Irak inhibitor free base, salts, and polymorphic forms 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

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480043585.7 (22) Application Date 2024.04.26 (30) Priority Data 63 / 499042 2023.04.28 US 63 / 590940 2023.10.17 US (85) PCT International Application Entering National Phase Date 2025.12.26 (86) PCT International Application Application Data PCT / US2024 / 026606 2024.04.26 (87) PCT International Application Publication Data WO2024 / 227051 EN 2024.10.31 (71) Applicant: Klom Therapeutics, Inc. Address: Massachusetts, USA (72) Inventors: M. Sorenson, R. Vasolona (74) Patent Agency: China Patent Agent (Hong Kong) Limited 72001 Patent Attorneys: Yu Miaolin, Yi Bin (51) Int.Cl. C07D 487 / 04 (2006.01) (54) Invention Title: IRAK Inhibitors, Free Bases, Salts and Polymorphs thereof (57) Abstract: This disclosure provides crystalline free bases of imidazo[1,2-b]pyridazine compounds and their salts. In some embodiments, the crystalline imidazo[1,2-b]pyridazine compounds are single crystals. This disclosure also provides methods of using the crystal form to treat certain diseases or conditions. Some embodiments include methods of using the crystal form to treat hematopoietic cancers, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML). Other embodiments provide disease treatment using the crystal form in combination with other therapies, such as cancer treatment. Claims 9 pages, Description 212 pages, Drawings 490 pages, CN 121487942 A 2026.02.06 CN 1 21 48 79 42 A 1. A crystal form of a mono-HCl salt of a compound of formula (1): Formula (1), wherein 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 peaks at 2.0916 ± 0.2°, 11.1062 ± 0.2°, and 2θ.One or more peaks at 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): Formula (2). 6. A crystal form of a free base of a compound of formula (1): Claims 1 / 9 page 2 CN 121487942 A Formula (1), characterized in that 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 peaks at 10.2265 ± 0.2°, 17.1029 ± 0.2°, and 2θ.One or more peaks at 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. A crystal form of a free base of a compound of formula (1): Formula (1) wherein 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)° and γ = 90°; iii) a volume of approximately 1972.8(4) ų; and / or iv) a crystal density dc = 1.348 g / cm³. 11. A crystal form of a p-toluenesulfonate of a compound of formula (1): Claims 2 / 9 pages 3 CN 121487942 A Formula (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 comprises 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 ±One or more peaks at 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 14. A crystal form of a tartrate salt of a compound of formula (1): Formula (1), wherein 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 ±One or more peaks at 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° at 2θ. (Claims 3 / 9, page 4, CN 121487942 A) 17. A crystal form of a methanesulfonate of a compound of formula (1): Formula (1), wherein 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 20. A benzenesulfonate of a compound of formula (1): Formula (1), wherein 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.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°. One or more peaks at 2θ: 0.2°, 23.8492 ± 0.2°, 24.8742 ± 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 crystalline 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 crystalline form according to claim 23 or 24, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutant FLT3. 26. The crystalline form according to claim 25, wherein the mutant FLT3 is D835Y mutant FLT3 or F691L mutant FLT3. 27. The crystalline form according to any one of claims 1-26, wherein: the water content of the crystalline form is less than or equal to about 3.0 wt.%, about 2.8 wt.%, about 2.6 wt.%, or about 2.4 wt.%.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 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; 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% or about 0.5% of formula (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 crystalline 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 at about 40°C and about 75% relative humidity: the water content of the crystalline 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 crystalline form contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, or about 97% relative humidity. 0.5%, 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 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. 29. A pharmaceutical composition comprising the 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 [the amount of the pharmaceutical composition claimed in the claims]. (Page 5 / 9 of the claim) CN 121487942 A The crystal form is 500 mg, about 1.0 mg to about 450 mg, about 1.0 mg to about 400 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 1.0 mg. The amount of salt crystal form of the free base is approximately 400 mg to 400 mg, approximately 1.0 mg to approximately 350 mg, approximately 1.0 mg to approximately 300 mg, approximately 1.0 mg to approximately 250 mg, approximately 1.0 mg to approximately 200 mg, approximately 1.0 mg to approximately 150 mg, or approximately 1.0 mg to approximately 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 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) - enantiomeric 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% or about 0.5% of formula (1) (S) - enantiomeric 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 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 contains greater than or equal to about 95%, about 95.5%, about 96.0%, about 96.5%, or about 97%. 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 enantiomeric 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 0.25% of the impurity. 34. A dosage form comprising the pharmaceutical composition according to any one of claims 29-33.35. The dosage form of claim 34, wherein the dosage form is a tablet or capsule. 36. A method of treating a disease or condition in 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 comprises parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. Claims 6 / 9 pages 7 CN 121487942 A 38. The method of claim 36 or 37, wherein the therapeutically effective amount is from about 0.005 mg / kg subject body weight to about 1,000 mg / kg subject body weight. 39. The method of 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 of any one of claims 36-39, wherein the disease or condition includes hematopoietic system cancer. 41. The method of any one of claims 36-39, wherein the disease or condition includes myelodysplastic syndrome (MDS) and / or acute myeloid leukemia (AML). 42. The method of claim 41, wherein: the MDS comprises an MDS with splicing factor mutations, an MDS with isocitrate dehydrogenase 1 mutations, or an MDS with isocitrate dehydrogenase 2 mutations; the AML comprises relapsed AML, refractory AML, relapsed / refractory AML, AML resistant to hypomethylating agents, AML resistant to venetoclax, AML resistant to both hypomethylating agents and venetoclax, monocyte AML, or monocyte-like AML; or the AML comprises an AML with splicing factor mutations, an 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 of claim 42, wherein: the MDS with splicing factor mutations comprises an MDS with U2AF1, SRSF2, SF3B1, or ZRSR2 splicing factor mutations; or the AML splicing factor mutations comprise AML 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, etc.Diseases, 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 said disease or condition includes at least one cancer selected from: 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 of any one of claims 36-39, wherein the disease or condition comprises 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 mellitus, Crohn's disease, colitis, and atopic dermatitis. 47. The method of 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 of any one of claims 36-39, wherein the disease or condition is an FLT3 inhibitor-resistant disease or condition. Claims 7 / 9, page 8, CN 121487942, A 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, mAb / immunotherapy, Plk inhibitors.Targeted inhibitors, MEK inhibitors, CDK inhibitors, CDK9 inhibitors, CDK8 inhibitors, retinoic acid receptor agonists, TP53 activators, CELMoD, 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 thereof; the CDK inhibitor is selected from CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1 and / or CDK9 inhibitor BAY1251152 and atuveciclib, or a pharmaceutically acceptable salt thereof; the immune checkpoint inhibitor is selected from ipilimumab, nivolumab, pembrolizumab or a pharmaceutically acceptable salt thereof; 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 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, a dexamethasone, methylprednisolone, or prednisolone-resistant disease or condition, or a CDK inhibitor-resistant disease or condition.Diseases or conditions resistant to palbociclib, THZ1, BAY 12511152, or atuveciclib; diseases or conditions resistant to DNA methyltransferase inhibitors; diseases or conditions resistant to azacitidine; diseases or conditions resistant to immune checkpoint inhibitors; diseases or conditions resistant to ipilimumab, nivolumab, or pembrolizumab; (Claims 8 / 9, page 9, CN 121487942 A) diseases or conditions resistant to BCL2 inhibitors and DNA methyltransferase inhibitors, or diseases or conditions resistant to venetoclax and azacitidine. 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 single 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 with the one or more adjunctive therapies in more than a single application or in more than a single composition. 57. The method of any one of claims 36-56, wherein the disease or condition is relieved by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject. Claims 9 / 9 pages 10 CN 121487942 A IRAK Inhibitor Free Base, Salt and Polymorphs thereof 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 Art

[0003] Myelodysplastic syndromes (MDS) are malignant, potentially fatal hematologic 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 reflux.Transformation into dominant leukemia.

[0004] MDS is a heterogeneous disease with limited treatment options and a lack of effective drugs that can provide a durable response. Current treatment options for MDS are limited, including allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapy (Ebert, 2010). While hematopoietic stem cell (HSC) transplantation can be considered a radical treatment for MDS, many elderly patients are unable to opt for this option and instead receive supportive care and transfusions to improve disease complications. Unfortunately, even after HSC transplantation, the MDS clone can persist 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 still experience treatment-related toxicities or relapse (Sekeres, 2010a). Overall, the efficacy of these treatments is mixed, and they typically only slightly extend life expectancy compared to supportive care. The complexity and heterogeneity of MDS, along with the lack of human xenograft 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 acquired 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] Several compounds are known to be available for the treatment of blood disorders and cancers such as MDS and AML, but their efficacy is limited. While known compounds such as quezartinib, giretinib, and kelenabil are available for the treatment of AML, some of these treatments fail to achieve complete or partial remission. For example, in some cases, treatment may lead to adaptive resistance or screening for inhibitor resistance mutations, such as quezartinib, particularly with repeated dosing, which may lead to desensitization to tumor cell proliferation inhibition (Melgar et al., 2019).

[0007] In the treatment of 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 still unmet needs in AML, including the need to improve overall survival, shorten hospital stays, and improve overall survival. (Instructions for Use 1 / 212 pages 11 CN)121487942 A Drugs that 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 therapeutic drugs that can slow the rate of transformation of MDS to AML and reduce transfusion dependence.

[0008] Therefore, it is necessary to develop methods for effectively treating 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 treatment method. Certain embodiments of this disclosure address one or more of the above-mentioned problems.

[0009] In one aspect, the present disclosure provides a crystal form of a free base of formula (1): Formula (1), characterized in that 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. In one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also contains 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 one embodiment, the crystal form is further characterized in that the X-ray powder diffraction pattern also includes 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°, One or more peaks at 2θ: 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 parameter a=9.0.5817(11)Å, b=20.916(2)Å, c=10.8470(12)Å, α=90°, β=114.836(4)°, γ=90°; iii) Volume approximately 1972.8(4)ų; and / or iv) Crystal density dc=1.348 g / cm³.

[0010] In another aspect, this disclosure provides a crystal form of a compound salt of formula (1): Formula (1), wherein the salt comprises a p-toluenesulfonic acid counterion, and the crystal form is characterized in that the X-ray powder diffraction pattern contains 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 in that the X-ray powder diffraction pattern also contains 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, the present disclosure provides a crystal form of a salt of a compound of formula (1): Formula (1), wherein the salt comprises a tartaric acid counterion, and the crystal form is characterized in that the X-ray powder diffraction pattern includes 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 in that the X-ray powder diffraction pattern also includes 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 another 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, the present disclosure provides a crystal form of a salt of a compound of formula (1): Formula (1), wherein the salt comprises a methanesulfonic acid counterion, and the crystal form is characterized in that the X-ray powder diffraction pattern includes one or more peaks at 4.1463 ± 0.2°, 11.3791 ± 0.2°, 17.4289 ± 0.2°, 20.4382 ± 0.2°, and 25.4454 ± 0.2° 2θ.The crystal form is further characterized by 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 its X-ray powder diffraction pattern. In one embodiment, the crystal form is further characterized by the X-ray powder diffraction pattern also 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] In another aspect, the present disclosure provides a crystal form of a salt of a compound of formula (1): Specification 3 / 212 pages 13 CN 121487942 A Formula (1), wherein the salt comprises a benzenesulfonic acid counterion, and the crystal form is characterized in that the X-ray powder diffraction pattern includes 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 in that the X-ray powder diffraction pattern also includes 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 another 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] In another aspect, the crystal form of the compound salt of formula (1) is: Formula (1), wherein the salt comprises 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 by an X-ray powder diffraction pattern containing one or more peaks at 2.0916±0.2°,One or more peaks at 2θ: 11.1062±0.2°, 20.9023±0.2°, 21.9400±0.2° and 27.5840±0.2°. 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): Specification 4 / 212 page 14 CN 121487942 A Formula (2).

[0015] Contains a dihydrochloride counterion and the crystal form is as 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 the 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.%.%; 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. 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, or about 1.0 mg...The crystal form is described in the form of 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 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 the following amounts: approximately 0.1 mg to 10,000 mg, approximately 1.0 mg to approximately 9,000 mg, approximately 1.0 mg to approximately 8,000 mg, approximately 1.0 mg to approximately 7,000 mg, approximately 1.0 mg to approximately 6,000 mg, approximately 1.0 mg to approximately 5,000 mg, approximately 1.0 mg to approximately 4,000 mg, approximately 1.0 mg to approximately 3,000 mg, approximately 1.0 mg to approximately 2,000 mg, approximately 1.0 mg to approximately 1,500 mg, approximately 1.0 mg to approximately 1,000 mg, approximately 1.0 mg to approximately 750 mg, approximately 1.0 mg to approximately 700 mg, approximately 1.0 mg to approximately 650 mg, approximately 1.0 mg to approximately 600 mg, approximately 1.0 mg to approximately 5 ... The amount of free base in crystalline form is approximately 1 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 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 comprises 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 pharmaceutical composition comprises 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 pharmaceutical composition comprises 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 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 more 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 pharmaceutical composition contains less than or equal to about 5.0%, about 4% water content of the enantiomer ... The pharmaceutical composition contains less than or equal to about 5.0%, 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 enantiomeric crystal form of formula (1) (S); 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.

[0018] In another aspect, this disclosure provides a method of treating a disease or condition in a subject, the method comprising administering to the subject the crystal form described herein or the pharmaceutical composition described herein, which contains 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...In this embodiment, the pharmaceutical composition disintegrates in the gastrointestinal tract of the subject within approximately 10 minutes, approximately 9 minutes, approximately 8 minutes, approximately 7 minutes, approximately 6 minutes, approximately 5 minutes, approximately 4 minutes, approximately 3 minutes, approximately 2 minutes, or approximately 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 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, 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 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 implementation, 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, and uterine cancer. In one embodiment, the disease or condition includes one or more of the following inflammatory diseases or autoimmune diseases: 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...This includes diffuse large B-cell lymphoma (DLBCL), wherein said 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, 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, 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 venetoc or a pharmaceutically acceptable salt thereof, and the BTK inhibitor...The agent 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 CDK4 / 6 inhibitor palbociclib, CDK7 inhibitor THZ1 and / or CDK9 inhibitor 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 administration or in a single composition with one or more adjunctive therapies. In one embodiment, the crystal form or composition described herein is administered separately from one or more adjunctive therapies in more than a single administration or in more than one composition. In one embodiment, the disease or condition is relieved by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject.

[0019] Figures 1A-1H show the results of raw material characterization. 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) and approximately 82% (bottom). Figure 1D: TGA and DSC patterns of raw materials with a purity of approximately 82%. Figure 1E: TGA and DSC patterns of raw materials with a purity of approximately 98%. Figure 1F: 1H NMR pattern of raw materials with a purity of approximately 82%. Figure 1G: 1H NMR pattern of raw materials with a purity of approximately 98%. Figure 1H: HPLC-UV chromatograms of raw materials with a purity of approximately 82% (top) and approximately 98% (bottom).

[0020] Figures 2A-2E show the characterization results of free base (FB) obtained from raw materials with a purity of approximately 82%. Figure 2A: 1H NMR of FB in MeOD-6 before vacuum drying (VD). Figure 2B: 1H NMR of FB in DMSO-6 before vacuum drying. Figure 2C: 1H NMR of FB in MeOD-6 after vacuum drying. Figure 2D: 1H NMR of FB in DMSO-6 after vacuum drying (step 19 in Table 1). Figure 2E: HPLC of FB after vacuum drying (VD).

[0021] Figures 3A-3E show the characterization results of FB (batch 1011-59-1) after vacuum drying. Figure 3A: FB image. Figure 3B: PLM image of FB. Figure 3C: PXRD spectrum of FB. Figure 3D: a) SM, b) FB (batch 1011-59-1) before VD and c) FB (batch 1011-59-1) after VD overlay. Figure 3E: TGA-DSC thermal analysis chromatogram of FB (batch 1011-62-4) after VD.

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

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

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

[0025] Figures 7A-7F show the LCMS and MS characterization results of the raw materials. Figures 7A-7B: LCMS spectra of the raw materials. Figures 7C-7D: MS of the raw materials at different retention times. Figures 7E-7F: MS of the two main LCMS peaks of the raw materials.

[0026] Figures 8A-8F show the LCMS and MS characterization results of FB (batch 1011-62-4). Figures 8A-8B: LCMS spectra of FB. Figures 8C-8D: MS of FB at different retention times. Figures 8E-8F: MS of the two main LCMS peaks of FB.

[0027] Figure 9 shows the HPLC calibration curve using FB (batch 1011-74-1) as a reference standard.

[0028] Figures 10A-10C show the characterization of FB (batch 1011-70-2) after vacuum drying and the 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). Figure 10C: TGA-DSC overlay of recovered FB.

[0029] Figures 11A-11C show the characterization results of the recovered FB (batch 1011-70-2). Figure 11A: 1H NMR spectrum of the recovered FB in deuterated dichloromethane before vacuum drying. Figure 11B: 1H NMR spectrum of the recovered FB after vacuum drying. Figure 11C: HPLC-UV chromatogram of the recovered FB after vacuum drying.

[0030] Figures 12A-12C show the characterization results of FB (batch 1011-74-1) obtained by salt decomposition of TSA-1. Figure 12A: 1H NMR spectrum of FB. Figure 12B: HPLC spectrum of FB. Figure 12C: TGA-DSC overlay of FB.

[0031] Figures 13A-13F show the HPLC-UV chromatograms related to the stability experiment in Table 6. Figure 13A: HPLC-UV chromatogram of the 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: HPLC-UV chromatogram of FB (batch 1011-63-2). Figure 13D: HPLC-UV chromatogram of buffer with initial pH 3.0 (after weekend pH 7.83). Figure 13E: HPLC-UV chromatogram of FB (batch 1011-63-3). Figure 13F: HPLC-UV chromatogram of buffer with initial pH 4.0 (after weekend pH 7.88).

[0032] Figure 14 is a PXRD overlay of the solids obtained in Table 7.

[0033] Figures 15A-15B are the characterization results of FB (batch 1011-84-1) obtained from raw materials with a purity of approximately 98%. Figure 15A: 1H NMR of FB after vacuum drying. Figure 15B: TGA-DSC overlay of FB after vacuum drying.

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

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

[0036] Figure 18 shows the PXRD overlay plots of 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 show the characterization results of ACE-1 (batch 1011-94-15). Figure 19A: 1H NMR spectrum of ACE-1 after overnight vacuum drying. Figure 19B: PXRD spectrum of ACE-1. Figure 19C: TGA-DSC overlay of ACE-1. TGA: Weight loss of 0.864% at 100℃, decomposition at 100℃. DSC: First endothermic peak at 110.70℃, second endothermic peak at 146.29℃.

[0038] Figures 20A-20C show the characterization results of ACE-2 (batch 1011-99-16). Figure 20A: PXRD spectrum of ACE-2. Figure 20B: 1H NMR spectrum of ACE-2. Figure 20C: TGA-DSC overlay of ACE-2. TGA: Weight loss of 0.746% at 100℃, decomposition at 100℃. DSC: First endothermic peak at 143.16℃.

[0039] Figure 21 shows the PXRD overlay plots of 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 show the stability evaluation results of the FB-1 control at time point t0. Figure 22A: FB-1 control stored in an open dish at 25℃ / 60% RH. Figure 22B: FB-1 control stored in an open dish at 40℃ / 75% RH. Figure 22C: FB-1 control stored in an open dish at 60℃. Figure 22D: FB-1 control stored in a closed dish at 25℃ / 60% RH. Figure 22E: FB-1 control stored in closed dishes at 40℃ / 75% RH. Figure 22F: FB-1 control stored in closed dishes at 60℃.

[0041] Figures 23A-23F show the stability evaluation results of the FB-1 control at 1-week time points. Figure 23A: FB-1 control stored in open dishes at 25℃ / 60% RH. Figure 23B: FB-1 control stored in open dishes at 40℃ / 75% RH. Figure 23C: FB-1 control stored in open dishes at 60℃. Figure 23D: FB-1 control stored in closed dishes at 25℃ / 60% RH. Figure 23E: FB-1 control stored in closed dishes at 40℃ / FB-1 control at 75% RH. Figure 23F: FB-1 control stored in closed dish at 60°C.

[0042] Figures 24A-24F show the stability assessment results of the FB-1 control at 2-week time points. Figure 24A: FB-1 control stored in open dish at 25°C / 60% RH. Figure 24B: FB-1 control stored in open dish at 40°C / 75% RH. Figure 24C: FB-1 control stored in open dish at 60°C. Figure 24D: FB-1 control stored in closed dish at 25°C / 60% RH. Figure 24E: FB-1 control stored in closed dish at 40°C / 75% RH. Figure 24F: FB-1 control stored in closed dish at 60°C.

[0043] Figures 25A-25F show the stability assessment results of FB-1 at 1-week time points. Figure 25A: FB-1 stored in an open dish at 25℃ / 60% RH. Figure 25B: FB-1 stored in an open dish at 40℃ / 75% RH. Figure 25C: FB-1 stored in an open dish at 60℃. Figure 25D: FB-1 stored in a closed dish at 25℃ / 60% RH. Figure 25E: FB-1 stored in a closed dish at 40℃ / 75% RH. Figure 25F: FB-1 stored in a closed dish at 60℃.

[0044] Figures 26A-26F show the stability evaluation results of FB-1 at 2-week time points. Figure 26A: FB-1 stored in an open dish at 25℃ / 60% RH. Figure 26B: FB-1 stored in an open dish at 40℃ / 75% RH. Figure 26C: FB-1 stored in an open dish at 60℃. Figure 26D: FB-1 stored in a closed dish at 25℃ / 60% RH. Figure 26E: FB-1 stored in a closed dish at 40℃ / 75% RH. Figure 26F: FB-1 stored in a closed dish at 60℃.

[0045] Figures 27A-27B are PXRD overlays of FB-1 in the stability assessment. Figure 27A: PXRD patterns of FB-1 and samples taken at 1 week (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: Atom labeling of compound 10⁶ for pKa prediction.

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

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

[0049] Figures 31A-31F are the characterization results of TSA-1 (batch 1011-89-1). Figure 31A: PLM of TSA-1. 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 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: 1H NMR spectrum of TSA-1. Figure 31F: HPLC-UV chromatogram of TSA-1.

[0050] Figures 32A-32E are the characterization results of TAR-1 (batch 1011-89-2). Figure 32A: PLM of TAR-1. Figure 32B: DVS of TAR-1 (8.046% weight gain at 80% RH). Figure 32C: PXRD spectrum of TAR-1. Figure 32D: TGA-DSC overlay 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: 1H NMR spectrum of TAR-1.

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

[0052] Figures 34A-34I are HPLC-UV chromatograms of TSA-1 polymorph screening described in Table 20. Figure 34A: TSA-1 (batch)Figure 34B: HPLC-UV chromatogram of TSA-1 polymorph obtained from iPAc. Figure 34C: HPLC-UV chromatogram of 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 TSA-1 polymorph obtained from water. Figure 34I: HPLC-UV chromatogram of TSA-1 polymorph obtained from acetone.

[0053] Figures 35A-35F are the characterization results of TSA-2 (batch 1011-75-2). Figure 35A: PLM of TSA-2. 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 of TSA-2. TGA: Weight loss 3.334% (room temperature to 100℃), decomposes at 250℃. DSC: First endothermic peak at 54.27℃, second endothermic peak (melting point of TSA-1) at 124.83℃, third endothermic peak (melting point of TSA-2) at 175.23℃. Figure 35E: 1H NMR spectrum of TSA-2. Figure 35F: HPLC-UV chromatogram of TSA-2.

[0054] Figures 36A-36B are PXRD patterns of TSA salts. Figure 36A: PXRD overlay plots of TSA-1 and TSA-2. Figure 36B: a) 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 (experiments in Table 23) PXRD overlay plots.

[0055] Figures 37A-37B show the characterization results of TSA-3 (batch 1011-91-8). Figure 37A: PXRD spectrum of TSA-3. Figure 37B: 1H NMR spectrum of TSA-3.

[0056] Figures 38A-38C show the two-week stability study data of TSA-2 (batch 1011-88-3) and TAR-1 (batch 1011-88-5). Figure 38A: Summary of stability assessments for TSA-2 and TAR-1. Figure 38B: PXRD overlay plots of TSA-2 and samples taken at 1 week (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 of TSA-2 and samples taken at 2 weeks (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 show the stability assessment results of the TSA-2 reference standard at time point t0. Figure 39A: TSA-2 control sample stored in an open dish at 25℃ / 60% RH. Figure 39B: TSA-2 control sample stored in an open dish at 40℃ / 75% RH. Figure 39C: TSA-2 control sample stored in an open dish at 60℃. Figure 39D: TSA-2 control sample stored in a closed dish at 25℃ / 60% RH. Figure 39E: TSA-2 control sample stored in a closed dish at 40℃ / 75% RH. Figure 39F: TSA-2 control sample stored in a closed dish at 60℃.

[0058] Figures 40A-40F show the stability assessment results of the TSA-2 control sample at 1 week. Figure 40A: TSA-2 control sample stored in an open dish at 25℃ / 60% RH. Figure 40B: TSA-2 control sample stored in an open dish at 40℃ / 75% RH. Figure 40C: TSA-2 control sample stored in an open dish at 60°C. Figure 40D: TSA-2 control sample stored in a closed dish at 25°C / 60% RH. Figure 40E: TSA-2 control sample stored in a closed dish at 40°C / 75% RH. Figure 40F: TSA-2 control sample stored in a closed dish at 60°C.

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

[0060] Figures 42A-42F show the stability assessment results of TSA-2 (batch 1011-88-3) at 1-week time points. Figure 42A: TSA-2 stored in open dishes at 25°C / 60% RH. Figure 42B: TSA-2 stored in open dishes at 40°C / 75% RH. Figure 42C: TSA-2 stored in open dishes at 60°C. Figure 42D: TSA-2 stored in closed dishes at 25°C / 60% RH. Figure 42E: TSA-2 stored in closed dishes at 40°C / 75% RH.TSA-2 at RH. Figure 42F: TSA-2 stored in closed dish at 60°C.

[0061] Figures 43A-43F show the stability evaluation results of TSA-2 (batch 1011-88-3) at 2-week time points. Figure 43A: TSA-2 stored in open dish at 25°C / 60% RH. Figure 43B: TSA-2 stored in open dish at 40°C / 75% RH. Figure 43C: TSA-2 stored in open dish at 60°C. Figure 43D: TSA-2 stored in closed dish at 25°C / 60% RH. Figure 43E: TSA-2 stored in closed dish at 40°C / 75% RH. Figure 43F: TSA-2 stored in closed dish at 60°C.

[0062] Figures 44A-44B are PXRD overlay plots of TAR-1 stability evaluation. Figure 44A: PXRD overlay of TAR-1 and samples taken at 1 week (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 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] Figures 45A-45F show the stability assessment results of TAR-1 reference at time point t0. Figure 45A: TAR-1 reference stored at 25℃ / 60% RH after opening. Figure 45B: TAR-1 reference stored at 40℃ / 75% RH after opening. Figure 45C: TAR-1 control sample stored in an open dish at 60°C. Figure 45D: TAR-1 control sample stored in a closed dish at 25°C / 60% RH. Figure 45E: TAR-1 control sample stored in a closed dish at 40°C / 75% RH. Figure 45F: TAR-1 control sample stored in a closed dish at 60°C.

[0064] Figures 46A-46F show the stability evaluation results of the TAR-1 control sample at 1-week time points. Figure 46A: TAR-1 control sample stored in an open dish at 25°C / 60% RH. Figure 46B: TAR-1 control sample stored in an open dish at 40°C / 75% RH. Figure 46C: TAR-1 control sample stored in an open dish at 60°C. Figure 46D: TAR-1 control sample stored in a closed dish 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℃.

[0065] Figures 47A-47F show the stability assessment results of TAR-1 control at 2 weeks. Figure 47A: TAR-1 control stored in an open dish at 25 °C / 60% RH. Figure 47B: TAR-1 control stored in an open dish at 40 °C / 75% RH. Figure 47C: TAR-1 control stored in an open dish at 60 °C. Figure 47D: TAR-1 control stored in a closed dish at 25 °C / 60% RH. Figure 47E: TAR-1 control stored in a closed dish at 40 °C / 75% RH. Figure 47F: TAR-1 control stored in a closed dish at 60 °C.

[0066] Figures 48A-48F show the stability assessment results of TAR-1 (batch 1011-88-5) at 1 week. Figure 48A: TAR-1 stored in an open dish at 25 °C / 60% RH. Figure 48B: TAR-1 stored in an open dish at 40℃ / 75% RH. Figure 48C: TAR-1 stored in an open dish at 60℃. Figure 48D: TAR-1 stored in a closed dish at 25℃ / 60% RH. Figure 48E: TAR-1 stored in a closed dish at 40℃ / 75% RH. Figure 48F: TAR-1 stored in a closed dish at 60℃.

[0067] Figures 49A-49F show the stability evaluation results of TAR-1 (batch 1011-88-5) at 2 weeks. Figure 49A: TAR-1 stored in an open dish at 25℃ / 60% RH. Figure 49B: TAR-1 stored in an open dish at 40℃ / 75% RH. Figure 49C: TAR-1 stored in an open dish at 60℃. Figure 49D: TAR-1 stored in a closed dish at 25℃ / 60% RH. Figure 49E: TAR-1 stored in closed dishes at 40°C / 75% RH. Figure 49F: TAR-1 stored in closed dishes at 60°C.

[0068] Figure 50 provides PLM images of the slurries obtained in Table 27.

[0069] Figures 51A-51E are PXRD patterns and DSC-TGA overlays of BSA-1 (batch 1011-79-1). Figure 51A: PXRD overlay images of a) BSA, b) BSA salt obtained from THF (wet cake, 1011-79-1C_wc), c) BSA salt obtained from THF after vacuum drying (1011-79-1C_pw), d) BSA salt obtained from EtOAc (wet cake, 1011-79-1D_wc), e) BSA salt obtained from EtOAc after vacuum drying (1011-79-1C_pw), f) BSA salt obtained from MeCN (wet cake, 1011-79-1B_wc), and g) 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.51E: DSC-TGA overlay of BSA-1 obtained from EtOAc.

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

[0071] Figure 53 is a PXRD overlay 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 54 is a PXRD overlay 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 shows the PXRD overlay 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 on page 12 / 212 of the specification (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 show the PXRD patterns and DSC-TGA overlays of maleate salts obtained in Table 27. Figure 56A: a) Maleic acid, b) Maleate obtained from MeCN (wet cake), c) Maleate obtained from MeCN after vacuum drying (1011-Figure 56B: PXRD pattern of MAL-1. Figure 56C: DSC-TGA overlay of MAL-1 obtained from MeCN.

[0075] Figures 57A-57D are the PXRD patterns and DSC-TGA overlays of methanesulfonate obtained in Table 27. Figure 57A: PXRD overlay 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 of MSA-1 obtained from MeCN. Figure 57C: DSC-TGA overlay of MSA-1 obtained from THF. Figure 57D: DSC-TGA overlay of MSA-1 obtained from EtOAc.

[0076] Figures 58A-58E show the characterization results of MSA-1 (batch 1011-85-3). Figure 58A: PLM of MSA-1. Figure 58B: DVS of MSA-1 (9.53% weight gain at 80% RH, hygroscopic). Figure 58C: PXRD spectrum 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: 1H NMR spectrum of MSA-1.

[0077] Figures 59A-59C show the results of two-week solid-state stability study of MSA-1 (batch 1011-88-6). Figure 59A: Summary of stability assessment. Figure 59B: PXRD overlay of MSA-1 and samples taken at 1 week (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 at 2 weeks (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 show the stability assessment results of MSA-1 reference at time point t0. Figure 60A: MSA-1 reference stored in an open dish at 25℃ / 60% RH. Figure 60B: MSA-1 reference stored in an open dish at 40℃ / 75% RH. Figure 60C: MSA-1 reference stored in an open dish at 60℃. Figure 60D: MSA-1 reference stored in a closed dish at 25℃ / 60% RH. Figure 60E: MSA-1 reference stored in a closed dish at 40℃ / 75% RH. Figure 60F: MSA-1 reference stored in a closed dish at 60℃.

[0079] Figures 61A-61F show the stability assessment results of MSA-1 reference at 1 week. Figure 61A: MSA-1 reference stored in an open dish at 25℃ / 60% RH. Figure 61B: MSA-1 control sample stored in an open dish at 40℃ / 75% RH. Figure 61C: MSA-1 control sample stored in an open dish at 60℃. Figure 61D: MSA-1 control sample stored in a closed dish at 25℃ / 60% RH. Figure 61E: MSA-1 control sample stored in a closed dish at 40℃ / 75% RH. Figure 61F: MSA-1 control sample stored in a closed dish at 60℃.

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

[0081] Figures 63A-63F show the stability evaluation results of MSA-1 (batch 1011-88-6) at 1 week. Figure 63A: MSA-1 stored in open dishes at 25°C / 60% RH. Figure 63B: MSA-1 stored in open dishes at 40°C / 75% RH. Figure 63C: MSA-1 stored in open dishes at 60°C. Figure 63D: MSA-1 stored in closed dishes at 25°C / 60% RH. Figure 63E: MSA-1 stored in a closed dish at 40°C / 75% RH (Instructions for Use, page 13 / 212, CN 121487942 A). Figure 63F: MSA-1 stored in a closed dish at 60°C.

[0082] Figures 64A-64F show the stability evaluation results of MSA-1 (batch 1011-88-6) at 2 weeks. Figure 64A: MSA-1 stored in an open dish at 25°C / 60% RH. Figure 64B: MSA-1 stored in an open dish at 40°C / 75% RH. Figure 64C: MSA-1 stored in an open dish at 60°C. Figure 64D: MSA-1 stored in a closed dish at 25°C / 60% RH.MSA-1 at RH. Figure 64E: MSA-1 stored in closed dishes at 40℃ / 75% RH. Figure 64F: MSA-1 stored in closed dishes at 60℃.

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

[0084] Figures 66A-66E show the DVS analysis of TSA-2 (batch 1011-75-2) and the 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: Overlay of PXRD patterns of a) TSA-2 and b) TSA-2 after DVS. Figure 66C: 1H NMR spectrum of TSA-2 after DVS. Figure 66D: 1H NMR overlay of a) TSA-2, b) TSA-2 and c) TSA-1 after DVS. Figure 66E: HPLC-UV chromatogram of TSA-2 after DVS.

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

[0086] Figures 68A-68B show the DVS analysis of TAR-1 and the characterization results of TAR-1 after DVS. Figure 68A: DVS of TAR-1 (batch 1011-76-5), with a weight gain of 8.046% at 80% RH. TAR-1 was non-deterministically identified as hygroscopic. Figure 68B: a) PXRD patterns of TAR-1 and b) TAR-1 after DVS.

[0087] Figures 69A-69B show the PXRD and DSC-TGA characterization results of L-aspartate obtained from the experiments in Table 27. Figure 69A: a) L-aspartic acid, b) L-aspartic acid salt obtained from MeCN (wet cake, 1011-79-4B_WC), c) L-aspartic acid salt obtained from MeCN after vacuum drying (1011-79-4B_PW), d) L-aspartic acid salt obtained from EtOH (wet cake, 1011-79-4A_WC), e) L-aspartic acid salt obtained from THF (wet cake, 1011-79-4C_WC), f)PXRD overlay of L-aspartate obtained from EtOAc (wet cake, 1011-79-4D_WC). Figure 69B: DSC-TGA overlay of ASP-1 obtained from MeCN.

[0088] Figures 70A-70C are the PXRD and DSC-TGA characterization results of glycolates obtained in Table 27. Figure 70A: 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), e) Glycolate obtained from MeCN after vacuum drying (GLY-2, 1011-79-7B_PW). Figure 70B: DSC-TGA overlay of GLY-1 obtained from EtOAc. Figure 70C: DSC-TGA overlay of GLY-2 obtained from MeCN.

[0089] Figures 71A-71J are HPLC-UV chromatograms of the salts obtained 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 71D: HPLC-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 salt 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] Figures 72A-72K are 1H NMR spectra of the salts obtained in Table 27. Figure 72A: 1H NMR spectrum of BSA salt obtained from MeCN. Figure 72B: 1H NMR spectrum of BSA salt obtained from THF. Figure 72C: 1H NMR spectrum of BSA salt obtained from EtOAc. Figure 72D: 1H NMR spectrum of ESA salt obtained from EtOAc. Figure 72E: 1H NMR spectrum of MSA salt obtained from MeCN. Figure 72F: 1H NMR spectrum of MSA salt obtained from THF. Figure 72G: 1H NMR spectrum of MSA salt obtained from EtOAc. Figure 72H: L-Aspartate obtained from MeCN1H NMR spectra. Figure 72I: 1H NMR spectrum of maleate obtained from MeCN. Figure 72J: 1H NMR spectrum of glycolate obtained from MeCN. Figure 72K: 1H NMR spectrum of glycolate obtained from EtOAc.

[0091] Figures 73A-73B are PXRD spectra of compound 106 mono-HCl salt SM.

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

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

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

[0095] Figure 77 is the DVS result of compound 106 mono-HCl salt SM (batch 1050-19-2).

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

[0097] Figure 79 is a PLM image 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 is the unit cell of the free basic form of compound 106, containing four molecules (Z' = 2).

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

[0100] Figure 82 is the crystal packing diagram of the free basic form of compound 106, showing infinite hydrogen bond 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 is a PXRD overlay diagram of the compound 106 FB-1 reference (top), the bulk solid of batch ZW-1109-07-A6 (middle), and the compound 106 simulated according to the crystal structure (bottom).

[0102] Figure 84 shows the free form of compound 106 SM (ID: ZW-1109-01-A) in Example 2 and an earlier project (Q3864).Figure 85 shows the XRPD overlay of FB-1.

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

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

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

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

[0107] Figure 89 shows the interconversion diagram of the free crystalline form of compound 106.

[0108] Figure 90 shows the 1H NMR spectrum of compound 106 FB-3 (ZW-1109-09-A7) in DMSO-6.

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

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

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

[0112] Figure 94 provides the DSC heating-cooling-heating curve of free SM of compound 106 (ZW-1109-01-A). Specification 15 / 212 pages 25 CN 121487942 A

[0113] Figure 95 is an overlay of 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).

[0114] Figure 96 is an overlay of XRPD spectra 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 by polymorph screening (ZW-1109-09-A5).

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

[0116] Figure 98 provides a PLM image of compound 106 mono-HCl salt SM (ID: 1050-19-2).

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

[0118] Figure 100 shows the spectrum of compound 106 mono-HCl salt SM (top image, ID: 1050-19-2).1H NMR spectra.

[0119] Figure 101 is a superimposed 1H NMR spectrum of compound 106 mono-HCl salt SM (top) and FB #966-195 (bottom), showing the chemical shift change.

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

[0121] Figure 103 provides a PLM image of compound 106 mono-HCl salt SM (ID: 1036-84-FS).

[0122] Figure 104 is a DSC-TGA spectrum of compound 106 HCl salt SM (ID: 1036-84-FS).

[0123] Figure 105 is the 1H NMR spectrum of compound 106 HCl salt SM (ID: 1036-84-FS).

[0124] Figure 106 is a superimposed image of the 1H NMR spectrum of batch 1036-84-FS (bottom) and batch 1050-19-2 (top).

[0125] Figure 107 is the HPLC chromatogram of FB (batch 966-195) w / 99.9 A%.

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

[0127] Figure 109 is the HPLC calibration curve of FB (batch 966-195).

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

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

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

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

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

[0133] Figure 115 is a polymorphic screening XRPD overlay of HCl-1 (compound 106 #1036-84-FS) at 50℃ / 3 days: a) HCl-1 reference, b-l) slurry in solvent.

[0134] Figure 116 is a polymorphic screening XRPD overlay of HCl-1 (compound 106 #1036-84-FS) at 50℃ / 3 days: a) HCl-1 reference, b-l) slurry in solvent.XRPD overlay plots of polymorph screening for compound 106 (#1036-84-FS) at 50°C / 3 days: a) HCl-1 reference, b-p) slurry in solvent.

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

[0136] Figure 118 shows XRPD overlay plots of polymorph screening for compound 106 (#1036-84-FS) at 50°C / 3 days: a) HCl-1 reference, b) compound 106 HCl in 2-butanol with an additional peak.

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

[0138] Figure 120 shows the repeat experiments for polymorph screening at 50°C: a) HCl-1 reference, b) first IPA polymorph screening, c) repeat attempts in IPA at 50°C / 5 days. Specification 16 / 212 pages 26 CN 121487942 A

[0139] Figure 121 shows the repeat experiments for polymorph screening at 50°C: a) HCl-1 reference, b) attempts in 2-butanol at 50°C / 5 days.

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

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

[0142] Figure 124 shows the polymorph 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)-j) organic solvent containing 2 vol% water.

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

[0144] Figure 126 shows the polymorph screening of compound 106 mono-HCl (batch 1036-84-FS) under room temperature liquid-phase assisted grinding: a) HCl-1 reference, b) -k) organic solvent.

[0145] Figure 127 shows the polymorph screening of compound 106 mono-HCl (batch 1036-84-FS) under room temperature solid-phase vapor diffusion: a) HCl-1 reference, b) -i) organic solvent.

[0146] Figure 128 shows the polymorphism screening of compound 106 mono-HCl (batch 1036-84-FS) at room temperature using liquid-phase vapor diffusion: a) HCl-1 reference, b)-c) organic solvent.

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

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

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

[0150] Figures 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 132B: HPLC chromatogram.

[0151] Figures 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] Figures 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] Figures 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] Figures 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] Figures 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] Figures 140A-140B provide a purity study of the solid obtained by separating mono-HCl (batch 1036-84-FS) after stirring at 20°C for 18 hours in 2-butanol containing 1 vol% H2O. (Instruction manual page 17 / 212, page 27, CN 121487942 A) Figure 140A: PLM image. Figure 140B: HPLC chromatogram.

[0159] Figures 141A-141B provide a purity study of the solid obtained after separating mono-HCl (batch 1036-84-FS) from 2-butanol containing 2 vol% H2O and stirring 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 after separating mono-HCl (batch 1036-84-FS) from 2-butanol containing 3 vol% H2O and stirring at 20°C for 18 hours. Figure 142A: PLM image. Figure 142B: HPLC chromatogram.

[0161] Figure 143 shows the 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 shows the 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 shows the 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 146 shows the XRPD 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.2-Butanol containing vol% water, c) 2-Butanol containing 2 vol% water, d) 2-Butanol containing 3 vol% water.

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

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

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

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

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

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

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

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

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

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

[0175] Figures 157A-157B provide the purity study of the solid obtained after separating mono-HCl (batch 1036-84-FS) in acetonitrile (ACN) containing 1 vol% H2O and stirring at 20°C for 1-3 days. Figure 157A: PLM image. Figure 157B: HPLC chromatogram. Instruction manual, 18 / 212 pages, 28 CN 121487942 A

[0176] Figures 158A-158B provide the purity study of the solid obtained after separation of mono-HCl (batch 1036-84-FS) 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 the purity study of the solid obtained after separation of mono-HCl (batch 1036-84-FS) in ACN containing 1 vol% H2O at 40°C for 1-3 days. Figure 159A: PLM image. Figure 159B: HPLC chromatogram.

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

[0179] Figure 161 shows the solubility curves of compound 106 mono-HCl (#1036-84-FS) in an organic solvent system containing 1 vol% water at different temperatures.

[0180] Figure 162 shows the XRPD overlay of the solubility of compound 106 mono-HCl (#1036-84-FS) in acetone containing 1 vol% water: a) HCl-1 reference, b) 20°C, c) 35°C, d) 40°C, e) 50°C.

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

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

[0183] Figure 165 is an XRPD superimposed graph of the solubility of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 vol% water.Figure 166 shows the HPLC chromatogram of impurity removal in IPA containing 8 vol% water at 25°C.

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

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

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

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

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

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

[0190] Figure 172 provides the solubility measurement results of compound 106 mono-HCl (#1036-84-FS) in pure IPA, IPA containing 1 vol% water, and IPA containing 8 vol% water at different temperatures.

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

[0192] Figure 174 is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 20 wt.% acetone antisolvent at 25℃ for impurity removal study.

[0193] Figure 175 is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 40 wt.% acetone antisolvent at 25℃ for impurity removal study.

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

[0195] Figure 177 is a HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in IPA containing 8 wt.% water and 80 wt.% acetone as a reverse solvent at 25°C. (Page 19 / 212 of the specification)29 CN 121487942 A HPLC chromatogram of impurity removal study in antisolvent at 25°C.

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

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

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

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

[0200] Figure 182 is a solubility curve of compound 106 mono-HCl (#1036-84-FS) in IPA containing 8 wt.% water and antisolvent (acetone and MTBE) at 25°C.

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

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

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

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

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

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

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

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

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

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

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

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

[0213] Figure 195 is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in cyclohexane for impurity removal studies. Specification 20 / 212 pages 30 CN 121487942 A

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

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

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

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

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

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

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

[0221] Figure 203 is an HPLC chromatogram of compound 106 mono-HCl (batch 1036-84-FS) in 1,4-dioxane for impurity removal.

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

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

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

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

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

[0227] Figure 209 is a 1H NMR spectrum of compound 106.

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

[0229] Figure 211 is the ROESY 2D spectrum of compound 106.

[0230] Figure 212 is the 19F NMR spectrum of compound 106.

[0231] Figure 213 is the 13C NMR spectrum of compound 106.

[0232] Figure 214 is the HSQC spectrum of compound 106.

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

[0234] Figure 216 is the 1H NMR spectrum of the HCl salt of compound 106.

[0235] Figure 217 is the 13C NMR spectrum of the HCl salt of compound 106.

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

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

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

[0239] Figure 221 is the gradient HMBC spectrum of compound 106 HCl salt. Specification 21 / 212 pages 31 CN 121487942 A

[0240] Figure 222 is the 19F NMR spectrum of compound 106 HCl salt.

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

[0242] Figure 224 is a typical working standard chromatogram for HPLC testing of S-enantiomer content levels in compound 106 capsules.

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

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

[0245] Figure 227 shows the DP stability results of a 10 mg dose after storage at 25℃±2℃ and 60%±5% room temperature and humidity for 3 months. 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 RRT listed reflects the current time point; previous RRTs may differ, 3 Test packaging.

[0246] Figure 228 shows the DP stability results of a 10 mg dose after storage at 40℃±2℃ and 75%±5% room temperature and humidity for 3 months. 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 RRT listed reflects the current time point; previous RRTs may differ, 3 Test packaging.

[0247] Figure 229 is a graph showing the DP stability results after 3 months of storage at 25℃±2℃ and 60%±5% room temperature and humidity for a 50mg dose. 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 RRT listed reflects the current time point; previous RRTs may differ, 3 Test packaging. Detailed Description of Embodiments

[0248] The following related applications are incorporated herein by reference in their entirety and for all purposes: International Publication No. WO 2018081738, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, filed October 30, 2017; U.S. Publication No. 2021 / 0292843, TREATMENT OF DISEASES ASSOCIATED WITH ACTIVATED IRAK, 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; US Patent No. 9,855,273, Combination Therapy for MDS, granted January 2, 2018; International Publication No. WO 2018038988, Compounds,Compositions, Methods for Treating Diseases, and Methods for Preparing Compounds, filed August 16, 2017; U.S. Patent No. 11,254,667, Substituted imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors, granted February 2, 2022; U.S. Publication No. 2022 / 0213094, Substituted Imidazo[l,2-a]pyridines as IRAK 1 / 4 and FLT3 Inhibitors, filed January 4, 2022; U.S. Publication No. 2020 / 0199123, Substituted imidazo[1,2-a]pyridines as IRAK 1 / 4 and FLT3 inhibitors, filed February 28, 2020; U.S. 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, Rational therapeutic 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. WO, Specification 22 / 212 pages, 32 CN 121487942 A 2023009833,Multi‑Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof,International Patent Application No. PCT / US2023 / 068520, Multi-Cyclic IRAK and FLT3 Inhibiting Compounds and Uses Thereof, filed July 29, 2022; 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 No. 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 comprising the crystalline form of compound 106 described herein (e.g., pharmaceutical compositions). Still other embodiments of the present invention include compositions using the crystalline form of compound 106 described herein to treat, for example, certain diseases. Some embodiments include methods of administration and treatment using the crystalline form of compound 106 described herein (e.g., in a composition or pharmaceutical composition). Further embodiments include methods of preparing the crystalline form disclosed herein. Still other embodiments include methods of 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, terminology should be understood as meaning as commonly understood by one of ordinary skill in the art.

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

[0253] The term "about" used in a numerical context indicates a range of ±10% of the numerical value unless otherwise explicitly stated.

[0254] Some compounds of the present 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 the present invention cover any optically active form, racemic form, stereoisomer form, polymorph, or mixture thereof. If the configuration of a chiral center in a 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 a cancer type, means a method or process 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 embodiments, monitoring involves a method or process for determining the therapeutic effect of a treatment a patient is receiving.

[0257] As used herein, "outcome" can refer to the result of a study. In some embodiments, "outcome" can refer to survival / death within a specific time frame. For example, "outcome" can refer to survival / death at 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer. In some embodiments, 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, the term "high-risk clinical trial" refers to a trial in which the test reagent has "above minimum risk" (as defined by the Institutional Review Board or IRB). In some embodiments, a high-risk clinical trial is a drug trial. Instructions for Use, Pages 23 / 212, CN 121487942 A

[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 embodiments, a low-risk clinical trial is a non-pharmacological trial. In some embodiments, a low-risk clinical trial is a trial involving the use of a monitor or clinical practice procedure. In some embodiments, 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 (e.g., preferably a human) patient 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 the broadest context unless otherwise stated, referring to achieving the desired pharmacological and / or physiological effects. Specifically, for example, "treatment" does not necessarily imply or require that the animal be treated until fully recovered. Thus, "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 aspects, "treatment" may not require or include prevention. Animals referred to herein as "treated" include, but are not limited to, preventive and therapeutic treatment. The effect may be preventative, i.e., complete or partial prevention of the disease or its symptoms, and / or may be 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, e.g., a human), which may include one or more of the following: (a) prevention of the development of the disease in a subject who may be susceptible but has not yet been diagnosed with the disease; (b) inhibition of the disease, i.e., prevention of its development; and (c) relief of the disease, i.e., causing the remission or elimination of the disease and / or alleviating one or more symptoms of the disease. In a particular aspect of the method, 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 an agent 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 an effective amount that achieves the desired and / or beneficial effect. An effective amount may be administered once or multiple times. In the method described herein, the therapeutically effective amount is an amount suitable for the therapeutic indication. The therapeutic indication refers to achieving any desired effect, such as alleviating, improving, stabilizing, reversing, slowing or delaying disease progression, improving quality of life, or prolonging life, or one or more of these effects. This achievement can be measured by any suitable method, such as tumor size or blood cell count measurements, or any other suitable measurement method.

[0264] As used herein, the term "marker" or "biomarker" refers to a biomolecule (e.g., nucleic acid, peptide, protein, hormone, etc.) whose presence or concentration can be detected and associated with a known condition (e.g., disease state). The term may also refer to differentially expressed genes.Therefore, its expression pattern can be used in the prediction, prognosis or diagnostic process of health or disease status, or in the identification of effective treatments or preventive therapies.

[0265] The term "mRNA isotype" as used herein refers to an alternative transcript of a specific mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened or aberrant mRNA, modified mRNA (e.g., containing any residue modification, capping variant, polyadenylation variant, 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 generated by 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 binding site. For example, when an excess of antibody reduces the amount of receptor binding to 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 the adhesion of the receptor to its corresponding receptor.

[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. "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] "Solvate" refers to a crystalline phase in which the compound is physically bound to one or more solvent molecules. A crystalline phase in which the compound is physically bound to one or more water molecules is called a "hydrate".

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

[0270] 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 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 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 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 compounds of the invention. Other embodiments of the invention are also discussed herein.

[0271] Compounds and compositions, including pharmaceutical compositionsOn one hand, this disclosure relates to compound 106: or salts, esters, solvates, optical isomers, geometric isomers, or salts of isomers 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, the counterion of which 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 IRAK1, IRAK4, IRAK1 / 4 and / or an FLT3 inhibitor. In one embodiment, the compound disclosed herein is IRAK1 / 4, a pan-FLT3 inhibitor.

[0273] In some embodiments, the compound may be in the form of salts, optical and geometric isomers and isomer salts. In other embodiments, as described on pages 25 / 212 of the specification, CN 121487942 A, the compounds may be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmaceutically acceptable salts, including but not limited to hydrochlorides, dihydrochlorides (bis-HCl), hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates. In some cases, for acidic compounds, the salts may contain metals, amines, or organic cations (e.g., quaternary ammonium salts). In other embodiments, simple derivatives of the compounds (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 means.

[0274] In some embodiments, the compounds of this disclosure have a chiral center and may 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, fractional crystallization, chiral chromatography, etc. See, for example, Eliel, E. L. & Wilen S. H., 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.

[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 be synthesized and / or separated.

[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 be radiolabeled with radioactive isotopes such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variants of the compounds disclosed herein, whether or not radioactive, are included within the scope of consideration.

[0277] In some embodiments, metabolites of the compounds disclosed herein may 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 compounds described herein (e.g., biologically active compounds). 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 biologically active compounds. Examples (non-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). The 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 non-solventized and solvated forms (including hydrated forms).Generally, the solvated form is equivalent to the unsolvated form and is included within the scope of the compounds considered. Some compounds of this disclosure 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, crystalline form of compound 106 and / or polymorph of compound 106) may be part of a 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%, to page 26 / 212 of the specification 36 CN 121487942 A Less than 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, crystal form of compound 106, and / or polymorph of compound 106) 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 exceeding about 75%, not exceeding about 90%, not exceeding about 95%, not exceeding about 99%, not exceeding about 99.99%, about 0 Purified or separated in amounts of 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, the present disclosure provides crystalline solid form of compound 106, or its salt, ester, solvate, optical isomer, geometric isomer, or isomer salt. In one embodiment, the present disclosure provides a single crystal of compound 106. In one embodiment, the present disclosure provides a single crystal of a salt of compound 106. In one embodiment, the present disclosure provides a crystalline solid form of a free base of compound 106. In one embodiment, the present disclosure provides a crystalline solid form of a salt of compound 106.Form. 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, the counterion of which 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.

[0283] Any polymorph 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 obtained X-ray powder diffraction patterns may contain one or more measurement errors, depending on the measurement conditions (such as equipment, sample preparation, or instrumentation). 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. They will also recognize that the position of 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 the amorphous form, 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 the drug into a final product suitable for patients.

[0285] In one aspect, this disclosure provides crystalline 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] Height [cts] Specification 27 / 212 pages 37 CN 121487942 A 1 8.51024175.51 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 Specification 28 / 212 pages 38 CN 121487942 A In some embodiments, 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] Height [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 1017.1858 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 Instruction Manual 29 / 212 pages 39 CN 121487942 A 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] Height [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 5.89In 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] Height [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 Specification 30 / 212 pages 40 CN 121487942 A 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 embodiments, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0289] In yet 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] Height [cts] 1 5.9392 967.34 2 7.076386.43 3 8.7637 1121.04 4 10.9989 459.04 5 11.8931 2025.27 Instruction Manual 31 / 212 pages 41 CN 121487942 A 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 Specification 32 / 212 pages 42 CN 121487942 A 45 33.7315 41.41 46 35.6161 27.48 47 36.1791 57.48 In some embodiments, 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 Instruction Manual 33 / 212 pages 43 CN 121487942 A 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 5536.2798 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 pattern contains one or more peaks selected from the following: Peak # Position [°2θ] Height [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 Specification 34 / 212 pages 44 CN 121487942 A 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 benzenesulfonic acid form of compound 106.Salt polymorph (BSA-1), characterized by an X-ray powder diffraction pattern containing one or more peaks selected from the following: Peak # Position [°2θ] Height [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 Specification 35 / 212 Page 45 CN 121487942 A 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 embodiments, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0293] In another aspect, this disclosure provides the ethanesulfonate crystal form of compound 106 and / or the ethanesulfonic acid salt 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 #Location [°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] Height [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 Specification 37 / 212 pages 47 CN 121487942 A 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 embodiments, each peak may independently include a deviation of ±0.1°, ±0.2° or ±0.3°.

[0295] In another aspect, this disclosure provides the methanesulfonate crystal form of compound 106 and / or the methanesulfonic acid of compound 106.The salt polymorph (MSA-1) is characterized by an X-ray powder diffraction pattern containing one or more peaks selected from the following: Peak # Position [°2θ] Height [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 Specification 38 / 212 pages 48 CN 121487942 A 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 embodiments, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0296] In another aspect, the present disclosure provides a monohydrochloric acid crystal form of compound 106 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] Height [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 1116.2725 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 Instruction Manual 39 / 212 Page 49 CN 121487942 A 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 embodiments, each peak may independently include a deviation of ±0.1°, ±0.2°, or ±0.3°.

[0297] In one embodiment, the present disclosure provides a crystal form of compound 106, characterized in that the 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°, 16.8018±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°, 28.6101±0.2°, 30.1759±0.2°, 31.5240±0.2°, 31.8408±0.2°, One or more peaks of 2θ at 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 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 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, the present disclosure provides a crystal form of compound 106, characterized in that the 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°, 22.3172±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°, 27.2423±0.2°, Instruction Manual 40 / 212 pages 50 CN 121487942 A 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°One or more peaks of 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 an acetate of compound 106. In some embodiments, the crystal form comprises a solvated acetate of compound 106.

[0299] In one embodiment, the present disclosure provides a crystal form of compound 106, characterized in that the X-ray powder diffraction pattern comprises a value 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°, 18.9193±0.2°, 19.4893±0.2°, 20.0171±0.2°, 21.6036±0.2°, 22.4177±0.2°, 23.5670±0.2°, 24.4393. One or more peaks of 2θ at ±0.2°, 25.0411±0.2°, 26.0228±0.2°, 26.6839±0.2°, 27.3926±0.2°, and 33.2748±0.2°. In some embodiments, the X-ray diffraction pattern includes 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 an acetate of compound 106. In some embodiments, the crystal form comprises a desolvated acetate of compound 106.

[0300] In one embodiment, the present disclosure provides a crystal form of compound 106, characterized in that the 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°One or more peaks of 2θ are included: 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, the present disclosure provides a crystal form of compound 106, characterized in that the 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±0.2°, 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° One or more peaks of 2θ at 25.4378±0.2°, 26.1134±0.2°, 26.6147±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°. InIn 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 p-toluenesulfonic acid monohydrate salt of compound 106. Specification 41 / 212 pages 51 CN 121487942 A

[0302] In one embodiment, the present disclosure provides a crystal form of compound 106, characterized in that the 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°, 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±0.2°, 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°, 36.2798One or more peaks of 2θ at ±0.2°, 36.7875±0.2°, 37.2640±0.2°, 37.8389±0.2°, 38.7782±0.2°, and 39.4366±0.2°. In some embodiments, the X-ray diffraction pattern includes 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 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 solvated p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises desolvated p-toluenesulfonate of compound 106. In some embodiments, the crystal form comprises amorphous p-toluenesulfonate of compound 106.

[0303] In one embodiment, the present disclosure provides a crystal form of compound 106, characterized in that the 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°, 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°, 25.9362±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 One or more peaks of ±0.2°, 35.2961±0.2°, and 36.2252±0.2° 2θ. In some embodiments, the X-ray diffraction pattern contains 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 (+)-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°, 14.2875±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°, 25.5863±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° 2θ (from a specification, page 42 / 212, CN 121487942 A, page 52) One or more peaks. In some embodiments, the X-ray diffraction pattern contains 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 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, the present disclosure provides a crystalline form of compound 106, characterized in that the X-ray powder diffraction pattern comprises a region selected from 2.1456±0.2°, 9.4378±0.2°, 10.5830±0.2°, 13.5242±0.0.2°, 15.6498±0.2°, 16.1666±0.2°, 18.2082±0.2°, 19.1561±0.2°, 19.5803±0.2°, 21.4651±0.2°, 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° One or more peaks at 30.1128±0.2° and 31.0951±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 the ethanesulfonate of compound 106. In some embodiments, the crystal form comprises the hydrated ethanesulfonate of compound 106. In some embodiments, the crystal form comprises the anhydrous benzenesulfonate of compound 106. In some embodiments, the crystal form comprises the solvated benzenesulfonate of compound 106. In some embodiments, the crystal form comprises the desolvated benzenesulfonate of compound 106. In some embodiments, the crystal form comprises the amorphous benzenesulfonate of compound 106.

[0306] In one embodiment, the present disclosure provides a crystal form of compound 106, characterized in that the X-ray powder diffraction pattern comprises a value 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°, 16.0301±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°. One or more peaks of 2θ at ±0.2°, 27.5537±0.2°, and 30.8678±0.2°. 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 maleate of compound 106. In some embodiments, the crystal form comprises the hydrated maleate of compound 106. In some embodiments, the crystal form comprises the anhydrous maleate of compound 106. In some embodiments, the crystal form comprises the solvated maleate of compound 106. In some embodiments...In one embodiment, the crystal form comprises the desolvated maleate of compound 106. In some embodiments, the crystal form comprises the amorphous maleate of compound 106.

[0307] In one embodiment, the present 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°, 24.4222. ±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 of 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 (see page 43 / 212 of CN 121487942, type A) comprises pure methanesulfonate of compound 106.

[0308] In one embodiment, the present 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, 22.9619, 23.3316, 23.6521, 24 .4120、24One or more peaks selected from the above peak groups are: 0.9258, 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, at least five, etc., 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 crystal 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). In one embodiment, the crystal 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 formula (1).(S)-Enantiomer. 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.

[0311] In one embodiment, the crystal form, when formed, comprises 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 a free base of compound 106. In one embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0312] In one embodiment, after being stored 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 for 6 months at about 25°C and about 60% relative humidity, the crystal form comprises more 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 for 6 months at about 25°C and about 60% relative humidity, 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 enantiomer of formula (1) (S). 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.

[0314] In one embodiment, after being stored at about 25°C and about 60% relative humidity for 6 months, the crystal form comprises small...Impurities of 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% may be present. 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.

[0315] In one embodiment, after being stored 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 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). In one embodiment, after being stored at about 40°C and about 75% relative humidity for 6 months, 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 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.

[0317] In one embodiment, after being stored at about 40°C and about 75% relative humidity for 6 months, the crystal 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...Contains soluble impurities. 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.

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

[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 during formation and after storage is measured as the area percentage of an HPLC chromatogram. In one embodiment, the chiral purity of the crystal form during 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 during formation are measured by ultra-high performance liquid chromatography (UPLC). In one embodiment, impurities present in the crystal form after storage at about 25°C and about 60% relative humidity for 6 months are measured by UPLC. In one embodiment, impurities present in the crystal form after storage at about 40°C and about 75% relative humidity for 6 months are measured by UPLC. In one embodiment, the percentage of each impurity in the crystal form during formation and after storage is measured as the area percentage of an UPLC chromatogram. In one embodiment, the impurity content in the crystal form during 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.

[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 contains 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 contains a lattice parameter a of about 15.0 Å to about 25.0 Å, about 16.0 Å to about 10.0 Å, or about 10.0 Å.The lattice parameter b is 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 contains 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 α 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 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 a volume of about 1950 Å to about 2000 Å 3, about 1955 Å 3 to about 1995 Å 3, about 1960 Å 3 to about 1990 Å 3, about 1965 Å 3 to about 1985 Å 3, about 1965 Å 3 to about 1980 Å 3, about 1970 Å 3 to about 1975 Å 3, or about 1972 Å 3. In one embodiment, the single crystal of the free base of compound 106 comprises a crystal density dc of about 0.9 g / cm3 to about 1.9 g / cm3, about 0.9 g / cm3 to about 1.8 g / cm3, about 0.9 g / cm3 to about 1.7 g / cm3, about 0.9 g / cm3 to about 1.6 g / cm3, about 1.0 g / cm3 to about 1.5 g / cm3, about 1.1 g / cm3 to about 1.4 g / cm3, about 1.2 g / cm3 to about 1.4 g / cm3, or about 1.35 g / cm3.

[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 compound 106 is as described elsewhere herein. 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.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 compound 106 crystal form. 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...In one embodiment, the crystal form comprises a free base of compound 106. In another embodiment, the crystal form comprises a monohydrochloride salt of compound 106.

[0325] In one embodiment, the pharmaceutical composition, when formed, comprises 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% of impurities. In one embodiment, the impurities comprise soluble impurities. In one embodiment, the crystal form comprises a free base of compound 106. In another 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 crystal form comprises compound 106 free base. In one embodiment, the crystal 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 drug...The 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 crystal form comprises compound 106 free base. In one embodiment, the crystal 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 the monohydrochloride of compound 106 as described on page 47 / 212 of CN 121487942 A.

[0331] 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 10%, about 9.0%, about 8.0%, about 7.0%, about 6.0%, about 5.0%, about 4.5%, about 4.0%, aboutImpurities of 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1.0%, about 0.5%, or about 0.25%. 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 after storage for 1 month or 3 months at about 25°C and about 60% relative humidity is measured by TGA. In one embodiment, the water content of the pharmaceutical composition after storage for 1 month or 3 months at about 40°C and about 75% relative humidity is measured by TGA.

[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 for 1 month or 3 months at about 25°C and about 60% relative humidity is measured by HPLC. In one embodiment, the chiral purity of the crystal form in the pharmaceutical composition after storage for 1 month or 3 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 during 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 during 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 during formation are measured by ultra-high performance liquid chromatography (UPLC). In one embodiment, impurities present in the pharmaceutical composition after storage for 1 month or 3 months at about 25°C and about 60% relative humidity are measured by UPLC. In one embodiment, impurities present in the pharmaceutical composition after storage for 1 month or 3 months at about 40°C and about 75% relative humidity are measured by UPLC. In one embodiment, the percentage of each impurity in the pharmaceutical composition during 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 during 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...The 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 the mono-HCl form of compound 106 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 mutation / inactivation 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 zabraline. In one embodiment, the therapeutic agent comprises a DNMT inhibitor. In one embodiment, the DNMT inhibitor is zabraline, 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...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 glasgib. In one embodiment, the therapeutic agent comprises an IDH1 inhibitor. In one embodiment, the IDH1 inhibitor is ivesicidinib. In one embodiment, the therapeutic agent comprises an IDH2 inhibitor. In one embodiment, the IDH2 inhibitor is ensididipine. 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 a common type in the art.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, WO 2021207632, US 8685660, US 20200361906, US 10695346, US 11142507, WO 2021198439, WO 2021201170, US 8153632, US 11013743, US 11135198, US Specification 49 / 212 pages 59 CN 121487942 A 20210299111, WO 2021190637, WO 2021188855, WO 2021188849, US 20210292299, US 11124836, US 10961527, US 20210284629, US 20210283265, WO 2021183994, WO 2021181233, US 11116755, WO 2021176045, WO 2021177816, WO 2021176049, WO 2021176349, US 20210275522, US 20210275491, US 20210277037, US 11111250, WO 2021142448, WO 2021172359, WO 2021174195, US 20210260209, US 20210261609, US 20210261636, US 20210261546, WO 2021168341, US 11014911, US 9932344, US 8415355, US 11091485, US 11091490, US 20210246422, US 20210246138, US 20210244715, US 11083722, US 11083728, US 20210238226, US 20190142835 , WO 2021155006 , WO 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US20100056524, US 20100048597, WO 2010013466, US 7655652, US 20100021420, US 7645775, US 7645762, US 20100004243, US 7642266, US 20090325931, US 7638518, US 20090318446, US 20090318430, US 7625732, US 7157455, US 7612079, US 7544689, US 7067661, US 20060281736, US 7235561, US 7226920, WO 2009115591, US 20090233928, US 20090226431, US 20090221581, US 20090208991, US 20050186261, WO 2009095265, WO 2009047298, US 7557110, US 20090170847, WO 2009010298, US 20090142337, US Description Page 53 / 212 63 CN 121487942 A 20090130118, US 7388010, WO 2007033208, US 20080188524, US 20090105687, US 20090099160, US 7511063, US 7511136, US 20090081645, US 20050209292, US 20090076268, US 7501257, WO 2009022104, WO 2009020580, US 7485638, US 20090029992, US 20090030005, US 6610677, WO 2008132138, US 7189716, US 20070238745, US 20080312223, US 7465728, US 6710227, US 20080293785, US 7456191, US 6916798, WO 2008137139, US 20080280906, US 7449544, US 20080275063, US7446195 , US 7446105 , WO 2008130569 , US 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6743785 , WO 2004004730, WO 2004031158, US 6720332, WO 2004028571, US 6716831, US 6713267, US 6710052 , US 6706718 , US 20040048849 , US 20030187007 , US 6696546 , US 6683095, US 20040010027, US 6677345, US 6630464, US 20030229105, US 6569878, US 20030215861 , US 6649608, US 20030064426 , WO 2003091700 , US 6642231 , US 6632820, US 6620818, US 20030166016, US 6596694, US 6586203, US 20030119816, US 20030113897 , US 20030114504 , US 6579903 , US 6576647 , US 6573044 , US Description Page 54 / 212 64 CN 121487942 A 6043030, US 20030049602, US 20030100477 , US 20030032177 , WO 2003030909, US 6319918 , WO 2003027299 , US 20030060397 , US 6504034 , WO 2002074742 , WO 2002053096 , US 20030018005 , US 6500846 , WO 2002100401 , US 6486166 , WO 2002072085, US 6462069, US 6451618, US 6420345, WO 2002051849, US 6413974, US 6414013, US 6407103, WO 2001083716, US 5672508, US 6291504, WO 2001038532, WO 2001027080, US 6303618, US 6290951, WO 2001055148, WOThe entire contents of the references to US 2001053293, US 6001868, US 6197804, WO 1999066055, US 6013646, WO 1999043676, US 5767258, 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 which 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 implementation scheme, 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 (Instructions for Use, page 55 / 212, 65 CN 121487942 A (LS-007); flavopiridol (alvocidib); dinaciclib; SNS-032 (BMS-387032); (RGB286638); (zortiraciclib, TG02, SB1317); (atuveciclib, BAY-1143572); (AZD4573); abemaciclib (LY2835219, Verzenio); Palbocicini (PD-0332991, Ibrance); Instruction manual 56 / 212 pages 66 CN 121487942 A Rebociglio (LEE-011, Kisqali); PF-06873600; trilaciclib(G1T28); lerociclib (G1T38); SHR-6390; milciclib (PHA-848125); FN-1501; inditinib (AGM-130); (+)-BPI-16350; AT-7519; Instruction manual 57 / 212 pages 67 CN 121487942 A AZD-4573; voruciclib (P-1446A-05); BCD-115; CT7001 (ICEC 0942); CYC-065; seliciclib (R-roscovitine, CY-202); SY-1365; roniciclib (BAY-1000394); THZ1; Instruction manual 58 / 212 pages 68 CN 121487942 ATHZ 2; THZ 5 3 1; E9; FMF-04-159-2; YKL-5-1 2 4; NU 6 3 0 0; SY-314; Instruction manual 59 / 212 pages 69 CN 121487942 A SY-351; dabrafenib; rebastinib; K03861; MC180295; BRD6989; SR-3029; nordihydroguaiac acid (NDGA); protaglandin E1; adapalene; Instruction manual 60 / 212 pages 70 CN 121487942 A fluspirilene; candesar tancilexil; indocyanine green; rafoxa nid e; H SD922; 20-223 (CP668863); roxyl-zhc-84; abemaciclib; vorinostat; cabozantinib; corticostatin A; Instructions for use 61 / 212 pages 71 CN 121487942 A MSC2530818; CCT251545; CCT251921; ZK-304709; riviciclib (P276-00); R547; AZD5438; AG-0 24 3 2 2; LDC 31 4 0; LDC 4 2 9 7; wogonin; CMPD 1 4; LDC 0 0 0 0 6 7; CMPD 9 3; sorafenib; senexin A; Instruction manual 62 / 212 page 72 CN 121487942 A senexin B; CMPD 2 0; CMPD 3 2; SEL 1 2 0; PHA-7 9 3 8 8 7; IIIM-2 9 0; olomoucine; rohitukine; F ascaplysin; hymenialdisine; Instruction manual 63 / 212 page 73 CN 121487942 A variolin B; konb u'a c id in A; Astrophytum; LY2857785; BS-181; ; ; ; ; Instruction manual 64 / 212 page 74 CN 121487942 A Instruction manual 65 / 212 pages 75 CN 121487942 A ; ... ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; BS-1 81 ; ; ; ; ; 71 / 212 pages 81 CN 121487942 A ; ...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 -OCH3, 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 R is -OCH3 and R' is -SF5; where R is F and R' is -CH3 or R is -SF5 and R' is H; Specification 75 / 212 pages 85 CN 121487942 A 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 cyclopropane-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 cyclopropane-1-1-yl, X is F and n is 1, or oxacyclobutane-3-yl, X is -CH3 and n is 1; Wherein R is 1,2-oxazol-3-yl or 3,4-difluorophenyl-1-yl; Wherein R is H, C(=O)NHCH3, -SO2NH2, SO2CH3, or 2,3-dihydroxypropyl-1-yl; Specification 76 / 212 pages 86 CN 121487942 A Wherein R is H, CH3, 2-aminoethyl-1-yl, 3-aminopropyl-1-yl, or 2,3-dihydroxypropyl-1-yl; Wherein R is H or -CH3; Wherein R is H, C(=O)NHCH3, or -SO2CH3; Wherein R is 3-fluorobenzyl or 3-fluoropyridin-3-yl; Wherein Aryl is 4-fluorophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 4-methylphenyl, 2-ethylphenyl, or 3-pyridinyl and R is H, cyclopropyl, cyclopentyl, or cycloheptyl; Wherein R is 2-phenylethyl-1-yl or (furan-2-yl)methyl; Specification 77 / 212 page 87 CN 121487942 A Wherein R is H or -C(=O)CH2OH; Wherein R is -NHC(=O)CH3 or -NHSO2CH3; Wherein 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-pyrazole-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; Specification 78 / 212 pages 88 CN 121487942 A 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)pyrrolidine-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 wherein 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 one 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 salts, optical and geometric isomers and isomers. Specification 79 / 212 pages 89 CN 121487942 A. In the form of a salt. In other embodiments, the therapeutic agent 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, 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 therapeutic agent (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 means.

[0344] In some embodiments, the therapeutic agent has a chiral center and may exist and be separated in 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 isotopic labels.Compounds labeled with radioactive names. 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, fractional 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, and 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 compounds known in the art to be too unstable to be synthesized and / or separated.

[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 radiolabeled with radioactive isotopes such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variants of the compounds disclosed herein, whether or not radioactive, are included within the scope of 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 biologically active compound). Prodrugs may be used for a variety of reasons known in the art, including, for example, ease of administration due to increased bioavailability when administered orally. Prodrugs may also have better solubility in pharmaceutical compositions than biologically active 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 be present in both non-solventized and solvated forms (including hydrated forms). Generally, solvated forms are equivalent to non-solventized forms and are included within the scope of the compounds considered. Some of the therapeutic agents disclosed herein may be present 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 the disclosure herein.

[0350] Pharmaceutical Compositions and Formulations In one embodiment, the present 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 to form a single composition. In one embodiment, the crystalline form of the free base or salt of compound 106 is co-administered with the therapeutic agent in a single dose or in a single composition. In another embodiment, the crystalline form of the free base or salt of compound 106 is co-administered with the therapeutic agent in multiple doses or in multiple compositions. In one embodiment, a composition comprising a crystal form of the free base or salt of compound 106 is administered to a subject simultaneously with a composition comprising a therapeutic agent. In another embodiment, a composition comprising a crystal form of the free base or salt of compound 106 is administered to a subject sequentially with a composition comprising a therapeutic agent. In one embodiment, a composition comprising a crystal 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 compounds of this disclosure (e.g., crystal forms of the free base or salt of compound 106). In one embodiment, a 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...The composition may also contain a formulation ingredient, adjuvant, or carrier. In some embodiments, the composition may also contain a BCL2 inhibitor. In some embodiments, the composition may be used in combination with a second composition containing a BCL2 inhibitor. In some embodiments, the BCL2 inhibitor may be venetoclax or a salt, isomer, derivative, or analog 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 substituent on the compound described herein. When the compounds disclosed herein contain relatively acidic functional groups, a base addition salt may be obtained by contacting a neutral form of such a compound 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, an acid addition salt may be obtained by contacting a neutral form of such a compound 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, hydrocarbonic 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 allows these compounds to be converted 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 obtained by contacting the salt with a base or acid and separating the parent compound in a conventional manner.Regeneration. 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 above-mentioned compounds (when a basic or acidic group is present in the structure) are also included in the scope of compounds considered herein. When acidic substituents (e.g., -NHSO3H, -COOH, and -P(O)(OH)2) are present, ammonium salts, sodium salts, potassium salts, calcium salts, etc., can be formed and used as dosage forms. Basic groups (e.g., amino or basic heteroaryl, or pyridyl) and acidic salts (e.g., hydrochloride, hydrobromide, acetate, maleate, palmitate, methanesulfonate, p-toluenesulfonate, etc.) can be used as dosage forms.

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

[0358] In some cases, the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, there may be inherent side effects (e.g., it may harm the patient or have some 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 may 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 a pharmaceutically aesthetically pleasing and palatable formulation. 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 tablet. 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 by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Specification 82 / 212 pages 92 CN 121487942 A

[0362] For the preparation of pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers may be solid or liquid. Solid form formulations include powders, tablets, pills, capsules, pouches, suppositories, and dispersible particles. Solid carriers can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials.

[0363] The compounds disclosed herein can be administered parenterally via injection or over time as free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts for in vivo application. Routes of administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavitary, or transdermal. For in vitro studies, the compounds can 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 subdivided solid mixed with the subdivided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary adhesive properties in appropriate proportions 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, and cocoa butter. The term "formulation" refers to the formulation of an active compound with an encapsulating material serving as a carrier into capsules, wherein...The active ingredient (with or without other carriers) is encapsulated and bound to a carrier. This includes capsules and lozenges. Tablets, powders, capsules, pills, capsules, and lozenges are available as solid dosage forms suitable for oral administration.

[0366] To prepare a suppository, a low-melting-point wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted, and the active ingredient is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a mold of suitable size and cooled to solidify.

[0367] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral administration, liquid formulations may 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 may 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 diluents or solvents (e.g., 1,3-butanediol solutions). Acceptable solvents, carriers, and solvents 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 suitable for 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 embodiments, 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 buffer media). Common carriers or excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and their 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, etc.) 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 instructions, pages 83 / 212, 93 CN 121487942 A 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 the 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 colorant, flavoring agent, stabilizer, and thickener. Aqueous suspensions suitable for oral administration can be prepared by dispersing a finely differentiated active ingredient with a viscous material (such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents) in water. Aqueous suspensions typically contain the active substance 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 esters 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 hexitol fractions (such as polyoxyethylene sorbitan monooleate); (e) condensation products of ethylene oxide and derivatives of fatty acids and hexitol fractions (such as polyoxyethylene sorbitan monooleate).

[0372] Also included are solid dosage forms intended to be converted into oral liquid formulations prior to use. Such 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] The pharmaceutical formulation is preferably a unit dosage form. This dosage form is further subdivided into unit doses containing an appropriate amount of the active ingredient. Unit dosageThe 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 a suitable number of these dosage forms in a packaged form.

[0374] In some embodiments, the pharmaceutical composition may contain one or more formulation ingredients. "Formulation ingredient" can be any suitable ingredient (e.g., suitable for 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., polysorbate)), oils (e.g., animal oils, vegetable oils (e.g., coconut oil or peanut oil), or mineral oils), oil derivatives (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerol), 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., the 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 (e.g., pharmaceutical composition formulations) may, in some embodiments, include those incorporating the drug (or controlled-release formulation) into food, food ingredients, feed, or beverages.

[0377] Some compounds have limited solubility in water, so 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). Specification 84 / 212 pages 94 CN 121487942 A

[0378] Viscosities higher than those of simple aqueous solutions help reduce formulation dispensing variability, decrease the separation of suspension or emulsion components, and / or improve formulation performance. Such thickeners include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, 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 polymers.Amounts of anionic mucosal mimic polymers, gelling polysaccharides, and finely segmented drug carrier matrices are used. 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 that can be used to improve 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 compounds disclosed herein, in the form of free compounds or pharmaceutically acceptable prodrugs, metabolites, analogs, derivatives, solvates, or salts, for administration to a subject. Common carriers or excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and their 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 one or more compositions comprising a crystalline form of the free base or salt of compound 106 as described above. If multiple administrations are present, 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 containing the compound described above. In some embodiments, at least one of the single or multiple administrations includes parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular 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 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 a method of treating a disease or condition, the method 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 a composition as described above.

[0384] 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, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, at least one of the one or more 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. In some embodiments, at least one compound of the one or more compositions is administered to the subject at an amount of 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 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, and glioma.The method is indicated for the treatment of at least one cancer selected from tumors, oral cancer, nasopharyngeal carcinoma, rectal cancer, gastric cancer, and uterine cancer, or one or more inflammatory or autoimmune diseases characterized by overactivity of IRAK1 and / or IRAK4, or a combination thereof. In some embodiments, the method is used to treat one or more inflammatory 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 a combination 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 DLBCL of the L265P MYD88 mutant (ABC) subtype.

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

[0387] In some embodiments, the subject is susceptible to AML and / or MDS, and / or said method prevents or improves future AML and / or MDS. In some embodiments, the method is performed after one or more of the following conditions: having myelodysplastic syndrome, having myeloproliferative disorder, experiencing 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 administering one or more compositions once or multiple times. 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 treatments, DNA methyltransferase inhibitors / hypomethylating agents, anthracyclines, histone deacetylase (HDAC) inhibitors.Drugs, purine nucleoside analogs (antimetabolites), isocitrate dehydrogenase 1 or 2 (IDH1 and / or IDH2) inhibitors, antibodies-drug package insert 86 / 212 pages 96 CN 121487942 A 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., I131-apamilstat); the mAb / immunotherapy includes anti-CD70 antibodies (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123 x...)...) and / or pracinostat; the purine nucleoside analogues (antimetabolites) include fludarabine, cladribine, and / or clofarab; 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., I131-apamilstat); the mAb / immunotherapy includes 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)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... Or refametinib; the CDK9 inhibitors include alvocidib and / or voruciclib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (a selective RARα agonist); the TP53 activators include APR-246 (Eprenetapopt); the smooth receptor antagonists include glasdegib; the ERK inhibitors include ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, including ulixertinib, SCH772984, ravoxertinib, MK-8353 and / or VTX-11e; the PI3K inhibitors include 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. This includes 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 includes parenteral administration, mucosal administration, intravenous administration, subcutaneous administration, topical 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 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 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. In some embodiments, the subject requires treatment.

[0392] In some embodiments, the method is used to treat hematopoietic system cancers. 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 of these cancers using IRAK1 and / orInflammatory diseases or autoimmune diseases characterized by 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 comprises 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 comprising a BCL2 inhibitor, or at least one of the compositions comprising a crystal form of the free base or salt of compound 106 further comprising 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 comprises venetoclax or a salt, isomer, derivative, or analogue thereof.

[0395] 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, etc.The drug comprises, or is in combination with, a group consisting of retinoic acid receptor agonists, TP53 activators, smooth receptor antagonists, ERK inhibitors, PI3K inhibitors, mTOR inhibitors, glucocorticoid receptor modulators, and EZH2 inhibitors. In some embodiments, the DNA methyltransferase inhibitor / hypomethylating agent includes azacytidyl, 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., I131-apamilstat); the mAb / immunotherapy includes anti-CD70 antibodies (e.g., ARGX-110, cusatuzumab), bispecific antibodies (e.g., floteuzumab (CD123 x...)...) and / or pracinostat; the purine nucleoside analogues (antimetabolites) include fludarabine, cladribine, and / or clofarab; 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., I131-apamilstat); 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 trehalose.Trametinib, Cobimetinib, Selumetinib, Pimasertib and / or The CDK9 inhibitors include refametinib; the CDK8 inhibitors include SEL120; the retinoic acid receptor agonists include ATRA (all-trans retinoic acid) and / or SY-1425 (a selective RARα agonist); the TP53 activators include APR-246 (Eprenetapopt); the smooth receptor antagonists include glasdegib; the ERK inhibitors include ERK2 / MAPK1 or ERK1 / MAPK3 inhibitors, including ulixertinib, SCH772984, ravoxertinib, MK-8353, and / or VTX-11e; the PI3K inhibitors include 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 inhibitor includes 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, administering to the subject a therapeutically effective amount of the free base of compound 106.Or a composition in the crystal form of a salt. In one embodiment, the composition comprising a therapeutically effective amount of the CDK inhibitor is administered to the subject. In one embodiment, the crystal 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 the subject of need.

[0397] In addition to the 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 the compounds disclosed herein (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 of this disclosure 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, FLT3 point mutations, FLT3 internal tandem repeat mutations, 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 4), and other related activities.The compounds disclosed herein may inhibit the activity of one or both of the following: FLT3 and FLT3 mutations (e.g., FLT3 juxtamembrane mutations, FLT3 kinase domain mutations, 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 more of the following: IRAK4, IRAK4 isoforms, IRAK4 mutations, IRAK1, IRAK1 isoforms, or IRAK1 mutations. 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 an 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. Ranges of values ​​using any combination of those described herein as upper and / or lower limits are also considered, such as, but not limited to, 1–10 nM.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., 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 (i.e., the concentration at which half-maximal inhibition is achieved) in its usual sense.

[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 that evolve from myelodysplastic syndromes, cancers that evolve from myeloproliferative disorders, and B-cell cancers.

[0401] In some embodiments, 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 a MYD88 mutation (such as L265P), follicular lymphoma, or marginal zone lymphoma, or combinations thereof.

[0402] In some embodiments, 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 intracellular signaling abnormalities 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, etc., and combinations thereof.

[0404] In some embodiments, compounds of the present disclosure (e.g., crystal forms of the free base or salt of compound 106) can be used in subjects (e.g., mammals, pigs, dogs, poultry (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, etc.). MDS treatable in mice, rats, and humans includes, but is not limited to: MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, MDS with isocitrate dehydrogenase 2 mutations, refractory cytopenia with monolineage abnormalities (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage abnormalities (e.g., refractory cytopenia with multilineage abnormalities and ring sideroblasts, and in animals / humans where the lesions are not limited to erythrocytes, such as significant leukocyte precursor cell and platelet precursor cell (megakaryocyte) developmental abnormalities), refractory anemia types I and II with blastosis, 5q- syndrome, megakaryocyte developmental abnormalities with fibrosis, and refractory cytopenia in childhood. In some implementations, treatable MDS includes, but is not limited to: hereditary MDS, MDS with increased risk due to genetic susceptibility, and 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., combination of radiotherapy with radiomethylenetetramine (such as busulfan, nitrosourea, or procarbazine, hydrazine (latency 5 to 7 years) or DNA topoisomerase inhibitors), MDS evolving from acquired aplastic anemia and Fanconi anemia following immunosuppressive therapy, MDS with increased risk due to splicing factor mutations, MDS with increased risk due to isocitrate dehydrogenase 1 mutations, and MDS with increased risk due to isocitrate dehydrogenase 2 mutations. Treatable animals include, but are not limited to, mammals, rodents, primates, monkeys (such as macaques, rhesus monkeys, and pig-tailed macaques), humans, dogs, and cats. Pigs, poultry (e.g., chickens), cattle, mice, rabbits, and rats. In these methods, the term "subject" may refer to 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, subjects (including mammals, pigs, dogs, poultry (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) with MDS treatable using the compounds of this disclosure (e.g., crystal forms of the free base or salt of compound 106) include, but are not limited to: MDS treatable 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 Or IRAK1 mutants (e.g., using IRAK1 mutant inhibitors). In some embodiments, treatable MDS includes, but is not limited to: MDS treatable by inhibiting IRAK4 (or its mutations), MDS treatable by inhibiting IRAK1 (or its mutations), or MDS treatable by simultaneously inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations). In some embodiments, treatable MDS includes, but is not limited to: MDS 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 embodiments, treatable MDS is characterized by enhanced IRAK4-Long expression and / or activity relative to IRAK4-Short, and / or theMDS is not driven by FLT3 mutations but expresses IRAK4-Long (based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S, 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 full).

[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., with inversions or translocations, such as MLLT3 / MLL with translocation of chromosomes 9 and 11). 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-associated AML, topoisomerase II). Inhibitor-associated AML, etc.), AML not otherwise classified (using a similar FAB classification system, such as microdifferentiated AML (M0), AML with minimal signs of maturity (M1), mature AML (M2), acute myelomonocytic leukemia (M4), acute monocytic leukemia (M5), acute erythroleukemia (M6), acute megakaryoblastic 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 phenotyped acute leukemia), AML with increased risk due to other hematologic 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 juxtamembranous mutations, etc. (Instructions page 92 / 212)102 CN 121487942 A AML with increased risk due to mutations, including AML with increased risk due to FLT3 intramural 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. In some embodiments, treatable AML includes AML 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 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 embodiments, the treatable 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, the use of the compounds disclosed herein (e.g., the crystal form of the free base or salt of compound 106) is therapeuticSubjects eligible for treatment (including mammals, pigs, dogs, birds (e.g., chickens), cattle, cats, primates, rodents, monkeys, rabbits, mice, rats, and humans) with hematopoietic system cancers including, but not limited to, those treatable by inhibiting (e.g., reducing activity or expression) one or more of the following targets (e.g., MDS, AML, DLBCL, etc., as previously described): FLT3 (e.g., using an FLT3 inhibitor), FLT3 mutant (e.g., using an FLT3 mutant inhibitor), IRAK4 (e.g., using an IRAK4 inhibitor), IRAK4 isoform, IRAK4 mutant (e.g., using an IRAK4 mutant inhibitor), IRAK1 (e.g., using an IRAK1 inhibitor), IRAK1 isoform, 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, intrauterine carcinoma, 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 embodiments, 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 embodiments, combined inhibition of FLT3 with IRAK4, IRAK1, or both can treat patients with FLT3 mutations who may develop resistance to FLT3 inhibitors due to adaptive resistance mechanisms (e.g., driven by IRAK).Inflammatory and autoimmune diseases. In some embodiments, the treatable inflammatory and autoimmune diseases are characterized by enhanced expression and / or activity of IRAK4-Long 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 splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations), treatment may include, but is not limited to, preventive treatment 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); inducing a bodily response to MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); and inhibiting the development or progression of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations). Inhibits or prevents the occurrence of symptoms associated with MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); reduces the severity of MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations); induces MDS (e.g., MDS with splicing factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations). [Installation manual 94 / 212 pages 104 CN 121487942 A]The remission 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 count); remission of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) caused by FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations); prevention of remission of MDS (e.g., MDS with splice factor mutations, MDS with isocitrate dehydrogenase 1 mutations, or MDS with isocitrate dehydrogenase 2 mutations) caused by FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations); prevention of 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). Relapse of MDS (or MDS with isocitrate dehydrogenase 2 mutation). In some implementations, treatment does not include prophylactic treatment for MDS (e.g., prevention or improvement of future MDS).

[0411] Regarding the treatment of hematopoietic system 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 (e.g., ABC DLBCL with MYD88 L265P mutation), follicular lymphoma or marginal zone lymphoma, etc., and combinations thereof), treatment may include, but is not limited to, prophylactic and therapeutic treatment. 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, or combinations thereof; improvement or mitigation of cancers such as acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloma, and non-Hodgkin's lymphoma.Symptoms associated with tumors, 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 associated with 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 It can inhibit the body's response to 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); and inhibit or prevent 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 mutation, follicular lymphoma, or marginal zone lymphoma, and their combinations). It can reduce the severity 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); and cause 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). (Instructions for use 95 / 212 pages 105 CN 121487942 A) Regression of one or more symptoms associated with cancer (such as tumor shrinkage) or other cancer-related symptoms (e.g., large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, or combinations thereof); regression 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, to achieve remission; by preventing or minimizing FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations) that cause 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) Remission of acute myeloid leukemia (AML) caused by FLT3 mutations (e.g., internal tandem repeat mutations or D835Y mutations); prevention of relapse of cancers (e.g., 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), DLBCL MYD88 mutation, follicular lymphoma or marginal zone lymphoma, etc., 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 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, 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 treatments). In some embodiments, 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 using 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 animals or...Human hematopoietic system cancers (e.g., 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, follicular lymphoma, or marginal zone lymphoma, and combinations thereof). Other embodiments include treatment following one or more of the following conditions: having a blood disorder, having myelodysplastic syndrome, having a myeloproliferative disorder, having undergone chemical exposure, exposure to ionizing radiation, or having received 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) comprising a compound of this disclosure (e.g., a free base or a 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 serially administered 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), bone marrow cancer, 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 from subject to subject, 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 a suitable effective dose may be determined under particular 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., a crystalline 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 from 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. For 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, at least one compound of this disclosure (e.g., the crystal form of the free base or salt of compound 106) can be administered to mammals, rodents, mice, rabbits, cats,Effective doses for animals such as 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 embodiments, 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 novel therapies.

[0415] In some embodiments, administration of at least one compound of this disclosure (e.g., the crystal 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. The corresponding primary treatment may include, but is 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 the treatment to the cancer and may limit additional systemic side effects. In other embodiments, the compounds of this disclosure (e.g., the 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., the 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 a subject who has not received the composition.

[0417] In some embodiments, the method may reduce the presence of MDS cells, AML cells, or cancer cells in the subject.Survival biomarkers. In one aspect, the method can reduce survival biomarkers of MDS, AML, and / or cancer cells. The biomarkers 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 form described herein and / or compositions containing the crystal form described herein are used in co...

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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