2,4-carboxylic acid-cyclobut-1-yl, or (2(hydroxymethyl)pyrrolid-1-yl)-2-one-ethyl-1-yl, R' is H or F and R” is H or -CH2CH3; Where R1 is -OH, R2 is H, R3 is H and R4 is H (meridianin A); R1 is -OH, R2 is H, R3 is Br and R4 is H (meridianin B); R1 is H, R2 is Br, R3 is H and R4 is H (meridianin C); R1 is H, R2 is H, R3 is Br and R4 is H (meridianin D); or R1 is -OH, R2 is H, R3 is H and R4 is Br (meridianin E); HH and Where R is piperidine-3-yl, pyrrolidine-3-yl, or morpholino-2-yl.

[0342] In one embodiment, the therapeutic agent comprises a BCL2 inhibitor and a DNMT inhibitor. In another embodiment, the therapeutic agent comprises venetoclax or a salt thereof, and azacitidine or a salt thereof.

[0343] In some embodiments, the one or more therapeutic agents may be in the form of salts, optical and geometric isomers, and isomeric salts. In other embodiments, the therapeutic agents may be in a variety of forms, such as uncharged molecules, molecular complex components, or non-irritating pharmaceutically acceptable salts, including but not limited to hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, for acidic compounds, the salt may contain a metal, amine, or organic cation (e.g., quaternary ammonium salt). In other embodiments, simple derivatives of the therapeutic agents (e.g., ethers, esters, or amides) may be employed, which have desirable retention and release properties but are readily hydrolyzed in vivo by pH, enzymes, or other suitable mechanisms.

[0344] In some embodiments, the therapeutic agent has a chiral center and can exist and be separated in both optically active and racemic forms. In other embodiments, the therapeutic agent may exhibit polymorphism. Some embodiments of this disclosure cover any racemic, optically active, polymorphic, or stereoisomeric forms or mixtures thereof of the compounds described herein, including isotopically labeled and radiolabeled compounds. See, for example, Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be separated by standard resolution techniques, including, for example, stepwise crystallization, chiral chromatography, etc. See, for example, Eliel, EL & Wilen SH, 1993, Stereochemistry in Organic Compounds; John Wiley & Sons, New York. The preparation of the optically active form can be accomplished by any suitable method, including but not limited to the resolution of the racemic form by recrystallization, synthesis from optically active raw materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.

[0345] In some embodiments, the therapeutic agent has an asymmetric center and can exist as a racemic mixture, a racemic mixture, or a single enantiomer or diastereomer, all of which are considered for use in the compounds and methods described herein. The compounds considered herein for use in the compounds and methods do not include those known in the art to be too unstable to synthesize and / or isolate.

[0346] The therapeutic agents disclosed herein may also contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be made with radioactive isotopes (such as tritium). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeling. All isotopic variants of the compounds disclosed herein, whether or not radioactive, are included in this consideration.

[0347] In some embodiments, metabolites of the therapeutic agents disclosed herein may be used in the methods disclosed herein.

[0348] In some embodiments, the therapeutic agents considered herein may be provided in prodrug form. The term "prodrug" refers to a compound that can be converted in vivo into the compound described herein (e.g., a bioactive compound). Prodrugs may be used for a variety of reasons known in the art, including, for example, ease of administration due to increased bioavailability from oral administration. Prodrugs may also have better solubility in pharmaceutical compositions than bioactive compounds. Examples (not limiting) of prodrugs are compounds administered in ester form (i.e., "prodrugs") to facilitate transmembrane transport (where water solubility is unfavorable for migration), but which, once inside the cell (where water solubility is favorable), are metabolized and hydrolyzed into carboxylic acids (the active entity). Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference for the limited purpose of describing procedures and preparation of suitable prodrug derivatives.

[0349] Some of the therapeutic agents disclosed herein may exist in both solvated and solvated forms (including hydrated forms). Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the compounds considered herein. Some of the therapeutic agents disclosed herein may exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods considered herein and are intended to fall within the scope of this disclosure.

[0350] Pharmaceutical compositions and formulations In one embodiment, this disclosure further relates to compositions comprising a crystalline form of the free base or salt of compound 106, and compositions comprising a therapeutic agent. Exemplary therapeutic agents are described elsewhere herein. In another embodiment, the crystalline form of the free base or salt of compound 106 is co-formulated with the therapeutic agent into a single composition. In one embodiment, the crystalline form of the free base or salt of compound 106 and the therapeutic agent are co-administered in a single dose or in a single composition. In another embodiment, the crystalline form of the free base or salt of compound 106 and the therapeutic agent are administered separately in multiple doses or in multiple compositions. In one embodiment, a composition comprising the crystalline form of the free base or salt of compound 106 and a composition comprising a therapeutic agent are administered to a subject simultaneously. In another embodiment, a composition comprising the crystalline form of the free base or salt of compound 106 and a composition comprising a therapeutic agent are administered to a subject sequentially. In one embodiment, a composition comprising the crystalline form of the free base or salt of compound 106 is co-administered (or administered for a specified time period) with a composition comprising a therapeutic agent, such that the subject is exposed to both inhibitors for a period of time during which a synergistic effect may occur.

[0351] Some embodiments of this disclosure include compositions comprising one or more of the compounds disclosed herein (e.g., a crystal form of the free base or salt of compound 106). In one embodiment, the composition comprising a compound of this disclosure further comprises one or more therapeutic agents described elsewhere herein. In one embodiment, this disclosure includes a single composition comprising one or more therapeutic agents described elsewhere herein. In some embodiments, the composition is a pharmaceutical composition, such as a composition suitable for administration to animals (e.g., mammals, primates, monkeys, humans, dogs, cats, pigs, mice, rabbits, rats, etc.). In some embodiments, a pharmaceutical composition comprising a crystal form disclosed herein and a pharmaceutically acceptable excipient is provided. The crystal form may be a free base or salt of compound 106, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, isomer salt, prodrug, or derivative thereof.

[0352] Further embodiments of this disclosure relate to compositions comprising the compounds described above. In some embodiments, the amount of the compound may be from about 0.0001% (by weight of the total composition) to about 99%. In some embodiments, the composition may also comprise a formulation ingredient, adjuvant, or carrier. In some embodiments, the composition may also comprise a BCL2 inhibitor. In some embodiments, the composition may be used in combination with a second composition comprising a BCL2 inhibitor. In some embodiments, the BCL2 inhibitor may be venetoclax or a salt, isomer, derivative, or analogue thereof.

[0353] The term "pharmaceutically acceptable salt" means a salt comprising an active compound prepared from a relatively non-toxic acid or base, depending on the specific substituents on the compound described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base under pure conditions or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds disclosed herein contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid under pure conditions or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid), and salts derived from relatively non-toxic organic acids (such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc.). Also included are amino acid salts (such as arginine salts) and organic acid salts (such as glucuronic acid or galacturonic acid) (see, for example, Berge et al., "Pharmaceutical Salts"). Journal of Pharmaceutical Science , 1977, 66 (1-19). Certain specific compounds disclosed herein contain both basic and acidic functional groups, which makes these compounds convertible into basic addition salts or acid addition salts.

[0354] The compounds disclosed herein may exist in salt form, such as salts formed with pharmaceutically acceptable acids. Therefore, compounds considered herein include such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts formed with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0355] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents).

[0356] Pharmaceutically acceptable salts of the aforementioned compounds (when basic or acidic groups are present in their structure) are also included within the scope of compounds considered herein. When acidic substituents are present (such as -NHSO3H, -COOH, and -P(O)(OH)2), ammonium, sodium, potassium, and calcium salts can be formed and used as dosage forms. Basic groups (such as amino or basic heteroaryl, or pyridyl) and acidic salts (such as hydrochlorides, hydrobromicates, acetates, maleates, palmitates, methanesulfonates, p-toluenesulfonates, etc.) can be used as dosage forms.

[0357] In addition, in embodiments containing R-COOH, pharmaceutically acceptable esters may be used, such as methyl esters, ethyl esters, tert-butyl esters, neopentyloxymethyl esters, and those esters known in the art for altering solubility or hydrolytic properties for use as sustained-release or prodrug formulations.

[0358] In some cases, the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, inherent side effects may exist (e.g., it may harm the patient or have a degree of toxicity or harm in some patients).

[0359] In some embodiments, one or more compounds of this disclosure (e.g., the crystal form of the free base or salt of compound 106) may be part of a pharmaceutical composition, and the amount thereof may be at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, not more than about 75%, not more than about 90%, not more than about 95%, not more than about 99%, not more than about 99.99%, about 0.001% to about 99%, about 0.001% to about 50%, about 0.1% to about 99%, about 1% to about 95%, about 10% to about 90%, or about 25% to about 75%. In some embodiments, the pharmaceutical composition may be presented in a dosage form suitable for topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, skin, nasal, vaginal, or ocular administration. In other embodiments, the pharmaceutical composition may be presented in a dosage form suitable for parenteral, mucosal, intravenous, subcutaneous, topical, intradermal, oral, sublingual, intranasal, or intramuscular administration. The pharmaceutical composition may be, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, patches, infusions, delivery devices, suppositories, enemas, injections, implants, sprays, aerosols, or other suitable forms.

[0360] In some embodiments, the compounds disclosed herein can be administered orally in the form of tablets, aqueous or oily suspensions, lozenges, sugar tablets, powders, granules, emulsions, capsules, syrups, or elixirs. Compositions for oral administration may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to prepare pharmaceutically aesthetically pleasing and palatable formulations. Therefore, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more of the compounds disclosed herein are also provided.

[0361] In some embodiments, the tablets contain a mixture of the active ingredient and a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing the tablets. These excipients may be, for example, (1) inert diluents such as calcium carbonate, lactose, mannitol, calcium phosphate, carboxymethyl cellulose, microcrystalline cellulose, or sodium phosphate; (2) granulating and disintegrants such as copovidone, corn starch, croscarmellose sodium, or alginate; (3) binders such as starch, gelatin, or gum arabic; and (4) lubricants such as magnesium stearate, sodium fumarate stearyl, stearic acid, or talc. These tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used.

[0362] For the preparation of pharmaceutical compositions from the compounds disclosed herein, a pharmaceutically acceptable carrier may be a solid or a liquid. Solid forms include powders, tablets, pills, capsules, pouches, suppositories, and dispersible granules. A solid carrier may be one or more substances that may also act as a diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulating material.

[0363] The compounds disclosed herein may be administered parenterally via injection or gradual perfusion over time for in vivo application, either as free compounds or as pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts. Routes of administration may include intravenous, intraperitoneal, intramuscular, subcutaneous, intracavitary, or transdermal administration. For in vitro studies, the compounds may be added to or dissolved in a suitable biologically acceptable buffer and added to cells or tissues.

[0364] In powder formulations, the carrier is a finely differentiated solid mixed with the finely differentiated active ingredients. In tablets, the active ingredients are mixed with a carrier having the necessary binding properties in an appropriate proportion and compressed into the desired shape and size.

[0365] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point waxes, cocoa butter, etc. The term "formulation" is intended to include the formulation of an active compound with an encapsulating material as a carrier into capsules, wherein the active component (with or without other carriers) is encapsulated and bound to the carrier. Similarly, this includes capsules and tablets. Tablets, powders, capsules, pills, capsules, and tablets are available as solid dosage forms suitable for oral administration.

[0366] To prepare suppositories, a low-melting-point wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted, and the active ingredients are uniformly dispersed in it by stirring. The molten homogeneous mixture is then poured into a mold of appropriate size and allowed to cool and solidify.

[0367] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injection, liquid formulations can be formulated as aqueous polyethylene glycol solutions.

[0368] When parenteral administration is required or desired, mixtures of the compounds disclosed herein are particularly suitable as injectable sterile solutions (preferably oily or aqueous solutions), suspensions, emulsions, or implants (including suppositories). The suspension can be formulated using suitable dispersants, wetting agents, and suspending agents mentioned above according to known methods. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral acceptable diluents or solvents (e.g., 1,3-butanediol solutions). Acceptable solvents, carriers, and susceptible media include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils are typically used as solvents or suspension media. Any mild fixative oil (including synthetic mono / diglycerides) can be used for this purpose. Additionally, fatty acids such as oleic acid can be used in the preparation of injectable formulations. In particular, carriers for parenteral administration include aqueous glucose solutions, physiological saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, etc. Ampoules provide a convenient unit dose. The compounds disclosed herein may also be encapsulated in liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures applicable to the pharmaceutical compositions and methods disclosed herein include, for example, those described in Pharmaceutical Science (17th edition, Mack Publishing, Easton, PA) and WO 96 / 05309, the contents of which are incorporated herein by reference.

[0369] In some implementations, parenteral formulations include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions (containing physiological saline and buffers). Common carriers or excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (such as sterile water, alcohols, glycerol, and polyhydroxy alcohols). Intravenous solvents include liquids and nutritional supplements. Parenteral solvents include sodium chloride solution, Ringer's glucose, glucose and sodium chloride, lactated Ringer's solution, etc. Preservatives and other additives (such as antimicrobial agents, antioxidants, chelating agents, growth factors, and inert gases) may also be present.

[0370] Preservatives include antimicrobial agents, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions and non-toxic excipients (containing salts, preservatives, buffers, etc.), as described, for example, in Remington's Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are incorporated herein by reference. The pH and precise concentration of the components of a pharmaceutical composition are adjusted according to conventional skills in the art. See, for example, Goodman and Gilman (eds.), 1990, The Pharmacological Basis for Therapeutics (7th ed.).

[0371] Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding appropriate amounts of coloring agents, flavoring agents, stabilizers, and thickeners. Aqueous suspensions suitable for oral administration can be prepared by dispersing finely differentiated active ingredients with viscous materials (such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents) in water. Aqueous suspensions typically contain active substances mixed with excipients suitable for making aqueous suspensions. Such excipients may be: (1) suspending agents (such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic); (2) dispersants or wetting agents, including: (a) natural phospholipids (such as lecithin); (b) condensation products of alkyl epoxides and fatty acids (such as polyoxyethylene stearate); (c) condensation products of ethylene oxide and long-chain fatty alcohols (such as heptadecanoethanol); (d) condensation products of ethylene oxide and derivatives of fatty acids and hexyl alcohols (such as polyoxyethylene sorbitan monooleate); (e) condensation products of ethylene oxide and derivatives of fatty acids and hexyl anhydrides (such as polyoxyethylene sorbitan monooleate).

[0372] This also includes solid dosage forms intended to be converted into oral liquid formulations before immediate use. These liquid formulations include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0373] Pharmaceutical formulations are preferably unit dosage forms. This dosage form is further subdivided into unit doses containing an appropriate amount of the active ingredient. A unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as blister-packed tablets, capsules, and powders in vials or ampoules. The unit dosage form itself can also be a capsule, tablet, sachets, or lozenge, or an appropriate number of these dosage forms packaged together.

[0374] In some embodiments, the pharmaceutical composition may contain one or more formulation ingredients. "Formulation ingredient" can be any suitable ingredient (e.g., applicable to a drug, drug dosage, drug release time, disease, disease state, or route of administration), including but not limited to water (e.g., boiling water, distilled water, filtered water, pyrogen-free water, or chloroform-containing water), sugars (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups thereof), ethanol, glycerol, glycols (e.g., propylene glycol), acetone, ethers, DMSO, surfactants (e.g., anionic, cationic, amphoteric, or nonionic surfactants (e.g., polysorbates)), oils (e.g., animal fats, vegetable oils (e.g., coconut oil or peanut oil), or mineral oils), oil derivatives (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., cysteine, methionine), antioxidants (e.g., vitamins (e.g., A, E, or C), selenium), retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens (e.g., methylparaben or propylparaben)), or combinations thereof.

[0375] In some embodiments, the pharmaceutical composition may be formulated to release the active ingredient (e.g., a crystal form of the free base or salt of compound 106) substantially immediately upon administration or at any predetermined time after administration. Such formulations may include, for example, controlled-release formulations, such as various controlled-release compositions and coatings.

[0376] Other formulations (such as pharmaceutical composition formulations) may include those in which the drug (or controlled-release formulation) is incorporated into food, food ingredients, feed, or beverages in some embodiments.

[0377] Some compounds have limited solubility in water, therefore surfactants or other suitable co-solvents may be required in the composition. Such co-solvents include: polysorbates 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyethylene 35 castor oil. Typical amounts of these co-solvents are from about 0.01% to about 2% (by weight).

[0378] Viscosities higher than those of simple aqueous solutions help reduce formulation dispensing variability, minimize separation of suspension or emulsion components, and / or improve formulation performance. Such thickeners include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations thereof. Typical amounts of these agents are from about 0.01% to about 2% (by weight).

[0379] The compositions disclosed herein may also contain components that provide sustained release and / or comfort. These components include high molecular weight anionic mucosal mimic polymers, gelling polysaccharides, and finely segmented drug carrier matrices. These components are discussed in detail in U.S. Patents 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference.

[0380] Various pharmaceutical compositions are provided for use in improving certain diseases and conditions. According to one embodiment, a pharmaceutical composition is formulated, alone or together with other drugs, using a carrier, excipients, and additives or excipients, by means of a compound disclosed herein, in the form of a free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, and is suitable for administration to a subject. Common carriers or excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (such as sterile water, alcohols, glycerol, and polyhydroxy alcohols). Intravenous carriers include liquids and nutritional supplements.

[0381] Various pharmaceutical compositions are provided for use in improving certain diseases and conditions. According to one embodiment, a pharmaceutical composition is formulated, alone or together with other drugs, using a carrier, excipients, and additives or excipients, by means of a compound disclosed herein, in the form of a free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, and is suitable for administration to a subject. Common carriers or excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents (such as sterile water, alcohols, glycerol, and polyhydroxy alcohols). Intravenous carriers include liquids and nutritional supplements.

[0382] Methods of treating and preventing diseases Other embodiments of this disclosure relate to methods of administering compounds to a subject, the methods comprising one or more administrations of a composition comprising a crystalline form of the free base or salt of compound 106 as described above. If multiple administrations are performed, the compositions may be the same or different. In some embodiments, at least one of the one or more compositions further comprises a formulation ingredient. In some embodiments, at least one of the one or more compositions comprises a composition comprising the compound as described above. In some embodiments, at least one of the one or more administrations comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, local administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, if multiple administrations are performed, at least one composition used in at least one administration is different from the composition used in at least another administration. In some embodiments, at least one compound of the one or more compositions may be administered to the subject in an amount from about 0.005 mg / kg of subject body weight to about 50 mg / kg of subject body weight. In some embodiments, the subject is a mammal, preferably a human, rodent, or primate.

[0383] Other embodiments of this disclosure relate to methods of treating a disease or condition, the methods comprising administering to a subject one or more times a composition comprising one or more compounds as described above. If multiple administrations are performed, the compositions may be the same or different. In some embodiments, the disease or condition may respond to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition. In some embodiments, at least one of the one or more compositions further comprises a formulation ingredient. In some embodiments, at least one of the one or more compositions comprises the composition as described above.

[0384] In some embodiments, at least one of the single or multiple administrations includes parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, local administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, at least one of the single or multiple administrations includes oral administration. In some embodiments, if multiple administrations are present, at least one composition used in at least one administration is different from the composition used in at least another administration. In some embodiments, at least one compound of the one or more compositions is administered to the subject in an amount from about 0.005 mg / kg of subject body weight to about 50 mg / kg of subject body weight. In some embodiments, the subject may be a mammal, preferably a human, rodent, or primate. In some embodiments, the subject requires treatment.

[0385] In some embodiments, the method is used to treat hematopoietic system cancers. In some embodiments, the method is used to treat myelodysplastic syndromes (MDS) and / or acute myeloid leukemia (AML). In some embodiments, the method is used to treat at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma. In some embodiments, the method is used to treat at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, gastric cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune diseases characterized by IRAK1 and / or IRAK4 overactivity, or combinations thereof. In some embodiments, the method is used to treat one or more inflammatory diseases or autoimmune diseases selected from chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, colitis, Crohn's disease, and atopic dermatitis, or combinations thereof. In some embodiments, the method is used to treat myelofibrosis. In some embodiments, the method is used to treat colitis. In some embodiments, the method is used to treat Crohn's disease. In some embodiments, the method is used to treat MDS, MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, or AML with enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or wherein said AML is not driven by FLT3 mutations but expresses IRAK4-Long. In some embodiments, the method is used to treat DLBCL, and said DLBCL includes the L265P MYD88 mutant (ABC) subtype of DLBCL.

[0386] In some embodiments, the method further includes administering a composition comprising a BTK inhibitor. In some embodiments, the BTK inhibitor includes ibrutinib.

[0387] In some embodiments, the subject is susceptible to AML and / or MDS, and / or the method prevents or improves future AML and / or MDS. In some embodiments, the method is performed after one or more of the following conditions: myelodysplastic syndrome, myeloproliferative disorder, chemical exposure, exposure to ionizing radiation, or receiving cancer treatment.

[0388] In some embodiments, the method further includes administering a composition comprising a BCL2 inhibitor, or at least one of the compounds described above further comprising a BCL2 inhibitor. In some embodiments, the compounds described above and the BCL2 inhibitor may be administered together or separately by one or more administrations of the composition. In some embodiments, the BCL2 inhibitor comprises venetoclax or its salts, isomers, derivatives, or analogs.

[0389] In some embodiments, the method further includes administering one or more additional therapies selected from one or more chemotherapy drugs, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smooth receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase inhibitor / hypomethylating agent includes azacytidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed 5:1 molar ratio); the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, and valproic acid. The purine nucleoside analogues (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody-drug conjugates include anti-CD33 antibodies (e.g., Ac225-lintuzumab, vadastuximab, or gejutuzumab-ozomicin) and / or anti-CD45 antibodies (e.g., I...). 131- apamisulstatin; the mAb / immunotherapy includes anti-CD70 antibodies (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123 x)). Anti-CD3 antibodies, anti-CTLA4 antibodies (e.g., ipilimumab), anti-PD1 / PDL1 antibodies (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 antibodies (e.g., 5F9 (Magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, selumetinib, pimasertib, and / or remetinib; the CDK9 inhibitors include alvocidib and / or vor... uciclib; the CDK8 inhibitor includes SEL120; the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and / or SY-1425 (a selective RARα agonist); the TP53 activator includes APR-246 (Eprenetapopt); the smooth receptor antagonist includes glasdegib; the ERK inhibitor includes ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, including ulixertinib, SCH772984, ravoxertinib, MK-8353 and / or VTX-11e; the PI3K inhibitor includes fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408) and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), everolimus and / or vistusertib (AZD2014);The glucocorticoid receptor modulators include agonists, including prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists, including mifepristone, miricorilant, and / or onapristone, and / or other binding ligands, including vamorolone (VBP15); and / or the EZH2 inhibitors include tazemetostat.

[0390] Further embodiments of this disclosure relate to the crystal form described above, in a method of treating a disease or condition, the method comprising inhibiting at least one of IRAK and FLT3 by administering one or more compositions comprising the compound, wherein, if multiple administrations are performed, the compositions may be the same or different. In some embodiments, the disease or condition may respond to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition. In some embodiments, at least one of the one or more compositions further comprises a formulation ingredient. In some embodiments, at least one of the one or more compositions comprises the composition described above. In some embodiments, at least one of the single or multiple administrations comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, local administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, at least one of the single or multiple administrations comprises oral administration. In some embodiments, if multiple administrations are performed, at least one composition used in at least one administration is different from the composition used in at least another administration.

[0391] In some embodiments, at least one compound contained in the one or more compositions may be administered to the subject at an amount of about 0.005 mg / kg subject body weight to about 50 mg / kg subject body weight. In some embodiments, the subject is a mammal, preferably a human, rodent, or primate. In some embodiments, the subject requires treatment.

[0392] In some embodiments, the method is used to treat cancers of the hematopoietic system. In some embodiments, the method is used to treat MDS and / or AML. In some embodiments, the method is used to treat at least one disease selected from the group consisting of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, and marginal zone lymphoma. In some embodiments, the method is used to treat at least one cancer selected from the group consisting of glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, gastric cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune diseases characterized by IRAK1 and / or IRAK4 overactivation, or combinations thereof. In some embodiments, the method is used to treat one or more inflammatory diseases or autoimmune diseases selected from the group consisting of chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, and type 1 diabetes, or combinations thereof. In some embodiments, the method is used to treat MDS, MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, or AML with enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or said AML not driven by FLT3 mutations but expressing IRAK4-Long. In some embodiments, the method is used to treat DLBCL, and said DLBCL comprises the L265P MYD88 mutant (ABC) subtype.

[0393] In some embodiments, the method further includes administering a composition comprising a BTK inhibitor. In some embodiments, the BTK inhibitor includes ibrutinib.

[0394] In some embodiments, the subject is susceptible to AML and / or MDS, and / or the method prevents or improves future AML and / or MDS. In some embodiments, the method is performed after one or more of the following conditions: myelodysplastic syndrome, myeloproliferative disorder, chemical exposure, exposure to ionizing radiation, or receiving cancer treatment. In some embodiments, the method further includes administering a composition containing a BCL2 inhibitor, or at least one of the compositions containing a crystal form of the free base or salt of compound 106 further containing a BCL2 inhibitor. In some embodiments, the crystal form of the free base or salt of compound 106 and the BCL2 inhibitor may be administered together or separately with one or more compositions in one or more administrations. In some embodiments, the BCL2 inhibitor includes venetoclax or its salts, isomers, derivatives, or analogs.

[0395] In some embodiments, the method further includes administering one or more additional therapies selected from the group consisting of one or more chemotherapy drugs, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smooth receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, and EZH2 inhibitors, or one or more combinations thereof. In some embodiments, the DNA methyltransferase inhibitor / hypomethylating agent includes azacytidine, decitabine, cytarabine, and / or guadecitabine; the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed 5:1 molar ratio); the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, and valproic acid. The purine nucleoside analogues (antimetabolites) include fludarabine, cladribine, and / or clofarabine; the isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors include ivosidenib and / or enasidenib; the antibody-drug conjugates include anti-CD33 antibodies (e.g., Ac225-lintuzumab, vadastuximab, or gejutuzumab-ozomicin) and / or anti-CD45 antibodies (e.g., I...). 131- apamisulstatin; the mAb / immunotherapy includes anti-CD70 antibodies (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123 x)). Anti-CD3 antibodies, anti-CTLA4 antibodies (e.g., ipilimumab), anti-PD1 / PDL1 antibodies (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and / or anti-CD47 antibodies (e.g., 5F9 (Magrolimab)); the Plk inhibitors include volasertib and / or rigosertib; the MEK inhibitors include trametinib, cobimetinib, selumetinib, pimasertib, and / or refumetinib; the CDK9 inhibitors include alvocidib and / or voru ciclib; the CDK8 inhibitor includes SEL120; the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and / or SY-1425 (a selective RARα agonist); the TP53 activator includes APR-246 (Eprenetapopt); the smooth receptor antagonist includes glasdegib; the ERK inhibitor includes ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, including ulixertinib, SCH772984, ravoxertinib, MK-8353 and / or VTX-11e; wherein the PI3K inhibitor includes fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408) and / or bimiralisib (PQR-309); the mTOR inhibitors include bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), everolimus and / or vistusertib (AZD2014);The glucocorticoid receptor modulators include agonists, including prednisolone, beclometasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists, including mifepristone, miricorilant, and / or onapristone, and / or other binding ligands, including vamorolone (VBP15); and / or the EZH2 inhibitors include tazemetostat.

[0396] In one aspect, this disclosure relates to a method of treating and / or preventing a disease or condition in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of the free base or salt of compound 106 and a therapeutically effective amount of a CDK inhibitor. In one embodiment, the subject is administered a composition comprising a therapeutically effective amount of the crystalline form of the free base or salt of compound 106. In one embodiment, the subject is administered a composition comprising a therapeutically effective amount of the CDK inhibitor. In one embodiment, the crystalline form of the free base or salt of compound 106 treats and / or prevents the disease or condition by inhibiting FLT3 (wild-type FLT3 and / or mutant FLT3) and IRAK4, IRAK1, or both IRAK4 and IRAK1 in the subject of need. In one embodiment, the CDK inhibitor treats and / or prevents the disease or condition by inhibiting one or more of CKD1, CKD2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13 in a subject in need.

[0397] In addition to their ability to inhibit IRAK, IRAK inhibitors have been shown to be selective for a variety of kinases. In some embodiments, the compounds described herein, such as the crystal form of the free base or salt of compound 106, have inhibitory activity against one or more kinases, such as interleukin-1 receptor-associated kinase (IRAK) and FMS-like tyrosine kinase 3 (FLT3). Inhibitory activity against one or more kinases (such as IRAK and FLT3) enables the use of compounds of this disclosure (e.g., crystal forms of the free base or salt of compound 106) to treat and / or prevent diseases in animals (e.g., mammals, pigs, dogs, poultry (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans), including but not limited to hematopoietic cancers (e.g., hematopoietic stem cell diseases in the bone marrow or myeloid-related diseases), MDS, AML, myeloproliferative disorders, and diseases associated with IRAK1, IRAK4, and / or FLT3 mutations (e.g., hematopoietic cancers) (e.g., mutations in the juxtamembrane region of FLT3, mutations in the FLT3 kinase domain, FLT3 point mutations, FLT3 internal tandem repeat mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations).

[0398] In some embodiments, the compounds disclosed herein can inhibit one or more of the following activities: FLT3, mutations in FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the FLT3 kinase domain, point mutations in FLT3, internal tandem repeat mutations in FLT3, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), IRAK4 (interleukin-1 receptor-associated kinase 4), isoforms of IRAK4, mutations in IRAK4, IRAK1 (interleukin-1 receptor-associated kinase 1), isoforms of IRAK1, and / or mutations in IRAK1. In some embodiments, the compounds of this disclosure may inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the FLT3 kinase domain, point mutations in FLT3, internal tandem repeat mutations in FLT3, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691LFLT3 mutations, or R834Q FLT3 mutations), and optionally inhibit one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAK1, isoforms of IRAK1, or mutations of IRAK1. In some embodiments, the compounds of this disclosure can inhibit the activity of one or both of FLT3 and FLT3 mutations (e.g., mutations in the juxtamembrane region of FLT3, mutations in the FLT3 kinase domain, FLT3 point mutations, FLT3 internal tandem repeat mutations, FLT3-ITD mutations, D835Y FLT3 mutations, D835V FLT3 mutations, F691L FLT3 mutations, or R834Q FLT3 mutations), and optionally inhibit one or both of IRAK4 and IRAK1, or isomers or mutations thereof. In some embodiments, the compounds of this disclosure can inhibit FLT3 and in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.

[0399] In some embodiments, the compound exhibits inhibitory activity against IRAK and / or FLT-3, with activity ≥1 µM, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 nM, or even higher. In some embodiments, the compounds exhibit inhibitory activity against IRAK and / or FLT-3 in the range of 0.1 nM to 1 nM, such as about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 nM. In some embodiments, the compounds described herein exhibit inhibitory activity against IRAK and / or FLT-3 in the range of ≤0.1 µM, such as about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. The range of values ​​for the upper and / or lower limits, using any combination of values ​​described herein, is also considered, such as, but not limited to, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM. In some embodiments, the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 µM, 1-10 µM, 10-100 µM, 100-200 µM, 200-500 µM, or even 500-1000 µM. It should be understood that, for quantitative purposes, the terms "activity," "inhibitory activity," "biological activity," "IRAK activity," "IRAK1 activity," "IRAK4 activity," "FLT-3 activity," etc., used for the inhibitory compounds disclosed herein can be quantified in various ways known in the art. Unless otherwise stated, such terms as used herein refer to IC50 in the usual sense. 50 (That is, the concentration at which half-maximal inhibition is achieved).

[0400] In some embodiments, hematopoietic cancers that can be treated in animals (e.g., mammals, pigs, dogs, poultry (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using compounds of this disclosure (e.g., the free base or salt crystal form of compound 106) include, but are not limited to: hematopoietic cancers and myeloid blood cell cancers, cancers at increased risk due to other blood disorders, cancers at increased risk due to chemical exposure (e.g., anticancer therapy or occupational chemical exposure), cancers at increased risk due to ionizing radiation (e.g., anticancer therapy), cancers evolving from myelodysplastic syndromes, cancers evolving from myeloproliferative disorders, and B-cell cancers.

[0401] In some implementations, treatable hematopoietic system cancers include, but are not limited to: MDS, AML, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., ABC DLBCL with MYD88 mutation (such as L265P), follicular lymphoma or marginal zone lymphoma, or combinations thereof.

[0402] In some implementations, cancers characterized by dysregulation of IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling abnormalities can be treated, including but not limited to: glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, gastric cancer, and uterine cancer, and combinations thereof.

[0403] In some embodiments, the compounds of this disclosure can be used to inhibit targets in other conditions characterized by overactivity of IRAK1 and / or IRAK4. According to a specific aspect of this disclosure, the compounds of this disclosure can be used to inhibit overactive IRAK1 and / or IRAK4 in conditions such as inflammatory diseases and autoimmune diseases characterized by overactivity of IRAK1 and / or IRAK4. In some embodiments, inflammatory and autoimmune diseases characterized by dysregulation (e.g., overactivity) of IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated abnormal intracellular signaling can be treated, including but not limited to: chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, and combinations thereof.

[0404] In some embodiments, MDS that can be treated in subjects (e.g., mammals, pigs, dogs, poultry (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) using compounds of this disclosure (e.g., the free base or salt form of compound 106) include, but are not limited to: MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, and refractory cytopenia with monolineage abnormalities (e.g., refractory anemia, refractory...). Neutropenia and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ringed sideroblasts, and in animals / humans where the lesions are not limited to erythrocytes, such as significant leukocyte precursor cell and platelet precursor cell (megakaryocyte) dysplasia), refractory anemia type I and II with blast cell proliferation, 5q- syndrome, megakaryocyte dysplasia with fibrosis, and refractory cytopenia in childhood. In some implementations, treatable MDS include, but is not limited to: hereditary MDS, MDS with increased risk due to genetic susceptibility, MDS with increased risk due to other blood disorders, MDS with increased risk due to chemical exposure, MDS with increased risk due to ionizing radiation, MDS with increased risk due to cancer treatment (e.g., a combination of radiotherapy and radioalkylating agents (such as busulfan, nitrosourea, or procarbazine (latency 5 to 7 years) or DNA topoisomerase inhibitors), MDS evolving from acquired aplastic anemia and Fanconi anemia following immunosuppressive therapy, and MDS due to splicing factor mutations. Increased-risk MDS includes MDS caused by isocitrate dehydrogenase 1 mutations and MDS caused by isocitrate dehydrogenase 2 mutations. Treatable animals include, but are not limited to, mammals, rodents, primates, monkeys (such as macaques, rhesus monkeys, and pig-tailed monkeys), humans, dogs, cats, pigs, poultry (such as chickens), cattle, mice, rabbits, and rats. In these methods, the term "subject" can refer to both human and non-human subjects. In some cases, said subjects require treatment (e.g., by exhibiting signs of disease, such as MDS, AML, cancer, autoimmune diseases, inflammation, etc., or by low blood cell counts).

[0405] In some embodiments, MDS treatable with the compounds disclosed herein (e.g., the crystal form of the free base or salt of compound 106) includes, but is not limited to, MDS treatable by inhibiting one or more of the following targets: FLT3 (e.g., using an FLT3 inhibitor), FLT3 mutants (e.g., using an FLT3 mutant inhibitor), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 mutants (e.g., using an IRAK4 mutant inhibitor), IRAK1 (e.g., using an IRAK1 inhibitor), and / or IRAK1 mutants (e.g., using an IRAK1 mutant inhibitor). In some embodiments, treatable MDS includes, but is not limited to, MDS treatable by inhibiting IRAK4 (or a mutation thereof), MDS treatable by inhibiting IRAK1 (or a mutation thereof), or MDS treatable by simultaneously inhibiting IRAK4 (or a mutation thereof) and IRAK1 (or a mutation thereof). In some implementations, treatable MDS includes, but is not limited to, MDS that can be treated by combined inhibition of FLT3 with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some implementations, combined inhibition of FLT3 with IRAK4, IRAK1, or both can treat tumors with FLT3 mutations that may develop resistance to FLT3 inhibitors due to adaptive resistance mechanisms (e.g., driven by IRAK). In some implementations, the therapeutic MDS is characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or the MDS is not driven by FLT3 mutations but expresses IRAK4-Long (based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, as described in, for example, U.S. Patent Application No. 16 / 339,692 and Smith et al. (2019) “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0406] In some embodiments, subjects (including mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) who can be treated with the compounds disclosed herein (e.g., the crystal form of the free base or salt of compound 106) have AML, including but not limited to: hereditary AML, AML with an increased risk of developing the disease due to genetic susceptibility, and AML with one or more recurrent genetic abnormalities (e.g., MLLT3 / MLL with inversions or translocations, such as MLLT3 / MLL with translocation of chromosomes 9 and 11 ("MLL")). AML with translocations of chromosomes 8 and 21, translocations or inversions of chromosome 16, translocations of chromosomes 9 and 11, promyelocytic leukemia (M3) with translocations of chromosomes 15 and 17, translocations of chromosomes 6 and 9, translocations or inversions of chromosome 3, etc., AML with translocations of chromosomes 1 and 22 (megakaryocytes), AML with myelodysplastic anomalies, and AML associated with previous chemotherapy or radiotherapy (e.g., alkylating agent-related AML, topoisomerase II inhibitor-related AML). AML not further classified (using a similar FAB classification system, such as microdifferentiated AML (M0), AML with minimal signs of maturation (M1), mature AML (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroleukemia (M6), acute megakaryocytic leukemia (M7), acute basophilic leukemia, acute panmyeloid leukemia with fibrosis, etc.), myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary medulloblastoma), unclassified and biphenotyped acute leukemia ( Also known as mixed phenotype acute leukemia, AML with increased risk due to other blood disorders, AML with increased risk due to chemical exposure, AML with increased risk due to ionizing radiation, AML evolving from myelodysplastic syndromes, AML evolving from myeloproliferative disorders, AML with increased risk due to FLT3 mutations, AML with increased risk due to FLT3 juxtamembrane mutations, AML with increased risk due to FLT3 juxtamembrane tandem repeat mutations, AML with increased risk due to FLT3 kinase domain mutations, AML with increased risk due to FLT3 D835Y mutations, AML with increased risk due to FLT3 D835V mutations, AML with increased risk due to FLT3 F691L mutations, and AML with increased risk due to FLT3 R834Q mutations, etc. In some implementations, treatable AML includes AML that can be treated by inhibiting one or more of the following targets: FLT3 (e.g., using an FLT3 inhibitor), FLT3 mutant (e.g., using an FLT3 mutant inhibitor), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 mutant (e.g., using an IRAK4 mutant inhibitor), IRAK1 (e.g., using an IRAK1 inhibitor), and / or IRAK1 mutant (e.g., using an IRAK1 mutant inhibitor).In some embodiments, treatable AML includes, but is not limited to: AML treatable by inhibiting IRAK4 (or its mutations), AML treatable by inhibiting IRAK1 (or its mutations), or AML treatable by simultaneously inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations). In some embodiments, treatable AML includes, but is not limited to: AML treatable by combined inhibition of FLT3 with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, combined inhibition of FLT3 with IRAK4, IRAK1, or both can treat tumors with FLT3 mutations that may develop resistance to FLT3 inhibitors due to adaptive resistance mechanisms (e.g., driven by IRAK). In some implementations, the therapeutic AML is characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or the AML is not driven by FLT3 mutations but expresses IRAK4-Long (based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, as described in, for example, U.S. Patent Application No. 16 / 339,692 and Smith et al. (2019) “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0407] In some embodiments, subjects (including mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) with hematopoietic system cancers treatable using the compounds disclosed herein (e.g., crystal forms of the free base or salt of compound 106) include, but are not limited to, hematopoietic system cancers (e.g., MDS, AML, DLBCL, etc., as previously described) that can be treated by inhibiting (e.g., reducing activity or expression) one or more of the following targets: FLT3 (e.g., using an FLT3 inhibitor), FLT3 mutant (e.g., using an FLT3 mutant inhibitor), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 isomer, IRAK4 mutant (e.g., using an IRAK4 mutant inhibitor), IRAK1 (e.g., using an IRAK1 inhibitor), IRAK1 isomer, or IRAK1 mutant (e.g., using an IRAK1 mutant inhibitor). In some embodiments, treatable hematopoietic cancers include, but are not limited to: cancers treatable by inhibiting FLT3 (or its mutations) and IRAK4 (or its mutations); hematopoietic cancers treatable by inhibiting FLT3 (or its mutations) and IRAK1 (or its mutations); or hematopoietic cancers treatable by inhibiting FLT3 (or its mutations), IRAK4 (or its isoforms or mutations), and IRAK1 (or its isoforms or mutations). In some embodiments, treatable hematopoietic cancers include, but are not limited to: hematopoietic cancers treatable by combined inhibition of FLT3 with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some embodiments, combined inhibition of FLT3 with IRAK4, IRAK1, or both can treat tumors with FLT3 mutations that may develop resistance to FLT3 inhibitors due to adaptive resistance mechanisms (e.g., driven by IRAK). In some implementations, the treatable hematopoietic cancer is characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or the hematopoietic cancer is not driven by FLT3 mutations but expresses IRAK4-Long (based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, as described in, for example, U.S. Patent Application No. 16 / 339,692 and Smith et al. (2019) “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0408] In some implementations, treatable cancers include, but are not limited to: glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, and uterine cancer, as well as combinations thereof, which can be treated by combining inhibition of FLT3 with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some implementations, combining inhibition of FLT3 with IRAK4, IRAK1, or both can treat tumors with FLT3 mutations that may develop resistance to FLT3 inhibitors due to adaptive resistance mechanisms (e.g., driven by IRAK). In some implementations, the treatable cancer is characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or the cancer is not driven by FLT3 mutations but expresses IRAK4-Long (based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, as described in, for example, U.S. Patent Application No. 16 / 339,692 and Smith et al. (2019) “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0409] In some implementations, treatable inflammatory and autoimmune diseases characterized by dysregulation (e.g., overactivity) of IRAK expression (IRAK1 and / or IRAK4) and / or IRAK-mediated intracellular signaling abnormalities include, but are not limited to: chronic inflammation (i.e., associated with viral and bacterial infections), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, colitis, Crohn's disease, atopic dermatitis, and combinations thereof, which can be treated by combined inhibition of FLT3 with IRAK4, IRAK1, or both IRAK4 and IRAK1. In some implementations, combined inhibition of FLT3 with IRAK4, IRAK1, or both can treat inflammatory and autoimmune diseases with FLT3 mutations that may develop resistance to FLT3 inhibitors due to adaptive resistance mechanisms (e.g., driven by IRAK). In some implementations, the treatable inflammatory and autoimmune diseases are characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or the inflammatory and autoimmune diseases are not driven by FLT3 mutations but express IRAK4-Long (based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, as described in, for example, U.S. Patent Application No. 16 / 339,692 and Smith et al. (2019) “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.” Nat Cell Biol 21(5): 640-650. DOI: 10.1038 / s41556-019-0314-5, both of which are incorporated herein by reference in their entirety).

[0410] Regarding the treatment of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations), treatment may include, but is not limited to, preventative and therapeutic treatment. Therefore, treatment may include, but is not limited to: preventing MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); reducing the risk of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); improving or alleviating the symptoms of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); and inducing treatment for MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); and triggering treatment for MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations). The therapeutic effects of MDS (mutated MDS, MDS with isocitrate dehydrogenase 1 mutation, or MDS with isocitrate dehydrogenase 2 mutation) on the body's response; inhibition of the development or progression of MDS (e.g., MDS with splicing factor mutation, MDS with isocitrate dehydrogenase 1 mutation, or MDS with isocitrate dehydrogenase 2 mutation); inhibition or prevention of the onset of symptoms associated with MDS (e.g., MDS with splicing factor mutation, MDS with isocitrate dehydrogenase 1 mutation, or MDS with isocitrate dehydrogenase 2 mutation); and reduction of MDS (e.g., MDS with splicing factor mutation, MDS with isocitrate dehydrogenase 1 mutation, or MDS with isocitrate dehydrogenase 2 mutation). The severity of MDS with splice factor mutations (e.g., MDS with isocitrate dehydrogenase 1 mutations or MDS with isocitrate dehydrogenase 2 mutations); the resolution of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) or one or more symptoms associated with MDS (e.g., increased blood cell counts); the remission of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); and the prevention or minimization of FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations). The treatment aims to: induce remission of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); prevent relapse of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) in animals / humans with intrinsic or acquired resistance to other MDS treatments (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); or prevent relapse of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) in animals / humans with intrinsic or acquired resistance to other MDS treatments. In some embodiments, the treatment does not include prophylactic treatment of MDS (e.g., prevention or improvement of future MDS).

[0411] Regarding the treatment of hematopoietic system cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation (e.g., ABC DLBCL with MYD88 L265P mutation), follicular lymphoma, or marginal zone lymphoma, and combinations thereof), treatment may include, but is not limited to, prophylactic and therapeutic treatments. Therefore, treatment may include, but is not limited to: prevention of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); and reduction of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL, etc.). Risk of MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof; improvement or relief of symptoms of cancers such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof; triggering symptoms of cancers such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL The body's response to MYD88 mutations, follicular lymphoma, or marginal zone lymphoma, and combinations thereof; to inhibit the development or progression of cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutations, follicular lymphoma, or marginal zone lymphoma, and combinations thereof);Suppress or prevent the occurrence of symptoms associated with cancer (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof); alleviate symptoms associated with cancer (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL). The severity of MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof; the severity of the cancer it causes (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL)). The regression of one or more symptoms associated with cancer (such as MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, or combinations thereof) or tumor shrinkage; the regression of cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL)). Remission of cancers (such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and their combinations) by preventing or minimizing FLT3 mutations (such as internal tandem repeat mutations or D835Y mutations); remission of acute myeloid leukemia by preventing or minimizing FLT3 mutations (such as internal tandem repeat mutations or D835Y mutations).Preventing relapse of cancers (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof) in animals / humans with intrinsic or acquired resistance to other cancer treatments (e.g., certain FLT3 inhibitors or MLL therapy). Relapse of MYD88-mutant leukemia, follicular lymphoma, or marginal zone lymphoma, or combinations thereof; or prevention of relapse of acute myeloid leukemia in animals / humans with intrinsic or acquired resistance to other cancer treatments (e.g., certain FLT3 inhibitors or MLL therapy). In some implementations, the treatment does not include prophylactic treatment for cancer (e.g., prevention or improvement of future cancer).

[0412] Treatment of the subject may be performed using any suitable method of administration (e.g., the method disclosed herein) and with any suitable dose of the disclosed compound (e.g., the crystal form of the free base or salt of compound 106). In some embodiments, the treatment method includes treating MDS in animals or humans (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations). In some embodiments, the treatment method includes treating hematopoietic system cancers in animals or humans (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, etc., and combinations thereof). Other embodiments include treatment following one or more of the following conditions: a blood disorder, myelodysplastic syndrome, myeloproliferative disorder, chemical exposure, exposure to ionizing radiation, or treatment for hematopoietic system cancers (e.g., chemotherapy, ionizing radiation, or both). Some embodiments of this disclosure include a method of treating a subject (e.g., an animal, such as a human or primate) with a composition (e.g., a pharmaceutical composition) containing a compound of this disclosure (e.g., a free base or crystal form of compound 106), the method comprising administering one or more such compositions once or multiple times; if multiple administrations are present, the compositions may be the same or different.

[0413] In some embodiments, the treatment method includes administering to a subject an effective dose of a composition comprising a compound of the present disclosure (e.g., a crystal form of the free base or salt of compound 106). As used herein, the term "effective dose" refers to a single or serial dose sufficient to affect treatment (e.g., treatment of MDS, including but not limited to MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations; or treatment of hematopoietic system cancers, including but not limited to acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof). In some embodiments, the effective dose may include the therapeutically effective dose as disclosed herein. In some embodiments, the effective dose may vary depending on the subject and the specific treatment being administered. For example, the exact dose required may vary depending on the subject's age and general condition, the specific adjuvant used (if applicable), the dosing regimen, etc. Therefore, the effective dose may vary depending on the specific circumstances, and an appropriate effective dose may be determined under specific conditions. The effective dose may include any dosage or compositional amount disclosed herein. In some embodiments, an effective dose of at least one compound of this disclosure (e.g., the crystal form of the free base or salt of compound 106) (which may be administered to subjects such as mammals, primates, monkeys, or humans) may be about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, or about 15 mg / kg. In some embodiments, the dose may be about 0.5 mg / kg body weight or about 6.5 mg / kg body weight.In certain circumstances, an effective dose of at least one compound of this disclosure (e.g., the crystal form of the free base or salt of compound 106) (which may be administered to subjects such as mammals, rodents, mice, rabbits, cats, pigs, or dogs) may be about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 80 mg / kg, about 100 mg / kg, or about 150 mg / kg. In some embodiments, an effective dose of at least one compound of this disclosure (e.g., the crystal form of the free base or salt of compound 106) (which can be administered to animals such as mammals, primates, monkeys, or humans) may be about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg. For certain conditions, the human dose may be about 20 mg / kg or about 100 mg / kg. In certain circumstances, an effective dose of at least one compound of this disclosure (e.g., the crystal form of the free base or salt of compound 106) (which may be administered to animals such as mammals, rodents, mice, rabbits, cats, pigs, or dogs) may be about 1 to about 1000 mg / kg body weight, about 5 to about 500 mg / kg body weight, about 10 to about 200 mg / kg body weight, about 25 to about 100 mg / kg body weight, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1000 mg / kg.

[0414] In some implementations, treatment may also include one or more surgical interventions, chemotherapy, radiation therapy, hormone therapy, immunotherapy, and adjuvant systemic therapy. Adjuvant therapy may include, but is not limited to, chemotherapy (e.g., temozolomide), radiation therapy, anti-angiogenic therapy (e.g., bevacizumab), and hormone therapy such as administration of luteinizing hormone-releasing hormone (LHRH) agonists; anti-estrogenic drugs such as tamoxifen; high-dose progestins; aromatase inhibitors; and / or adrenalectomy. Chemotherapy may be used as a single agent or in combination with known or new therapies.

[0415] In some embodiments, administration of at least one compound of this disclosure (e.g., a crystalline form of the free base or salt of compound 106) to a subject is part of adjuvant cancer therapy or adjuvant cancer treatment. Adjuvant therapy includes treating the cancers disclosed herein through the mechanisms disclosed herein, including but not limited to tumors. Corresponding primary treatments may include, but are not limited to, surgery, chemotherapy, or radiation therapy. In some cases, adjuvant therapy may be a combination of a chemokine receptor antagonist with a conventional cytotoxic drug or immunotherapy, which may improve the specificity of treatment for cancer and potentially limit additional systemic side effects. In other embodiments, the compounds of this disclosure (e.g., a crystalline form of the free base or salt of compound 106) may be used in combination with other chemotherapeutic agents as adjuvant therapy. The use of compounds of this disclosure (e.g., a crystalline form of the free base or salt of compound 106) may, in certain circumstances, shorten the duration of administration of two drugs or drug combinations, thereby reducing side effects.

[0416] In some embodiments, administration to a subject may reduce the incidence of one or more symptoms associated with MDS / AML / a certain hematopoietic system cancer. In some embodiments, the administration may reduce bone marrow failure, immune dysfunction, transformation to overt leukemia, or a combination thereof in the subject compared to subjects who have not received the composition.

[0417] In some implementations, the method can reduce survival markers of MDS cells, AML cells, or cancer cells in a subject. In one aspect, the method can reduce survival markers of MDS, AML, and / or cancer cells. These markers may be selected from survival over time, proliferation, growth, migration, colony formation, chromatin assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or combinations thereof.

[0418] In one embodiment, the crystal forms described herein and / or compositions comprising the crystal forms described herein are used in combination with or in conjunction with a CDK inhibitor in one or more administrations. Various CDK isoforms play key regulatory roles in cell cycle progression in multiple cell types, and these pathways are dysregulated in hematopoietic cancers and solid tumors. Non-selective CDK inhibitors have shown efficacy in various hematologic cancer models (Whittaker SR et al., Pharmacology & Therapeutics (2017) 173:83-105). In one embodiment, the CDK inhibitor is a CDK9 inhibitor.

[0419] The cyclin-dependent kinase 9 (CDK9) pathway is dysregulated in AML, making its targeting an attractive therapeutic approach. Inhibition of CDK9 leads to downregulation of cell survival genes regulated by superenhancers such as MCL-1, MYC, and cyclin D1. Because first-generation CDK9 inhibitors are non-selective, predictive biomarkers are currently being utilized to help identify patients most likely to respond to CDK9 inhibitors, improving efficacy and safety. In one embodiment, the CDK9 inhibitor is lavindulgence (alvocidib), a polyserine / threonine cyclin-dependent kinase inhibitor that has shown in vitro and clinical activity in AML when used in combination with timed sequential chemotherapy regimens. In another embodiment, the CDK9 inhibitor is BAY1143752 (atuveciclib), which has been shown in vitro to have antiproliferative activity against HeLa cells and MOLM-12 AML cells. BAY1143752 also significantly inhibited the growth of MOLM-13 and MV4-11 xenograft tumors in nude mice and rats, and demonstrated good tolerability in both models. In another embodiment, the CDK9 inhibitor is NVP-2, which has shown antiproliferative activity against various leukemia cell lines and induced MCL-1 loss and apoptosis in MOLT4 ALL cells within four hours. In yet another embodiment, the CDK inhibitor is THAL-SNS-032, which has been shown to selectively induce CDK9 degradation with minimal effect on the protein levels of other CDKs, although it retains the ability to block the activity of these kinases.

[0420] combination therapy In some embodiments, the treatments disclosed herein may include the use of other drugs (e.g., antibiotics) or therapies to treat a disease, such as MDS / AML / a certain hematopoietic system cancer. For example, antibiotics may be used to treat infections and may be used in combination with the compounds disclosed herein to treat a disease (e.g., an infection). In other embodiments, intravenous immunoglobulin (IVIG) therapy may be used as part of a treatment regimen (i.e., in addition to the administration of the compounds disclosed herein). For example, treatment regimens for various cancers may involve one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, etc.

[0421] Therefore, in some embodiments, the compounds and / or compositions described herein may be administered once or multiple times in combination with one or more BCL2 inhibitors, BTK inhibitors, chemotherapy, targeted therapy, replacement therapy, immunotherapy, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, CAR-T cell therapy, Plk inhibitors, MEK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, smooth receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, or EZH2 inhibitors, or one or more combinations thereof, to a subject; if multiple administrations are performed, the compositions may be the same or different. In some embodiments, if multiple administrations are performed, at least one composition used in at least one administration is different from the composition used in at least another administration.

[0422] In particular, synergistic effects have been demonstrated when IRAK inhibitors are used in combination with apoptosis regulators / inhibitors (e.g., BCL2 inhibitors). As described in U.S. Patent Application No. 16 / 804,518 (the entire contents of which are incorporated herein by reference), exemplary apoptosis / BCL2 inhibitors have shown synergistic effects when used in combination with exemplary IRAK inhibitors in a variety of AML cell lines. Venetoclax has been used as a representative apoptosis / BCL2 inhibitor.

[0423] When the concentration of the exemplary IRAK inhibitor was combined with venetoclax, the potency of venetoclax unexpectedly increased by approximately 50-fold. According to a specific aspect of this disclosure, this synergistic combination allows for improved efficacy of venetoclax at lower doses, thereby avoiding at least some of the toxicities observed in clinical practice. According to that specific aspect, the degree of interaction depends on the dose ratio combination used, with lower concentrations of the exemplary IRAK inhibitor causing a larger shift in the IC50 of venetoclax. This unexpected and significant shift in the venetoclax IC50 far exceeds an additive effect, demonstrating an unexpected synergistic interaction between the two drugs even in cell lines that do not express the activated FLT3 mutant.

[0424] Therefore, this disclosure covers methods for treating diseases or conditions that respond to IRAK inhibition, including administering to a subject a composition comprising an IRAK inhibitory compound, wherein certain embodiments of the method may further involve administering an apoptosis modulator. The apoptosis modulator may comprise a BTK and / or a BCL2 inhibitor. The BTK and BCL2 inhibitors may be, for example, those known in the art. In some embodiments, the method may include the step of administering an apoptosis modulator to a subject. In some embodiments, the apoptosis modulator may comprise a BCL2 inhibitor selected from ABT-263 (Navitoclax), ABT-737, ABT-199 (Venetoc), GDC-0199, GX15-070 (Obatoclax) (all purchased from AbbVie Laboratories), HA14-1, S1, 2-methoxyantimycin A3, gossypol, AT-101, apogossypol, WEHI-539, A-1155463, BXI-61, BXI-72, TW37, MIM1, UMI-77, etc., and combinations thereof. Those skilled in the art will understand that many known BCL2 inhibitors are available for use according to this disclosure. In some embodiments, the BCL2 inhibitor comprises venetoclax.

[0425] In some embodiments, the administration step includes administering to the subject a composition comprising an IRAK inhibitor and a BCL2 inhibitor. In some embodiments, the administration step includes co-administration of a composition comprising an IRAK inhibitor and a composition comprising a BCL2 inhibitor.

[0426] In some embodiments, the IRAK inhibitor is a compound of this disclosure (e.g., a crystal form of the free base or salt of compound 106) or an isomer, derivative or analog thereof, and the BCL2 inhibitor is venetoclax or a salt, isomer, derivative or analog thereof.

[0427] In some embodiments, the method may further involve administering an immunomodulatory agent to the subject. The immunomodulatory agent may include, for example, lenalidomide (Revlimid; Celgene). In some embodiments, the method may involve administering an epigenetic modulator. The epigenetic modulator may include, for example, a hypomethylating agent, such as azacitidine, decitabine, or a combination thereof.

[0428] In some embodiments, the compounds and / or compositions described herein may be administered to a subject, either co- or in combination with one or more BTK inhibitors (e.g., ibrutinib or its salts, isomers, derivatives or analogs thereof), once or multiple times.

[0429] For example, the compounds and / or compositions described herein may be used, in combination with one or more of the following drugs, by single or multiple administration: DNA methyltransferase inhibitors / hypomethylating agents, such as azacitidine, decitabine, cytarabine, and / or guardicitabine; anthracyclines, such as daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and / or CPX-351 (a combination of cytarabine and daunorubicin in a fixed 5:1 molar ratio); histone deacetylase (HDAC) inhibitors. Examples of anti-drug drugs include vorinostat, perbisstat, valproic acid, and / or plascinonastat; purine nucleoside analogs (antimetabolites), such as fludarabine, cladribine, and / or clofarabine; isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, such as evanixib and / or encilidipine; antibody-drug conjugates, such as anti-CD33 antibodies (e.g., Ac225-lintuzumab, vadastuximab, or gemtuzumab-ozomicin) and / or anti-CD45 antibodies (e.g., I...). 131- apamisulstatumab, etc.; mAbs / immunotherapy, such as anti-CD70 antibodies (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123 x CD3)), anti-CTLA4 antibodies (e.g., ipilimumab), anti-PD1 / PDL1 antibodies (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, PDR001, MBG453) and / or anti-CD47 antibodies (e.g., 5F9 (Magrolimab)); Plk inhibitors, such as volasertib and / or rigosertib; MEK inhibitors, such as trametinib, cobitinib, selenotinib, pimasertib and / or remetinib; CDK9 inhibitors, such as alvocidib and / or voruciclib; CDK8 inhibitors, such as SEL120; retinoic acid receptor agonists, such as ATR. A (all-trans retinoic acid) and / or SY-1425 (a selective RARα agonist); TP53 activators, such as APR-246 (Eprenetapopt); smooth receptor antagonists, such as glasdegib; ERK inhibitors, such as ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, such as ulixertinib, SCH772984, ravoxertinib, MK-8353 and / or VTX-11e; PI3K inhibitors, such as fimepinostat (CUDC-907), alpelisib, leniolisib (CDZ-173), pilaralisib (XL147, SAR245408) and / or bimiralisib (PQR-309), etc.; mTOR inhibitors, such as bimiralisib (PQR-309), sapanisertib (TAK-228, INK-128), ridaforolimus (MK-8669, AP-23573), everolimus, and / or vivisertib (AZD2014), etc.; glucocorticoid receptor modulators, such as agonists including prednisolone, beclomethasone, methylprednisolone, prednisone, fluticasone, budesonide, dexamethasone, and / or cortisol, and / or antagonists including mifepristone, miricorilant, and / or onapristone, and / or other binding ligands including vamorolone (VBP15), etc.; and / or EZH2 inhibitors, such as tazemetostat, etc. In some embodiments, compositions containing such compounds, when used in combination with an EZH2 inhibitor, may be used for the prevention of secondary malignancies. Other therapies will be described below and constitute combination therapies within the context of this disclosure.

[0430] Chemotherapy / Targeted Therapy / Alternative Therapy Cancer is typically treated with chemotherapy and / or targeted and / or alternative therapies. Chemotherapy works by indiscriminately targeting rapidly dividing cells, including both healthy and tumor cells, while targeted cancer therapies work by interfering with specific molecules or molecular targets involved in cancer growth and progression. Targeted therapies are typically specific to cancer cells with minimal damage to normal cells. Approved and / or clinical trial-stage chemotherapy and targeted therapies are known to those skilled in the art. Any such compounds may be used in the practice of this disclosure.

[0431] For example, approved chemotherapy drugs include abitrexate (methotrexate injection), abraxane (Paclitaxel injection), adcetris (Brentuximab Vedotin injection), adriamycin (Doxorubicin), adrucil injection (5-FU (fluorouracil)), afinitor (Everolimus), afinitorDisperz (Everolimus), alimta (PEMETREXED), alkeran injection (Melphalan injection), alkeran ets (Melphalan), aredia (Pamidronate), arimidex (Anastrozole), aromasin (Exemestane), aranon (Nelarabine), arzerra (Ofatumumab injection), avastin (Bevacizumab), beleodaq (Belinostat injection), and bexxar. Tositumomab, BiCNU (Carmustine), blenoxane (Bleomycin), blincyto (Blinatumomab injection), bosulif (Bosutinib), busulfex injection (Busulfan injection), campath (Alemtuzumab), camptosar (Irinotecan), caprelsa (Vandetanib), casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), cerubidine (Daunorubicin), clolar (Clofarabine injection), cometriq (Cabozantinib), cosmegen (Dactinomycin), cotellic (Cobimetinib), cyramza (Ramucirumab injection), cytosarU (Adarosaponin), cytoxan (Cytoxan), cytoxan injection (Cyclophosphamide) (Injection), dacogen (Decitabine), daunoXome (Daunorubicin lipid complex injection), decadron (dexamethasone), depoCyt (arachidonic acid lipid complex injection),Dexamethasone Intensol, dexpak Taperpak, docetaxel, doxil (Doxorubicin lipid complex injection), droxia, DTIC (Decarbazine), eligard (Leuprolide), ellence (Ellence (epirubicin)), eloxatin (Eloxatin), elspar (Asparaginase), emcyt (Estramustine), erbitux (Cetuximab), erivedge (Vismodegib), erwinaze (Asparaginase Erwinia chrysanthemi), ethyol (Amifostine), etopophos (Etoposide injection), eulexin (Flutamide), fareston (Toremifene), farydak (Panobinostat), faslodex (Fulvestrant), femara (Letrozole), firmagon (Degarelix injection), fludara (Fludarabine), folex (methotrexate injection), folotyn (Pralatrexate injection), FUDR (FUDR (floxuridine)), gazyva (Obinutuzumab injection), gemzar (Gemcitabine), gilotrif (Afatinib), gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (hydroxyurea), Ibrance (palbocicib), Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Imbruvica (ibrutinib), Inlyta (Axitinib), Intron A alfab (Interferon alfa-2a),Iressa (Gefitinib), Istodax (Romidepsin injection), Ixempra (Ixabepilone injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel injection), Kadcyla (Ado-trastuzumab Emtansine), Keytruda (Pembrolizumab injection), Kyprolis (Carfilzomib), Lanvima (Lenvatinib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lonsurf (Trifluridine and Tipiracil), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lynparza (Olaparib), Lysodren (Mitotane), MarqiboKit (Vincristine Lipid complex injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate injection), Mustargen (Dichloroethylmethylamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar injection (Cyclophosphamide injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Odomzo (Sonidegib),Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), onxol (Paclitaxel injection), opdivo (Nivolumab injection), panretin (Alitretinoin), paraplatin (Carboplatin), perjeta (Pertuzumab injection), platinol (Cisplatin), platinol (Cisplatin injection), platinolAQ (Cisplatin), platinolAQ (Cisplatin injection), pomalyst (Pomalidomide), prednisone Intensol (Prednisone), proleukin (Aldesleukin), purinethol (Mercaptopurine), reclast (Zoledronic acid), revlimid (Lenalidomide), rheumatrex (methotrexate), rituxan (Rituximab), roferonA alfaa (Interferon alfa-2a), rubex (Doxorubicin), sandostatin (Octreotide), sandostatinLAR Depot (Octreotide), soltamox (Tamoxifen), sprycel (Dasatinib), sterapred (Prednisone), sterapred DS (Prednisone), stivarga (Regorafenib), supprelin LA (Histrelin Implant), sutent (Sunitinib), sylatron (Peginterferon Alfa-2b injection (Sylatron)), sylvant (Siltuximab injection), synribo (Omacetaxine injection), tabloid (thioguanine), taflinar (Dabrafenib), tarceva (Erlotinib), targretin Capsules (Bexarotene), tasigna (Decarbazine), taxol (Paclitaxel injection),taxotere (Docetaxel), temodar (Temozolomide), temodar (Temozolomide injection), tepadina (Thiotepa), thalomid (Thalidomide), theraCys BCG (BCG), thioplex (Thiotepa), TICEBCG (BCG), toposar (Etoposide injection), torisel (Temsirolimus), treanda (Bendamustine hydrochloride), trelstar (Triptorelin injection), trexall (methotrexate), trisenox (Arsenic trioxide), tykerb (lapatinib), unituxin (Dinutuximab injection), valstar (Valrubicin Intravesical), vantas (Histrelin Implant), vectibix (Panitumumab), velban (Vinblastine), velcade (Bortezomib), vepesid (Etoposide), vepesid (Etoposide injection), vesanoid (Tretinoin), vidaza (azacitidine), vincasarPFS (Vincristine), vincrex (Vincristine), votrient (Pazopanib), vumon (Teniposide), wellcovorin IV (Leucovorin injection), xalkori (Crizotinib), xeloda (Capecitabine), xtandi (Enzalutamide), yervoy (Ipilimumab injection), yondelis (Trabectedin injection), zaltrap (Ziv-aflibercept injection), zanosar (Streptozocin), zelboraf (Vemurafenib), zevalin (Ibritumomab Tiuxetan), zoladex (Goserelin), zolinza (Vorinostat), zometa (Zoledronic acid), zortress (Everolimus)zydelig (Idelalisib), zykadia (Ceritinib), zytiga (Abiraterone), and their analogues and derivatives. For example, approved targeted therapies include ado-trastuzumab emtansine (Kadcyla), afatinib (Gilotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campath), axitinib (Inlyta), belimumab (Benlysta), belinostat (Beleodaq), bevacizumab (Avastin), bortezomib (Velcade), bosutinib (Bosulif), brentuximabvedotin (Adcetris), cabozantinib (Cabometyx [tablets], Cometriq [capsules]), canakinumab (Ilaris), carfilzomib (Kyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), and crizotinib. (Xalkori), dabrafenib (Tafinlar), daratumumab (Darzalex), dasatinib (Sprycel), denosumab (Xgeva), dinutuximab (Unituxin), elotuzumab (Empliciti), erlotinib (Tarceva), everolimus (Afinitor), gefitinib (Iressa), ibritumomab tiuxetan (Zevalin), ibrutinib (Imbruvica), idelalisib (Zydelig), imatinib (Gleevec), ipilimumab (Yervoy), ixazomib (Ninlaro), lapatinib (Tykerb), lenvatinib (Lenvima), necitumumab (Portrazza), nilotinib (Tasigna), nivolumab (Opdivo), obinutuzumab (Gazyva), ofatumumab (Arzerra, HuMax-CD20)olaparib (Lynparza), osimertinib (Tagrisso), palbociclib (Ibrance), panitumumab (Vectibix), panobinostat (Farydak), pazopanib (Votrient), pembrolizumab (Keytruda), pertuzumab (Perjeta), ponatinib (Iclusig), ramucirumab (Cyramza), rapamycin, regorafenib (Stivarga), rituximab (Rituxan, Mabthera), romidepsin (Istodax), ruxolitinib (Jakafi), siltuximabuximab (Sylvant), sipuleucel-T (Provenge), sirolimus, sonidegib (Odomzo), sorafenib (Nexavar), sunitinib, tamoxifen, tamolomulib (Torisel), tocilizumab Actemra, tofacitinib (Xeljanz), tositumomab (Bexxar), trametinib (Mekinist), trastuzumab (Herceptin), vandetanib (Caprelsa), vemurafenib (Zelboraf), Venclexta, Erivedge, vorinostat (Zolinza), ziv-aflibercept (Zaltrap), and their analogues and derivatives.

[0432] Those skilled in the art can determine appropriate chemotherapy and / or targeted therapy and / or alternative therapy regimens, including approved treatments and those in clinical trials or development stages. Some targeted therapies are also immunotherapies. In the practice disclosed herein, any relevant chemotherapy, targeted therapy, and alternative therapy treatment strategy may be employed, alone or in combination with one or more additional cancer therapies.

[0433] Immunotherapy In some implementations, immunotherapy includes cell-based immunotherapies, such as therapies involving cells that elicit an immune response (e.g., lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTLs), antibodies and their derivatives (e.g., monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemically labeled antibodies, etc.), immune checkpoint inhibitors, vaccines (e.g., cancer vaccines (e.g., tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector vaccines, etc.), such as oncophage, sipuleucel-T, etc.), immunomodulators (e.g., interleukins, cytokines, chemokines, etc.), local immunotherapies (e.g., imiquimod, etc.), injectable immunotherapy, adoptive cell transfer, oncolytic virus therapy (e.g., talimogene laherparepvec (T-VEC), etc.), immunosuppressive drugs, worm therapy, and other non-specific immunotherapies. Immune checkpoint inhibitor immunotherapy is a therapy that targets one or more specific proteins or receptors, such as PD-1, PD-L1, CTLA-4, etc. Immune checkpoint inhibitor immunotherapies include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda). Non-specific immunotherapies include cytokines, interleukins, and interferons. In some implementations, the immunotherapy assigned to or administered to the subject may include interleukins and / or interferons (IFNs) and / or one or more suitable antibody-based agents, such as denilein and / or antibody-based agents selected from the group consisting of ado-trastuzumab emtansine, alenzusumab, atezolizumab, bevacizumab, bonatuzumab, brentuximab vemetuximab, cetuximab, caputuzumab, gemtuzumab, teimozumab, ipilimumab, natezumab, nimotuzumab, nivolumab, ofamumab, panitumumab, pembrolizumab, rituximab, tosimomumab, trastuzumab, vivatuxin, etc. In some implementations, the immunotherapy assigned to or administered to the subject may include indoleamine 2,3-dioxygenase (IDO) inhibitors, adoptive T-cell therapy, viral therapy (T-VEC), and / or any other immunotherapy whose efficacy primarily depends on antitumor immunity.

[0434] Those skilled in the art can determine suitable immunotherapy regimens, including approved treatments and those in clinical trials or development stages. In the practice of this disclosure, any relevant immunotherapy treatment strategy may be employed, either alone or in combination with one or more additional cancer therapies.

[0435] Other cancer treatments In addition to chemotherapy, targeted therapy, alternative therapy, and immunotherapy, cancer can be treated with other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplantation, precision medicine, etc.; such treatments and the compounds and compositions used therein are known to those skilled in the art. Any of these treatment strategies may be employed in the practice of this disclosure.

[0436] Alternative treatment strategies have also been used for various types of cancer. Such treatments can be used alone or in combination with any other treatment modality. These include exercise, massage, relaxation techniques, yoga, acupuncture, aromatherapy, hypnosis, music therapy, dietary changes, nutrition and dietary supplements, etc.; such treatments are known to those skilled in the art. In the practice disclosed herein, any such treatment strategy may be used alone or in combination with one or more additional cancer therapies.

[0437] Dosage and route of administration Other embodiments of this disclosure may include methods of administering or treating an animal / human, the methods of which may include treatment with an effective amount of at least one compound of this disclosure (e.g., a crystal form of the free base or salt of compound 106), the amount being sufficient to treat an organism having, being suspected of having, or being susceptible to a disease, condition, or disorder, or to produce a desired physiological effect. In some embodiments, the composition or pharmaceutical composition comprises at least one compound of the present disclosure (e.g., a crystal form of the free base or salt of compound 106), which may be administered to animals (e.g., mammals, primates, monkeys, or humans) in amounts of about 0.005 to about 50 mg / kg body weight, about 0.01 to about 15 mg / kg body weight, about 0.1 to about 10 mg / kg body weight, about 0.5 to about 7 mg / kg body weight, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / ...

Claims

1. A crystal form of a mono-HCl salt of a compound of formula (1): Equation (1), The crystal form is characterized by an X-ray powder diffraction pattern containing peaks at 6.8619 ± 0.2°, 11.3373 ± 0.2°, 14.5399 ± 0.2°, 17.1417 ± 0.2° and 23.6521 ± 0.2° 2θ.

2. The crystal form according to claim 1, wherein the X-ray powder diffraction pattern further includes one or more peaks at 14.7217 ± 0.2°, 16.2725 ± 0.2°, 22.4223 ± 0.2°, 23.3316 ± 0.2° and 28.8331 ± 0.2° 2θ.

3. The crystal form according to claim 1 or 2, wherein the X-ray powder diffraction pattern further includes one or more peaks at 2.0916 ± 0.2°, 11.1062 ± 0.2°, 20.9023 ± 0.2°, 21.9400 ± 0.2° and 27.5840 ± 0.2° 2θ.

4. The crystal form according to any one of claims 1-3, wherein the X-ray powder diffraction pattern further comprises 11.6132 ± 0.2°, 13.7106 ± 0.2°, 14.3405 ± 0.2°, 15.3177 ± 0.2°, 17.5260 ± 0.2°, 17.6282 ± 0.2°, 18.8337 ± 0.2°, 20.0236 ± 0.2°, 20.8136 ± 0.2°, 21.0463 ± 0.2°, 22.9619 ± 0.2°, 24.4120 ± 0.2°, 24.9258 ± 0.2°, 26.0850 ± 0.2°, 26.4484 ± 0.2°, 26.7151 ± One or more peaks at 2θ: 0.2°, 26.9745 ± 0.2°, 27.2880 ± 0.2°, 27.8954 ± 0.2°, 28.1817 ± 0.2°, 28.3383 ± 0.2°, 29.2852 ± 0.2°, 29.8645 ± 0.2°, 32.2115 ± 0.2°, 33.1644 ± 0.2°, 33.5088 ± 0.2°, 33.8427 ± 0.2°, 34.6622 ± 0.2°, 35.6915 ± 0.2°, 36.3485 ± 0.2°, 37.3533 ± 0.2°, and 38.0511 ± 0.2°.

5. The crystal form according to any one of claims 1-4, wherein the mono-HCl salt has formula (2): Equation (2).

6. The crystal form of a free base of a compound of formula (1): Equation (1), Its features The X-ray powder diffraction pattern contains one or more peaks at 8.5102 ± 0.2°, 13.4583 ± 0.2°, 16.3830 ± 0.2°, 20.0082 ± 0.2°, and 24.6817 ± 0.2° 2θ.

7. The crystal form according to claim 6, wherein the X-ray powder diffraction pattern further includes one or more peaks at 11.2514 ± 0.2°, 16.8018 ± 0.2°, 20.9239 ± 0.2°, 22.2447 ± 0.2° and 28.6101 ± 0.2° 2θ.

8. The crystal form according to claim 6 or 7, wherein the X-ray powder diffraction pattern further includes one or more peaks at 10.2265 ± 0.2°, 17.1029 ± 0.2°, 18.3658 ± 0.2°, 22.6040 ± 0.2° and 23.6583 ± 0.2° 2θ.

9. The crystal form according to any one of claims 6-8, wherein the X-ray powder diffraction pattern further comprises 12.4152 ± 0.2°, 15.6546 ± 0.2°, 18.5476 ± 0.2°, 19.1056 ± 0.2°, 19.3265 ± 0.2°, 20.4980 ± 0.2°, 21.3232 ± 0.2°, 23.2420 ± 0.2°, 24.2705 ± 0.2°, 25.8013 ± 0.2°, 26.1668 ± 0.2°, 27.1774 ± 0.2°, 27.5557 ± 0.2°, 28.1259 ± 0.2°, 30.1759 ± 0.2°, 31.5240 ± One or more peaks at 2θ: 0.2°, 31.8408 ± 0.2°, 32.3075 ± 0.2°, 32.8563 ± 0.2°, 33.7388 ± 0.2°, 36.0412 ± 0.2°, 36.7705 ± 0.2°, 37.7457 ± 0.2°, and 39.0376 ± 0.2°.

10. The crystal form of a free base of a compound of formula (1): Equation (1) The crystal form described herein comprises a single crystal, characterized in that One or more of the following: i) Monoclinic space group P21; ii) Lattice parameters a=9.5817(11)Å, b=20.916(2)Å, c=10.8470(12)Å, α=90°, β=114.836(4)° and γ=90°; iii) The volume is approximately 1972.8(4) Å. 3 ; and / or iv) Crystal density d c = 1.348 g / cm 3 .

11. A crystal form of p-toluenesulfonate of a compound of formula (1): Equation (1) The crystal form is characterized by an X-ray powder diffraction pattern containing one or more peaks at 5.1743 ± 0.2°, 8.1663 ± 0.2°, 10.3704 ± 0.2°, 14.4880 ± 0.2° and 16.8942 ± 0.2° 2θ.

12. The crystal form according to claim 11, wherein the X-ray powder diffraction pattern further includes one or more peaks at 7.0186 ± 0.2°, 11.7589 ± 0.2°, 12.5062 ± 0.2°, 13.2636 ± 0.2°, 14.0747 ± 0.2°, 14.2385 ± 0.2°, 17.6050 ± 0.2°, 21.1626 ± 0.2°, 25.1678 ± 0.2°, and 26.2810 ± 0.2° 2θ.

13. The crystal form according to claim 11 or 12, wherein the X-ray powder diffraction pattern further comprises 9.1859 ± 0.2°, 14.7418 ± 0.2°, 15.1588 ± 0.2°, 15.6231 ± 0.2°, 16.2702 ± 0.2°, 17.9401 ± 0.2°, 19.0641 ± 0.2°, 19.8933 ± 0.2°, 20.5140 ± 0.2°, 21.1626 ± 0.2°, 21.7948 ± 0.2°, 22.4148 ± 0.2°, 23.0891 ± 0.2°, 23.8417 ± 0.2°, 24.6896 ± 0.2°, 24.8272 ± One or more peaks at 2θ: 0.2°, 26.7775 ± 0.2°, 27.4170 ± 0.2°, 28.1822 ± 0.2°, 29.0287 ± 0.2°, 29.9521 ± 0.2°, 31.4883 ± 0.2°, and 33.1844 ± 0.2°.

14. A crystal form of the tartrate salt of a compound of formula (1): Equation (1), The crystal form is characterized by an X-ray powder diffraction pattern containing one or more peaks at 7.7633 ± 0.2°, 8.2996 ± 0.2°, 12.4661 ± 0.2°, 15.5489 ± 0.2° and 24.7464 ± 0.2° 2θ.

15. The crystal form according to claim 14, wherein the X-ray powder diffraction pattern further includes one or more peaks at 4.1463 ± 0.2°, 11.3791 ± 0.2°, 14.1011 ± 0.2°, 17.4289 ± 0.2°, 18.6536 ± 0.2°, 19.1095 ± 0.2°, 20.4382 ± 0.2°, 22.5011 ± 0.2°, 25.1566 ± 0.2°, and 25.4454 ± 0.2° 2θ.

16. The crystal form according to claim 14 or 15, wherein the X-ray powder diffraction pattern further comprises 10.1216 ± 0.2°, 13.7867 ± 0.2°, 16.6578 ± 0.2°, 19.3112 ± 0.2°, 19.6662 ± 0.2°, 20.8586 ± 0.2°, 21.3540 ± 0.2°, 22.8792 ± 0.2°, 23.4372 ± 0.2°, 23.7287 ± 0.2°, 25.9362 ± 0.2°, 26.4885 ± 0.2°, 26.7874 ± 0.2°, 27.7072 ± 0.2°, 28.1883 ± 0.2°, 29.5023 ± One or more peaks at 0.2°, 31.4659 ± 0.2°, 33.1605 ± 0.2°, 35.2961 ± 0.2° and 36.2252 ± 0.2° 2θ.

17. A crystal form of the methanesulfonate salt of a compound of formula (1): Equation (1), The crystal form is characterized by an X-ray powder diffraction pattern containing one or more peaks at 13.8951 ± 0.2°, 15.8697 ± 0.2°, 18.4951 ± 0.2°, 19.5773 ± 0.2° and 21.5492 ± 0.2° 2θ.

18. The crystal form according to claim 17, wherein the X-ray powder diffraction pattern further includes one or more peaks at 2θ: 9.4332 ± 0.2°, 10.7336 ± 0.2°, 15.3077 ± 0.2°, 16.2453 ± 0.2°, 21.7550 ± 0.2°, 22.5396 ± 0.2°, 23.8137 ± 0.2°, 25.6827 ± 0.2°, 27.3636 ± 0.2°, and 28.4083 ± 0.2°.

19. The crystal form according to claim 17 or 18, wherein the X-ray powder diffraction pattern further comprises 13.1847 ± 0.2°, 20.4125 ± 0.2°, 23.1636 ± 0.2°, 24.4222 ± 0.2°, 24.9633 ± 0.2°, 26.2564 ± 0.2°, 26.5213 ± 0.2°, 26.7162 ± 0.2°, 28.0011 ± 0.2°, 30.0138 ± 0.2°, 30.6070 ± 0.2°, 32.0467 ± 0.2°, 33.2600 ± 0.2°, 34.7889 ± 0.2°, 36.4246 ± 0.2°, 37.0117 ± One or more peaks at 0.2°, 37.5445 ± 0.2°, 38.3512 ± 0.2° and 39.4875 ± 0.2° 2θ.

20. A crystal form of a benzenesulfonate of formula (1): Equation (1), The crystal form is characterized by X-ray powder diffraction patterns containing peaks at 13.3296 ± 0.2°, 14.2875 ± 0.2°, 14.6072 ± 0.2°, 17.6593 ± 0.2° and 20.4010 ± 0.2° 2θ.

21. The crystal form according to claim 20, wherein the X-ray powder diffraction pattern further includes one or more peaks at 6.0882 ± 0.2°, 8.8966 ± 0.2°, 11.2206 ± 0.2°, 12.2073 ± 0.2°, 14.1225 ± 0.2°, 16.6160 ± 0.2°, 21.5845 ± 0.2°, 21.9720 ± 0.2°, 25.5863 ± 0.2°, and 27.1334 ± 0.2° 2θ.

22. The crystal form according to claim 20 or 21, wherein the X-ray powder diffraction pattern further comprises 7.1501 ± 0.2°, 12.9781, 15.5340 ± 0.2°, 15.8947 ± 0.2°, 16.9428 ± 0.2°, 17.8182 ± 0.2°, 18.1970 ± 0.2°, 19.2161 ± 0.2°, 19.4884 ± 0.2°, 19.9886 ± 0.2°, 20.1070 ± 0.2°, 20.9762 ± 0.2°, 22.5384 ± 0.2°, 23.3474 ± ​​0.2°, 23.5613 ± 0.2°, 23.8492 ± 0.2°, 24.8742 ± One or more peaks at 2θ: 0.2°, 25.1031 ± 0.2°, 25.9489 ± 0.2°, 26.2968 ± 0.2°, 26.5983 ± 0.2°, 28.4875 ± 0.2°, 29.1808 ± 0.2°, 29.8640 ± 0.2°, 30.6238 ± 0.2°, 31.5579 ± 0.2°, 32.7200 ± 0.2°, and 33.4281 ± 0.2°.

23. The crystal form according to any one of claims 1-22, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4 and FLT3.

24. The crystal form according to any one of claims 1-23, wherein the compound is an inhibitor of IRAK1 and IRAK4, and not an inhibitor of FLT3.

25. The crystal form according to claim 23 or 24, wherein FLT3 is selected from WT FLT3, activated FLT3 and mutant FLT3.

26. The crystal form according to claim 25, wherein the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3.

27. The crystal form according to any one of claims 1-26, wherein: The water content of the crystal form is less than or equal to about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%; and / or The crystal form comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0% or about 99.5% of the enantiomer of formula (1) (R); and / or The crystal form comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0% or about 0.5% of the (1) (S)-enantiomer; and / or The crystal form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% of impurities.

28. The crystal form according to any one of claims 1-27, wherein after being stored for 6 months at about 25°C and about 60% relative humidity, or after being stored for 6 months at about 40°C and about 75% relative humidity: The water content of the crystal form is less than or equal to about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, about 2.4 wt.%, about 2.2 wt.%, about 2.0 wt.%, about 1.8 wt.%, about 1.6 wt.%, about 1.4 wt.%, about 1.2 wt.%, about 1.0 wt.%, about 0.8 wt.%, about 0.6 wt.%, about 0.4 wt.%, or about 0.2 wt.%; and / or The crystal form comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0% or about 99.5% of the enantiomer of formula (1) (R); and / or The crystal form comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0% or about 0.5% of the (1) (S)-enantiomer; and / or The crystal form contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% of impurities.

29. A pharmaceutical composition comprising a crystal form according to any one of claims 1-28, and a formulation ingredient, adjuvant, or carrier.

30. The pharmaceutical composition of claim 29, comprising about 0.1 mg to 10,000 mg, about 1.0 mg to about 9,000 mg, about 1.0 mg to about 8,000 mg, about 1.0 mg to about 7,000 mg, about 1.0 mg to about 6,000 mg, about 1.0 mg to about 5,000 mg, about 1.0 mg to about 4,000 mg, about 1.0 mg to about 3,000 mg, about 1.0 mg to about 2,000 mg, about 1.0 mg to about 1,500 mg, about 1.0 mg to about 1,000 mg, about 1.0 mg to about 750 mg, about 1.0 mg to about 700 mg, about 1.0 mg to about 650 mg, about 1.0 mg to about 600 mg, about 1.0 mg to about 550 mg, about 1.0 mg to about 500 mg, about 1.0 mg to about 450 mg, about 1.0 mg to about 400 mg. The crystal form is expressed in mg, about 1.0 mg to about 350 mg, about 1.0 mg to about 300 mg, about 1.0 mg to about 250 mg, about 1.0 mg to about 200 mg, about 1.0 mg to about 150 mg, or about 1.0 mg to about 100 mg.

31. The pharmaceutical composition of claim 29, comprising amounts equivalent to about 0.1 mg to 10,000 mg, about 1.0 mg to about 9,000 mg, about 1.0 mg to about 8,000 mg, about 1.0 mg to about 7,000 mg, about 1.0 mg to about 6,000 mg, about 1.0 mg to about 5,000 mg, about 1.0 mg to about 4,000 mg, about 1.0 mg to about 3,000 mg, about 1.0 mg to about 2,000 mg, about 1.0 mg to about 1,500 mg, about 1.0 mg to about 1,000 mg, about 1.0 mg to about 750 mg, about 1.0 mg to about 700 mg, about 1.0 mg to about 650 mg, about 1.0 mg to about 600 mg, about 1.0 mg to about 550 mg, about 1.0 mg to about 500 mg, about 1.0 mg to about 450 mg, about 1.0 mg to about 400 mg. The amount of salt crystal form of free base is approximately 1 mg, about 1.0 mg to about 350 mg, about 1.0 mg to about 300 mg, about 1.0 mg to about 250 mg, about 1.0 mg to about 200 mg, about 1.0 mg to about 150 mg, or about 1.0 mg to about 100 mg.

32. The pharmaceutical composition according to any one of claims 29-31, wherein: The water content of the pharmaceutical composition is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.0 wt.%, about 1.0 wt.%, about 0.5 wt.%, or about 0.25 wt.%; and / or The pharmaceutical composition comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomeric crystal form of formula (1) (R); and / or The pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the (1) (S)-enantiomer crystal form; and / or The pharmaceutical composition contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% of impurities.

33. The pharmaceutical composition according to any one of claims 29-32, wherein after storage for 3 months at about 25°C and about 60% relative humidity or after storage for 3 months at about 40°C and about 75% relative humidity: The water content of the pharmaceutical composition is less than or equal to about 10.0 wt.%, about 9.0 wt.%, about 8.0 wt.%, about 7.0 wt.%, about 6.0 wt.%, about 5.0 wt.%, about 4.0 wt.%, about 3.0 wt.%, about 2.0 wt.%, about 1.0 wt.%, about 0.5 wt.%, or about 0.25 wt.%; and / or The pharmaceutical composition comprises greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, or about 99.5% of the enantiomeric crystal form of formula (1) (R); and / or The pharmaceutical composition comprises less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, or about 0.5% of the (1) (S)-enantiomer crystal form; and / or The pharmaceutical composition contains less than or equal to about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25% of impurities.

34. A dosage form comprising the pharmaceutical composition according to any one of claims 29-33.

35. The dosage form according to claim 34, wherein the dosage form is a tablet or a capsule.

36. A method of treating a disease or condition of a subject in need, the method comprising administering to the subject a crystal form comprising any one of claims 1-28, a pharmaceutical composition comprising any one of claims 29-33, or a dosage form comprising any one of claims 34-35, containing a therapeutically effective amount of a free base of formula (1) or any salt thereof.

37. The method of claim 36, wherein the administration includes parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, local administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.

38. The method of claim 36 or 37, wherein the therapeutically effective dose is from about 0.005 mg / kg of subject body weight to about 1,000 mg / kg of subject body weight.

39. The method according to any one of claims 36-38, wherein the crystal form, pharmaceutical composition or dosage form disintegrates in the gastrointestinal tract of the subject within about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes or about 1 minute.

40. The method according to any one of claims 36-39, wherein the disease or condition includes hematopoietic system cancer.

41. The method according to any one of claims 36-39, wherein the disease or condition includes myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML).

42. The method according to claim 41, wherein: The MDS includes MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, and MDS with isocitrate dehydrogenase 2 mutations. The AML includes relapsed AML, refractory AML, relapsed / refractory AML, AML resistant to hypomethylating agents, AML resistant to venetoclax, AML resistant to both hypomethylating agents and venetoclax, monocytic AML, or monocytic-like AML; or The AML includes AML with splicing factor mutations, AML with enhanced IRAK4-long expression and / or activity relative to IRAK4-short, and / or wherein the AML is not driven by an FLT3 mutation but expresses IRAK4-long.

43. The method according to claim 42, wherein: The MDS with splicing factor mutations include MDS with U2AF1, SRSF2, SF3B1, or ZRSR2 splicing factor mutations; or The AML splicing factor mutations include AMLs with U2AF1 or SF3B1 splicing factor mutations.

44. The method according to any one of claims 36-39, wherein the disease or condition includes lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, non-Hodgkin's lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.

45. The method according to any one of claims 36-39, wherein the disease or condition comprises at least one cancer selected from the following: glioblastoma multiforme, myelofibrosis, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, gastric cancer, and uterine cancer.

46. ​​The method according to any one of claims 36-39, wherein the disease or condition includes one or more inflammatory diseases or autoimmune diseases selected from: chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren's syndrome, ankylosing spondylitis, systemic sclerosis, type 1 diabetes, Crohn's disease, colitis, and atopic dermatitis.

47. The method according to any one of claims 36-39, wherein the disease or condition comprises diffuse large B-cell lymphoma (DLBCL), and wherein the DLBCL comprises the L265P MYD88 mutant (ABC) subtype of DLBCL or the S219C MYD88 mutant (GCB) subtype of DLBCL.

48. The method according to any one of claims 36-39, wherein the disease or condition is an FLT3 inhibitor-resistant disease or condition.

49. The method according to any one of claims 36-39, wherein the disease or condition is FLT3 inhibitor-resistant acute myeloid leukemia (AML), FLT3 inhibitor-resistant refractory acute myeloid leukemia (AML), or FLT3 inhibitor-resistant relapsed acute myeloid leukemia (AML).

50. The method according to any one of claims 36-49, further comprising administering to the subject one or more adjunctive therapies selected from: chemotherapeutic agents, BCL2 inhibitors, immunomodulators, BTK inhibitors, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibody-drug conjugates, mAbs / immunotherapy, Plk inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CE LMoD, smooth receptor antagonists, ERK inhibitors (including ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors), PI3K inhibitors, mTOR inhibitors, steroids or glucocorticoids, steroid or glucocorticoid receptor modulators, EZH2 inhibitors, hedgehog (Hh) inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, aminopeptidase / leukotriene A4 hydrolase inhibitors, FLT3 / Axl / ALK inhibitors, FLT3 / KIT / PDGFR, PKC and / or KDR inhibitors, Syk inhibitors, E-selectin inhibitors, NEDD8 activators, MDM2 inhibitors, PLK1 inhibitors, Aura A inhibitors, aurora kinase inhibitors, EGFR inhibitors, AuroraB / C / VEGFR1 / 2 / 3 / FLT3 / CSF-1R / Kit / PDGFRA / B inhibitors, AKT 1, 2 and / or 3 inhibitors, ABL1 / 2 / SRC / EPHA2 / LCK / YES1 / KIT / PDGFRB / FYN inhibitors, farnesyltransferase inhibitors, BRAF / MAP2K1 / MAP2K2 inhibitors, Menin-KMT2A / MLL inhibitors, immune checkpoint inhibitors and multi-kinase inhibitors.

51. The method of claim 50, wherein the additional therapy is at least one of a BCL2 inhibitor, a BTK inhibitor, a glucocorticoid, a CDK inhibitor, an immune checkpoint inhibitor, and a DNA methyltransferase inhibitor.

52. The method according to claim 50 or 51, wherein: The BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. The BTK inhibitor is ibrutinib or a pharmaceutically acceptable salt thereof. The glucocorticoid is selected from dexamethasone, methylprednisolone, prednisolone, or a pharmaceutically acceptable salt of any one of them. The CDK inhibitor is selected from the CDK4 / 6 inhibitor palbociclib, the CDK7 inhibitor THZ1 and / or the CDK9 inhibitors BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt of any one thereof. The immune checkpoint inhibitor is selected from ipilimumab, nivolumab, pembrolizumab, or a pharmaceutically acceptable salt of any one of them, or The DNA methyltransferase inhibitor is azacitidine or a pharmaceutically acceptable salt thereof.

53. The method according to any one of claims 50-52, wherein the disease or symptom is: BCL2 inhibitor resistance diseases or conditions Venetoclax resistance disease or condition BTK inhibitor resistance diseases or conditions, ibrutinib resistance diseases or conditions Diseases or conditions sensitive to anti-inflammatory glucocorticoids, Dexamethasone, methylprednisolone, or prednisolone resistance diseases or conditions CDK inhibitor resistance diseases or conditions For diseases or conditions resistant to palbociclib, THZ1, BAY 12511152, or atuveciclib. DNA methyltransferase inhibitor resistance diseases or conditions Azacitidine resistance disease or condition Immune checkpoint inhibitor resistance diseases or conditions Diseases or conditions resistant to ipilimumab, nivolumab, or pembrolizumab. Diseases or conditions resistant to BCL2 inhibitors and DNA methyltransferase inhibitors, or Venetoclax and azacitidine resistance diseases or conditions.

54. The method according to any one of claims 50-53, wherein the disease or condition is BCL2 inhibitor-resistant acute myeloid leukemia (AML), venetoclax-resistant AML, BCL2 inhibitor-resistant refractory AML, venetoclax-resistant refractory AML, BCL2 inhibitor-resistant relapsed AML, or venetoclax-resistant relapsed AML.

55. The method of claim 50, wherein the crystal form of any one of claims 1-28, the composition of any one of claims 29-33, or the dosage form of any one of claims 34-35 is administered in a single application or in a composition with the one or more adjunctive therapies.

56. The method of claim 50, wherein the crystal form of any one of claims 1-28, the composition of any one of claims 29-33, or the dosage form of any one of claims 34-35 is administered separately from the one or more adjunctive therapies in more than one administration or in more than one composition.

57. The method according to any one of claims 36-56, wherein the disease or symptom is relieved by inhibiting at least one of IRAK1, IRAK4 and FLT3 in the subject.

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