Crystalline forms of irreversible menin-MLL inhibitor n-[4-[4-(4-morpholinyl)-7h-pyrrolo [2, 3-d] pyrimidin-6-yl] phenyl]-4-[[3 (R)-[(1-oxo-2-propylen-1-yl) amino]-1-piperidinyl] methyl]-2-pyridinecarboxamide for treatment of cancer

Abstract

The present invention relates to crystalline forms of N-[4-[4-(4-morpholinyl)-7H-pyrrolo [2, 3-d] pyrimidin-6-yl] phenyl]-4-[[3 (R)-[(1-oxo-2-propylen-1-yl) amino]-1-piperidinyl] methyl]-2-pyridinecarboxamide (formula (I)). The compounds of formula (I) are irreversible menin-MLL inhibitors for the treatment of, for example, cancer (including, for example, lymphoma and leukemia), as well as autoimmune diseases. Disclosed are crystalline forms characterized by, for example, XRPD, FTIR, DSC, and TGA, as well as pharmacodynamic data. # imgabs0 #

Description

Cross-references

[0001] This application claims and enjoys the benefits of U.S. Provisional Patent Application No. 63 / 235,662 filed on August 20, 2021, U.S. Provisional Patent Application No. 63 / 279,053 filed on November 12, 2021, and U.S. Provisional Patent Application No. 63 / 310,076 filed on February 14, 2022, the contents of each of which are incorporated herein by reference in their entirety. Field of the Invention

[0002] The present invention describes a covalent inhibitor of menin-MLL, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, including stereoisomers, crystalline forms, solvates and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the above covalent inhibitors of menin-MLL interaction and methods of using the above covalent inhibitors of menin-MLL interaction to treat diseases or conditions that would benefit from inhibition of menin-MLL activity. Background of the Invention

[0003] The histone-lysine N-methyltransferase 2 (KMT2) protein family, currently composed of at least five members, methylates lysine 4 on the histone H3 tail in important regulatory regions of the genome, thereby conferring key functions by regulating chromatin structure and DNA accessibility (Morera, Lübbert, and Jung., Clin. Epigenetics 8, 57-(2016)). These enzymes are known to play an important role in regulating gene expression during early development and hematopoiesis (Rao & Dou., Nat. Rev. Cancer 15, 334-346 (2015)).

[0004] The human KMT2 family was originally named the mixed lineage leukemia (MLL) family due to the role of the first discovered member, KMT2A, in this type of disease, and is still commonly referred to as MLL1 or MLL in routine clinical practice.

[0005] KMT2A (MLL1) is often found to be cytogenetically targeted in several types of leukemia (e.g., ALL and AML), and in those cases where balanced chromosomal translocations are found, these often target KMT2A (MLL1) and one of the more than 80 translocation partner genes documented to date (Winters and Bernt, Front. Pediatr. 5, 4 (2017)). These chromosomal abnormalities often result in the formation of fusion genes encoding fusion proteins that are believed to be causally related to the onset and / or progression of the disease. Inhibition of menin may be a promising strategy for the treatment of MLL-related diseases, including leukemia. Summary of the Invention

[0006] The present invention describes covalent inhibitors of menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs and amorphous phases thereof, and methods of use thereof. The present invention also describes pharmaceutically acceptable salts of inhibitors of menin-MLL interaction, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs and amorphous phases thereof, and methods of use thereof. N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide and stereoisomers and pharmaceutically acceptable salts thereof are used in the preparation of a medicament for treating a disease or condition associated with menin-MLL activity. N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is a covalent inhibitor of menin-MLL interaction.

[0007] The present invention also provides a method for preparing a crystalline form of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide. The present invention further describes pharmaceutical compositions comprising the crystalline form and methods of using covalent inhibitors of menin-MLL interactions to treat diseases or conditions, including diseases or conditions in which covalent inhibition of menin-MLL interactions provides a therapeutic benefit to a mammal suffering from the disease or condition.

[0008] In one embodiment, the covalent inhibitor of menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, is the (R)-isomer. In another embodiment, the covalent inhibitor of menin-MLL interaction is the (S)-isomer.

[0009] In a particular embodiment, the covalent inhibitor of the menin-MLL interaction is N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide.

[0010] In one embodiment, the covalent inhibitor of the menin-MLL interaction is anhydrous N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide.

[0011] In another embodiment, the covalent inhibitor of menin-MLL interaction is anhydrous crystalline form of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide.

[0012] In a further embodiment, the covalent inhibitor of the menin-MLL interaction is an anhydrous amorphous form of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide.

[0013] In another embodiment, the covalent inhibitor of menin-MLL interaction is a crystalline hydrate of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide.

[0014] In a further embodiment, the covalent inhibitor of the menin-MLL interaction is an amorphous hydrate of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide.

[0015] In one embodiment, the covalent inhibitor of menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, is the (R)-isomer, which is designated as Compound A. In certain embodiments, Compound A is substantially free of the other enantiomer. In certain embodiments, Compound A is isolated. In certain embodiments, Compound A is in enantiomeric excess.

[0016] In one embodiment, the covalent inhibitor of menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, is the (S)-isomer, which is designated as Compound B. In certain embodiments, Compound B is substantially free of the other enantiomer. In certain embodiments, Compound B is isolated. In certain embodiments, Compound B is in enantiomeric excess. Form A

[0017] In a specific aspect, the present invention describes Form A of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) having at least one of the following properties: (a) with Figure 1A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 10.4±0.1°2θ, 14.7±0.1°2θ, 17.1±0.1°2θ, 21±0.1°2θ, 24.9±0.1°2θ, 29.5±0.1°2θ, and 34.1±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 17.1±0.1°2θ, 21.0±0.1°2θ, 24.9±0.1°2θ, and 29.5±0.1°2θ; (d) a differential scanning calorimetry (DSC) thermogram having an endothermic peak starting at about 234.6°C and peaking at about 245°C; or (e) any combination thereof.

[0018] In some embodiments, Form A is a crystalline form. In some embodiments, Form A is a hydrate.

[0019] In some embodiments, Form A has Figure 1A In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in: XRPD Table A: XRPD pattern of free form Pattern A (Compound A, Form A) serial number angle* d value Net Strength Total Strength Relative Strength 1 3.472° 25.42665A 817.224 988.968 100.0％ 2 10.395° 8.50313A 59.0212 198.748 7.2％ 3 14.717° 6.01444A 65.3863 347.962 8.0％ 4 17.137° 5.17011A 546.417 915.709 66.9％ 5 21.029° 4.22120A 309.975 720.606 37.9％ 6 24.866° 3.57780A 405.254 738.189 49.6％ 7 29.485° 3.02703A 125.412 381.519 15.3％ 8 34.050° 2.63088A 49.0499 244.102 6.0％ *±0.1°

[0020] In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, or 8 of 3.5±0.1°2θ, 10.4±0.1°2θ, 14.7±0.1°2θ, 17.1±0.1°2θ, 21±0.1°2θ, 24.9±0.1°2θ, 29.5±0.1°2θ, and 34.1±0.1°2θ.

[0021] In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 17.1±0.1°2θ, 21.0±0.1°2θ, 24.9±0.1°2θ, and 29.5±0.1°2θ.

[0022] In some embodiments, Form A has a melting temperature of about 245 °C.

[0023] In some embodiments, the thermogravimetric analysis (TGA) thermogram of Form A shows a 1.80% weight loss up to about 200 °C.

[0024] In some embodiments, the DSC thermogram of Form A has an endothermic peak starting at about 234.6 °C and peaking at about 245.0 °C.

[0025] In some embodiments, Form A is hygroscopic. Form B

[0026] In a specific embodiment, the present invention describes Form B of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), which has at least one of the following characteristics: (a) with Figure 2A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, or 8 of 5.9±0.1°2θ, 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ; or (d) combinations thereof.

[0027] In some embodiments, Form B is a crystalline form. In some embodiments, Form B is a hydrate.

[0028] In some embodiments, Form B has Figure 2A In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in: XRPD Table B: XRPD pattern of free form Pattern B (Compound A, Form B) serial number angle* d value Net Strength Total Strength Relative Strength 1 5.925° 14.90443A 40.3324 148.819 7.6％ 2 8.587° 10.28913A 58.2126 208.″167 11.0％ 3 10.522° 8.40127A 58.0415 236.296 10.9％ 4 12.611° 7.01369A 188.498 390.785 35.5％ 5 16.854° 5.25634A 132.691 407.283 25.0％ 6 19.039° 4.65756A 198.523 520.924 37.4％ 7 20.454° 4.33858A 334.602 672.713 63.1％ 8 24.632° 3.61124A 530.528 845.184 100.0％ *±0.1°

[0029] In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.9±0.1°2θ, 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ.

[0030] In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ.

[0031] In some embodiments, the thermogravimetric analysis (TGA) thermogram of Form B shows a 1.350% weight loss up to about 100 °C.

[0032] In some embodiments, Form B is hygroscopic. Form C

[0033] In a specific aspect, the present invention describes Form C of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), which has at least one of the following properties: (a) with Figure 3A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of 5.2±0.1°2θ, 5.9±0.1°2θ, 7.2±0.1°2θ, 8.7±0.1°2θ, 10.6±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.1±0.1°2θ, 15.9±0.1°2θ, 17.5±0.1°2θ, 18.1±0.1°2θ, and 20.1±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.2±0.1°2θ, 5.9±0.1°2θ, 8.7±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.9±0.1°2θ, and 17.5±0.1°2θ; (d) a DSC thermogram having an endothermic peak starting at about 150.23° C. and peaking at about 156.86° C.; or (e) any combination thereof.

[0034] In some embodiments, Form C is a crystalline form. In some embodiments, Form C is a solvate. In some embodiments, Form C is a 2,2,2-trifluoroethanol (TFE) solvate.

[0035] In some embodiments, Form C has Figure 3A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in .

[0036] In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern substantially the same as shown below: XRPD Table C: XRPD pattern of free form Pattern C (Compound A, Form C) serial number angle* d value Net Strength Total Strength Relative Strength 1 5.186° 17.02747A 133.727 225.336 58.9％ 2 5.861° 15.06777A 130.303 222.034 57.4％ 3 7.211° 12.24949A 55.5581 144.593 24..5％ 4 8.657° 10.20582A 139.726 224.000 61.6％ 5 10.554° 8.37575A 54.3884 141.714 24.0％ 6 12.161° 7.27219A 226.948 332.463 100.0％ 7 14.347° 6.16879A 117.349 238.66″1 51.7％ 8 15.054° 5.88057A 115.107 239.909 50.7％ 9 15.857° 5.58433A 155.055 281.563 68.3％ 10 17.464° 5.07388A 125.43·1 248.′146 55.3％ 11 18.107° 4.89517A 110.474 228.981 48.7％ 12 20.068° 4.42109A 105.704 209.415 46.6％ *±0.1°

[0037] In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.2±0.1°2θ, 5.9±0.1°2θ, 7.2±0.1°2θ, 8.7±0.1°2θ, 10.6±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.1±0.1°2θ, 15.9±0.1°2θ, 17.5±0.1°2θ, 18.1±0.1°2θ, and 20.1±0.1°2θ.

[0038] In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.2±0.1°2θ, 5.9±0.1°2θ, 8.7±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.9±0.1°2θ, and 17.5±0.1°2θ.

[0039] In some embodiments, the DSC thermogram of Form C has an endothermic peak starting at about 150.23 °C and peaking at about 156.86 °C.

[0040] In some embodiments, Form C is hygroscopic. Form D

[0041] In a specific aspect, the present invention describes Form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), which has at least one of the following properties: (a) with Figure 4A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of 3.4±0.1°2θ, 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3±0.1°2θ, 15.6±0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 8.7±0.1°2θ, 10.7±0.1°2θ, 15.6±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, and 24.2±0.1°2θ; (d) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 40° C. and 75% relative humidity (RH) for at least one week; (e) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 25° C. and 92% RH for at least one week; (f) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in a sealed container at 60° C. and 75% RH for at least one week; (g) Basically similar to Fig.9A Infrared (IR) spectrum shown; (h) Infrared (IR) spectroscopy ( Fig.9A ) at about 3332cm -1 、About 2853cm -1 、About 1561cm -1 、About 1524cm -1 、About 1319cm -1 、About 1258cm -1 , and about 1067cm -1 A peak appears at (i) Basically similar to Fig.10 Thermogravimetric analysis (TGA) thermogram shown; (j) Basically similar to Fig.11 DSC thermogram shown; (k) a DSC thermogram having an endothermic peak starting at about 260.5° C. and peaking at about 273° C.; (l) Basically similar to Fig.12 shown 1 H NMR (nuclear magnetic resonance) spectroscopy; (m) Hygroscopicity and absorption of approximately 2.1% water observed from 40% RH to 70% RH at 25°C; (n) an aqueous solubility of about 0.004 mg / mL observed at about pH 4.5; or (o) any combination thereof.

[0042] In some embodiments, Form D is a crystalline form.

[0043] In some embodiments, Form D is a hydrate.

[0044] In some embodiments, Form D has Figure 4A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in .

[0045] In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern substantially the same as shown below: XRPD Table D: XRPD pattern of free form Pattern D (Compound A, Form D) serial number angle* d value Net Strength Total Strength Relative Strength 1 3.354° 26.32488A 123.441 290.6 42.8％ 2 5.314° 16.61580A 32.3960 129.144 11.2％ 3 6.986° 12.64352A 59.6702 163.276 20.7％ 4 8.689° 10.16814A 145.824 261.449 50.6％ 5 10.747° 8.22587A 139.539 268.016 48.4％ 6 12.900° 6.85704A 27.2461 166.544 9.4％ 7 14.250° 6.21032A 54.4465 202.156 18.9％ 8 15.632° 566419A 130.038 299.722 45.1％ 9 16.982° 5.21684A 81.8461 276.600 28.4％ 10 18.461° 4.80220A 228.372 444.437 79.2％ 11 19.618° 4.52148A 193.879 421.715 67.2％ 12 21.514° 4.12702A 55.4205 289.294 19.2％ 13 24.150° 3..68223A 288.350 503.268 100.0％ *±0.1°

[0046] In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3±0.1°2θ, 15.6±0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ.

[0047] In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 8.7±0.1°2θ, 10.7±0.1°2θ, 15.6±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, and 24.2±0.1°2θ.

[0048] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 40°C and 75% RH for at least one week.

[0049] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 25°C and 92% RH for at least one week.

[0050] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in a sealed container at 60°C and 75% RH for at least one week.

[0051] In some embodiments, Form D has substantially similar Fig.9A Infrared (IR) spectrum shown.

[0052] In some embodiments, Form D has a peak at about 3332 cm -1 、About 2853cm -1 、About 1561cm -1 、About 1524cm -1 、About 1319cm -1 、About 1258cm -1 , and about 1067cm -1 Infrared (IR) spectrum with a peak at .

[0053] In some embodiments, Form D has a melting temperature of about 272-274 °C.

[0054] In some embodiments, Form D has substantially similar Fig.10 Thermogravimetric analysis (TGA) thermogram shown.

[0055] In some embodiments, Form D has substantially similar Fig.11 DSC thermogram shown.

[0056] In some embodiments, the DSC thermogram of Form D has an endothermic peak starting at about 260.5 °C and peaking at about 273 °C.

[0057] In some embodiments, Form D has substantially similar Fig.12 shown 1 H NMR (nuclear magnetic resonance) spectrum.

[0058] In some embodiments, Form D is hygroscopic.

[0059] In some embodiments, Form D has an aqueous solubility of about 0.004 mg / mL observed at about pH 4.5. Form E

[0060] In a specific aspect, the present invention describes Form E of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), which has at least one of the following properties: (a) with Figure 5AAn X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) At 3.4±0.1°2θ, 4.7±0.1°2θ, 6.3±0.1°2θ, 6.9±0.1°2θ, 7.1±0.1°2θ, 7.6±0.1° 2θ, 8.6±0.1°2θ, 9.3±0.1°2θ, 10.8±0.1°2θ, 12±0.1°2θ, 12.5±0.1°2θ, 13±0.1°2θ , 13.8±0.1°2θ, 15.7±0.1°2θ, 16.2±0.1°2θ, 16.7±0.1°2θ, 17±0.1°2θ, 17.5±0.1° 2θ, 18.4±0.1°2θ, 18.6±0.1°2θ, 19.6±0.1°2θ, 20.7±0.1°2θ, 21.4±0.1°2θ, 22.2± 1, 2, 3, 4, 5 of 0.1°2θ, 23±0.1°2θ, 24.2±0.1°2θ, 25.3±0.1°2θ, 26±0.1°2θ, 28±0.1°2θ, 29.2±0.1°2θ, 30.5±0.1°2θ, 31.6±0.1°2θ, 33.6±0.1°2θ, and 34.5±0.1°2θ. 33, or 34; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.7±0.1°2θ, 7.7±0.1°2θ, 10.8±0.1°2θ, 13.8±0.1°2θ, 17.0±0.1°2θ, 18.4±0.1°2θ, and 18.6±0.1°2θ; (d) a DSC thermogram having an endothermic peak starting at about 112.34° C. and peaking at about 137.26° C.; or (e) any combination thereof.

[0061] In some embodiments, Form E is a crystalline form. In some embodiments, Form E is a DMSO solvate.

[0062] In some embodiments, Form E has Figure 5A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in .

[0063] In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern substantially the same as shown below: XRPD Table E: XRPD pattern of free form Pattern E (Compound A, Form E) *±0.1°

[0064] In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern at 4±0.1°2θ, 4.7±0.1°2θ, 6.3±0.1°2θ, 6.9±0.1°2θ, 7.1±0.1°2θ, 7.6±0.1°2θ, 8.6±0.1°2θ, 9.3±0.1°2θ, 10.8±0.1°2θ, 12±0.1°2θ, 12.5±0.1°2θ, 13±0.1°2θ, 13.8±0.1°2θ, 15.7±0.1°2θ, 16.2±0.1°2θ, 16.7±0.1°2θ, 17±0.1°2θ, 18. 1°2θ, 17.5±0.1°2θ, 18.4±0.1°2θ, 18.6±0.1°2θ, 19.6±0.1°2θ, 20.7±0.1°2θ, 21.4±0.1°2θ, 22.2±0.1°2θ, 23±0.1°2θ, 24.2±0 There are characteristic peaks at .1°2θ, 25.3±0.1°2θ, 26±0.1°2θ, 28±0.1°2θ, 29.2±0.1°2θ, 30.5±0.1°2θ, 31.6±0.1°2θ, 33.6±0.1°2θ, and 34.5±0.1°2θ.

[0065] In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.7±0.1°2θ, 7.7±0.1°2θ, 10.8±0.1°2θ, 13.8±0.1°2θ, 17.0±0.1°2θ, 18.4±0.1°2θ, and 18.6±0.1°2θ.

[0066] In some embodiments, the DSC thermogram of Form E has an endothermic peak starting at about 112.34 °C and peaking at about 137.26 °C.

[0067] In some embodiments, Form E is hygroscopic. Form F

[0068] In a specific aspect, the present invention describes Form F of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), which has at least one of the following properties: (a) with Fig. 6A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) At 4.2±0.1°2θ, 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 12±0.1°2θ, 12.2±0 .1°2θ, 12.5±0.1°2θ, 14.4±0.1°2θ, 15±0.1°2θ, 16±0.1°2θ, 16.8±0.1°2θ, 17. 2±0.1°2θ, 17.5±0.1°2θ, 17.8±0.1°2θ, 18.8±0.1°2θ, 19.2±0.1°2θ, 20.1±0.1 °2θ, 20.5±0.1°2θ, 21.7±0.1°2θ, 22.1±0.1°2θ, 23.4±0.1°2θ, 24.2±0.1°2θ, 2 1, 2, 3, or 4 of 5.3±0.1°2θ, 25.5±0.1°2θ, 26.3±0.1°2θ, 27.1±0.1°2θ, 29±0.1°2θ, 30.3±0.1°2θ, 31.6±0.1°2θ, 33.1±0.1°2θ, 34.3±0.1°2θ, and 35.6±0.1°2θ , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 X-ray powder diffraction (XRPD) pattern with characteristic peaks at ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 11.9±0.1°2θ, 12.2±0.1°2θ, 14.4±0.1°2θ, 15.0±0.1°2θ, and 20.5±0.1°2θ; or (d) combinations thereof.

[0069] In some embodiments, Form F is a crystalline form.

[0070] In some embodiments, Form F is a solvate. In some embodiments, Form F is a heteosolvate. In some embodiments, Form F is a disolvate. In some embodiments, Form F is a MeOH / DCM (1:1) heterosolvate or disolvate.

[0071] In some embodiments, Form F has Fig. 6A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in .

[0072] In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern substantially the same as shown below: XRPD Table F: XRPD pattern of free form Pattern F (Compound A, Form F) *±0.1°

[0073] In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern at 4.2±0.1°2θ, 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 12±0.1°2θ, 12.2±0.1°2θ, 12.5±0.1°2θ, 14.4±0.1°2θ, 15±0.1°2θ, 16±0.1°2θ, 16.8±0.1°2θ, 17.2±0.1°2θ, 17.5±0.1°2θ, 17.8±0.1°2θ, 18.8±0.1°2θ, 19.2±0.1°2θ, 20. .1°2θ, 20.1±0.1°2θ, 20.5±0.1°2θ, 21.7±0.1°2θ, 22.1±0.1°2θ, 23.4±0.1°2θ, 24.2±0.1°2θ, 25.3±0.1°2θ, 25.5±0.1°2θ There are characteristic peaks at , 26.3±0.1°2θ, 27.1±0.1°2θ, 29±0.1°2θ, 30.3±0.1°2θ, 31.6±0.1°2θ, 33.1±0.1°2θ, 34.3±0.1°2θ, and 35.6±0.1°2θ.

[0074] In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 11.9±0.1°2θ, 12.2±0.1°2θ, 14.4±0.1°2θ, 15.0±0.1°2θ, and 20.5±0.1°2θ.

[0075] In some embodiments, Form F is hygroscopic. Form G

[0076] In a specific aspect, the present invention describes Form G of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), which has at least one of the following properties: (a) with Fig. 7AAn X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, or 6 of 8±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ; or (d) combinations thereof.

[0077] In some embodiments, Form G is a crystalline form. In some embodiments, Form G is a TFE solvate.

[0078] In some embodiments, Form G has Fig. 7A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in .

[0079] In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern substantially the same as shown below: XRPD Table G: XRPD pattern of free form Pattern G (Compound A, Form G) *±0.1°

[0080] In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, or 6 of 8.1±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ.

[0081] In some embodiments, Form G is hygroscopic. Form J

[0082] In a specific aspect, the present invention describes Form J of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), which has at least one of the following properties: (a) with Fig. 8AAn X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) At 3.5±0.1°2θ, 4.5±0.1°2θ, 6.4±0.1°2θ, 8.7±0.1°2θ, 10.2±0.1°2θ, 11.3±0.1°2θ, 11.8±0.1°2θ, 13.2± 0.1°2θ, 13.6±0.1°2θ, 14±0.1°2θ, 14.6±0.1°2θ, 15.4±0.1°2θ, 16.1±0.1°2θ, 16.6±0.1°2θ, 16.9±0.1°2θ, 1 7.2±0.1°2θ, 18.3±0.1°2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, 20.8±0.1°2θ, 21.6±0.1°2θ, 23.5±0.1°2θ, 23.8±0 .1°2θ, 24.6±0.1°2θ, 24.9±0.1°2θ, 25.2±0.1°2θ, 25.8±0.1°2θ, 26.2±0.1°2θ, 26.7±0.1°2θ, 26.8±0.1°2θ, 27.4±0.1°2θ, 27.7±0.1°2θ, 28.7±0.1°2θ, 29.3±0.1°2θ, 30.1±0.1°2θ, 31.2±0.1°2θ, 31.8±0.1°2θ, 34.1± 1, 2, 3 of 0.1°2θ, 34.9±0.1°2θ, 35.6±0.1°2θ, 36.4±0.1°2θ, 36.7±0.1°2θ, 38.5±0.1°2θ, and 38.8±0.1°2θ, an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44 positions; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 4.5±0.1°2θ, 19.1±0.1°2θ, 21.6±0.1°2θ, 22.5±0.1°2θ, and 27.4±0.1°2θ; (d) Hygroscopicity and absorption of about 2.1% water observed from 40% RH to 70% RH at 25°C; (e) an aqueous solubility of about 0.004 mg / mL observed at about pH 4.5; or (f) combinations thereof.

[0083] In some embodiments, Form J is a crystalline form. In some embodiments, Form J is an anhydrate.

[0084] In some embodiments, Form J has Fig. 8A The X-ray powder diffraction (XRPD) pattern is substantially the same as shown in .

[0085] In some embodiments, Form J has an X-ray powder diffraction (XRPD) pattern at 3.5 ± 0.1 ° 2θ, 4.5 ± 0.1 ° 2θ, 6.4 ± 0.1 ° 2θ, 8.7 ± 0.1 ° 2θ, 10.2 ± 0.1 ° 2θ, 11.3 ± 0.1 ° 2θ, 11.8 ± 0.1 ° 2θ, 13.2 ± 0.1 ° 2θ, 13.6 ± 0.1 ° 2θ, 14 ± 0.1 ° 2θ, θ, 14.6±0.1°2θ, 15.4±0.1°2θ, 16.1±0.1°2θ, 16.6±0.1°2θ, 16.9±0.1°2θ, 17.2±0. 1°2θ, 18.3±0.1°2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, 20.8±0.1°2θ, 21.6±0.1°2θ, 23.5± 0.1°2θ, 23.8±0.1°2θ, 24.6±0.1°2θ, 24.9±0.1°2θ, 25.2±0.1°2θ, 25.8±0.1°2θ, 26 .2±0.1°2θ, 26.7±0.1°2θ, 26.8±0.1°2θ, 27.4±0.1°2θ, 27.7±0.1°2θ, 28.7±0.1°2θ, There are characteristic peaks at 29.3±0.1°2θ, 30.1±0.1°2θ, 31.2±0.1°2θ, 31.8±0.1°2θ, 34.1±0.1°2θ, 34.9±0.1°2θ, 35.6±0.1°2θ, 36.4±0.1°2θ, 36.7±0.1°2θ, 38.5±0.1°2θ, and 38.8±0.1°2θ.

[0086] In some embodiments, Form J has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 4.5±0.1°2θ, 19.1±0.1°2θ, 21.6±0.1°2θ, 22.5±0.1°2θ, and 27.4±0.1°2θ.

[0087] In some embodiments, Form J is hygroscopic. preparation

[0088] In another aspect, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) from about 50 wt % to about 80 wt % of one or more diluents; (c) from about 1 wt % to about 10 wt % of one or more disintegrants; (d) from about 0.2 wt % to about 3 wt % of one or more glidants; and (e) from about 0.2 wt % to about 1.0 wt % of one or more lubricants.

[0089] In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphates, calcium sulfates, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the glidant is pregelatinized corn starch and lactose. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as cross-linked polyvinyl pyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is cross-linked polyvinyl pyrrolidone. In some embodiments, the glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, starch, and talc. In some embodiments, the glidant is fumed silica. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

[0090] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 mg to about 500 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) pregelatinized corn starch and lactose in a total amount of about 20 wt % to about 80 wt %; (c) from about 3 wt % to about 10 wt % of crospovidone; (d) from about 0.1 wt % to about 1.0 wt % fumed silica; and (e) from about 0.1 wt % to about 1.0 wt % magnesium stearate.

[0091] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) a total amount of about 70 wt % to about 80 wt % of pregelatinized corn starch and lactose; (c) from about 3 wt % to about 10 wt % of crospovidone; (d) from about 0.1 wt % to about 1.0 wt % fumed silica; and (e) from about 0.1 wt % to about 1.0 wt % magnesium stearate.

[0092] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 wt % to about 30 wt % of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) from about 25 wt % to about 65 wt % pregelatinized corn starch and from about 25 wt % to about 40 wt % lactose; (c) from about 1 wt % to about 10 wt % of crospovidone; (d) from about 0.1 wt % to about 1.0 wt % fumed silica; and (e) from about 0.1 wt % to about 1.0 wt % magnesium stearate.

[0093] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 wt % to about 25 wt % of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 25 wt % to about 60 wt % pregelatinized corn starch and about 25 wt % to about 40 wt % lactose; (c) from about 1 wt % to about 10 wt % of crospovidone; (d) from about 0.1 wt % to about 1.0 wt % fumed silica; and (e) from about 0.1 wt % to about 1.0 wt % magnesium stearate.

[0094] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 25, 50, 100, 150, 200, or 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 37 wt % pregelatinized corn starch (Starch 1500); (c) about 36% lactose (FastFlo Lactose 316); (d) about 5 wt % of crospovidone; (e) about 1 wt % fumed silica; and (f) about 0.5 wt % magnesium stearate.

[0095] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 25, 50, 100, 150, 200, or 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 52 wt % pregelatinized corn starch (Starch 1500); (c) about 27% lactose (FastFlo Lactose 316); (d) about 4 wt % of crospovidone; (e) about 0.8 wt % fumed silica; and (f) about 0.4 wt % magnesium stearate.

[0096] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 25, 50, 100, 150, 200, or 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 21 wt % pregelatinized corn starch (Starch 1500); (c) about 37% lactose (FastFlo Lactose 316); (d) about 5 wt % of crospovidone; (e) about 1 wt % fumed silica; and (f) about 0.5 wt % magnesium stearate.

[0097] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 25, 50, 100, 150, 200, or 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 28 wt % pregelatinized corn starch (Starch 1500); (c) about 27% lactose (FastFlo Lactose 316); (d) about 4 wt % of crospovidone; (e) about 0.8 wt % fumed silica; and (f) about 0.4 wt % magnesium stearate.

[0098] In certain embodiments, the pharmaceutical preparation is substantially homogeneous. In certain embodiments, the pharmaceutical preparation is granular. In certain embodiments, the intragranular composition is a composition according to one of the above embodiments. In certain embodiments, the extragranular composition comprises pregelatinized corn starch, such as Starch 1500.

[0099] In some embodiments, the diluent is selected from the group consisting of: lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphates, calcium sulfates, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is pregelatinized corn starch and lactose. In some embodiments, the disintegrant is selected from the group consisting of: natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as cross-linked polyvinyl pyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is cross-linked polyvinyl pyrrolidone. In some embodiments, the glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, starch, and talc. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

[0100] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 mg to about 250 mg of crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 70 wt % to about 80 wt % pregelatinized corn starch and lactose; (c) about 5 wt % of crospovidone; (d) about 0.5 wt% to 1 wt% fumed silica; and (e) about 0.2 wt% to 0.5 wt% magnesium stearate.

[0101] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 wt % to about 25 wt % of crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 70 wt % to about 80 wt % pregelatinized corn starch and lactose; (c) about 5 wt % of crospovidone; (d) about 0.5 wt% to 1 wt% fumed silica; and (e) about 0.2 wt% to 0.5 wt% magnesium stearate.

[0102] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 25 mg of crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 70 wt % to about 80 wt % pregelatinized corn starch and lactose; (c) about 5 wt % of crospovidone; (d) about 0.5 wt% to 1 wt% fumed silica; and (e) about 0.2 wt% to 0.5 wt% magnesium stearate.

[0103] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 100 mg of crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 70 wt % to about 80 wt % pregelatinized corn starch and lactose; (c) about 5 wt % of crospovidone; (d) about 0.5 wt% to 1 wt% fumed silica; and (e) about 0.2 wt% to 0.5 wt% magnesium stearate.

[0104] In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form A. In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form B. In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form C. In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form D. In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form E. In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form F. In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form G. In some embodiments of the above pharmaceutical formulation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form J.In some embodiments of the aforementioned pharmaceutical preparation embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, Form F, Form G, and Form J. In another embodiment of the aforementioned pharmaceutical preparation embodiments provided by the present invention, it is a pharmaceutical preparation, wherein the dosage form is a hard gelatin capsule.

[0105] In another aspect, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline Form A; (b) from about 50 wt % to about 80 wt % of one or more diluents; (c) from about 1 wt % to about 10 wt % of one or more disintegrants; (d) from about 0.2 wt % to about 3 wt % of one or more glidants; and (e) from about 0.2 wt % to about 1.0 wt % of one or more lubricants.

[0106] In some embodiments, the diluent is selected from the group consisting of: lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphates, calcium sulfates, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of: natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as cross-linked polyvinyl pyrrolidone, sodium alginate, clay, and gum. In some embodiments, the disintegrant is cross-linked sodium carboxymethyl cellulose. In some embodiments, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and waxes. In some embodiments, the lubricant is magnesium stearate.

[0107] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline Form D; (b) about 70 wt % to about 80 wt % pregelatinized corn starch and lactose; (c) about 5 wt % of crospovidone; (d) about 0.5 wt% to 1 wt% fumed silica; and (e) about 0.2 wt% to 0.5 wt% magnesium stearate.

[0108] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 wt % to about 25 wt % of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline Form D; (b) about 37.2 wt % pregelatinized corn starch and about 35.6 wt % lactose; (c) about 5 wt % of crospovidone; (d) about 1 wt % fumed silica; and (e) about 0.5 wt % magnesium stearate.

[0109] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) about 10 wt % to about 25 wt % of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline Form D; (b) about 52 wt % pregelatinized corn starch and about 27.3 wt % lactose; (c) about 3.8 wt % of crospovidone; (d) about 0.8 wt % fumed silica; and (e) about 0.4 wt % magnesium stearate.

[0110] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) 25 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline form D; (b) about 45.2 mg of pregelatinized corn starch and about 43.44 mg of lactose; (c) about 6.1 mg of crospovidone; (d) about 1.2 mg of fumed silica; and (e) about 0.61 mg of magnesium stearate.

[0111] In some embodiments, the present invention provides a pharmaceutical formulation for oral administration comprising: (a) 100 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline form D; (b) about 330.6 mg of pregelatinized corn starch and about 173.8 mg of lactose; (c) about 24.3 mg of crospovidone; (d) about 4.9 mg of fumed silica; and (e) about 2.4 mg of magnesium stearate.

[0112] In another aspect, the present invention provides a pharmaceutical formulation comprising: a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; b) about 50 wt % to about 80 wt % of one or more diluents; c) about 1 wt % to about 10 wt % of a disintegrant; d) about 0.2 wt % to about 3 wt % of a glidant; and e) about 0.2 wt % to about 1.0 wt % of a lubricant; wherein the formulation is in unit dosage form in a bottle or blister pack. In certain embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil. In some embodiments, the present invention provides a pharmaceutical formulation comprising: (a) 25 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 37.2 wt % pregelatinized corn starch and about 35.6 wt % lactose; (c) about 5 wt % of crospovidone; (d) about 1 wt % fumed silica; and (e) about 0.5 wt % magnesium stearate. Wherein the formulation is in the form of a unit dose in a bottle or blister pack. In certain embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil. In some embodiments, the present invention provides a pharmaceutical formulation comprising: a) 100 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 330.6 mg of pregelatinized corn starch and about 173.8 mg of lactose; (c) about 24.3 mg of crospovidone; (d) about 4.9 mg of fumed silica; and (e) about 2.4 mg of magnesium stearate. Wherein the formulation is in the form of a unit dose in a bottle or a blister pack. In certain embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil.

[0113] In another embodiment, the present invention provides a package comprising one or more separate blister pockets, wherein each blister pocket contains a unit dosage form comprising: a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) from about 50 wt % to about 80 wt % of one or more diluents; (c) from about 1 wt % to about 10 wt % of one or more disintegrants; (d) from about 0.2 wt % to about 3 wt % of one or more glidants; and (e) from about 0.2 wt % to about 1.0 wt % of one or more lubricants. Each blister pack contains a metal or plastic foil.

[0114] In another aspect, the present invention provides a pharmaceutical formulation comprising: a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline Form A; (b) from about 50 wt % to about 80 wt % of one or more diluents; (c) from about 1 wt % to about 10 wt % of one or more disintegrants; (d) from about 0.2 wt % to about 3 wt % of one or more glidants; and (e) from about 0.2 wt % to about 1.0 wt % of one or more lubricants. Wherein the formulation is in the form of a unit dose in a bottle or blister pack. In certain embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil. In some embodiments, the present invention provides a pharmaceutical formulation comprising: a) 25 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 37.2 wt % pregelatinized corn starch and about 35.6 wt % lactose; (c) about 5 wt % of crospovidone; (d) about 1 wt % fumed silica; and (e) about 0.5 wt % magnesium stearate. Wherein the formulation is in the form of a unit dose in a bottle or blister pack. In certain embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil. In some embodiments, the present invention provides a pharmaceutical formulation comprising: a) 100 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 52 wt % pregelatinized corn starch and about 27.3 wt % lactose; (c) about 3.8 wt % of crospovidone; (d) about 0.8 wt % fumed silica; and (e) about 0.4 wt % magnesium stearate. Wherein the formulation is in the form of a unit dose in a bottle or a blister pack. In certain embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil.

[0115] In another embodiment, the present invention provides a package comprising one or more separate blister pockets, wherein each blister pocket contains a unit dosage form comprising: a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline Form A; (b) from about 50 wt % to about 80 wt % of one or more diluents; (c) from about 1 wt % to about 10 wt % of one or more disintegrants; (d) from about 0.2 wt % to about 3 wt % of one or more glidants; and (e) from about 0.2 wt % to about 1.0 wt % of one or more lubricants. Each blister pack contains a metal or plastic foil.

[0116] In one embodiment, the present invention provides a kit containing a plurality of oral dosage forms, such as tablets or capsules; packaging, such as a jar containing the oral dosage form; and instructions for use of the oral dosage form according to the method of the present invention. Unit dose packaging (e.g., blister packaging) provides a useful way to package oral dosage forms of the formulation of the present invention, and in other embodiments, when combined with instructions for use, is embodied as a kit. In other embodiments, detailed product information is contained in the instructions for use in the kit. Blister packaging is particularly suitable for solid oral dosage forms, and in further embodiments, for example, for alternate day dosing regimens. In one embodiment, the solid unit dosage form of the formulation of the present invention is contained in a blister package, with instructions for daily administration of one or more tablets or capsules, so that the dosage of the formulation of the present invention is fully administered. In another embodiment, the solid unit dosage form is contained in a blister package, with instructions for alternating daily administration of one or more tablets or capsules, so that the daily dose is fully administered.

[0117] In one aspect, the present invention provides methods of treating a patient by administering Compound A. In some embodiments, the present invention provides methods of inhibiting menin-MLL interactions in a mammal or treating a disease, disorder or condition in a mammal that would benefit from inhibition of menin-MLL interactions, comprising administering to the mammal a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0118] In another aspect, the invention provides the use of Compound A for inhibiting menin-MLL interaction or for treating a disease, disorder or condition that would benefit from inhibition of menin-MLL interaction.

[0119] On the other hand, the present invention provides the use of Compound A for treating KRAS mutant cancer in mammals. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the KRAS mutation is a KRAS G12 mutation. In certain embodiments, the KRAS mutation is a KRAS G12C, G12V, G13D, or G12D mutation. In certain embodiments, the KRAS mutation is a G12C mutation. In certain embodiments, the KRAS mutation is a G12V mutation. In certain embodiments, the KRAS mutation is a G13D mutation. In certain embodiments, the KRAS mutation is a G12D mutation. In certain embodiments, Compound A is in a form or pharmaceutical formulation as described elsewhere herein.

[0120] In another aspect, the present invention provides the use of Compound A for treating cancer in a mammal (eg, a human patient) that does not exhibit a KRAS mutation.

[0121] On the other hand, the present invention provides the use of Compound A for treating diffuse large B-cell lymphoma in a mammal (e.g., a human patient). In certain embodiments, the mammal suffers from triple-hit lymphoma. In certain embodiments, the mammal suffers from double expresser lymphoma. In certain embodiments, the mammal suffers from multiple myeloma. In certain embodiments, Compound A is in a form or pharmaceutical preparation as described elsewhere herein.

[0122] In certain embodiments, Compound A is in crystalline Form D.

[0123] In certain embodiments, the mammal (eg, patient) has double hit lymphoma (DHL). In certain embodiments, the mammal (eg, patient) has triple hit lymphoma (THL).

[0124] In certain embodiments, the mammal (eg, patient) has Double Expressor Lymphoma (DEL).

[0125] In another aspect, the present invention provides the use of Compound A for treating diffuse multiple myeloma in a mammal (eg, a human patient). In certain embodiments, Compound A is in a form or pharmaceutical formulation as described elsewhere herein.

[0126] In some embodiments, crystalline Compound A is administered to a human.

[0127] In some embodiments, crystalline Compound A is administered orally.

[0128] In other embodiments, crystalline Compound A is used to formulate a medicament that inhibits menin-MLL interaction. In some other embodiments, crystalline Compound A is used to formulate a medicament that inhibits menin-MLL interaction.

[0129] On the one hand, the present invention provides a method for treating cancer in a mammal, comprising administering to the mammal a pharmaceutical composition of the present invention further comprising compound A. In some embodiments, the cancer is a B-cell malignancy. In some embodiments, the cancer is a B-cell malignancy selected from chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is acute lymphocytic leukemia (ALL). In some embodiments, the mammal or subject has MLL / KMT2A gene rearrangement. In some embodiments, the mammal or subject has ATM mutation. In some embodiments, the mammal or subject has NPM1 mutation. In some embodiments, the mammal or subject has TP53 mutation. In some embodiments, the mammal or subject has NOTCH1 mutation. In some embodiments, the mammal or subject has WT1 mutation. In some embodiments, the mammal or subject has RAS mutation. In some embodiments, the mammal or subject has a KRAS mutation. In some embodiments, the mammal or subject has a KRASG12C mutation. In some embodiments, the mammal or subject has a KRAS G12D mutation. In some embodiments, the mammal or subject has a KRAS G12V mutation. In some embodiments, the mammal or subject has a KRAS G13D mutation. In some embodiments, the mammal or subject has a TET2 mutation. In some embodiments, the mammal or subject has MYC amplification. In some embodiments, the mammal or subject has a chromosome 13 deletion karyotype (del (13q) karyotype). In some embodiments, the mammal or subject has a chromosome 12 trisomy karyotype (trisomy 12karyotype). In some embodiments, the cancer is a lymphoma, a leukemia, or a solid tumor. In some embodiments, the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, burkitt lymphoma / leukemia, or lymphomatoid granulomatosis.In some embodiments, when a mammal or subject has cancer, an anticancer agent is administered to the mammal or subject in addition to one of the above compounds or embodiments. In one embodiment, the anticancer agent is an inhibitor of mitogen-activated protein kinase signaling.

[0130] In one aspect, the present invention provides a method for treating an inflammatory disease or an autoimmune disease in a mammal, comprising administering to the mammal a pharmaceutical composition of the present invention comprising Compound A. In some embodiments, the inflammatory disease is asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, suppurative hidradenitis, laryngitis, mastitis, meningitis, spinal cord inflammation ...encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, encephalitis, enceph Myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. In some embodiments, the autoimmune disease is inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome ( syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease disease), chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvar pain.

[0131] The present invention provides an article of manufacture comprising packaging material, compound A within the packaging material, and a label indicating that compound A is used to inhibit menin-MLL activity.

[0132] In a further aspect, the present invention provides a method for treating an autoimmune disease in a mammal, comprising administering Compound A to the mammal.

[0133] In a further aspect, the present invention provides a method of treating a heteroimmune disease or disorder in a mammal comprising administering Compound A to said mammal.

[0134] In a further aspect, the present invention provides a method of treating an inflammatory disease in a mammal, comprising administering Compound A to the mammal.

[0135] In a further aspect, the present invention provides a method of treating cancer in a mammal, comprising administering Compound A to said mammal.

[0136] In a further aspect, the present invention provides a method for treating a thromboembolic disorder in a mammal, comprising administering to the mammal Compound A. The thromboembolic disorder includes, but is not limited to, myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass grafting, restenosis after aortocoronary bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, or deep vein thrombosis.

[0137] In another aspect, the present invention provides a method for treating inflammation, comprising administering an effective amount of Compound A to the mammal at least once.

[0138] In a further aspect, the present invention provides a method for treating cancer, comprising administering to the mammal at least once an effective amount of Compound A. The type of cancer may include, but is not limited to, pancreatic cancer, colorectal cancer, non-small cell lung cancer, and other solid tumors or blood tumors.

[0139] On the other hand, the present invention provides a method for treating a respiratory disease, comprising administering an effective amount of Compound A to the mammal at least once. In a further embodiment of this aspect, the respiratory disease is asthma. In a further embodiment of this aspect, the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, and seasonal asthma.

[0140] In another aspect, the present invention provides a method for preventing rheumatoid arthritis and / or osteoarthritis, comprising administering an effective amount of Compound A to the mammal at least once.

[0141] In another aspect, the present invention provides a method for treating skin inflammatory reactions, comprising administering an effective amount of Compound A to the mammal at least once. Such skin inflammatory reactions include, for example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scars. In another aspect, the present invention provides a method for reducing psoriatic lesions of the skin, joints, or other tissues or organs, comprising administering an effective amount of Compound A to the mammal.

[0142] In any of the foregoing aspects, the invention provides further embodiments wherein Compound A is administered: (a) systemically to a mammal; (b) orally to a mammal; (c) intravenously to a mammal; (d) by inhalation; (e) by nasal administration; (f) by injection to a mammal; (g) topically (i.e., transdermally) to a mammal; (h) by ophthalmic administration; or (i) rectally to a mammal.

[0143] In any of the foregoing aspects, the invention provides further embodiments comprising a single administration of Compound A, including further embodiments wherein Compound A is administered: (i) multiple times over the course of a day; (ii) continuously; or (iii) continuously.

[0144] In any of the foregoing aspects, it is a further embodiment comprising multiple administrations of Compound A, including further embodiments wherein Compound A is administered in the following manner: (i) Compound A is administered as a single dose; (ii) the time between multiple administrations is every 6 hours; and (iii) Compound A is administered to the mammal every 8 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of Compound A is suspended or the dose of Compound A administered is temporarily reduced. In certain embodiments, at the end of the drug holiday, administration of Compound A is resumed. The length of the drug holiday may vary from 2 days to 1 year.

[0145] In some embodiments related to any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), Compound A, or a pharmaceutically acceptable salt or solvate thereof, is optically pure (i.e., the chiral purity determined by HPLC is greater than 99%). In some embodiments related to any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), Compound A, or a pharmaceutically acceptable salt or solvate thereof, is replaced by: a) Compound A, or a pharmaceutically acceptable salt or solvate thereof, of lower chiral purity; b) N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(

[0066] The invention relates to a pharmaceutically acceptable salt or solvate thereof comprising the following: c) racemic N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, or a pharmaceutically acceptable salt or solvate thereof; or b) racemic N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, or a pharmaceutically acceptable salt or solvate thereof.

[0146] In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), amorphous Compound A is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form A) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form B) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form C) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form D) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form E) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form F) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form G) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form J) is used.

[0147] In any specific embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form D) is used.

[0148] In some embodiments related to any embodiment disclosed in the present invention (including methods, uses, formulations, combination therapies, etc.), Compound A or a pharmaceutically acceptable salt thereof is replaced by an active metabolite of Compound A. In some embodiments, the active metabolite is in a crystalline form. In some embodiments, the active metabolite is in an amorphous phase. In a further embodiment, the metabolite is separated. In some embodiments related to any embodiment disclosed in the present invention (including methods, uses, formulations, combination therapies, etc.), Compound A or a pharmaceutically acceptable salt thereof is replaced by a prodrug of Compound A, or a deuterated analog of Compound A, or a pharmaceutically acceptable salt thereof. In a specific embodiment, Compound A is in crystalline form D.

[0149] Other purposes, features and advantages of the methods and compositions described in the present invention will become apparent from the following detailed description of the invention. However, it should be understood that the detailed description of the invention and the specific examples, although indicating specific embodiments, are given only by way of illustration, because various changes and modifications within the spirit and scope of the present invention will be apparent to those skilled in the art. The section headings used in the present invention are only for organizational purposes and should not be interpreted as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals and papers, are hereby expressly incorporated by reference in their entirety for any purpose. Incorporation by Reference

[0150] All publications and patent application publications mentioned in this specification are incorporated herein by reference to the extent applicable and relevant. BRIEF DESCRIPTION OF THE DRAWINGS

[0151] Figure 1A An X-ray powder diffraction (XRPD) pattern of Form A is shown.

[0152] Figure 2A The X-ray powder diffraction (XRPD) pattern of Form B is shown.

[0153] Figure 3A An X-ray powder diffraction (XRPD) pattern of Form C is shown.

[0154] Figure 4A The X-ray powder diffraction (XRPD) pattern of Form D is shown.

[0155] Figure 5A The X-ray powder diffraction (XRPD) pattern of Form E is shown.

[0156] Fig. 6A An X-ray powder diffraction (XRPD) pattern of Form F is shown.

[0157] Fig. 7A An X-ray powder diffraction (XRPD) pattern of Form G is shown.

[0158] Fig. 8A An X-ray powder diffraction (XRPD) pattern of Form J is shown.

[0159] Fig.9A An infrared (IR) spectrum of the free form Model D is provided.

[0160] Fig.10 A thermogravimetric analysis (TGA) thermogram of Form D is shown.

[0161] Fig.11 The DSC thermogram of Form D is shown.

[0162] Fig.12 The NMR spectrum of Form D is shown.

[0163] Fig.13 An XRPD pattern of pattern D is shown.

[0164] Fig.14 The TGA thermogram of Pattern D after drying at 50° C. for 3 hours (ie, Pattern D-Drying) is shown.

[0165] Fig.15 The DSC thermogram of mode D after drying at 50° C. for 3 hours (ie, mode D-drying) is shown.

[0166] Fig.16 The results of pattern D after drying at 50°C for 3 hours are shown. 1 H NMR spectrum (ie, mode D-dry).

[0167] Fig.17 A PLM photograph of free form Pattern D after drying at 50° C. for 3 hours (ie, Pattern D-Drying) is shown.

[0168] Fig.18 An XRPD pattern of Pattern D (ie, Pattern D-THF-water-dry) is shown.

[0169] Fig.19 A TGA thermogram of Mode D (ie, Mode D-THF-water-dry) is shown.

[0170] Fig. 20 The DSC thermogram of Mode D (ie, Mode D-THF-water-dry) is shown.

[0171] Fig.21 The results of mode D (i.e., mode D-THF-water-drying) are shown. 1 H NMR spectrum.

[0172] Fig. 22 Shown is an XRPD overlay of Mode D (50 mg) after 10 minutes of milling simulation experiment.

[0173] Fig.23 Shown is the mDSC thermogram of mode D (50 mg) after 10 minutes of grinding simulation experiment.

[0174] Fig.24 Shown is an XRPD overlay of pattern D (600 mg) after 10 minutes of milling simulation experiment.

[0175] Fig.25 Shown is the mDSC thermogram of Mode D (600 mg) after 10 minutes of grinding simulation experiment.

[0176] Fig.26 Shown is an XRPD overlay of mode D (2g) after 10 minutes of milling simulation experiment.

[0177] Fig. 27 Shown is the mDSC thermogram of mode D (2 g) after 10 minutes of grinding simulation experiment.

[0178] Fig.28A The cohorts, groups, dose escalation and dose expansion strategies of the Phase 1 clinical trial are shown.

[0179] Fig.28B Shown are the antiproliferative effects and effective cell killing rates of representative DLBCL cell lines treated with Compound A or PS-341 at 8 dose concentrations ranging from 0.005 μM to 10 μM after 4 days of treatment in DHL (DB, Toledo, DOHH2), THL (VAL), DEL (U2932), and GCB (SUDH8L) DLBCL subtypes.

[0180] Fig.28C Shown are the antiproliferative effects and cell lethality of representative MM cell lines treated with Compound A or PS-341 at eight dose concentrations ranging from 0.005 μM to 10 μM in MM1.R, JJN3, SKMM1 and SKMM2 cell lines after 4 days of treatment.

[0181] Fig.28D Shown are relative viabilities of patient-derived DLBCL triple hit lymphoma (THL) and MYC amplified PDX samples treated with Compound A or a clinically reversible menin inhibitor after 6 days of treatment.

[0182] Fig.28E Shown is the inhibition of cell proliferation of bone marrow mononuclear cells (BMMCs) derived from newly diagnosed (A, B) and relapsed / refractory (R / R) (C, D) MM patients after 6 days of treatment with Compound A or PS-341.

[0183] Fig.28F Compound A is shown to reduce menin protein in DLBCL cells.

[0184] Fig.29 A shows that Compound A induces cell killing of the KRAS G12C cell line.

[0185] Fig.29 B shows the changes in gene expression of KRAS and MEN1 KRAS mutant cell lines.

[0186] Fig.29 C shows that compound A inhibits the growth of KRAS mutant cells in vitro.

[0187] Fig. 30A Shown are the percentage (%) growth inhibition of ex vivo PDX tissues.

[0188] Fig. 30B Ex vivo PDX tissue dose response curves are shown.

[0189] Fig.31 It was shown that Compound A caused a >90% reduction in BCL2 transcript at 24 hours post-treatment in MOLM-13 AML cells.

[0190] Figures 32A and 32B show growth inhibition of patient-derived CLLPDX samples treated with Compound A or a clinically reversible menin inhibitor after 6 days of treatment, arranged by genetic background (A) or Rai-Binet stage (B) where data were available.

[0191] Figure 32C shows dose response curves for CLL PDX samples treated with Compound A or a clinically reversible menin inhibitor, which exhibited clinical features of progression after prior treatment with bendamustine and showed high sensitivity to Compound A with >98.5% cell lethality.

[0192] FIG32D shows dose response curves of CLL PDX samples treated with Compound A or a clinically reversible menin inhibitor, which exhibited clinical features of progression after prior treatment with ibrutinib and showed high sensitivity to Compound A with >98.5% cell lethality.

[0193] FIG32E shows dose response curves of CLL PDX samples treated with Compound A or a clinically reversible menin inhibitor, which exhibited clinical features of progression after prior treatment with ibrutinib and venetoclax and showed high sensitivity to Compound A with >98.5% cell lethality.

[0194] Fig.33 Compound P, a covalent inhibitor of the menin-MLL interaction, is shown. DETAILED DESCRIPTION OF THE INVENTION

[0195] The diverse roles played by the menin-MLL interaction in various hematopoietic cell functions suggest that small molecule inhibitors of the menin-MLL interaction, such as Compound A, may be useful for reducing the risk of or treating a variety of diseases that are affected by or affect many cell types of the hematopoietic lineage, including, for example, autoimmune diseases, heteroimmune disorders or diseases, inflammatory diseases, cancer (e.g., B-cell proliferative disorders), and thromboembolic diseases.

[0196] In some embodiments, Compound A can be used to treat autoimmune diseases in mammals, including, but not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease disease), chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvar pain.

[0197] In some embodiments, Compound A can be used to treat a heteroimmune disease or disorder in a mammal, including, but not limited to, graft-versus-host disease, transplantation, infusion, anaphylaxis, allergy (e.g., to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0198] In some embodiments, Compound A can be used to treat inflammatory diseases in mammals, including but not limited to asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, suppurative hidradenitis, Laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0199] In other embodiments, the methods described herein can be used to treat cancer, such as B-cell proliferative disorders, including, but not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

[0200] In further embodiments, the methods described herein can be used to treat thromboembolic disorders including, but not limited to, myocardial infarction, angina pectoris (including unstable angina), reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass grafting, restenosis after aortocoronary bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorders, pulmonary embolism, and deep vein thrombosis. Hematologic malignancies

[0201] In certain embodiments, the present invention discloses a method of treating a hematological malignancy in an individual in need thereof, comprising administering an amount of Compound A to the individual.

[0202] In some embodiments, the hematological malignancy is non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL or non-CLL / SLL lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma (Burkitt's lymphoma), non-Burkitt high-grade B-cell lymphoma or extranodal marginal zone B-cell lymphoma. In some embodiments, the hematological malignancy is acute or chronic myeloid (or myeloid) leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, or precursor B-cell acute lymphocytic leukemia. In some embodiments, the hematological malignancy is acute myeloid leukemia (AML). In some embodiments, the hematological malignancy is acute promyelocytic leukemia (AMPL). In some embodiments, the hematological malignancy is acute lymphocytic leukemia (ALL). In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematological malignancy is double hit lymphoma (DHL). In some embodiments, the hematological malignancy is triple hit lymphoma (THL). In some embodiments, the hematological malignancy is double hit / triple hit lymphoma (DHL / THL). In some embodiments, the hematological malignancy is a double-expressing lymphoma (DEL). In some embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematological malignancy is multiple myeloma (MM). In some embodiments, the hematological malignancy is Burkitt's lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma (FL). In some embodiments, the hematological malignancy is transformed follicular lymphoma. In some embodiments, the hematological malignancy is marginal zone lymphoma.

[0203] In some embodiments, the hematological malignancy is relapsed or refractory non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicular lymphoma (FL), relapsed or refractory CLL, relapsed or refractory SLL, relapsed or refractory multiple myeloma, relapsed or refractory Waldenstrom's macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or refractory non-Burkitt's high-grade B-cell lymphoma, relapsed or refractory extranodal marginal zone B-cell lymphoma. In some embodiments, the hematological malignancy is relapsed or refractory acute or chronic myeloid (or myeloid) leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphocytic leukemia, or relapsed or refractory precursor B-cell acute lymphocytic leukemia. In some embodiments, the hematological malignancy is relapsed or refractory acute myeloid leukemia (AML). In some embodiments, the hematological malignancy is relapsed or refractory acute promyelocytic leukemia (AMPL). In some embodiments, the hematological malignancy is relapsed or refractory acute lymphocytic leukemia (ALL). In some embodiments, the hematological malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematological malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematological malignancy is relapsed or refractory double hit lymphoma (DHL). In some embodiments, the hematological malignancy is relapsed or refractory triple hit lymphoma (THL). In some embodiments, the hematological malignancy is relapsed or refractory double hit / triple hit lymphoma (DHL / THL). In some embodiments, the hematological malignancy is relapsed or refractory double expression lymphoma (DEL). In some embodiments, the hematological malignancy is relapsed or refractory Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematological malignancy is relapsed or refractory multiple myeloma (MM). In some embodiments, the hematological malignancy is relapsed or refractory Burkitt's lymphoma.In some embodiments, the hematological malignancy is relapsed or refractory follicular lymphoma (FL).

[0204] In some embodiments, the hematological malignancy is a hematological malignancy classified as high risk. In some embodiments, the hematological malignancy is high risk CLL or high risk SLL.

[0205] B-cell lymphoproliferative disorders (BCLD) are blood tumors and include non-Hodgkin's lymphoma, multiple myeloma and leukemia in particular. BCLD can originate from lymphoid tissue (e.g., lymphoma) or bone marrow (e.g., leukemia and myeloma), both of which are associated with uncontrolled growth of lymphocytes or white blood cells. There are multiple subtypes of BCLD, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). The course and treatment of BCLD depend on the BCLD subtype; however, even within each subtype, the clinical manifestations, morphological appearance and response to treatment are all different.

[0206] Malignant lymphoma is the neoplastic transformation of cells mainly present in lymphoid tissue. Two groups of malignant lymphoma are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphoma infiltrate the reticuloendothelial tissue. However, they are different in tumor cell origin, site of onset, systemic symptoms and response to treatment (Freedman et al., "Non-Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (a publication approved by the American Cancer Society, BC Decker Inc., Hamilton, Ontario, 2003)). Non-Hodgkin's lymphoma

[0207] In certain embodiments, the present invention discloses a method of treating non-Hodgkin's lymphoma in an individual in need thereof, comprising administering an amount of Compound A to the individual.

[0208] In certain embodiments, the present invention further discloses a method of treating relapsed or refractory non-Hodgkin's lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A. In some embodiments, the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, or relapsed or refractory CLL.

[0209] Non-Hodgkin's lymphoma (NHL) is a group of various malignant tumors that mainly originate from B cells. NHL may occur in any organ related to the lymphatic system, such as the spleen, lymph nodes or tonsils, and may occur at any age. NHL is usually characterized by lymphadenopathy, fever and weight loss. NHL is divided into B-cell NHL or T-cell NHL. Lymphomas associated with lymphoproliferative diseases after bone marrow or stem cell transplantation are usually B-cell NHL. In the Working Formulation classification scheme, NHL is divided into low-grade, moderate-grade and high-grade categories according to its natural history (see, "The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49 (1982): 2112-2135). Low-grade lymphomas are indolent, with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med. 311: 1471-1475). Although chemotherapy can put most indolent lymphomas into remission, cure rates are low, and most patients will eventually relapse and require further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors but have a greater chance of being cured with chemotherapy. However, a large percentage of these patients will relapse and require further treatment.

[0210] A non-limiting list of B-cell NHLs includes Burkitt's lymphoma (e.g., endemic Burkitt's lymphoma and sporadic Burkitt's lymphoma), cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), diffuse small cell and large cell mixed lymphoma, diffuse small cleaved cell lymphoma, diffuse small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, follicular lymphoma, follicular small cleaved cell lymphoma (grade 1), follicular small cleaved cell and large cell mixed lymphoma (grade 2), follicular large cell lymphoma (grade 3), intravascular large B-cell lymphoma, intravascular lymphomatosis, large cell immunoblastic Lymphoma, large cell lymphoma (LCL), lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), extranodal marginal zone B cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma, primary mediastinal B cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenstrom's macroglobulinemia, and primary central nervous system (CNS) lymphoma. Other non-Hodgkin's lymphomas are also encompassed within the scope of the invention and should be apparent to those of ordinary skill in the art. DLBCL

[0211] In certain embodiments, the present invention discloses a method of treating DLCBL in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory DLCBL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0212] The term "diffuse large B-cell lymphoma (DLBCL)" used in the present invention refers to a tumor of germinal center B lymphocytes with a diffuse growth pattern and a high and medium proliferation index. DLBCL accounts for about 30% of all lymphomas, and there may be a variety of morphological variants, including central blast subtypes, immunoblast subtypes, T cell / tissue cell-rich subtypes, anaplastic subtypes, and plasmablast subtypes. Genetic testing has shown that DLBCL has different subtypes. These subtypes appear to have different prospects (i.e., prognosis) and responses to treatment. DLBCL can affect any age group, but mainly occurs in the elderly (e.g., the average age is around 60 years old).

[0213] In certain embodiments, the present invention discloses a method for treating diffuse large B-cell lymphoma, activated B-cell-like subtype (ABC-DLBCL) in an individual in need thereof, comprising administering to the individual a covalent inhibitor of menin-MLL interaction in an amount of 300 mg / day to up to and including 1000 mg / day. ABC subtype diffuse large B-cell lymphoma (ABC-DLBCL) is believed to be caused by post-germinal center B cells that are arrested during plasma cell differentiation. ABC subtype DLBCL (ABC-DLBCL) accounts for approximately 30% of the total number of DLBCL diagnoses. It is considered to be the most difficult to cure molecular subtype of DLBCL, and therefore, patients diagnosed with ABC-DLBCL generally show significantly reduced survival rates compared to individuals with other types of DLCBL. ABC-DLBCL is most commonly associated with chromosomal translocations that deregulate the germinal center master regulator BCL6 and mutations that inactivate the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation.

[0214] One particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is that mediated by the nuclear factor (NF)-κB transcription complex. The NF-κB family consists of five members (p50, p52, p65, c-rel, and RelB) that form homodimers and heterodimers and act as transcription factors that mediate a variety of proliferative, apoptotic, inflammatory, and immune responses and are essential for normal B-cell development and survival. NF-κB is widely used by eukaryotic cells as a gene regulator that controls cell proliferation and cell survival. Therefore, many different types of human tumors misregulate NF-κB, that is, NF-κB is constitutively active. Active NF-κB turns on gene expression that maintains cell proliferation and protects cells from conditions that would otherwise cause cell death via apoptosis.

[0215] The dependence of ABC DLBCL on NF-κB depends on a signaling pathway upstream of the IkB kinase that consists of CARD11, BCL10, and MALT1 (i.e., the CBM complex). Interference with the CBM pathway abolishes NF-κB signaling and induces apoptosis in ABC DLBCL cells. The molecular basis for constitutive activity of the NF-κB pathway is the subject of ongoing investigation, but several somatic alterations in the ABC DLBCL genome clearly trigger this pathway. For example, somatic mutations in the coiled-coil domain of CARD11 in DLBCL enable this signaling scaffold protein to spontaneously form protein-protein interactions with MALT1 and BCL10, leading to IKK activity and NF-κB activation. Constitutive activity of the B cell receptor signaling pathway is associated with NF-κB activation in ABC DLBCL with wild-type CARD11, which is associated with mutations in the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activating mutations in the signaling adaptor MYD88 activate NF-κB and cooperate with B cell receptor signaling to maintain survival of ABC DLBCL cells. In addition, inactivating mutations in A20, a negative regulator of the NF-κB pathway, occur almost exclusively in ABC DLBCL.

[0216] Indeed, genetic alterations affecting multiple components of the NF-κB signaling pathway have recently been identified in more than 50% of ABC-DLBCL patients, and these lesions promote constitutive NF-κB activation, thereby promoting lymphoma growth. Among these are mutations in CARD11 (approximately 10% of cases), a lymphocyte-specific cytoplasmic scaffolding protein that, together with MALT1 and BCL10, forms the BCR signalosome, which transmits signals from antigen receptors to downstream mediators of NF-κB activation. An even larger proportion of cases (~30%) carry biallelic lesions that inactivate the negative NF-κB regulator A20. In addition, high levels of expression of NF-κB target genes have been observed in ABC-DLBCL tumor samples. See, e.g., U. Klein et al., (2008), Nature Reviews Immunology 8:22-23; RE Davis et al., (2001), Journal of Experimental Medicine 194:1861-1874; G. Lentz et al., (2008), Science 319:1676-1679; M. Compagno et al., (2009), Nature 459:712-721; and L. Srinivasan et al., (2009), Cell 139:573-586).

[0217] DLBCL cells of the ABC subtype, such as OCI-Ly10, have chronic active BCR signaling and are very sensitive to the covalent inhibitors of menin-MLL interaction described in the present invention. The covalent inhibitors of menin-MLL interaction described in the present invention effectively and irreversibly inhibit the growth of OCI-Ly10 (EC 50 Continuous exposure = 10 nM, EC 50 One hour pulse = 50 nM). In addition, apoptosis induction was observed in OCILy10 as shown by caspase activation, Annexin-V flow cytometry, and an increase in sub-G0 fraction. Follicular lymphoma

[0218] In certain embodiments, the present invention discloses a method of treating follicular lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory follicular lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0219] As used herein, the term "follicular lymphoma" refers to any of several types of non-Hodgkin's lymphoma in which lymphoma cells aggregate into nodules or follicles. The term "follicular" is used because the cells tend to grow in a round or nodular pattern in the lymph nodes. The average age of patients with this type of lymphoma is about 60 years old. CLL / SLL

[0220] In certain embodiments, the present invention discloses a method of treating CLL or SLL in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory CLL or SLL, comprising administering to the individual a therapeutically effective amount of Compound A.

[0221] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are often considered the same disease, but they present slightly differently. Where the cancer cells gather determines whether the disease is called CLL or SLL. When the cancer cells are mainly in the lymph nodes, lima bean-shaped structures in the lymphatic system (a system in the body made up mostly of tiny blood vessels), the disease is called SLL. SLL accounts for about 5% to 10% of all lymphomas. When most of the cancer cells are in the blood and bone marrow, the disease is called CLL.

[0222] Both CLL and SLL are slow-growing diseases, and although CLL is more common, it tends to grow slower. CLL and SLL are treated the same way. These diseases are generally not considered curable with standard treatments, but most people live longer than ten years, depending on the stage of the disease and how fast it grows. Sometimes, over time, these slow-growing lymphomas can change into more aggressive lymphomas.

[0223] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. An estimated 100,760 people in the United States have CLL or are in remission. Most (>75%) newly diagnosed CLL patients are over the age of 50. Current CLL treatment focuses on controlling the disease and its symptoms rather than curing it completely. CLL is treated with chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms can sometimes be treated with surgery (splenectomy to remove the enlarged spleen) or by radiation therapy (to "de-swell" the enlarged lymph nodes). Although CLL progresses slowly in most cases, CLL is generally considered incurable. Certain CLLs are classified as high risk. As used herein, "high-risk CLL" means CLL with at least one of the following characteristics: 1) 17p13-; 2) 11q22-; 3) unmutated IgVH together with ZAP-70+ and / or CD38+; or 4) trisomy 12.

[0224] CLL is usually treated when a person's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the person's quality of life.

[0225] Small lymphocytic leukemia (SLL) is very similar to CLL described above and is also a cancer of the B cells. In SLL, the abnormal lymphocytes primarily affect the lymph nodes. However, in CLL, the abnormal cells primarily affect the blood and bone marrow. In both cases, the spleen may be affected. SLL accounts for about 1 in 25 cases of all non-Hodgkin lymphomas. SLL can occur at any time from young adulthood to old age, but it is rare before the age of 50. SLL is considered an indolent lymphoma. This means that the disease progresses very slowly and patients often survive for several years after diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well to a variety of chemotherapy drugs, it is generally considered incurable. Although some cancers tend to be more common in one sex or the other, SLL causes about half of all cases and deaths between men and women. The average age at diagnosis is 60 years old.

[0226] Although SLL is indolent, it is progressive. The common pattern of this disease is one of high response rate to radiation therapy and / or chemotherapy, with a period of remission. After a few months or years, relapse is inevitable. Retreatment will produce a response again, but the disease will relapse again. This means that although the short-term prognosis of SLL is quite good, many patients will develop fatal complications of recurrent disease over time. Considering the age of individuals who are usually diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment of such diseases with minimal side effects and without affecting the patient's quality of life. The present invention meets this long-standing need in the art. Mantle cell lymphoma

[0227] In certain embodiments, the present invention discloses a method of treating mantle cell lymphoma (MCL) in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory mantle cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0228] The term "mantle cell lymphoma" as used herein refers to a subtype of B cell lymphoma that is attributed to CD5 positive antigen primary pre-germinal center B cells within the mantle zone surrounding the normal germinal center follicles. MCL cells typically overexpress cyclin D1 due to the t(11:14) chromosomal translocation in the DNA. More specifically, the translocation occurs at t(11;14)(q13;q32). Only about 5% of lymphomas are of this type. The cell size is small to medium. Males are most commonly affected. The average age of patients is in the early 60s. The lymphoma is usually widespread at the time of diagnosis, involving the lymph nodes, bone marrow, and often the spleen. Mantle cell lymphoma is not a very fast growing lymphoma, but it is difficult to treat. Marginal zone B-cell lymphoma

[0229] In certain embodiments, the present invention discloses a method of treating marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0230] The term "marginal zone B-cell lymphoma" as used herein refers to a group of related B-cell tumors that involve lymphoid tissue in patchy areas outside the marginal zone, the follicular mantle zone. Marginal zone lymphomas account for about 5% to 10% of lymphomas. The cells in these lymphomas appear very small under a microscope. Marginal zone lymphomas are divided into three main types, including extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma. MALT

[0231] In certain embodiments, the present invention discloses a method of treating MALT in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory MALT in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0232] The term "mucosa-associated lymphoid tissue (MALT) lymphoma" as used in the present invention refers to marginal zone lymphoma with extranodal clinical manifestations. Most MALT lymphomas are low-grade, but a few initially present as intermediate-grade non-Hodgkin lymphomas (NHL) or evolve from low-grade malignancies. Most MALT lymphomas occur in the stomach, and approximately 70% of gastric MALT lymphomas are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been found, the most common of which is trisomy 3 or t(11;18). Many other MALT lymphomas are also associated with bacterial or viral infections. The average age of MALT lymphoma patients is about 60 years old. Nodal marginal zone B-cell lymphoma

[0233] In certain embodiments, the present invention discloses a method of treating lymph node marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory lymph node marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0234] The term "nodal marginal zone B-cell lymphoma" refers to an indolent B-cell lymphoma that occurs primarily in the lymph nodes. This disease is rare, accounting for only 1% of all non-Hodgkin lymphomas (NHL). Nodal marginal zone B-cell lymphoma is most often diagnosed in older patients, and women are more likely to develop the disease than men. This disease is classified as a marginal zone lymphoma because the mutation occurs in the marginal zone of the B cells. Because the disease is confined to the lymph nodes, this disease is also classified as a nodal disease. Splenic marginal zone B-cell lymphoma

[0235] In certain embodiments, the present invention discloses a method of treating splenic marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0236] The term “splenic marginal zone B-cell lymphoma” refers to a specific low-grade small B-cell lymphoma included in the World Health Organization classification. The typical features are splenomegaly, moderate lymphocytosis with villous morphology, an intrasinusoidal pattern of multivisceral involvement, especially bone marrow involvement, and a relatively indolent course. Tumor progression with increasing blastic forms and aggressive behavior has been observed in a minority of patients. Both molecular and cytogenetic studies have shown heterogeneous results, which may be due to the lack of standardized diagnostic criteria. Burkitt's lymphoma

[0237] In certain embodiments, the present invention discloses a method of treating Burkitt's lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory Burkitt's lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0238] The term "Burkitt lymphoma" refers to a common type of non-Hodgkin lymphoma (NHL) that affects children. It is a highly aggressive B-cell lymphoma that usually starts and affects parts of the body other than the lymph nodes. Although Burkitt lymphoma grows rapidly, it is usually curable with modern, intensive treatments. There are two main types of Burkitt lymphoma: sporadic and endemic.

[0239] Endemic Burkitt's lymphoma. This disease affects more children than adults, and 95% of cases are associated with infection with the Epstein Barr Virus (EBV). It occurs mainly around equatorial Africa, where about half of childhood cancers are Burkitt's lymphoma. The disease is characterized by a high probability of involving the jaws, which is a rather unique feature that is rarely seen in sporadic Burkitt's disease. It also commonly involves the abdomen.

[0240] Sporadic Burkitt's lymphoma. The type of Burkitt's lymphoma that affects other parts of the world, including Europe and America, is the sporadic form. In these areas, it is also primarily a disease of children. Although one in five patients has direct evidence of Epstein-Barr virus (EBV) infection, the EBV link is not as strong as with the endemic form. In more than 90% of children, the abdomen is most prominently affected in addition to lymph node involvement. Bone marrow involvement is more common than in the sporadic form. Waldenstrom's Macroglobulinemia

[0241] In certain embodiments, the present invention discloses a method of treating Waldenstrom's macroglobulinemia in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory macroglobulinemia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0242] The term "Waldenstrom's macroglobulinemia," also known as lymphoplasmacytic lymphoma, is a cancer that affects a subtype of white blood cells called lymphocytes. It is characterized by the uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by the production of an antibody called immunoglobulin M (IgM) by the lymphoma cells. IgM antibodies circulate in large amounts in the blood, causing the liquid portion of the blood to thicken, like syrup. This reduces blood flow to many organs, leading to vision problems (due to poor blood circulation behind the eyes) and neurological problems caused by poor blood flow to the brain (i.e., headaches, dizziness, and confusion). Other symptoms may include feeling tired and weak, and bleeding easily. The underlying cause is not fully understood, but many risk factors have been identified, including the genetic locus 6p21.3 on chromosome 6. The risk of developing WM is increased 2-3 times in people with a personal history of autoimmune diseases with autoantibodies, especially those at higher risk associated with hepatitis, human immunodeficiency virus, and rickettsial diseases. Multiple Myeloma

[0243] In certain embodiments, the present invention discloses a method of treating myeloma in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method of treating relapsed or refractory myeloma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0244] Multiple myeloma, also known as MM, myeloma, plasma cell myeloma or Kahler's disease (named after Otto Kahler), is a cancer of white blood cells called plasma cells. Plasma cells are a type of B cell, an important part of the immune system responsible for producing antibodies in humans and other vertebrates. Plasma cells are produced in the bone marrow and transported through the lymphatic system. leukemia

[0245] In certain embodiments, the present invention discloses a method for treating leukemia in an individual in need thereof, comprising administering to the individual an amount of Compound A. In certain embodiments, the present invention further discloses a method for treating relapsed or refractory leukemia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0246] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually white blood cells. Leukemia is a broad term that covers a range of diseases. The first distinction is between acute and chronic forms.

[0247] Acute leukemia is characterized by a rapid increase in immature blood cells. This crowding makes it impossible for the bone marrow to produce healthy blood cells. Acute leukemia requires immediate treatment because the malignant cells grow and accumulate quickly, then spill into the bloodstream and spread to other organs in the body. Acute leukemia is the most common form of childhood leukemia.

[0248] Chronic leukemia is characterized by an excessive accumulation of relatively mature but still abnormal white blood cells. It usually takes months or years to progress, with the cells being produced at a much higher rate than normal, resulting in many abnormal white blood cells in the blood. Chronic leukemia occurs mainly in older people, but can theoretically occur in any age group.

[0249] In addition, these diseases are subdivided according to the type of blood cells affected. This classification divides leukemia into lymphoblastic leukemia or lymphocytic leukemia and myeloid leukemia or bone marrow leukemia: (i) lymphoblastic leukemia or lymphocytic leukemia, the cancer develops in a type of bone marrow cell that normally gives rise to lymphocytes, which are cells of the immune system that fight infection; and (ii) myeloid leukemia or bone marrow leukemia, the cancer develops in a type of bone marrow cell that normally gives rise to red blood cells, some other types of white blood cells, and platelets.

[0250] Within these major categories, there are several subcategories, including, but not limited to, acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also known as precursor B lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL). Thus, in certain embodiments, the present invention discloses a method of treating acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also known as precursor B lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hairy cell leukemia (HCL) in an individual in need thereof, comprising administering to the individual an amount of Compound A. In some embodiments, the leukemia is a relapsed or refractory leukemia. In some embodiments, the leukemia is relapsed or refractory acute lymphoblastic leukemia (ALL), relapsed or refractory precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also known as precursor B lymphoblastic leukemia), relapsed or refractory acute myeloid leukemia (AML), relapsed or refractory chronic myeloid leukemia (CML), or relapsed or refractory hairy cell leukemia (HCL). In some embodiments, the mammal or subject has an MLL / KMT2A gene rearrangement. In some embodiments, the mammal or subject has an NPM1 mutation. In some embodiments, the mammal or subject has a TP53 mutation. In some embodiments, the mammal or subject has a NOTCH1 mutation. In some embodiments, the mammal or subject has a del(13q) karyotype. In some embodiments, the mammal or subject has a trisomy 12 karyotype.

[0251] Symptoms, diagnostic tests, and prognostic tests for each of the above conditions are known. See, for example, Harrison's Principles of Internal Medicine. ,” 16th ed., 2004, McGraw-Hill Inc. Dey et al. (2006), Cytojournal 3(24), and the “Revised European American Lymphoma” (REAL) classification system (see, e.g., the website maintained by the U.S. National Cancer Institute).

[0252] A variety of animal models can be used to establish therapeutically effective dosage ranges for compounds that are covalent inhibitors of menin-MLL interactions (eg, Compound A) for treating any of the aforementioned diseases.

[0253] The therapeutic efficacy of Compound A for any of the aforementioned diseases can be optimized during the course of treatment. For example, a mammal or subject being treated can undergo a diagnostic assessment to correlate the alleviation of disease symptoms or pathology with the inhibition of in vivo Menin-MLL activity achieved by administering a given dose of Compound A. Thus, the amount of the covalent inhibitor of the menin-MLL interaction inhibitor compound administered to the mammal or subject can be increased or decreased as needed to maintain an optimal level of inhibition for treating the disease state of the mammal or subject.

[0254] Compound A can irreversibly inhibit menin-MLL and can be used to treat mammals suffering from menin-MLL or menin-MLL-mediated conditions or diseases, including but not limited to cancer, autoimmune diseases and other inflammatory diseases. Compound A has been shown to be effective against a variety of diseases and conditions described herein.

[0255] In some embodiments, Compound A is used to prepare a medicament for treating any of the aforementioned conditions (eg, an autoimmune disease, an inflammatory disease, an allergic disease, a B-cell proliferative disease, or a thromboembolic disease). In some embodiments, the cancer is a B-cell proliferative disorder.

[0256] In some embodiments, the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, lymphocytic leukemia, ALL, a soft tissue tumor, glioblastoma, a pancreatic tumor, or renal cell carcinoma.

[0257] In some embodiments, the cancer is a juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, or bladder cancer.

[0258] In some embodiments, the cancer is bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, choroidoma, or cardiac tumor, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, midline tract cancer, and / or non-Hodgkin lymphoma.

[0259] In some embodiments, the cancer is multiple endocrine neoplasm syndrome, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, and / or multiple myeloma.

[0260] In some embodiments, the cancer is merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, or a primary central nervous system (CNS) cancer.

[0261] In some embodiments, the cancer is hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hypopharyngeal cancer, intraocular melanoma, kidney cancer, laryngeal cancer, lip and oral cancer, hepatocellular carcinoma, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous neck cancer, or oral cancer.

[0262] In some embodiments, the cancer is multiple endocrine neoplasm syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, lymphoma, prostate cancer, colorectal cancer, or transitional cell carcinoma.

[0263] In some embodiments, the cancer is retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestinal cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or a virus-induced cancer. In some embodiments, the method relates to the treatment of a non-cancerous hyperproliferative disease, such as benign skin hyperplasia (e.g., psoriasis), restenosis, or a prostate disease (e.g., benign prostatic hypertrophy (BPH)).

[0264] In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, and / or colorectal cancer.

[0265] In some embodiments, the cancer is CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, and / or gastric cancer.

[0266] In certain embodiments, the invention provides a method for treating the following disease or illness, which comprises administering a compound provided by the present invention to the mammal. In some embodiments, the disease or illness is ALL (acute lymphoblastic lymphoma), DLBCL (diffuse large B cell lymphoma), FL (follicular lymphoma), RCC (renal cell carcinoma), children's medulloblastoma, glioblastoma, pancreatic tumor or cancer, liver cancer (hepatocellular carcinoma), prostate cancer (Myc), triple negative breast cancer (Myc), AML (acute myeloid leukemia) or MDS (myelodysplastic syndrome). In some embodiments, the disease or illness is early-onset dystonia. In some other embodiments, the disease or illness is Kabuki Syndrome (Kabuki Syndrome).

[0267] In some embodiments, the disease or disorder is a p53-driven tumor.

[0268] In some embodiments, the disease or condition is a MYC-driven tumor. It has been documented that MYC is widely involved in a variety of cancers, and it is estimated that MYC expression is elevated or dysregulated in up to 70% of human cancers. High levels of MYC expression are associated with aggressive human prostate cancer and triple-negative breast cancer (Gurel et al., Mod Pathol. 2008 Sep; 21(9): 1156-67; Palaskas et al., Cancer Res. 2011 Aug 1; 71(15): 5164-74). Experimental models of Myc-mediated tumorigenesis have shown that established tumors are addicted to Myc, and dysregulated Myc expression can lead not only to Myc addiction, but also to nutrient addiction. These Myc-induced changes provide unique opportunities for new therapeutic strategies. Despite the fact that normal proliferating cells (stem cell compartments and immune cells) also use MYC for renewal, many studies have focused on targeting Myc for cancer treatment. Strategies to inhibit MYC expression, disrupt Myc-Max dimerization, inhibit Myc-Max DNA binding, and interfere with key Myc target genes have emerged (Dang et al. Cell. 2012, 149(1): 22-35).

[0269] In some embodiments, Compound A can be used to treat menin-dependent acute myeloid leukemia (AML), menin-dependent diffuse large B-cell lymphoma (DLBCL), menin-dependent double hit / triple hit lymphoma (DHL / THL), menin-dependent double-expressing lymphoma (DEL), and menin-dependent multiple myeloma (MM).

[0270] In some embodiments, Compound A can be used to treat menin-independent acute myeloid leukemia (AML), menin-independent diffuse large B-cell lymphoma (DLBCL), menin-independent double hit / triple hit lymphoma (DHL / THL), menin-independent double-expressing lymphoma (DEL), and menin-independent multiple myeloma (MM).

[0271] In some embodiments, Compound A can be used to treat menin-dependent cancers. In some embodiments, Compound A can be used to treat menin-independent cancers.

[0272] In some embodiments, Compound A can be used to treat menin-dependent hematological malignancies. In some embodiments, Compound A can be used to treat menin-independent hematological malignancies.

[0273] In some embodiments, Compound A can be used to treat hematological malignancies involving mutations in the nucleophosmin (NMP1) gene. In some embodiments, Compound A can be used to treat hematological malignancies that do not involve mutations in the nucleophosmin (NMP1) gene.

[0274] In some embodiments, Compound A can be used to treat hematological malignancies involving rearranged MLL. In some embodiments, Compound A can be used to treat hematological malignancies that do not rearrange MLL.

[0275] In some embodiments, Compound A can be used to treat MYC-dependent acute myeloid leukemia (AML), MYC-dependent diffuse large B-cell lymphoma (DLBCL), MYC-dependent double hit / triple hit lymphoma (DHL / THL), MYC-dependent double-expressing lymphoma (DEL), and MYC-dependent multiple myeloma (MM).

[0276] In some embodiments, Compound A can be used to treat MYC-independent acute myeloid leukemia (AML), MYC-independent diffuse large B-cell lymphoma (DLBCL), MYC-independent double hit / triple hit lymphoma (DHL / THL), MYC-independent double-expressing lymphoma (DEL), and MYC-independent multiple myeloma (MM).

[0277] In some embodiments, Compound A can be used to treat relapsed / refractory (R / R) acute leukemia (AL), DLBCL, and MM.

[0278] In some embodiments, Compound A can be used to treat cancers involving p53 gene mutations. In some embodiments, Compound A can be used to treat cancers that do not involve p53 gene mutations.

[0279] In some embodiments, Compound A can be used to treat cancers involving RAS gene mutations. In some embodiments, Compound A can be used to treat cancers involving KRAS gene mutations. In some embodiments, Compound A can be used to treat cancers that do not involve KRAS gene mutations.

[0280] In some embodiments, Compound A can be used to treat CLL patients, wherein the patients have overexpressed BCL2. In some embodiments, Compound A can be used to treat CLL patients, wherein the patients do not overexpress BCL2.

[0281] In some embodiments, Compound A can be used to treat cancers involving ATM gene mutations. In some embodiments, Compound A can be used to treat cancers that do not involve ATM gene mutations.

[0282] In some embodiments, Compound A can be used to treat cancers involving Notch1 gene mutations. In some embodiments, Compound A can be used to treat cancers that do not involve Notch1 gene mutations.

[0283] In some embodiments, Compound A can be used to treat cancers involving TP53 gene mutations. In some embodiments, Compound A can be used to treat cancers that do not involve TP53 gene mutations.

[0284] In some embodiments, Compound A can be used to treat cancers involving WT1 gene mutations. In some embodiments, Compound A can be used to treat cancers not involving WT1 gene mutations.

[0285] In some embodiments, Compound A can be used to treat cancers involving KMT2A gene mutations. In some embodiments, Compound A can be used to treat cancers that do not involve KMT2A gene mutations.

[0286] In some embodiments, Compound A can be used to treat cancers involving TET2 gene mutations. In some embodiments, Compound A can be used to treat cancers that do not involve TET2 gene mutations.

[0287] In some embodiments, Compound A can be used to treat cancers involving a chromosome 13 deletion (Del(13q)) gene mutation. In some embodiments, Compound A can be used to treat cancers that do not involve a chromosome 13 deletion (Del(13q)) gene mutation.

[0288] In some embodiments, Compound A can be used to treat cancers involving a Trisomy 12 gene mutation. In some embodiments, Compound A can be used to treat cancers that do not involve a Trisomy 12 gene mutation. Compound A and its pharmaceutically acceptable salts

[0289] "Compound A" or "N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide" or any other suitable name refers to a compound having the following structure:

[0290] A variety of pharmaceutically acceptable salts are formed from Compound A and include: - an acid addition salt formed by the reaction of compound A with an organic acid, wherein the organic acid includes aliphatic monobasic and dibasic carboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, and the like; and includes, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like; - Acid addition salts formed by the reaction of compound A with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0291] The term "pharmaceutically acceptable salt" in relation to Compound A refers to salts of Compound A that do not cause significant irritation to a mammal to which they are administered and that do not substantially abrogate the biological activity and properties of the neutral compound.

[0292] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms (solvates). Solvates contain stoichiometric or non-stoichiometric solvents and are formed in the process of product formation or separation from a pharmaceutically acceptable solvent, such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, and the like. On the one hand, 3 types of solvents can be used but are not limited to form solvates. The categories of solvents are defined in, for example, the "Impurities: Residual Solvents Guide, Q3C (R3)" (November 2005) of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, a solvate of Compound A or a pharmaceutically acceptable salt thereof is conveniently prepared or formed during the process of the present invention. In some embodiments, a solvate of Compound A is anhydrous. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof exists in a non-solvated form. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof exists in a non-solvated form and is anhydrous.

[0293] In other embodiments, Compound A or its pharmaceutically acceptable salt is prepared in various forms, including but not limited to amorphous phase, crystalline form, ground form, and nanoparticle form. In some embodiments, Compound A or its pharmaceutically acceptable salt is amorphous. In some embodiments, Compound A or its pharmaceutically acceptable salt is amorphous and anhydrous. In some embodiments, Compound A or its pharmaceutically acceptable salt is crystalline. In some embodiments, Compound A or its pharmaceutically acceptable salt is crystalline and anhydrous.

[0294] With respect to composition, the term "substantially free of" or "substantially absent" refers to that the composition comprises at least 50wt%, 60wt%, 70wt%, 75wt%, 80wt%, 85wt% or 90wt%, in certain embodiments, comprises at least 95wt%, 98wt%, 99wt% or 100wt%, or in certain embodiments, comprises at least 95wt%, 98wt%, 99wt% or 100wt% of the specified enantiomer of the compound. In certain embodiments, in the method and compound provided by the invention, the compound is substantially free of one of two enantiomers. In certain embodiments, in the method and compound provided by the invention, the compound is substantially free of another enantiomer.

[0295] Similarly, with respect to a composition, the term "isolated" means that the composition comprises at least 50 wt%, 60 wt%, 70 wt%, 75 wt%, 85 wt%, 90 wt%, 95 wt%, 98 wt%, or 99 wt% to 100 wt% of the compound, the remainder comprising the other enantiomer.

[0296] As used herein, "enantiomeric excess (ee)" refers to a dimensionless molar ratio describing the purity of a chiral substance containing, for example, a single stereocenter. For example, an enantiomeric excess of zero would represent a racemate (e.g., a 50:50 mixture of enantiomers, or no excess of one enantiomer relative to the other). As a further example, an enantiomeric excess of 99 would represent an almost stereopure enantiomer compound (i.e., a large excess of one enantiomer relative to the other). Enantiomeric excess percentage, %ee = ([(R)-compound] - [(S)-compound]) / ([(R)-compound] + [(S))-compound]) x 100, wherein the (R)-compound > (S)-compound; or %ee = ([(S)-compound] - [(R)-compound]) / ([(S)-compound] + [(R)-compound]) x 100, wherein the (S)-compound > (R)-compound.

[0297] In some embodiments, Compound A is prepared as outlined in US Pat. No. 11,084,825. Amorphous Compound A

[0298] In some embodiments, Compound A is amorphous and anhydrous. In some embodiments, Compound A is amorphous. In some embodiments, the X-ray powder diffraction (XRPD) pattern of amorphous Compound A shows a lack of crystallinity. Compound A, Form A

[0299] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form A. Crystalline Form A of Compound A is characterized by having at least one of the following properties: (a) with Figure 1A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 10.4±0.1°2θ, 14.7±0.1°2θ, 17.1±0.1°2θ, 21±0.1°2θ, 24.9±0.1°2θ, 29.5±0.1°2θ, and 34.1±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 17.1±0.1°2θ, 21.0±0.1°2θ, 24.9±0.1°2θ, and 29.5±0.1°2θ; (d) a differential scanning calorimetry (DSC) thermogram having an endothermic peak starting at about 234.6° C. and peaking at about 245° C.; or (e) any combination thereof.

[0300] In some embodiments, Form A of Compound A is characterized by having at least two properties selected from (a) to (e). In some embodiments, Form A of Compound A is characterized by having at least three properties selected from (a) to (e). In some embodiments, Form A of Compound A is characterized by having at least four properties selected from (a) to (e). In some embodiments, Form A of Compound A is characterized by having all five properties selected from (a) to (e).

[0301] In some embodiments, Form A has Figure 1A In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 10.4±0.1°2θ, 14.7±0.1°2θ, 17.1±0.1°2θ, 21.0±0.1°2θ, 24.9±0.1°2θ, 29.5±0.1°2θ, and 30.0±0.1°2θ.

[0302] In some embodiments, Form A is non-hygroscopic. In some embodiments, Form A is hygroscopic.

[0303] In some embodiments, Form A is obtained from: ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptane, a methanol / water mixture, or an acetone / heptane mixture. In some embodiments, Form A is obtained from: ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptane, or an acetone / heptane mixture.

[0304] In some embodiments, Form A is unsolvated. In some embodiments, Form A is anhydrous. In some embodiments, Form A is solvated. In some embodiments, Form A is hydrated or is a hydrate. Compound A, Form B

[0305] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form B. Crystalline Form B of Compound A is characterized by having at least one of the following properties: (a) with Figure 2A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.9±0.1°2θ, 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ; or (d) combinations thereof.

[0306] In some embodiments, Form B of Compound A is characterized by having at least two properties selected from (a) to (d). In some embodiments, Form B of Compound A is characterized by having at least three properties selected from (a) to (d). In some embodiments, Form B of Compound A is characterized by having all four properties selected from (a) to (d).

[0307] In some embodiments, Form B has Figure 2A In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ.

[0308] In some embodiments, Form B is obtained from a mixture of methanol and water.

[0309] In some embodiments, Form B is non-solvated. In some embodiments, Form B is anhydrous. In some embodiments, Form B is solvated. In some embodiments, Form B is hydrated. Compound A, Form C

[0310] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form C. Crystalline Form C of Compound A is characterized by having at least one of the following properties: (a) with Figure 3A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.2±0.1°2θ, 5.9±0.1°2θ, 7.2±0.1°2θ, 8.7+0.1°2θ, 10.6±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.1±0.1°2θ, 15.9±0.1°2θ, 17.5±0.1°2θ, 18.1±0.1°2θ, and 20.1±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.2±0.1°2θ, 5.9±0.1°2θ, 8.7±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.9±0.1°2θ, and 17.5±0.1°2θ; (d) a DSC thermogram having an endothermic peak starting at about 150.23° C. and peaking at about 156.86° C.; or (e) any combination thereof.

[0311] In some embodiments, Form C of Compound A is characterized by having at least two properties selected from (a) to (e). In some embodiments, Form C of Compound A is characterized by having at least three properties selected from (a) to (e). In some embodiments, Form C of Compound A is characterized by having at least four properties selected from (a) to (e). In some embodiments, Form C of Compound A is characterized by having all five properties selected from (a) to (e).

[0312] In some embodiments, Form C has Figure 3AIn some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.2±0.1°2θ, 5.9±0.1°2θ, 7.2±0.1°2θ, 8.7±0.1°2θ, 10.6±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.1±0.1°2θ, 15.9±0.1°2θ, 17.5±0.1°2θ, 18.1±0.1°2θ, and 20.1±0.1°2θ. In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.2±0.1°2θ, 5.9±0.1°2θ, 8.7±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.9±0.1°2θ, and 17.5±0.1°2θ. Compound A, Form D

[0313] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form D. Crystalline Form D of Compound A is characterized by having at least one of the following properties: (a) with Figure 4A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3±0.1°2θ, 15.6±0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 8.7±0.1°2θ, 10.7±0.1°2θ, 15.6±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, and 24.2±0.1°2θ; (d) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 40° C. and 75% relative humidity (RH) for at least one week; (e) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 25° C. and 92% RH for at least one week; (f) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in a sealed container at 60° C. and 75% RH for at least one week; (g) Basically similar to Fig.9A Infrared (IR) spectrum shown; (h) Infrared (IR) spectroscopy ( Fig.9A ) at about 3332cm -1 、About 2853cm -1 (Unmarked), about 1561cm -1 (Unmarked), about 1523cm -1 、About 1438cm -1 、About 1257cm -1 、1112cm -1 , and about 930cm -1 A peak appears at (i) Basically similar to Fig.10 Thermogravimetric analysis (TGA) thermogram shown; (j) Basically similar to Fig.11 DSC thermogram shown; (k) a DSC thermogram having an endothermic peak starting at about 260.5° C. and peaking at about 273° C.; (l) Basically similar to Fig.12 shown 1 H NMR (nuclear magnetic resonance) spectroscopy; (m) Hygroscopicity and absorption of approximately 2.1% water observed from 40% RH to 70% RH at 25°C; (n) an aqueous solubility of about 0.004 mg / mL observed at about pH 4.5; or (o) any combination thereof.

[0314] In some embodiments, Form D of Compound A is characterized by having at least two properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least three properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least four properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least five properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least six properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least seven properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least eight properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least nine properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having at least ten properties selected from (a) to (n). In some embodiments, Form D of Compound A is characterized by having properties (a) to (n).

[0315] In some embodiments, Form D has Figure 4A In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4+0.1°2θ, 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3±0.1°2θ, 15.6+0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ. In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4±0.1°2θ, 8.7±0.1°2θ, 10.7±0.1°2θ, 15.6+0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, and 24.2±0.1°2θ.

[0316] In some embodiments, Form D has substantially similar Fig.10 Thermogravimetric analysis (TGA) thermogram shown.

[0317] In some embodiments, Form D has substantially similar Fig.11 DSC thermogram shown.

[0318] In some embodiments, Form D has substantially similar Fig.12 NMR spectrum shown.

[0319] In some embodiments, Form D is derived from methyl isobutyl ketone (MIBK). In some embodiments, Form D is solvated. In some embodiments, Form D is solvated with methyl isobutyl ketone (MIBK). Compound A, Form E

[0320] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form E. Crystalline Form E of Compound A is characterized by having at least one of the following properties: (a) with Figure 5A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) At 3.4±0.1°2θ, 4.7±0.1°2θ, 6.3±0.1°2θ, 6.9±0.1°2θ, 7.1±0.1°2θ, 7.6±0.1°2θ, 8.6±0.1°2θ, 9.3±0.1°2θ, 10.8±0.1°2θ , 12±0.1°2θ, 12.5±0.1°2θ, 13±0.1°2θ, 13.8±0.1°2θ, 15.7±0.1°2θ, 16.2±0.1°2θ, 16.7±0.1°2θ, 17±0.1°2θ, 17.5±0.1°2θ, 1 an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.4±0.1°2θ, 18.6±0.1°2θ, 19.6±0.1°2θ, 20.7±0.1°2θ, 21.4±0.1°2θ, 22.2±0.1°2θ, 23±0.1°2θ, 24.2±0.1°2θ, 25.3±0.1°2θ, 26±0.1°2θ, 28±0.1°2θ, 29.2±0.1°2θ, 30.5±0.1°2θ, 31.6±0.1°2θ, 33.6±0.1°2θ, and 34.5±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 4.7±0.1°2θ, 7.7±0.1°2θ, 10.8±0.1°2θ, 13.8±0.1°2θ, 17.0±0.1°2θ, 18.4±0.1°2θ, and 18.6±0.1°2θ; (d) a DSC thermogram having an endothermic peak starting at about 112.34° C. and peaking at about 137.26° C.; or (e) any combination thereof.

[0321] In some embodiments, Form E of Compound A is characterized by having at least two properties selected from (a) to (d). In some embodiments, Form E of Compound A is characterized by having at least three properties selected from (a) to (d). In some embodiments, Form E of Compound A is characterized by having all four properties selected from (a) to (d).

[0322] In some embodiments, Form E has Figure 5A In some embodiments, Form E has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . In some embodiments, Form E has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . In some embodiments, Form E has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . In some embodiments, Form E has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . In some embodiments, Form E has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . The invention also provides an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 34.5±0.1°2θ, 35.6±0.1°2θ, 36.4±0.1°2θ, 38.6±0.1°2θ, and 39.5±0.1°2θ. In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.7±0.1°2θ, 7.7±0.1°2θ, 10.8±0.1°2θ, 13.8±0.1°2θ, 17.0±0.1°2θ, 18.4±0.1°2θ, and 18.6±0.1°2θ. Compound A, Form F

[0323] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form F. Crystalline Form F of Compound A is characterized by having at least one of the following properties: (a) with Fig. 6A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) At 4.2±0.1°2θ, 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 12±0.1°2θ, 12.2±0.1°2θ, 12.5±0.1°2θ, 14.4±0.1°2θ, 15±0. 1°2θ, 16±0.1°2θ, 16.8±0.1°2θ, 17.2±0.1°2θ, 17.5±0.1°2θ, 17.8±0.1°2θ, 18.8±0.1°2θ, 19.2±0.1°2θ, 20.1±0.1°2θ, 2 an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 0.5±0.1°2θ, 21.7±0.1°2θ, 22.1±0.1°2θ, 23.4±0.1°2θ, 24.2±0.1°2θ, 25.3±0.1°2θ, 25.5±0.1°2θ, 26.3±0.1°2θ, 27.1±0.1°2θ, 29±0.1°2θ, 30.3±0.1°2θ, 31.6±0.1°2θ, 33.1±0.1°2θ, 34.3±0.1°2θ, and 35.6±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 11.9±0.1°2θ, 12.2±0.1°2θ, 14.4±0.1°2θ, 15.0±0.1°2θ, and 20.5±0.1°2θ; or (d) combinations thereof.

[0324] In some embodiments, Form F of Compound A is characterized by having at least two properties selected from (a) to (d). In some embodiments, Form F of Compound A is characterized by having at least three properties selected from (a) to (d). In some embodiments, Form F of Compound A is characterized by having all four properties selected from (a) to (d).

[0325] In some embodiments, Form F has Fig. 6AIn some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern at 4.2±0.1°2θ, 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 12±0.1°2θ, 12.2±0.1°2θ, 12.5±0.1°2θ, 14.4±0.1°2θ, 15±0.1°2θ, 16±0.1°2θ, 16.8±0.1°2θ, 17.2±0.1°2θ, 17.5±0.1°2θ, 17.8±0.1°2θ, 18.8±0.1°2θ, 19.2±0.1°2θ, 20.1±0.1 The invention also provides an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 20.5±0.1°2θ, 21.7±0.1°2θ, 22.1±0.1°2θ, 23.4±0.1°2θ, 24.2±0.1°2θ, 25.3±0.1°2θ, 25.5±0.1°2θ, 26.3±0.1°2θ, 27.1±0.1°2θ, 29±0.1°2θ, 30.3±0.1°2θ, 31.6±0.1°2θ, 33.1±0.1°2θ, 34.3±0.1°2θ, and 35.6±0.1°2θ. In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.3±0.1°2θ, 8.6±0.1°2θ, 8.8±0.1°2θ, 11.9±0.1°2θ, 12.2±0.1°2θ, 14.4±0.1°2θ, 15.0±0.1°2θ, and 20.5±0.1°2θ. Compound A, Form G

[0326] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form G. Crystalline Form G of Compound A is characterized by having at least one of the following properties: (a) with Fig. 7A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ; or (d) combinations thereof.

[0327] In some embodiments, Form F of Compound A is characterized by having at least two properties selected from (a) to (d). In some embodiments, Form F of Compound A is characterized by having at least three properties selected from (a) to (d). In some embodiments, Form F of Compound A is characterized by having all four properties selected from (a) to (d).

[0328] In some embodiments, Form G has Fig. 7A In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in . In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ. In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.1±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ. Compound A, Form J

[0329] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is crystalline Form J. Crystalline Form J of Compound A is characterized by having at least one of the following properties: (a) with Fig. 8A An X-ray powder diffraction (XRPD) pattern substantially the same as shown in; (b) At 3.5±0.1°2θ, 4.5±0.1°2θ, 6.4±0.1°2θ, 8.7±0.1°2θ, 10.2±0.1°2θ, 11.3±0.1 °2θ, 11.8±0.1°2θ, 13.2±0.1°2θ, 13.6±0.1°2θ, 14±0.1°2θ, 14.6±0.1°2θ, 15.4±0. 1°2θ, 16.1±0.1°2θ, 16.6±0.1°2θ, 16.9±0.1°2θ, 17.2±0.1°2θ, 18.3±0.1°2θ, 19. 1±0.1°2θ, 20.5±0.1°2θ, 20.8±0.1°2θ, 21.6±0.1°2θ, 23.5±0.1°2θ, 23.8±0.1°2θ, 24.6±0.1°2θ, 24.9±0.1°2θ, 25.2±0.1°2θ, 25.8±0.1°2θ, 26.2±0.1°2θ, 26.7±0.1 °2θ, 26.8±0.1°2θ, 27.4±0.1°2θ, 27.7±0.1°2θ, 28.7±0.1°2θ, 29.3±0.1°2θ, 30.1± an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 0.1°2θ, 31.2±0.1°2θ, 31.8±0.1°2θ, 34.1±0.1°2θ, 34.9±0.1°2θ, 35.6±0.1°2θ, 36.4±0.1°2θ, 36.7±0.1°2θ, 38.5±0.1°2θ, and 38.8±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.5±0.1°2θ, 4.5±0.1°2θ, 19.1±0.1°2θ, 21.6±0.1°2θ, 22.5±0.1°2θ, and 27.4±0.1°2θ; (d) Hygroscopicity and absorption of about 2.1% water observed from 40% RH to 70% RH at 25°C; or (e) any combination thereof.

[0330] In some embodiments, Form J of Compound A is characterized by having at least two properties selected from (a) to (e). In some embodiments, Form J of Compound A is characterized by having at least three properties selected from (a) to (e). In some embodiments, Form J of Compound A is characterized by having at least four properties selected from (a) to (e). In some embodiments, Form J of Compound A is characterized by having all five properties selected from (a) to (e).

[0331] In some embodiments, Form J has Fig. 8AIn some embodiments, Form J has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . In some embodiments, Form J has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . In some embodiments, Form J has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . In some embodiments, Form J has X-ray powder diffraction (XRPD) patterns substantially the same as those shown in . , 15.4±0.1°2θ, 16.1±0.1°2θ, 16.6±0.1°2θ, 16.9±0.1°2θ, 17.2±0.1°2θ, 18.3±0.1° 2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, 20.8±0.1°2θ, 21.6±0.1°2θ, 23.5±0.1°2θ, 23.8±0. 1°2θ, 24.6±0.1°2θ, 24.9±0.1°2θ, 25.2±0.1°2θ, 25.8±0.1°2θ, 26.2±0.1°2θ, 26.7 ±0.1°2θ, 26.8±0.1°2θ, 27.4±0.1°2θ, 27.7±0.1°2θ, 28.7±0.1°2θ, 29.3±0.1°2θ, 30 In some embodiments, Form J has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.5±0.1°2θ, 4.5±0.1°2θ, 19.1±0.1°2θ, 21.6±0.1°2θ, 22.5±0.1°2θ, and 27.4±0.1°2θ. Preparation of crystalline forms

[0332] In some embodiments, a crystalline form of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is prepared as described in the Examples. It should be noted that the solvents, temperatures and other reaction conditions set forth herein may vary. Suitable solvent

[0333] Therapeutic agents that can be applied to mammals (e.g., humans) are prepared by following regulatory guidelines. Such government regulatory guidelines are called good manufacturing practices (GMP). GMP guidelines outline acceptable levels of contamination for active therapeutic agents, for example, the amount of residual solvents in the final product. Acceptable solvents are those that are suitable for use in GMP facilities and meet industrial safety issues. Solvent categories are defined, for example, in the "Impurities: Residual Solvents Guide, Q3C (R3) (November 2005)" of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

[0334] Solvents are divided into three categories. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents that have limited use in the preparation of therapeutic agents. Class 3 solvents are solvents with low toxicity and low risk to human health. Data for Class 3 solvents show low toxicity in acute or short-term studies and are negative in genotoxicity studies.

[0335] Class 1 solvents that should be avoided include: benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, and 1,1,1-trichloroethane.

[0336] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene, and xylene.

[0337] Class 3 solvents with low toxicity include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0338] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacturing of the APIs. In some cases, practical manufacturing techniques cannot completely remove the solvents. Appropriate selection of solvents for synthesizing APIs can improve yields or determine characteristics such as crystal form, purity, and solubility. Therefore, solvents are a critical parameter in the synthesis process.

[0339] In some embodiments, the composition comprising compound A comprises an organic solvent. In some embodiments, the composition comprising compound A comprises a residual amount of an organic solvent. In some embodiments, the composition comprising compound A comprises a residual amount of 3 types of solvents. In some embodiments, the organic solvent is a 3 type of solvent. In some embodiments, the 3 types of solvents are selected from the group consisting of: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, isopropylbenzene, dimethyl sulfoxide, ethanol, ethyl acetate, ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the 3 types of solvents are selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropyl alcohol, and ethanol. In one embodiment, the 3 types of solvents are ethyl acetate. In one embodiment, the class 3 solvent is isopropyl acetate. In one embodiment, the class 3 solvent is tert-butyl methyl ether. In one embodiment, the class 3 solvent is heptane. In one embodiment, the class 3 solvent is isopropanol. In one embodiment, the class 3 solvent is ethanol. Some terminology

[0340] Unless otherwise defined, all technical terms and scientific terms used in the present invention have the same meaning as those commonly understood by the technicians familiar with the claimed target. It should be understood that the above general description and the following detailed description are only exemplary and explanatory and do not limit any claimed target. In this application, unless otherwise clearly specified, the use of the singular includes the plural. It must be pointed out that, unless the context clearly specifies otherwise, the singular forms "one / kind / item" and "described" used in this specification and the accompanying claims include plural referents. In the present invention, unless otherwise specified, "or" is used to represent "and / or". In addition, the use of the term "including" and other forms (such as "include", "includes" and "included") is not restrictive.

[0341] The section headings used in this invention are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this invention, including but not limited to patents, patent application publications, articles, books, manuals, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.

[0342] The terms "acceptable" or "pharmaceutically acceptable", as used herein, with respect to a formulation, composition or ingredient, means that it has no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0343] As used herein, "amelioration" of the symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to any reduction in severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, persistent or transient, which is attributable to or associated with the administration of the compound or composition.

[0344] "Bioavailability" refers to the percentage of an administered compound (e.g., Compound A) that is delivered into the systemic circulation of the animal or human being studied. The total exposure to the drug (AUC) when administered intravenously is (0-∞) ) is generally defined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which a compound (eg, Compound A) is absorbed into the systemic circulation when a pharmaceutical composition is taken orally compared to intravenous injection.

[0345] "Plasma concentration" refers to the concentration of a compound (e.g., Compound A) in the plasma component of blood in a subject. It should be understood that the plasma concentration of a compound (e.g., Compound A) may vary significantly between subjects due to changes in metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of a compound (e.g., Compound A) may vary from subject to subject. Similarly, values ​​such as maximum plasma concentration (C max ) or the time to reach maximum plasma concentration (T max ) or the total area under the plasma concentration-time curve (AUC (0-∞) ) and the like may vary from subject to subject. Due to this variability, the amount required to constitute a "therapeutically effective amount" of a compound (e.g., Compound A) may vary from subject to subject.

[0346] As used herein, the term "co-administered" or its analogs is intended to encompass the administration of selected therapeutic agents to a single subject, and is intended to include treatment regimens in which the drugs are administered by the same or different routes of administration or at the same or different times.

[0347] The term "effective amount" or "therapeutically effective amount" used in the present invention refers to the amount of the administered agent or compound sufficient to alleviate one or more symptoms of the disease or disorder being treated to a certain extent. The result can be to reduce and / or alleviate the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount required for the composition including the compound disclosed in the present invention to provide a clinically significant reduction in disease symptoms without undue adverse side effects. The appropriate "effective amount" for any individual case can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a preventive effective amount. The "effective amount" of the compound disclosed in the present invention is an amount that can effectively achieve the desired pharmacological effect or therapeutic improvement without undue adverse side effects. It should be understood that the "effective amount" or "therapeutically effective amount" can vary between subjects, which is due to differences in the metabolism of the compound (e.g., Compound A), the age, weight, general condition of the subject, the severity of the disorder being treated, and the judgment of the prescribing physician. By way of example only, the therapeutically effective amount can be determined by routine experiments including but not limited to dose escalation clinical trials.

[0348] The term "enhance" or "enhancing" refers to increasing or prolonging the potency or duration of a desired effect. As an example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong, in potency or duration, the effect of a therapeutic agent during the treatment of a disease, disorder, or condition. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of a therapeutic agent in treating a disease, disorder, or condition. When used in a subject, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0349] The term "identity" used in the present invention refers to that two or more sequences or subsequences are identical. In addition, the term "substantial identity" used in the present invention refers to that two or more sequences are compared and compared according to the maximum identity (such as measured by using a comparison algorithm or by manual comparison and visual inspection) on a comparison window or a specified area, and the same sequence unit reaches a certain percentage. For example only, if the sequence unit has about 60% identity, about 65% identity, about 70% identity, about 75% identity, about 80% identity, about 85% identity, about 90% identity or about 95% identity on a specified area, then two or more sequences can be "substantially identical". Such percentages are used to describe the "percent identity" of two or more sequences. Sequence identity can exist in a region with a length of at least about 75-100 continuous units, a region with a length of about 50 continuous units, or when not specified, in the entire sequence. This definition also refers to the complementary sequence of the test sequence. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are identical, and are "substantially identical" if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. Identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, when not specified, over the entire sequence of the polypeptide sequence. Additionally, by way of example only, two or more polynucleotide sequences are identical when the nucleic acid residues are identical, and are "substantially identical" if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. The identity can exist over a region that is at least about 75-100 nucleotides in length, over a region that is about 50 nucleotides in length, or, where not specified, across the entire sequence of a polynucleotide sequence.

[0350] As used herein, the terms "inhibition" of menin, "inhibiting" menin, or an "inhibitor" of menin refer to inhibiting the activity of menin, such as the menin-MLL interaction and activity.

[0351] The term "covalent inhibitor" as used herein refers to a compound that, when in contact with a target protein (e.g., menin or menin-MLL), results in the formation of a new covalent bond with or within the protein, and one or more biological activities of the target protein (e.g., phosphotransferase activity) are altered, reduced, or abolished regardless of the subsequent presence of the covalent inhibitor. In certain embodiments, the inhibitor is irreversible.

[0352] The term "covalent menin inhibitor" as used herein refers to a menin inhibitor that can form a covalent bond with an amino acid residue of menin. In certain embodiments, the inhibitor is irreversible.

[0353] As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.

[0354] As used herein, the term "modulator" refers to a compound that changes the activity of a molecule. For example, a modulator can cause the magnitude of a certain activity of a molecule to increase or decrease compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that reduces the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely blocks one or more activities of a molecule. In certain embodiments, a modulator is an activator that increases the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modulator produces an activity that does not occur in the absence of the modulator.

[0355] The term "prophylactically effective amount" as used herein refers to the amount of the composition applied to a patient that will alleviate one or more symptoms of the disease, condition or disorder being treated to a certain extent. In such preventive applications, such an amount may depend on the patient's health status, body weight, etc. It is considered to be well within the skill of those skilled in the art to determine such a prophylactically effective amount by routine experimentation (including but not limited to a dose escalation clinical trial).

[0356] The term "subject", "individual" or "patient" used in the present invention refers to an animal as a target of treatment, observation or experiment. By way of example only, the subject may be, but is not limited to, a mammal, including, but not limited to, a human.

[0357] As used herein, the term "target activity" or "target activity" refers to a biological activity that can be regulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or condition.

[0358] As used herein, the term "target protein" refers to a molecule, or a portion of a protein, that can be bound by a selective binding compound. In certain embodiments, the target protein is menin.

[0359] As used herein, the terms "treat", "treating" or "treatment" include alleviating, alleviating or ameliorating symptoms of a disease or disorder; preventing other symptoms; ameliorating or preventing potential metabolic causes of symptoms; inhibiting a disease or disorder, such as arresting the development of a disease or disorder; alleviating a disease or disorder; causing regression of a disease or disorder; alleviating symptoms caused by a disease or disorder; or stopping symptoms of a disease or disorder. The terms "treat", "treating" or "treatment" include, but are not limited to, preventive and / or therapeutic treatments.

[0360] As used in the present invention, IC 50 It refers to the amount, concentration or dose of a particular test compound that achieves a 50% inhibition of a maximal response (such as inhibition of menin) in an assay measuring such a response.

[0361] As used in the present invention, EC 50 It refers to the dose, concentration or amount at which a specific test compound causes a dose-dependent response that is 50% of the maximum expression of a specific response induced, caused or enhanced by the specific test compound. Pharmaceutical compositions / preparations

[0362] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers (including adjuvants and auxiliary agents) that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any known techniques, carriers and adjuvants can be used as appropriate and understood in the art. In addition to those pharmaceutical compositions described herein, overviews of other pharmaceutical compositions can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Eaton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated herein by reference in its entirety.

[0363] As used in the present invention, a pharmaceutical composition refers to a mixture of the compound described in the present invention (e.g., Compound A) and other chemical components (such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients). The pharmaceutical composition facilitates the administration of the compound to a subject (e.g., a mammal). When practicing the methods of treatment or methods of use provided by the present invention, a therapeutically effective amount of, for example, Compound A is administered to a subject (e.g., a mammal) suffering from a disease, disorder or condition to be treated in the form of a pharmaceutical composition. In one embodiment, the subject is a mammal. In one embodiment, the mammal is a human being. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the efficacy or potency of the compound used, and other factors. The compound may be used independently or in combination with one or more therapeutic agents as components of the mixture.

[0364] As used herein, the term "drug combination" or "drug combination" refers to a product produced by mixing or combining more than one active ingredient and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that, for example, the active ingredients of Compound A and a co-agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that, for example, Compound A and the active ingredients of a co-agent are administered to a patient simultaneously, concurrently or sequentially in separate entity forms without specific intervening time limits, wherein such administration provides effective levels of these two compounds in the patient's body. The latter is also applicable to cocktail therapy, for example, the administration of three or more active ingredients.

[0365] In some embodiments, crystalline compound A is incorporated into a pharmaceutical composition to provide a solid oral dosage form. In other embodiments, crystalline compound A is used to prepare a pharmaceutical composition other than an oral solid dosage form. The pharmaceutical preparation of the present invention can be applied to a subject by a variety of routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal routes of administration. The pharmaceutical preparation of the present invention includes but is not limited to aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release preparations, controlled release preparations, fast melt preparations, tablets, capsules, pills, delayed release preparations, sustained release preparations, pulse release preparations, multi-particle preparations, and mixed immediate release and controlled release preparations.

[0366] Pharmaceutical compositions containing the compounds of the present invention may be manufactured in conventional manner, eg, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. Dosage form

[0367] The pharmaceutical compositions of the present invention can be formulated for administration to a subject (e.g., a mammal) by any conventional means, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term "subject" is used to refer to an animal, such as a mammal, including humans or non-humans. The terms "patient" and "subject" are used interchangeably.

[0368] In addition, the pharmaceutical composition of the present invention comprising Compound A can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[0369] Pharmaceutical preparations for oral use can be prepared by mixing one or more solid excipients with one or more compounds of the invention, optionally grinding the resulting mixture and, if necessary, processing the granular mixture to obtain tablets or dragee cores after adding suitable auxiliary agents. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate) may be added.

[0370] Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin and sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer may be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0371] In some embodiments, the solid dosage form disclosed in the present invention may be in the following forms: tablets (including suspension tablets, fast-melt tablets, chewable disintegrating tablets, fast-disintegrating tablets, effervescent tablets or caplets), pills, powders (including sterile packaged powders, dispensable powders or effervescent powders), capsules (including soft capsules or hard capsules, such as capsules made of gelatin derived from animals or HPMC derived from plants, or "pellet capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulse release dosage forms, multi-particulate dosage forms, pellets, granules or aerosols. In other embodiments, the pharmaceutical composition is in the form of a powder. In other embodiments, the pharmaceutical composition is in the form of a tablet, including but not limited to a fast-melt tablet. In addition, the pharmaceutical composition described in the present invention can be administered in a single capsule form or in multiple capsule dosage forms. In some embodiments, the pharmaceutical composition is administered in the form of two, three or four capsules or tablets.

[0372] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of Compound A with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as being uniform, it is meant that the particles of Compound A are uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. Individual unit doses may also include a film coating that disintegrates upon oral ingestion or upon contact with a diluent. Such preparations can be made by conventional pharmacological techniques.

[0373] Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) grinding, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) melting. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, and the like.

[0374] The solid pharmaceutical dosage form of the present invention may include compound A and one or more pharmaceutically acceptable additives, such as compatible carriers, adhesives, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. In other cases, a standard coating procedure, such as the procedure described in Remington's Pharmaceutical Sciences, 20th Edition (2000), is used to provide a film coat around the preparation of compound A. In one embodiment, some or all particles of compound A are coated. In another embodiment, some or all particles of compound A are microencapsulated. In yet another embodiment, the particles of compound A are not microencapsulated and are not coated.

[0375] Suitable carriers that can be used in the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0376] Suitable fillers that can be used in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starches, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0377] In order to release the compound (e.g., Compound A) from the solid dosage form matrix as effectively as possible, disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. Disintegrants help the dosage form matrix to rupture by swelling or capillary action when moisture is adsorbed to the dosage form. Suitable disintegrants that can be used in the solid dosage form of the present invention include, but are not limited to, natural starches such as corn starch or potato starch; pregelatinized starches such as National 1551 or or sodium starch glycolate, such as or Cellulose, such as wood products; methylcrystalline cellulose, e.g. PH101, PH102, PH105, P100, Ming and Methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose Cross-linked carboxymethyl cellulose or cross-linked croscarmellose; cross-linked starch, such as sodium starch glycolate; cross-linked polymers, such as crospovidone; cross-linked polyvinyl pyrrolidone; alginates, such as alginic acid or a salt of alginic acid, such as sodium alginate; clays, such as HV (magnesium aluminum silicate); gums such as agar, guar, locust bean gum, galaya, pectin or tragacanth; sodium starch glycolate; bentonite; natural sponge; surfactant; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate combined with starch; and the like. In some embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as cross-linked polyvinyl pyrrolidone, sodium alginate, clay, and gums. In some embodiments provided herein, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0378] Binders impart cohesion to solid oral dosage form formulations. For powder-filled capsule formulations, they aid in plug formation that can be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms of the present invention include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., ), hydroxypropyl methylcellulose (e.g., Hydroxypropyl methylcellulose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. ), ethyl cellulose (e.g. ) and microcrystalline cellulose (e.g. ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinyl pyrrolidone / vinyl acetate copolymer, cross-linked polyvinylpyrrolidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars (such as sucrose (e.g. ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. ), lactose), natural or synthetic gums (such as gum arabic, tragacanth, gum ghatti), esparto mucilage, starch, polyvinyl pyrrolidone (e.g. CL, CL, XL-10 and K-12), larch arabinogalactan, Polyethylene glycol, waxes, sodium alginate, and the like.

[0379] Generally speaking, 20-70% binder content is used in powder-filled gelatin capsule formulations. The amount of binder used in tablet formulations varies with the use of direct compression, wet granulation, roller granulation or other excipients (such as fillers that can themselves act as moderate binders). The binder content of the formulation can be determined by a formulation technician in the field, but the binder content in tablet formulations is usually up to 70%.

[0380] Suitable lubricants or glidants that can be used in the solid dosage form of the present invention include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts (such as aluminum, calcium, magnesium, zinc), stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol (such as Carbowax TM In some embodiments provided by the present invention, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and waxes. In some embodiments provided by the present invention, the lubricant is magnesium stearate.

[0381] Suitable diluents that can be used for the solid dosage form of the present invention include, but are not limited to sugars (including lactose, sucrose and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins, and the like. In some embodiments provided by the present invention, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided by the present invention, the diluent is microcrystalline cellulose.

[0382] The term "water-insoluble diluent" refers to compounds typically used in pharmaceutical preparations, such as calcium phosphate, calcium sulfate, starches, modified starches, and microcrystalline cellulose, and microcellulose (e.g., with a density of about 0.45 g / cm 3 , such as Avicel, powdered cellulose), and talc.

[0383] Suitable wetting agents that can be used in the solid dosage form of the present invention include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g. ), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS, and the like.

[0384] Suitable surfactants that can be used in the solid dosage form of the present invention include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g. (BASF)), and the like. In some embodiments provided by the present invention, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided by the invention, the surfactant is sodium lauryl sulfate.

[0385] Suitable suspending agents that can be used in the solid dosage form of the present invention include, but are not limited to, polyvinyl pyrrolidone, such as polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25 or polyvinyl pyrrolidone K30; polyethylene glycol, such as polyethylene glycol having a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000; vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethyl cellulose, methyl cellulose , hydroxypropyl methylcellulose, polysorbate-80, hydroxyethylcellulose; sodium alginate; gums such as tragacanth and gum arabic, guar gum, and xanthan gum; sugars; cellulosic materials such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose; polysorbate-80; sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; povidone; and the like.

[0386] Suitable antioxidants that can be used in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0387] It should be understood that there is a large amount of overlap between the additives used in the solid dosage forms of the present invention. Therefore, the additives listed above should be considered as merely illustrative and not limiting of the types of additives that can be included in the solid dosage forms of the present invention. Those skilled in the art can easily determine the amount of such additives based on the specific characteristics required.

[0388] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, the plasticizer is generally a high boiling point solid or liquid. A suitable plasticizer accounting for about 0.01% by weight to about 50% by weight (w / w) of the coating composition may be added. Plasticizers include, but are not limited to diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, grease agents, stearates, and castor oil.

[0389] Compressed tablets are solid dosage forms made by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of the compound (e.g., Compound A) from the formulation. In other embodiments, the film coating helps achieve patient compliance (e.g., coating or sugar coating). including The film coating generally ranges from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablet includes one or more excipients.

[0390] Capsules can be prepared, for example, by placing the main blend of the preparation of the compound (e.g., Compound A) inside the capsule. In some embodiments, the preparation (non-aqueous suspension and solution) is placed in a soft gelatin capsule. In other embodiments, the preparation is placed in a standard gelatin capsule or a non-gelatin capsule (such as a capsule comprising HPMC). In other embodiments, the preparation is placed in a pellet-type capsule, wherein the capsule can be swallowed as a whole or the capsule can be opened and the contents can be sprayed on the food and then eaten. In some embodiments, the therapeutic dose is divided into multiple (e.g., two, three or four) capsules. In some embodiments, the entire dose of the preparation is delivered in one capsule form.

[0391] In various embodiments, particles of Compound A are dry blended with one or more excipients and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0392] In another case, the dosage form may include a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulated material. Exemplary materials include, but are not limited to, pH adjusters, erosion accelerators, defoamers, antioxidants, flavoring agents, and carrier materials (such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents).

[0393] The materials suitable for microencapsulation of the present invention include materials compatible with the compound (e.g., compound A) that fully separate the compound (e.g., compound A) from other incompatible excipients. Materials compatible with the compound (e.g., compound A) are those materials that delay the release of the compound (e.g., compound A) in vivo.

[0394] Exemplary microencapsulation materials suitable for delayed release of formulations containing the compounds of the invention include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as or Nisso HPC; low-substituted hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methyl cellulose ethers (HPMC), such as Seppifilm-LC, Metolose SR, -E, Opadry YS, Primaflo, Benecel MP824 and Benecel MP843; methylcellulose polymers such as Hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Ethyl cellulose (EC) and its mixtures, such as E461, Polyvinyl alcohol (PVA), such as Opadry AMB; hydroxyethyl cellulose, such as Carboxymethyl celluloses and salts of carboxymethyl cellulose (CMC), such as Polyvinyl alcohol and polyethylene glycol copolymers, such as Kollicoat Monoglycerides (Myver01); triglycerides (KLX); polyethylene glycols; modified food starch; acrylic acid polymers, and mixtures of acrylic acid polymers and cellulose ethers, such as EPO, L30D-55, FS 30D, L100-55, L100, S100, RDl00, E100, L12.5, S12.5, NE30D, and NE 40D; cellulose acetate phthalate, sepifilms, such as mixtures of HPMC and stearic acid; cyclodextrins; and mixtures of said materials.

[0395] In other embodiments, plasticizers (such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 800, PEG 1450, and PEG 3350), stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulation material suitable for delayed release of the pharmaceutical composition is from USP or National Formulary (NF). In other embodiments, the microencapsulation material is Klucel. In other embodiments, the microencapsulation material is methylcellulose.

[0396] The microencapsulated compound (e.g., Compound A) can be formulated by methods known to those of ordinary skill in the art. Such known methods include, for example, spray drying, turntable-solvent method, hot melt method, spray cooling method, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at a liquid-gas or solid-gas interface, pressurized extrusion, or spray solvent extraction bath. In addition, several chemical techniques such as complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in a liquid medium, in-situ polymerization, drying in a liquid, and desolvation in a liquid medium can also be used. In addition, other methods such as roller pressing, extrusion / spheronization, coacervation, or nanoparticle coating can also be used.

[0397] In one embodiment, the particles of Compound A are microencapsulated prior to formulation into one of the above forms. In yet another embodiment, some or most of the particles are coated prior to further formulation using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0398] In other embodiments, the solid dosage formulation of Compound A is plasticized (coated) with one or more layers. Illustratively, the plasticizer is generally a high boiling point solid or liquid. A suitable plasticizer may be added to the coating composition in an amount of about 0.01% by weight to about 50% by weight (w / w). Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, grease agents, stearates, and castor oil.

[0399] In other embodiments, powders or powders including formulations with Compound A can be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders or powders can be prepared, for example, by mixing the formulation with optional pharmaceutical excipients to form a bulk blend composition. Other embodiments also include a suspending agent and / or a wetting agent. This bulk blend is uniformly subdivided into unit dose packages or multi-dose package units.

[0400] In some other embodiments, effervescent powder is also prepared according to the present invention. Effervescent salts have been used to disperse medicine in water for oral administration. Effervescent salts are particles or coarse powders, which contain medicines in a dry mixture generally consisting of sodium bicarbonate, citric acid and / or tartaric acid. When the salt of the composition of the present invention is added to water, the acid and base react to release carbon dioxide gas, thereby causing "effervescence". The example of effervescent salts includes, for example, the following ingredients: a mixture of sodium bicarbonate or sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination causing carbon dioxide release can be used to replace the combination of sodium bicarbonate and citric acid and tartaric acid, as long as the ingredient is suitable for medical use and produces about 6.0 or higher pH.

[0401] In some embodiments, the solid dosage form of the present invention can be formulated into an enteric-coated delayed-release oral dosage form (that is, formulated into an oral dosage form of the pharmaceutical composition of the present invention that is released in the small intestine of the gastrointestinal tract using an enteric coating). The enteric-coated dosage form can be a compressed or molded or extruded tablet / mold (coated or uncoated) of granules, powders, pellets, beads or granules containing active ingredients and / or other composition components, and the granules, powders, pellets, beads or granules themselves are coated or uncoated. The enteric-coated oral dosage form can also be a capsule (coated or uncoated) of pellets, beads or granules containing a solid carrier or composition that is itself coated or uncoated.

[0402] The term "delayed release" as used herein refers to delivery such that the compound can be released at some generally predictable location in the intestinal tract, which is further away than the location where the release is achieved when there is no delayed release change. In some embodiments, the method of delayed release is via coating. Any coating should be applied to a sufficient thickness so that the entire coating is insoluble in gastrointestinal fluids at a pH below about 5, but dissolves at a pH of about 5 and above. It is expected that any anionic polymer that exhibits pH-dependent solubility characteristics can be used as an enteric coating in the methods and compositions of the present invention, thereby delivering to the lower gastrointestinal tract. In some embodiments, the polymers described in the present invention are anionic carboxylic acid polymers. In other embodiments, the polymers and compatible mixtures thereof and some of their characteristics include, but are not limited to: Shellac, also known as purified shellac, is a refined product obtained from the resin secretions of insects. This coating dissolves in a medium with a pH of more than 7; · Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available soluble in organic solvents, aqueous dispersions or dry powders. Eudragit series RL, NE and RS are insoluble in the gastrointestinal tract but are permeable and are primarily used for colon targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach but soluble in the intestine; Cellulose derivatives. Examples of suitable cellulose derivatives include: ethyl cellulose; and reaction mixtures of cellulose acetate esters and phthalic anhydride. The efficacy may vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH>6. Aquateric (FMC) is an aqueous solution-based system and is a spray-dried CAP psuedolatex with particles <1 μm. Other components in Aquateric may include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The efficacy may vary based on the degree and type of substitution. For example, HPMCPs such as HP-50, HP-55, HP-55S, HP-55F grades are suitable. The performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5; AS-MG (MF), which dissolves at pH 5.5; and AS-HG (HF), which dissolves at higher pH. These polymers are provided in granular form or fine powder form for aqueous dispersions; and polyvinyl acetate phthalate (PVAP). PVAP dissolves in pH>5 and has low permeability to water vapor and gastric fluid.

[0403] In some embodiments, the coating may contain and generally contains plasticizers and possible other coating excipients well known in the art, such as colorants, talc and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (triacetin), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers will generally contain 10-25% by weight plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating is applied using conventional coating techniques such as spray or pan coating. The recommended coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired local delivery site in the intestinal tract is reached.

[0404] Colorants, anti-adherents, surfactants, defoamers, lubricants (such as carnauba wax or PEG) may be added to the coating instead of plasticizers to dissolve or disperse the coating material and improve the coating performance and the coated product.

[0405] In other embodiments, the formulations of the present invention including compound A are delivered using a pulsatile dosage form. Pulsatile dosage forms are capable of providing one or more immediate release pulses at a predetermined time point or at a specific location after a controlled lag time. Many other types of controlled release systems are known to ordinary technicians and are suitable for use with the formulations of the present invention. Examples of such delivery systems include, for example, polymer-based systems such as polylactic acid and polyglycolic acid, polyanhydrides and polycaprolactones; porous matrices; non-polymer-based systems, which are lipids, including sterols such as cholesterol, cholesterol esters and fatty acids; or neutral fats such as monoglycerides, diglycerides and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings; bioerodible dosage forms; compressed tablets using conventional adhesives and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2 ndEd., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983, each of which is specifically incorporated herein by reference.

[0406] In some embodiments, the present invention provides a pharmaceutical composition comprising particles of compound A and at least one dispersant or suspending agent for oral administration to a subject. The formulation can be a powder and / or granules for suspension, and when mixed with water, a substantially uniform suspension is obtained.

[0407] It should be understood that there is overlap between the additives listed above that can be used in the aqueous dispersion or suspension described in the present invention, because a given additive is often classified differently by different practitioners in the field, or is often used for any of several different functions. Therefore, the additives listed above should be considered as merely illustrative and not limiting of the types of additives that can be included in the formulations described in the present invention. The amount of such additives can be readily determined by those skilled in the art based on the specific properties desired. Dosage and treatment regimen

[0408] In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is from 300 mg / day to up to and including 1000 mg / day. In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is from 420 mg / day to up to and including 840 mg / day. In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is about 420 mg / day, about 560 mg / day, or about 840 mg / day. In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, about 500 mg / day, about 525 mg / day, about 550 mg / day, about 560 mg / day, about 575 mg / day, about 600 mg / day , about 625 mg / day, about 650 mg / day, about 675 mg / day, about 700 mg / day, about 725 mg / day, about 750 mg / day, about 775 mg / day, about 800 mg / day, about 825 mg / day, about 840 mg / day, about 850 mg / day, about 875 mg / day, about 900 mg / day, about 925 mg / day, about 950 mg / day, about 975 mg / day, or about 1000 mg / day. In some embodiments, the amount of Compound A administered to a mammal is about 420 mg / day. In some embodiments, the amount of Compound A administered to a mammal is about 560 mg / day. In some embodiments, the AUC of Compound A is about 1.5-2.0. 0-24 From about 150ng*h / mL to about 3500ng*h / mL. In some embodiments, the AUC of Compound A is 0-24 In some embodiments, Compound A is administered orally. In some embodiments, Compound A is administered once a day, twice a day, or three times a day. In some embodiments, Compound A is administered daily. In some embodiments, Compound A is administered once a day. In some embodiments, Compound A is administered once every other day. In some embodiments, Compound A is a maintenance therapy.

[0409] In certain embodiments, the dose of Compound A is selected from 25mg to 1000mg. In certain embodiments, the dose of Compound A is selected from 25mg to 750mg. In certain embodiments, the dose of Compound A is selected from 25mg to 650mg. In certain embodiments, the dose of Compound A is selected from 25mg to 500mg. In certain embodiments, the dose of Compound A is selected from 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 325mg, 500mg and 650mg. In certain embodiments, the dose of Compound A is 25mg. In certain embodiments, the dose of Compound A is 50mg. In certain embodiments, the dose of Compound A is 75mg. In certain embodiments, the dose of Compound A is 100mg. In certain embodiments, the dose of Compound A is 125mg. In certain embodiments, the dose of Compound A is 150mg. In certain embodiments, the dose of Compound A is 175mg. In certain embodiments, the dose of Compound A is 200mg. In certain embodiments, the dose of Compound A is 325 mg. In certain embodiments, the dose of Compound A is 500 mg. In certain embodiments, the dose of Compound A is 650 mg.

[0410] In certain embodiments, Compound A is administered once daily. In certain embodiments, Compound A is administered twice daily. In certain embodiments, Compound A is administered three times daily. In certain embodiments, Compound A is administered four times daily. In certain embodiments, Compound A is administered daily in divided doses. In certain embodiments, Compound A is administered daily for a period of 28 days.

[0411] Compound A can be used to prepare a medicament for inhibiting menin or its homologues, or for treating a disease or condition that would benefit at least in part from the inhibition of menin or its homologues, including a subject diagnosed with a hematological malignancy. In addition, a method for treating any disease or condition described in the present invention in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof in a therapeutically effective amount.

[0412] Compositions containing Compound A may be administered for preventive, therapeutic, or maintenance therapy. In some embodiments, compositions containing Compound A are administered for therapeutic applications (e.g., administered to subjects diagnosed with hematological malignancies). In some embodiments, compositions containing Compound A are administered for therapeutic applications (e.g., administered to subjects susceptible to hematological malignancies or at risk of developing hematological malignancies). In some embodiments, compositions containing Compound A are administered to patients in remission as maintenance therapy.

[0413] The amount of Compound A will depend on the use (e.g., therapeutic, preventive, or maintenance). The amount of Compound A will depend on the severity and course of the disease or illness, previous treatment, the patient's health, weight, and response to the drug, and the judgment of the treating physician. It is considered to be well known to those skilled in the art to determine such therapeutically effective amounts by routine experiments (including, but not limited to, dose escalation clinical trials). In some embodiments, the amount of Compound A is 10 mg / day to up to and including 250 mg / day. In some embodiments, the amount of Compound A is 25 mg / day to up to and including 300 mg / day. In some embodiments, the amount of Compound A is 25 mg / day to up to and including 100 mg / day. In some embodiments, the amount of Compound A is about 25 mg / day. In some embodiments, the amount of Compound A is about 50 mg / day. In some embodiments, the amount of Compound A is about 100 mg / day. In some embodiments, the amount of Compound A is about 150 mg / day. In some embodiments, the amount of Compound A is about 200 mg / day. In some embodiments, the amount of Compound A is about 250 mg / day. In some embodiments, the amount of Compound A is 2 mg / kg / day to up to and including 13 mg / kg / day. In some embodiments, the amount of Compound A is 2.5 mg / kg / day to up to and including 8 mg / kg / day. In some embodiments, the amount of Compound A is 2.5 mg / kg / day to up to and including 6 mg / kg / day. In some embodiments, the amount of Compound A is 2.5 mg / kg / day to up to and including 4 mg / kg / day. In some embodiments, the amount of Compound A is about 2.5 mg / kg / day. In some embodiments, the amount of Compound A is about 8 mg / kg / day.

[0414] In some embodiments, the pharmaceutical composition of the present invention comprises about 25 mg of Compound A. In some embodiments, a capsule formulation comprising about 100 mg of Compound A is prepared. In some embodiments, 1, 2, 3, 4, or 5 capsules of the capsule formulation are administered daily. In some embodiments, 3 or 4 capsules are administered daily. In some embodiments, 3 140 mg capsules are administered once daily. In some embodiments, 4 140 mg capsules are administered once daily. In some embodiments, the capsule is administered once daily. In other embodiments, the capsule is administered multiple times daily.

[0415] In some embodiments, Compound A is administered once daily. In some embodiments, Compound A is administered twice daily. In some embodiments, Compound A is administered three times daily. In some embodiments, Compound A is administered four times daily.

[0416] In some embodiments, Compound A is administered until disease progression, unacceptable toxicity, or based on individual choice. In some embodiments, Compound A is administered daily until disease progression, unacceptable toxicity, or based on individual choice. In some embodiments, Compound A is administered every other day until disease progression, unacceptable toxicity, or based on individual choice.

[0417] If the patient's condition does improve, the compound (e.g., Compound A) may be continuously administered at the doctor's discretion; alternatively, the drug administration dose may be temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). The duration of a drug holiday may vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday may be between 10% and 100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0418] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced to a level at which the improved disease, disorder, or condition is maintained, depending on the symptoms. However, patients may require intermittent treatment for a long period of time, depending on any recurring symptoms.

[0419] The amount of a given drug corresponding to such dosage will vary depending on factors such as the specific compound, the severity of the disease, the identity (e.g., weight) of the subject or host to be treated, but is generally determined in a manner known in the art, based on the specific circumstances surrounding the individual case (including, for example, the specific drug being administered, the route of administration, and the subject or host being treated). However, in general, the dosage employed for adult treatment is generally in the range of 0.02 mg per day to 5000 mg per day, or about 1 mg per day to 1500 mg per day. The desired dosage may be conveniently presented in a single dosage form, or as divided doses administered simultaneously (or over a shorter period of time), or at appropriate intervals, for example, as sub-doses twice, three times, four times or more per day.

[0420] The pharmaceutical composition of the present invention may be in the form of a unit dosage form suitable for a single administration of an exact dose. In a unit dosage form, the preparation is divided into unit doses containing an appropriate amount of one or more compounds (e.g., Compound A). The unit dose may be in a packaged form containing a discrete amount of preparation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. The aqueous suspension composition may be packaged in a single dose non-reclosable container. Alternatively, a multi-dose reclosable container may be used, in which case a preservative is typically included in the composition. By way of example only, preparations for parenteral injection may be in unit dosage form, including but not limited to ampoules or multi-dose containers, to which a preservative is added. In some embodiments, each unit dosage form contains 140 mg of Compound A. In some embodiments, one unit dosage form is administered to an individual every day. In some embodiments, two unit dosage forms are administered to an individual every day. In some embodiments, three unit dosage forms are administered to an individual every day. In some embodiments, four unit dosage forms are administered to an individual every day.

[0421] The foregoing ranges are only suggested ranges, as the number of variables regarding individual treatment regimens is large, and it is not uncommon for deviations from these recommended values ​​to be significant. Such dosages may vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual patient, the severity of the disease or condition to be treated, and the physician's judgment.

[0422] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to determining the LD 50 (i.e., 50% population lethal dose) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD 50 / ED 50Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use, for example, in humans. The dosage of such compounds is preferably within the range that includes the ED with minimal toxicity. 50 The dosage may vary within this range depending on the dosage form and route of administration used. Combination therapy

[0423] In certain embodiments, it may be appropriate to combine or co-administer Compound A with another therapeutic agent.

[0424] In one embodiment, the compositions and methods of the present invention may also be used in combination with other therapeutic agents, which are selected for their specific use for the condition being treated. Generally speaking, in embodiments employing combination therapy, the compositions of the present invention and other agents do not have to be administered in the form of the same pharmaceutical composition, and may have to be administered by different routes due to different physical and chemical characteristics. In one embodiment, the initial administration may be performed according to a predetermined regimen, and then the dosage, mode of administration, and time of administration may be further modified based on the observed effects.

[0425] In various embodiments, the compounds may be administered in parallel (e.g., simultaneously, substantially simultaneously, or within the same treatment regimen) or sequentially, depending on the nature of the disease, the patient's condition, and the actual choice of compound used. In certain embodiments, the order of administration of each therapeutic agent and the number of administration repetitions are determined during the treatment regimen based on an assessment of the disease being treated and the patient's condition.

[0426] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.

[0427] The individual compounds of such combinations are administered sequentially or simultaneously in separate or combined pharmaceutical preparations. In one embodiment, the individual compounds are administered simultaneously in a combined pharmaceutical preparation. Those skilled in the art will appreciate the appropriate dosage of known therapeutic agents.

[0428] The combinations or associations mentioned in the present invention are conveniently used in the form of a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier.

[0429] In certain embodiments, disclosed herein are methods of treating cancer in an individual in need thereof, comprising administering to the individual an amount of Compound A. In some embodiments, the method further comprises administering a second cancer treatment regimen.

[0430] In some embodiments, administering a covalent inhibitor of menin-MLL interaction prior to a second cancer treatment regimen reduces immune-mediated responses to the second cancer treatment regimen. In some embodiments, administering Compound A prior to atumumab reduces immune-mediated responses to atumumab.

[0431] In some embodiments, the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises a B cell receptor pathway inhibitor. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCγ inhibitor, a PKCβ inhibitor, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises an antibody, a B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapy agent, a DNA damaging agent, a proteasome inhibitor, a Cyp3A4 inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jak1 / 2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.

[0432] In some embodiments, the second cancer treatment regimen is a BCL-2 inhibitor. In some embodiments, the second cancer treatment regimen is selected from the group consisting of: oblimersen (G3139), ABT-737 (CAS Registry No. 852808-04-9), navitoclax (ABT-263) and venetoclax (ABT-199). In some embodiments, the second cancer treatment regimen is ABT-199 (venetoclax, RG7601, GDC-0199, CAS Registry No. 1257044-40-8, or 4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide). In some embodiments, the second cancer treatment regimen is ABT-199 (venetoclax) and the treatment is synergistic.

[0433] In some embodiments, the second cancer treatment regimen comprises chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

[0434] In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab.

[0435] In some embodiments, the second cancer treatment regimen comprises bendamustine and rituximab.

[0436] In some embodiments, the second cancer treatment regimen comprises fludarabine, cyclophosphamide, and rituximab.

[0437] In some embodiments, the second cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally rituximab.

[0438] In some embodiments, the second cancer treatment regimen comprises etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab.

[0439] In some embodiments, the second cancer treatment regimen comprises dexamethasone and lenalidomide.

[0440] In some embodiments, the second cancer treatment comprises a proteasome inhibitor. In some embodiments, the second treatment comprises bortezomib. In some embodiments, the second cancer treatment comprises epoxyketone. In some embodiments, the second cancer treatment comprises epoxomicin. In some embodiments, the second cancer treatment comprises tetrapeptide epoxyketone. In some embodiments, the second cancer treatment comprises carfilzomib. In some embodiments, the second cancer treatment comprises disulfram, epigallocatechin-3-gallate, salinosporamide A, ONX0912m, CEP-18770, MLN9708, or MG132.

[0441] In some embodiments, the second cancer treatment comprises a Cyp3A4 inhibitor. In some embodiments, the second cancer treatment comprises indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, and / or nefazodone. In some embodiments, the second cancer treatment comprises ketoconazole.

[0442] In some embodiments, the second cancer treatment comprises a Janus kinase (JAK) inhibitor. In some embodiments, the second treatment comprises Lestaurtinib, Tofacitinib, Ruxolitinib, CYT387, Baricitinib, or Pacritinib.

[0443] In some embodiments, the second cancer treatment comprises a histone deacetylase inhibitor (HDAC inhibitor, HDI). In some embodiments, the second cancer treatment comprises a hydroxamic acid (or hydroxamate) such as trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589), a cyclic tetrapeptide such as trapoxin B, a depsipeptide, a benzamide such as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), a phenylbutyrate, an electrophilic ketone, or a fatty acid compound such as valproic acid.

[0444] Other cancer treatment options include: nitrogen mustards such as bendamustine, chlorambucil, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, prednimustine, and trofosfamide; alkyl sulfonates such as busulfan, mannosulfan, and treosulfan; ethyleneimines such as carboquinone, thiotepa, and trimethoprim-sulfaquinone; nitrosoureas such as carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, and streptozotocin; epoxides such as etoglucagon; other alkylating agents such as dacarbazine, dibromomannitol, pipobroman, and temozolomide; folic acid analogs, For example, methotrexate, pemetrexed, pralatrexate and raltitrexed; purine analogs, such as cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine and thioguanine; pyrimidine analogs, such as azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine and tegafur; vinca alkaloids, such as vinblastine, vincristine, vindesine, vinflunine and vinorelbine; podophyllotoxin derivatives, such as etoposide and teniposide; colchicine derivatives, such as colcemid; taxanes, such as docetaxel, paclitaxel and polyglutamic acid paclitaxel (paclitaxel poliglumex); other plant alkaloids and natural products, such as trabectedin; actinomycetes, such as actinomycin; anthracyclines, such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, and daunorubicin; other cytotoxic antibiotics, such as bleomycin, ixabepilone, mitomycin, and plicamycin; platinum compounds, such as carboplatin, cisplatin, oxaliplatin, and satraplatin; methylhydrazines, such as procarbazine; sensitizers, such as aminolevulinic acid, ivproximol, methyl aminolevulinate, porfimer sodium, and temoporfin; protein kinase inhibitors, such as dasatinib, alitiniboine, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, and temsirolimus; other antineoplastic drugs, such as alitretinoin, altretinoin, amzacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin, estramustine, hydroxyurea, irinotecan, lonidamine, masorol, miltefosein, mitofosin, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, sitimagene ceradenovec), thiazofurine, topotecan, tretinoin, and vorinostat; estrogens, such as diethylstilbenol, ethinyl estradiol, fosfostilbenol, and polyestradiol phosphate; progestins, such as progesterone, medroxyprogesterone, and megestrol;Gonadotropin-releasing hormone analogs, such as buserelin, goserelin, leuprolide, and triptorelin; antiestrogens, such as fulvestrant, tamoxifen, and toremifene; antiandrogens, such as bicalutamide, flutamide, and nilutamide; enzyme inhibitors, such as aminoglutethimide, anastrozole, exemestane, formestane, letrozole, and vorozole; other hormone antagonists, such as abarelix and degarelix; immunostimulants, such as histamine dihydrochloride, mifamurtide, and phenytoin. ide), pidotimod, plerixafor, roquinimex, and thymopentin; immunosuppressants such as everolimus, gusperimus, leflunomide, mycophenolic acid, and sirolimus; calcineurin inhibitors such as cyclosporine and tacrolimus; other immunosuppressants such as azathioprine, lenalidomide, methotrexate, and thalidomide; and radiopharmaceuticals such as iobenguane. ;

[0445] Other cancer treatment options include interferons, interleukins, tumor necrosis factors, growth factors, or their analogs.

[0446] Other cancer treatment options include: immunostimulants such as ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, and sargramostim; interferons such as interferon alpha natural, interferon alpha-2a, interferon alpha-2b, interferon alfacon-1, interferon alpha-n1, interferon beta natural, interferon beta-1a, interferon beta-1b, interferon gamma, pegylated interferon alpha-2a, and pegylated interferon alpha-2b; interleukins such as aldesleukin and oprelleukin; other immunostimulants such as BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifastatin, pegademase, pidotimod, plerixafor, polyinosinic acid (PCP), cytosine, ... I: C), polyICLC, roquine, tasonermin, and thymopentin; immunosuppressants, such as abatacept, abetimus, afacept, anti-lymphocyte immunoglobulin (horse), anti-thymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muromonab-CD3, mycophenolic acid, natalizumab, and sirolimus; TNFα inhibitors, such as adalimumab, afelimomab, certolizumab pegol These include abpegol, etanercept, golimumab, and infliximab; interleukin inhibitors, such as anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, and ustekinumab; calcineurin inhibitors, such as cyclosporine and tacrolimus; and other immunosuppressants, such as azathioprine, lenalidomide, methotrexate, and thalidomide.

[0447] Other cancer treatment options include Adalimumab, Alemtuzumab, Basiliximab, Bevacizumab, Cetuximab, Certolizumab pegol, Daclizumab, Eculizumab, Efalizumab, Gemtuzumab, Ibritumomab tiuxetan, Infliximab, Muromonab-CD3, Natalizumab, Panitumumab, Ranibizumab, Rituximab, Tositumomab, Trastuzumab, or their analogs, or a combination thereof.

[0448] Other cancer treatment options include: monoclonal antibodies such as alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, and trastuzumab; immunosuppressants such as eculizumab, efalizumab, muromonab-CD3, and natalizumab; TNF Alpha inhibitors, such as adalimumab, afelimomab, certolizumab pegol, golimumab, and infliximab; interleukin inhibitors, such as basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab, and ustekinumab; radiopharmaceuticals, such as ibritumomab tiuxetan tiuxetan and tositumomab; other monoclonal antibodies, such as abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetin, pendetide, cixutumumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab, inotuzumabozogamicin), ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab umab, ramacurimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab, tucotuzumabcelmoleukin, veltuzumab, visilizumab, volociximab, and zalutumumab.

[0449] Other cancer treatment options include drugs that affect the tumor microenvironment, such as cell signaling networks (e.g., phosphatidylinositol 3-kinase (PI3K) signaling pathways, signaling from B cell receptors and IgE receptors). In some embodiments, the second drug is a PI3K signaling inhibitor or a syc kinase inhibitor. In one embodiment, the syk inhibitor is R788. In another embodiment, the second drug is a PKCγ inhibitor, such as enzastaurin.

[0450] Examples of drugs that affect the tumor microenvironment include: PI3K signaling inhibitors, syc kinase inhibitors, protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib and temsirolimus; other angiogenesis inhibitors such as GT-111, JI-101 and R1530; other kinase inhibitors such as AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, BI 811283, BI6727, BIBF1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinaciclib, dovitinib lactate, E7050, EMD1214063, ENMD-2076, fostamatinib disodium salt disodium), GSK2256098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, linifan ib), LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON01919.Na, OSI-027, OSI-930, Btk inhibitors, PF-00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763, ramucirumab, regorafenib, RO5185426, SAR103168, SCH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232, TTP607, XL147, XL228, XL281RO5126766, XL418, and XL765. .

[0451] Other examples of anticancer agents used in combination with a covalent inhibitor compound of menin-MLL interaction (e.g., Compound A) include: inhibitors of mitogen-activated protein kinase signaling, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituximab).

[0452] Other anticancer agents that can be used in combination with a covalent inhibitor compound of the menin-MLL interaction (e.g., Compound A) include: Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, and Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; binasafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carrnustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine;dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride hydrochloride); hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin I1 (including recombinant interleukin II or rIL2), interferon α-2a, interferon α-2b; interferon α-n1; interferon α-n3; interferon β-1a; interferon γ-1b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid acid; nocodazoie; nogalamycin; orrnaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin, puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, spalfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0453] Other anticancer agents that can be used in combination with a covalent inhibitor compound of the menin-MLL interaction (e.g., Compound A) include: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenosine; adolesin; aldesleukin; ALL-TK antagonists; hexamethylmelamine; ambamustine; amidox; and amifotine. mifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; irreversible inhibitors of angiogenesis; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; anti-androgen prostate cancer; anti-estrogen; anti-neoplaston; antisense oligonucleotides; glycine aphidicolin glycinate; apoptosis gene regulators; apoptosis regulators; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; diazotyrosine; baccatin III derivatives IIIderivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta-lactam derivatives; beta-alethine; beta-clarithromycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; binefad; bistratene A; bizeresin; breflate; bropiridamine; budotitane; buthioninesulfoximine; calcipotriol; calciphosphotin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamide-triazole; CaRest M3; CARN 700; cartilage-derived inhibitor; cardzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B;cetrorelix; chlorambucil; chloroquinoxalinesulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; colismycin A A); clitrimycin B; combretastatin A4; combretastatin analogs; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinone; eycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron dolasetron; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; ethidium bromide; epirubicin; epristeride; estrogen nitrogen mustard analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezlastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadoliniumtexaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylenediethylamide; hypericin; ibandronic acid acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor 1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iodoxorubicin; 4-naphthoic acid; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate triacetate; lanreotide; leinamycin; lelagostine; lentinan sulfae; leptolstatin; letrozole; leukemia inhibitory factor; interferon-alpha; leuprolide+estrogen+progesterone; leuprolide; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide7; lobaplatin; lombricine; lometrexol; lonidamine;losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; cleavable peptides; maitansine; mannostatin A A); marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; dibromodulanol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multidrug resistance gene inhibitors; multiple tumor suppressor factor l-based therapy; nitrogen mustard anticancer agent; Indian Ocean sponge B (mycaperoxide B); mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitric oxide antioxidants; nitrullyn;O6-Benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A A); platinum B; plasminogen activator inhibitors; platinum complexes; platinum compounds; platinum-triamine complexes; porfimer sodium; porfiromycin; prednisone; propyl diacridone; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors; microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; rhodopsin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated retiptine; rhenium Re 186 Etidronate; rhizobactin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex;rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; oligonucleotides; signal transduction inhibitors; signal transduction regulators; single-chain antigen-binding proteins; sizofiran; sobuzoxane; sodium borocarb; sodium phenylacetate; solverol; somatomedin-binding proteins; sonermin; sparsosic acid; skamycin D; spiromustine; splenopentin; spongistatin 1 1); squalamine; stem cell inhibitors; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonists; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium sodium); pyralidone; tellurapyrylium; irreversible telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonists; thymotrinan; thyroid stimulating hormone; tinethyl etiopurpurin; tirapazamine; titanocenyl dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector systems, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and statins.

[0454] Still other anticancer agents that can be used in combination with a covalent inhibitor compound of the menin-MLL interaction (e.g., Compound A) include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustards (e.g., dichloromethyldiethylamine, cyclophosphamide, and chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine and lomustine, etc.), or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, and pentostatin).

[0455] Examples of alkylating agents that can be used in combination with a covalent inhibitor compound of the menin-MLL interaction (e.g., Compound A) include, but are not limited to, nitrogen mustards (e.g., dichloromethyldiethylamine, cyclophosphamide, chlorambucil, and melphalan, etc.), ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, and streptozotocin, etc.), or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, and cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, and pentostatin).

[0456] Since stabilized microtubules act by arresting cells in the G2-M phase, examples of anticancer agents that can be used in combination with covalent inhibitor compounds that can interact with menin-MLL (e.g., Compound A) include, but are not limited to, the following marketed drugs and drugs in development: erbulol (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mivobulin isethionate (also known as styrene), and styrene-13 (also known as styrene-13). isethionate (also known as CI-980), vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as altohetin A and altohetin C), Spongistatins (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), Cemadotin hydrochloride (also known as cypermethrin), cypermethrin ... hydrochloride, also known as LU-103793 and NSC-D-669356), epothilones (epothilones such as epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pha rmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,Also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Nostoc 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Cyanocyanin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (ParkerHughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt.Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt.Sinai School of Medicine,Also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A and Z-Eleutherobin), Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (AstaMedica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (AstaMedica), Medica), D-68836 (AstaMedica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth), D-82317 (zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0457] In certain embodiments, when a subject suffers from an autoimmune disease, an inflammatory disease, or an allergic disease or is at risk of suffering from such diseases, Compound A can be used in any combination with one or more of the following therapeutic agents: immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate mofetil, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), nonsteroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulphonanilides), Cox-2 specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF-alpha binding proteins (such as infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-beta, interferon-gamma, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, or anticholinergics. Kit or product

[0458] For use in therapeutic applications described herein, the present invention also describes kits and articles. Such kits may include carriers, packages, or containers separated to receive one or more containers (such as vials, tubes, and the like), each container including one of the individual elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container may be made of various materials such as glass or plastic.

[0459] The articles provided by the present invention contain packaging materials. Packaging materials for packaging pharmaceutical products include, for example, those described in U.S. Patent No. US5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packaging, bottles, tubes, bags, containers, bottles, and any packaging materials suitable for selected formulations and predetermined administration and treatment modes.

[0460] In some embodiments, the compound or composition of the present invention is present in a package or dispenser device, which may contain one or more unit dosage forms containing active ingredients. The compound or composition of the present invention is packaged alone or with another compound or another ingredient or additive. In some embodiments, the package contains one or more containers containing one or more ingredients of the pharmaceutical composition of the present invention. In some embodiments, the package contains metal or plastic foil, such as a blister package. In some embodiments, the package or dispenser device is accompanied by instructions for use, such as instructions for using the compound or composition to treat tumor diseases. In some embodiments, the package or dispenser is accompanied by precautions related to the container, the form of which is prescribed by a government agency that manages the manufacture, use or sale of drugs, and the precautions reflect the form in which the agency approves the drug for human or veterinary administration. In some embodiments, such precautions are, for example, prescription drug labels approved by the U.S. Food and Drug Administration or approved product inserts. In some embodiments, the composition includes a compound of the present invention (e.g., compound A) formulated in a compatible pharmaceutical carrier, and it is prepared, placed in an appropriate container and labeled for treatment of the indicated condition.

[0461] For example, the container may contain Compound A, optionally in the form of a composition or in combination with another drug described herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[0462] The kit typically includes a label listing the contents and / or instructions for use, and a package insert with instructions for use. A set of instructions is also typically included.

[0463] In one embodiment, the label may be located on or associated with the container. In one embodiment, the label may be located on the container when the letters, numbers or other characters forming the label are attached, molded or etched on the container itself; the label may be associated with the container when the label is present in a receptacle or carrier that also holds the container, such as in the form of a package insert. In one embodiment, the label may be used to indicate the contents for a specific therapeutic application. The label may also indicate the contents, such as instructions for use in the methods described herein.

[0464] In certain embodiments, the pharmaceutical composition can be presented with a package or dispenser device, which may contain a unit dosage form of a compound provided by the present invention (e.g., Compound A). The package may, for example, contain a metal or plastic foil, such as a blister package. In one embodiment, the package or dispenser device may be accompanied by instructions for administration. In one embodiment, the package or dispenser may also be accompanied by precautions associated with the container, the form of which is regulated by a government agency that regulates the manufacture, use or sale of pharmaceuticals, and the precautions reflect that the agency approves the drug form for human or veterinary administration. For example, such precautions may be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In one embodiment, a composition comprising a compound provided by the present invention (e.g., Compound A) formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for use in treating the indicated condition.

[0465] In another aspect, the present invention describes deuterated analogs of Compound A [N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, deuterated analogs] as covalent inhibitors of menin-MLL interactions, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs and amorphous phases thereof, and methods of use thereof. In certain embodiments, only one hydrogen is replaced by deuterium. In certain embodiments, one or more hydrogens are replaced by deuterium.

[0466] In certain embodiments, the deuterated analog of Compound A is:

[0467] wherein deuterium is attached to any one or more positions selected from 2, 3, 5, 6, 13, 15, 19, 20, 22, 23, 26, 28, 29, 31, 33-37, 40 and 42 as shown above.

[0468] In certain embodiments, deuterium is attached to any one or more positions selected from 2, 3, 5, and 6 as shown above. In certain embodiments, deuterium is attached to any one or more positions selected from 13 and 15 as shown above. In certain embodiments, deuterium is attached to any one or more positions selected from 19, 20, 22, and 23 as shown above. In certain embodiments, deuterium is attached to any one or more positions selected from 26, 28, and 29 as shown above. In certain embodiments, deuterium is attached to position 31 as shown above. In certain embodiments, deuterium is attached to any one or more positions selected from 33-36 as shown above. In certain embodiments, deuterium is attached to any one or more positions selected from 40-42 as shown above.

[0469] In certain embodiments, the deuterated analog of Compound A is:

[0470] In certain embodiments, one or more hydrogens of the central pyridine ring are replaced with deuterium.

[0471] In another aspect, the present invention describes a covalent inhibitor of menin-MLL interaction, namely compound P, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs and amorphous phases thereof, and methods of use thereof. In certain embodiments, only one hydrogen in compound P is replaced by deuterium.

[0472] In another aspect, the present invention describes deuterated analogs of Compound P as covalent inhibitors of menin-MLL interactions, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs and amorphous phases thereof, and methods of use thereof. In certain embodiments, only one hydrogen in Compound P is replaced by deuterium. In certain embodiments, one or more hydrogens of Compound P are replaced by deuterium.

[0473] In certain embodiments, the deuterated analog of Compound P is:

[0474] wherein deuterium is attached to any one or more positions selected from 1, 3, 4, 6, 13, 14, 16, 18-20, 23, 24, 27, 33, 36, 37, 39 and 40 as shown above.

[0475] In certain embodiments, deuterium is attached to any one or more positions selected from 1, 3, 4, and 6 as indicated above.

[0476] In certain embodiments, deuterium is attached to any one or more positions selected from 13, 14, and 16 as shown above.

[0477] In certain embodiments, deuterium is attached to any one or more positions selected from 18-20 as indicated above.

[0478] In certain embodiments, deuterium is attached to any one or more positions selected from 23 and 24 as shown above.

[0479] In certain embodiments, deuterium is attached to position 27 as indicated above.

[0480] In certain embodiments, deuterium is attached to any one or more positions selected from 33 as shown above.

[0481] In certain embodiments, deuterium is attached to any one or more positions selected from 36, 37, 39, and 40 as shown above.

[0482] In certain embodiments, the deuterated analog of Compound P is: Example

[0483] The following ingredients, formulations, processes and procedures for preparing compounds and practicing methods disclosed herein correspond to the compounds and methods described above. Preparation of Compound A

[0484] Compound A was prepared according to the method described in US Pat. No. 11,084,825 (incorporated by reference in its entirety).

[0485] Alternatively, compound A can be prepared according to the following synthesis scheme: Example 1: Preparation of a crystalline form of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) Preparation of Polymorph Form A

[0486] Compound A in its HCl salt form was dissolved in deionized water (3.00 vol) and saturated aqueous NaHCO3 was slowly added to the mixture until the solution was neutral (pH=7). Solids precipitated during the addition. The solids were collected by filtration and washed with MeOH (2.00 vol). The filter cake was dried in a 45°C oven for 24 hours to give Compound A in its free base form. Preparation of Model B

[0487] Compound A was dissolved in DCM: MeOH (1: 1, 150 vol), and resin (SMA-905, 50% by weight) was added. The mixture was then stirred at 65°C for 12 hours. The mixture was then cooled to 25°C and filtered. The filtrate was concentrated in vacuo to give Compound A. Preparation of Polymorph Form C

[0488] Pattern C was successfully prepared using the following procedure. • Weigh approximately 200 mg of Compound A into a 4 mL glass vial. TFE (2.2 mL) was then added to the vial. The resulting suspension was maintained as a slurry at 50°C for about 2 hours; the resulting slurry was then stirred for about 3 days in the dark. - The solids were isolated by filtration and the wet cake was studied by XRPD. Moderate crystalline pattern C was obtained as a light yellow solid. XRPD, TGA, DSC and 1 The solid was further characterized by H NMR. Characterization of Mode C Description “ / / ”: Not performed Preparation of Polymorph Form E

[0489] Pattern E (DMSO solvate): About 50 mg of Compound A was equilibrated in DMSO (0.4 mL) at 25°C with stirring. After one day, additional DMSO (0.4 mL) was added to maintain the resulting suspension. After equilibration for two weeks, the solid was isolated by centrifugal filtration to give Pattern E. Preparation of Polymorph Pattern G

[0490] Pattern G (TFE solvate): About 30 mg of Compound A was dissolved in TFE (2 mL). The resulting solution was filtered through a 0.45 μm nylon filter. The resulting clear solution was slowly evaporated at ambient temperature. After 8 days, the residual solid was analyzed by XRPD to obtain Pattern G. Preparation of Polymorph Form F

[0491] Pattern F was successfully prepared using the following procedure. • Weigh approximately 250 mg of Compound A into an 8 mL glass vial. Add MeOH:DCM (1:1 v / v, 4 mL) to the vial. The resulting suspension was kept as a slurry at 25°C for about two hours and then stirred for about 5 days in the dark. - The solids were isolated by filtration and the wet cake was studied by XRPD. Highly crystalline pattern F was obtained as a light yellow solid. 1 The solid was further characterized by H NMR. Characterization of Mode F Description “ / / ”: Not performed Preparation of Polymorph Pattern D

[0492] Pattern D, Compound A, Pattern D-Drying was successfully prepared using the following procedure. Weigh approximately 500 mg of Compound A into an 8 mL glass vial. Add THE:water (80:20 v / v, 8 mL) into the vial. The resulting suspension was kept as a slurry at 50°C for about 4 days in the dark. • The solids were separated by filtration and the wet cake was dried under vacuum at 50°C for about 3 hours. ·Highly crystalline pattern D was obtained as a light yellow solid (yield 54%). 1 The dried solid was further characterized by H NMR, KF and DVS. Preparation of polymorph pattern D-1

[0493] Pattern D, Compound A, Pattern D - THF-water-drying was successfully prepared using the following procedure. Weigh approximately 8 g of Compound A into a 120 mL glass vial. Add THF; water (80:20 v / v, 80 mL) into the vial to maintain suspension. - The resulting suspension was kept as a slurry at 50°C for about 2 days in the dark. - THF:water (80:20 v / v, 20 mL) was added to maintain the resulting suspension. • The solids were separated by filtration and the wet cake was dried under vacuum at 50°C for about 12 hours. 6.66 g of moderate crystalline pattern D was obtained as a light yellow solid (yield 82.5%). By XRPD, TGA, DSC, 1 The dried solid was further characterized by H NMR and KF.

[0494] Manual grinding to prepare the amorphous free form

[0495] The amorphous free form was successfully prepared using the following procedure, Mode D - Milling - Amorphous Free Form. • 2 g of free form Mode D were manually ground using a mortar and pestle for 10 minutes. 1.83 g of amorphous free form was obtained as a light yellow solid (yield 91.5%). The yellow powder was studied by XRPD and mDSC. Preparation of amorphous free form by manual grinding

[0496] The characterization of Compound A Amorphous Free Form, Sample Mode D - Milled - Amorphous Free Form is reported in the table below.

[0497] The characterization of Compound A Form Mode D, Sample Scale-Up - Mode D - THF-Water-Drying is reported in the table below. Description: “ / / ”: Not performed Preparation of Polymorph Pattern J

[0498] Compound A in the form of HCl salt was dissolved in deionized water (3.00 vol) and saturated aqueous NaHCO3 was slowly added to the mixture until pH = 7. Solids precipitated during the addition. The solids were then collected by filtration and washed with MeOH (2.00 vol). The filter cake was dried in an oven at 45°C for 24 hours to give Compound A as Pattern J. Example 2: X-ray powder diffraction (XRPD)

[0499] X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS or Bruker AXS D8 diffractometer. Bruker AXS C2 GADDS

[0500] X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a HiStar 2D area detector. The X-ray optics consisted of a single Goebel coupled to a 0.3 mm pinhole collimator. The X-ray beam was scanned in θ-θ continuous scanning mode with a sample-detector distance of 20 cm and an effective 2θ range of 3.2°-29.7°. Typically, the sample was exposed to the X-ray beam for 120 seconds. The software used for data acquisition was GADDS, version WNT 4.1.16, and the data were analyzed and presented using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2.

[0501] Environmental conditions

[0502] Samples run under ambient conditions were prepared as flat plate specimens using raw powder without grinding. Approximately 1-2 mg of sample was gently pressed onto a glass slide to obtain a flat surface.

[0503] Non-ambient conditions

[0504] Samples run under non-ambient conditions were mounted on a silicon wafer with thermally conductive compound. The samples were then heated to the appropriate temperature (unless otherwise stated) at a rate of 10°C / min and subsequently held isothermally for 1 minute before starting data acquisition. Bruker AXS D8 Advance

[0505] X-ray powder diffraction patterns were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), a θ-2θ goniometer, and V4 divergence and receiving slits, a Ge monochromator, and a Lynxeye detector. The instrument was performance checked using a certified Corundum standard (NIST 1976). The software used for data acquisition was Diffrac Plus XRDCommander v2.5.0, and the data were analyzed and presented using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2. Samples run under ambient conditions were prepared as flat plate samples using raw powder. The sample was gently loaded into a cavity cut out of a polished zero background (510) silicon wafer. The sample rotated through its own plane during analysis. Details of the data acquisition are as follows: · Angular range: 2 to 42° 2θ Step length: 0.05°20 Acquisition time: 0.5s / step XRPD of Form A

[0506] The X-ray powder diffraction of Form A is as follows Figure 1A Characteristic peaks include: 3.5±0.1°2θ, 10.4±0.1°2θ, 14.7±0.1°2θ, 17.1±0.1°2θ, 21±0.1°2θ, 24.9±0.1°2θ, 29.5±0.1°2θ, and 34.1±0.1°2θ. XRPD of Form B

[0507] The X-ray powder diffraction of Form B is as follows Figure 2ACharacteristic peaks include: 5.9±0.1°2θ, 8.6±0.1°2θ, 10.5±0.1°2θ, 12.6±0.1°2θ, 16.9±0.1°2θ, 19±0.1°2θ, 20.5±0.1°2θ, and 24.6±0.1°2θ. XRPD of Form C

[0508] The X-ray powder diffraction of Form C is as follows Figure 3A Characteristic peaks include: 5.2±0.1°2θ, 5.9±0.1°2θ, 7.2±0.1°2θ, 8.7±0.1°2θ, 10.6±0.1°2θ, 12.2±0.1°2θ, 14.3±0.1°2θ, 15.1±0.1°2θ, 15.9±0.1°2θ, 17.5±0.1°2θ, 18.1±0.1°2θ, and 20.1±0.1°2θ. XRPD of Form D

[0509] The X-ray powder diffraction of Form D is as follows Figure 4A shown. Characteristic peaks include: 3.4±0.1°2θ, 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3± 0.1°2θ, 15.6±0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ.

[0510] The crystallinity was not affected after storage at 40°C / 75%RH for one week, or at 25°C / 92%RH for one week. XRPD of Form E

[0511] The X-ray powder diffraction of Form E is as follows Figure 5AAs shown. The characteristic peaks include: 3.4 ± 0.1° 2θ, 4.7 ± 0.1° 2θ, 6.3 ± 0.1° 2θ, 6.9 ± 0.1° 2θ, 7.1 ± 0.1° 2θ, 7.6 ± 0.1° 2θ, 8.6 ± 0.1° 2θ, 9.3 ± 0.1° 2θ, 10.8 ± 0.1° 2θ, 12 ± 0.1° 2θ, 12.5 ± 0.1° 2θ, 13 ± 0.1° 2θ, 13.8 ± 0.1° 2θ, 15.7 ± 0.1° 2θ, 16.2 ± 0.1° 2θ, 16.7 ± 0.1° 2θ, 17 ± 0.1° 2θ, 17.5 ± 0.1° 2θ, 18.4 ± 0.1° 2θ, 18.6 ± 0.1° 2θ, 19.6 ± 0.1° 2θ, 20.7 ± 0.1° 2θ, 21.4 ± 0.1° 2θ, 22.2 ± 0.1° 2θ, 23 ± 0.1° 2θ, 24.2 ± 0.1° 2θ, 25.3 ± 0.1° 2θ, 26 ± 0.1° 2θ, 28 ± 0.1° 2θ, 29.2 ± 0.1° 2θ, 30.5 ± 0.1° 2θ, 31.6 ± 0.1° 2θ, 33.6 ± 0.1° 2θ, and 34.5 ± 0.1° 2θ. XRPD of Form F

[0512] The X-ray powder diffraction of Form F is as Fig. 6A shown. The characteristic peaks include: 4.2 ± 0.1° 2θ, 6.3 ± 0.1° 2θ, 8.6 ± 0.1° 2θ, 8.8 ± 0.1° 2θ, 12 ± 0.1° 2θ, 12.2 ± 0.1° 2θ, 12.5 ± 0.1° 2θ, 14.4 ± 0.1° 2θ, 15 ± 0.1° 2θ, 16 ± 0.1° 2θ, 16.8 ± 0.1° 2θ, 17.2 ± 0.1° 2θ, 17.5 ± 0.1° 2θ, 17.8 ± 0.1° 2θ, 18.8 ± 0.1° 2θ, 19.2 ± 0.1° 2θ, 20.1 ± 0.1° 2θ, 20.5 ± 0.1° 2θ, 21.7 ± 0.1° 2θ, 22.1 ± 0.1° 2θ, 23.4 ± 0.1° 2θ, 24.2 ± 0.1° 2θ, 25.3 ± 0.1° 2θ, 25.5 ± 0.1° 2θ, 26.3 ± 0.1° 2θ, 27.1 ± 0.1° 2θ, 29 ± 0.1° 2θ, 30.3 ± 0.1° 2θ, 31.6 ± 0.1° 2θ, 33.1 ± 0.1° 2θ, 34.3 ± 0.1° 2θ, and 35.6 ± 0.1° 2θ. XRPD of Form G

[0513] The X-ray powder diffraction of Form G is as Fig. 7ACharacteristic peaks include: 8±0.1°2θ, 10.2±0.1°2θ, 12.1±0.1°2θ, 16.8±0.1°2θ, 19.2±0.1°2θ, and 24.6±0.1°2θ. XRPD of Form J

[0514] The X-ray powder diffraction of Form J is as follows Fig. 8A The characteristic peaks include: 3.5±0.1°2θ, 4.5±0.1°2θ, 6.4±0.1°2θ, 8.7±0.1°2θ, 10.2±0.1°2θ, 11.3±0.1°2θ, 11.8±0.1°2θ, 13.2±0.1°2θ, 13.6±0.1°2θ, 14±0.1°2θ, 14.6±0.1°2θ, 15.4±0.1°2θ, 16.1±0.1°2θ, 16.6±0.1°2θ, 16.9±0.1°2θ, 17.2±0.1°2θ, 18.3±0 .1°2θ, 19.1±0.1°2θ, 20.5±0.1°2θ, 20.8±0.1°2θ, 21.6±0.1°2θ, 23.5±0.1°2θ, 23.8±0.1°2θ, 24.6±0.1°2θ, 24.9±0.1°2θ, 25.2±0.1°2θ, 25.8±0.1°2θ, 26.2±0 .1°2θ, 26.7±0.1°2θ, 26.8±0.1°2θ, 27.4±0.1°2θ, 27.7±0.1°2θ, 28.7±0.1°2θ, 29.3±0.1°2θ, 30.1±0.1°2θ, 31.2±0.1°2θ, 31.8±0.1°2θ, 34.1±0.1°2θ, 34.9±0 .1°2θ, 35.6±0.1°2θ, 36.4±0.1°2θ, 36.7±0.1°2θ, 38.5±0.1°2θ, and 38.8±0.1°2θ. Simulated XRPD of Form D

[0515] A simulated XRPD pattern of Form D was generated. The simulated X-ray powder diffraction pattern of Form D is shown at Figure 4A middle. Characteristic peaks include: 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3±0.1°2θ , 15.6±0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ. Example 4: Fourier Transform-Infrared (FrIR)

[0516] Data were collected on a Perkin-Elmer Spectrum One equipped with a universal attenuated total reflectance (ATR) sampling accessory. Data were collected and analyzed using Spectrum v5.0.1 software.

[0517] The infrared spectrum of Form D shows Fig.9A The characteristic peaks observed in the infrared spectrum of Form D include -1 (Unmarked), about 2853cm -1 (Unmarked), about 1561cm -1 (Unmarked), about 1523cm -1 、About 1438cm -1 、About 1257cm -1 、1112cm -1 , and about 930cm -1 The peak value at . Example 5: Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

[0518] DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Heat capacity calibration was performed using sapphire, and energy and temperature calibration was performed using certified indium. Typically, 0.5-3 mg of each sample was placed in an aluminum pan with a pinhole and heated from 25°C to 300°C at a rate of 10°C / min. Unless otherwise stated, a dry nitrogen purge of 50 mL / min was maintained for the sample. The modulated temperature DSC was performed using a basic heating rate of 2°C / min and a temperature modulation parameter of ±0.318°C (amplitude) per 60 seconds (cycle). The instrument control software was Advantage for Q Series v2.8.0.392 and Thermal Advantage v4.8.3, and the data were analyzed using Universal Analysis v4.4A.

[0519] TGA data are collected on a TA Instruments Q500 TGA equipped with a sixteen-bit automatic sampler. The instrument is temperature calibrated using a certified aluminum nickel alloy (Alumel and Nickel). Typically, 3-10 mg of each sample is loaded into a pre-weighed aluminum DSC pan and heated to 350 ° C from ambient temperature at a speed of 10 ° C / min. Unless otherwise stated, a nitrogen purge of 60 mL / min is maintained for the sample. The instrument control software is Advantage for Q Series v2.8.0.392 and Thermal Advantage v4.8.3, and Universal Analysis v4.4A is used to analyze the data. Form A

[0520] In DSC (heating rate: 10°C / min or 20°C / min), an endothermic peak was observed to start at about 234.6°C and peak at about 245°C. Form C

[0521] In DSC (heating rate: 10°C / min or 20°C / min), an endothermic peak was observed to start at about 150-151°C and peak at about 156-157°C. Form D

[0522] In DSC (heating rate: 10°C / min or 20°C / min), an endothermic peak was observed starting at about 260-261°C and peaking at about 273°C. Form E

[0523] In DSC (heating rate: 10°C / min or 20°C / min), an endothermic peak was observed starting at about 112-113°C and peaking at about 137-138°C.

[0524] In some embodiments, the purity of Form A is greater than 95% by HPLC analysis. In some embodiments, the purity of Form A is greater than 96% by HPLC analysis. In some embodiments, the purity of Form A is greater than 97% by HPLC analysis. In some embodiments, the purity of Form A is greater than 98% by HPLC analysis. In some embodiments, the purity of Form A is greater than 99% by HPLC analysis. In some embodiments, the purity of Form A is 99.8% by HPLC analysis.

[0525] In some embodiments, the purity of Form B is greater than 95% by HPLC analysis. In some embodiments, the purity of Form B is greater than 96% by HPLC analysis. In some embodiments, the purity of Form B is greater than 97% by HPLC analysis. In some embodiments, the purity of Form B is greater than 98% by HPLC analysis. In some embodiments, the purity of Form B is greater than 99% by HPLC analysis. In some embodiments, the purity of Form B is 97.8% by HPLC analysis. In some embodiments, the purity of Form B is 99.8% by HPLC analysis.

[0526] In some embodiments, the purity of Form C is greater than 95% by HPLC analysis. In some embodiments, the purity of Form C is greater than 96% by HPLC analysis. In some embodiments, the purity of Form C is greater than 97% by HPLC analysis. In some embodiments, the purity of Form C is greater than 98% by HPLC analysis. In some embodiments, the purity of Form C is greater than 99% by HPLC analysis. In some embodiments, the purity of Form C is 99.4% by HPLC analysis.

[0527] In some embodiments, the purity of Form D is greater than 95% by HPLC analysis. In some embodiments, the purity of Form D is greater than 96% by HPLC analysis. In some embodiments, the purity of Form D is greater than 97% by HPLC analysis. In some embodiments, the purity of Form D is greater than 98% by HPLC analysis. In some embodiments, the purity of Form D is greater than 99% by HPLC analysis. In some embodiments, the purity of Form D is 99.4% by HPLC analysis.

[0528] In some embodiments, the purity of Form E is greater than 95% by HPLC analysis. In some embodiments, the purity of Form E is greater than 96% by HPLC analysis. In some embodiments, the purity of Form E is greater than 97% by HPLC analysis. In some embodiments, the purity of Form E is greater than 98% by HPLC analysis. In some embodiments, the purity of Form E is greater than 99% by HPLC analysis. In some embodiments, the purity of Form E is 99.4% by HPLC analysis.

[0529] In some embodiments, the purity of Form F is greater than 95% by HPLC analysis. In some embodiments, the purity of Form F is greater than 96% by HPLC analysis. In some embodiments, the purity of Form F is greater than 97% by HPLC analysis. In some embodiments, the purity of Form F is greater than 98% by HPLC analysis. In some embodiments, the purity of Form F is greater than 99% by HPLC analysis. In some embodiments, the purity of Form F is 99.4% by HPLC analysis.

[0530] In some embodiments, the purity of Form G is greater than 95% by HPLC analysis. In some embodiments, the purity of Form G is greater than 96% by HPLC analysis. In some embodiments, the purity of Form G is greater than 97% by HPLC analysis. In some embodiments, the purity of Form G is greater than 98% by HPLC analysis. In some embodiments, the purity of Form G is greater than 99% by HPLC analysis. In some embodiments, the purity of Form G is 99.4% by HPLC analysis. Solid oral dosage form

[0531] In some embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into a solid oral dosage form. In some embodiments, the crystallinity of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is maintained in a solid oral dosage form. In some embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into tablets. In some embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into pills. In some embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into a capsule. In some embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is placed in a capsule containing no excipients or containing excipients. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form A. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form B. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form C.In any of these embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form D. In any of these embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form E. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form F. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, and Form F. Example 6: Capsule Preparation

[0532] In one embodiment, a capsule formulation of Compound A for administration to humans is prepared using the following ingredients: Table 1. Capsule formulations

[0533] In some embodiments, the manufacturing method includes the steps of weighing the specified amounts of ingredients, mixing them together and adding them to capsules of appropriate size, and sealing the capsules. In some embodiments, the capsules are stored at room temperature for a long period of time until use. Example 7: Compound A

[0534] The process steps for making compound A capsules (25 mg and 100 mg) are described as follows (Tables 2 and 3). The API is mixed with pregelatinized starch, lactose, cross-linked polyvinylpyrrolidone and colloidal silicon dioxide in a drum mixer. The resulting mixture is ground using a conical grinder (to de-agglomerate). The ground mixture is mixed again in a drum mixer. Magnesium stearate is added and the powders are mixed. The mixture is roller compacted. For 100 mg capsules, extragranular pregelatinized starch is added to the granules and mixed. The final mixture is filled into capsules using a semi-manual process. The capsules are dusted / polished, checked for metal condition, and weight classified. Table 2 Composition of Compound A Capsules (25 mg) Table 3 Composition of Compound A Capsules (100 mg) *Correction factors may be used to account for API potency **Adjust pregelatinized starch to accommodate API correction factor Example 8: Safety and tolerability study of compound A in chronic lymphocytic leukemia

[0535] The safety, tolerability, PK / PD, and clinical activity of increasing doses of Compound A were determined in an open-label, dose-escalation study of Compound A. When administered to adult patients (i.e., patients ≥18 years of age) with R / R acute leukemia (including ALL, AML, and acute mixed phenotype leukemia (AMPL)), the compound was administered daily in a 28-day cycle using an accelerated titration design (ATD) with doses escalated according to a modified Fibonacci sequence (i.e., using an increment ratio of 2.00 for the initial increment, 1.67 for the second increment, 1.50 for the third increment, and then 1.33 for all subsequent dose levels).

[0536] Two separate dose escalations are conducted in parallel, with the dose escalation arms (A, B) selectively enrolling patients who have not received (A) or are receiving (B) drugs that inhibit cytochrome P450 3A4 (CYP3A4) activity. After the optimal biological dose (OBD) is determined, two expansion cohorts (differentiated by whether patients are receiving CYP3A4 inhibitors) will be conducted late in phase 1, each consisting of approximately 12 patients with R / R acute leukemia to further evaluate the safety and tolerability of the drug when administered with the OBD and to determine the initial efficacy signal. If a single OBD can be determined, a single expansion cohort consisting of approximately 24 patients with R / R acute leukemia will be conducted.

[0537] Compound A is administered as an oral dose once daily in a 28-day cycle. The dose is escalated and / or expanded up to the potential maximum tolerated dose to determine the optimal biological dose and the recommended Phase 2 dose.

[0538] In Phase 2, patients with acute leukemia were recruited. Patients included subjects with R / R AML, ALL, or AMPL, wherein the subjects contained mixed lineage leukemia gene rearrangement (MLL, also known as lysine methyltransferase 2A, KMT2A), MLL / KMT2A partial tandem duplication (MLL-PTD), PICALM-AF10 (also known as CALM-AF10) rearrangement, nuclear phosphoprotein 1 (NPM1) mutation, meningioma 1 (MN1) translocation, or CCAAT enhancer binding protein α (CEBP / A) mutation. Patients received continuous 28-day cycles of treatment starting on Day 1. Throughout the study, the pharmacokinetics and pharmacodynamics of the patients were evaluated. Endpoints included complete remission, complete remission with partial hematological recovery, overall survival, and event-free survival. Example 9: Safety and tolerability study of compound A in chronic lymphocytic leukemia

[0539] Objective: The objective of this study was to determine the safety and optimal dose of oral administration of Compound A (25 mg / day or 100 mg / day) in patients with B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma / diffuse well-differentiated lymphocytic lymphoma. Main outcome measures: Safety and tolerability of compound A (frequency, severity, and relevance of adverse events). Secondary outcome measures: Pharmacokinetic / pharmacodynamic assessments. Tumor response: Overall response rate and duration of response as defined by the most recent CLL and SLL (B-cell lymphoma) guidelines. Eligibility: 18 years of age or older; both men and women are eligible.

[0540] Inclusion criteria: 1. Only for the initial treatment group: men and women aged ≥65 years, diagnosed with CLL / SLL, and requiring treatment according to NCI or international working group guidelines 11-14. 2. Only for the relapsed / refractory group: men and women aged 18 years and older, diagnosed with relapsed / refractory CLL / SLL, and unresponsive to treatment (i.e., failed ≥2 previous CLL / SLL treatments, and for subjects with CLL, at least one treatment regimen must contain a purine analog (e.g., fludarabine)). 3. Weight ≥40 kg. 4. ECOG performance status ≤2. 5. If sexually active and able to reproduce, agree to take contraceptive measures during the study and within 30 days after the last dose of study medication. 6. Willing and able to participate in all required assessments and procedures in this study protocol, including swallowing capsules without difficulty. 7. Able to understand the purpose and risks of this study and provide a signed and dated informed consent and authorization for the use of protected health information (in accordance with national and local subject privacy regulations).

[0541] Exclusion criteria: 1. The investigator believes that the presence of life-threatening diseases, medical conditions or organ system dysfunction may endanger the safety of the subjects, interfere with the absorption or metabolism of compound A (PO), or expose the study results to excessive risks. 2. Any immunotherapy, chemotherapy, radiotherapy or experimental treatment within 4 weeks before the first dose of study drug (corticosteroids are allowed to treat disease-related symptoms, but they need to be removed 1 week before the study drug is administered). 3. Lymphoma involving the central nervous system (CNS). 4. Major surgery within 4 weeks before the first dose of study drug. 5. Creatinine>1.5 times the upper limit of normal (ULN); total bilirubin>1.5 times ULN (unless due to Gilbert's disease); and aspartate aminotransferase (AST) or alanine aminotransferase (ALT)>2.5 times ULN, unless disease-related. 6. Concomitant use of drugs known to cause QT prolongation or torsade de pointes. 7. Significant abnormalities in the screening electrocardiogram (ECG), including left bundle branch block, type II 2nd degree atrioventricular block, 3rd degree block, bradycardia, and QTc>470 milliseconds. 8. Lactating or pregnant. Example 10: Safety and efficacy of Compound A in subjects with relapsed / refractory (R / R) mantle cell lymphoma (MCL)

[0542] The primary objective of this trial is to evaluate the efficacy of Compound A in relapsed / refractory (R / R) subjects with mantle cell lymphoma (MCL). The secondary objective is to evaluate the safety of a daily fixed dosing regimen of Compound A (25 mg / day or 100 mg / day in capsule form) in this patient population. Main outcome measure: The number of participants who responded to Compound A was determined. Secondary outcome measures: Measuring the number of participants with adverse events as a measure of safety and tolerability Measuring pharmacokinetics to help determine how the body responds to the study drug Patient-reported outcomes (measuring the number of participants with reported outcomes to determine health-related quality of life). Eligibility: 18 years of age or older; both men and women are eligible. Inclusion criteria: Males and females ≥18 years of age. ECOG performance status ≤2. Pathologically confirmed MCL with documented overexpression of cyclin D1 or t(11;14) and measurable disease on cross-sectional imaging, ≥2 cm in longest diameter and measurable in two perpendicular dimensions. Documented failure to achieve at least partial response (PR) to the most recent treatment regimen or documented disease progression after the most recent treatment regimen. At least one but no more than five prior treatment regimens for MCL (Note: Subjects who have received ≥2 cycles of prior treatment with bortezomib, either as a monotherapy or as part of a combination therapy regimen, will be considered bortezomib-exposed). Willing and able to participate in all required assessments and procedures of the study protocol, including swallowing capsules without difficulty. Able to understand the purpose and risks of this study and provide signed and dated informed consent and authorization for the use of protected health information (in accordance with national and local subject privacy regulations). Major exclusion criteria: prior chemotherapy within 3 weeks, nitrosourea within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radio-immunoconjugates or toxin-immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within two weeks of the first dose of study drug. Any life-threatening disease, medical condition, or organ system dysfunction that the investigator believes may compromise the safety of the subject, interfere with the absorption or metabolism of Compound A capsules, or put the study results at undue risk. Clinically significant cardiovascular disease, such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within six months of screening, or any class 3 or 4 heart disease defined by the New York Heart Association functional classification. Malabsorption syndrome, disease that significantly affects gastrointestinal function, or gastric or small bowel resection or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete intestinal obstruction. Any of the following laboratory abnormalities: 1. Absolute neutrophil count (ANC) <750 cells / mm 3 (0.75 x10 9 / L), unless bone marrow involvement is documented. 2. Platelet count <50,000 cells / mm 3 (50 x 10 9 / L), regardless of transfusion support, unless bone marrow involvement is documented. 3. Serum aspartate aminotransferase (AST / SGOT) or alanine aminotransferase (ALT / SGPT) ≥ 3.0 times the upper limit of normal (ULN). 4. Creatinine > 2.0 times ULN. Example B1a Pan-KRAS inhibitory activity in vitro

[0543] This example evaluates the ability of the compounds provided by the present invention to inhibit the proliferation of KRAS mutant cells.

[0544] The inhibitory effect on cell proliferation was studied in the human pancreatic KRAS mutant cell lines MIA PaCa-2, HuP-T4, HPAF-II, the human lung KRAS mutant cell line NCI-H358, and the human colon KRAS mutant cell lines SW837, SW60, and NCI-H747. Cells were maintained in RPMI-1640 medium (ThermoFisher catalog number 61870036), Eagle's minimal essential medium (EMEM, ATCC catalog number 30-2003), Leibovitz's L-15 medium (L-15, ATCC catalog number 30-2008), supplemented with 10% heat-inactivated FBS (ThermoFisher catalog number A31605) and 1% Pen-Strep (ThermoFisher catalog number 10378016) according to the cell line supplier's medium requirements, and cultured at 37° C. in a humidified incubator containing 5% CO 2. Cells grew by attachment to the culture flasks and were maintained at 70%-80% cell confluence.

[0545] ATP is present in all metabolically active cells and is considered a marker of viable cells. CellTiter-Glo kit (Promega catalog number G7572) was used according to the supplier's experimental recommendations based on the addition of ATP to The number of metabolically active living cells in culture was determined by a luminescent ATP monitoring system (Kawano et al.,...

Claims

1. Compound represented by formula (I): N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, or a pharmaceutically acceptable salt thereof.

2. Compound represented by formula (II): N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(S)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, which is in enantiomeric excess.

4. A compound according to any one of the preceding claims having an enantiomeric excess of at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

5. A composition comprising a compound according to any one of the preceding claims, wherein The relative weight of the compound in the composition is at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% compared to the total weight of all stereoisomers of the compound in the composition.

6. Compound represented by formula (III) (Compound P): or a pharmaceutically acceptable salt thereof.

7. A compound according to any one of the preceding claims, wherein The compounds are pharmaceutically acceptable salts.

8. A pharmaceutical preparation for oral administration, comprising: (a) from about 10 mg to about 250 mg of a compound or composition according to any one of the preceding claims; (b) from about 50 wt % to about 80 wt % of one or more diluents; (c) from about 1 wt % to about 10 wt % of one or more disintegrants; (d) from about 0.2 wt % to about 3 wt % of one or more glidants; and (e) from about 0.2 wt % to about 1.0 wt % of one or more lubricants.

9. The pharmaceutical preparation according to claim 8, wherein The diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc.

10. The pharmaceutical preparation according to claim 9, wherein The diluents are pregelatinized corn starch and lactose.

11. The pharmaceutical preparation according to claim 8, wherein The disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinyl pyrrolidone, sodium alginate, clay, and gums.

12. The pharmaceutical preparation according to claim 8, wherein The disintegrant is crospovidone.

13. The pharmaceutical preparation according to claim 8, wherein The glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, starch, and talc.

14. The pharmaceutical preparation according to claim 13, wherein The flow aid is fumed silica.

15. The pharmaceutical preparation according to claim 8, wherein The lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and waxes.

16. The pharmaceutical preparation according to claim 15, wherein The lubricant is magnesium stearate.

17. The pharmaceutical preparation according to claim 8, wherein The diluents were pregelatinized corn starch and lactose, the disintegrant was crospovidone, the glidant was fumed silicon dioxide, and the lubricant was magnesium stearate.

18. The pharmaceutical preparation according to claim 8, comprising: (a) about 25, 50, 100, 150, 200, or 250 mg of the compound; (b) about 70 wt % to about 80 wt % pregelatinized corn starch and lactose; (c) about 5 wt % of crospovidone; (d) about 0.5 wt% to 1 wt% fumed silica; and (e) about 0.2 wt% to 0.5 wt% magnesium stearate.

19. The pharmaceutical preparation according to any one of claims 8 to 18, wherein The dosage form is a hard gelatin capsule.

20. A package comprising one or more separate blister bags, wherein: Each blister pack contains a unit dosage form comprising: a) about 25, 50, 100, 150, 200, or 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; b) from about 70 wt % to about 80 wt % of a diluent; c) from about 3 wt % to about 10 wt % of a disintegrant; d) from about 0.5 wt % to about 1 wt % of a glidant; and e) about 0.2 wt % to about 1.0 wt % of a lubricant; Each blister pack contains a metal or plastic foil.

21. The package according to claim 20, wherein Each unit dosage form contains: a) about 25, 50, 100, 150, 200, or 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; b) 70 wt % to 80 wt % of pregelatinized corn starch and lactose; c) 2 wt % to 5 wt % of crospovidone; d) 0.5 wt% to 1 wt% fumed silica; and e) 0.2 wt% to 1.0 wt% of magnesium stearate.

22. Form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 4A ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of 3.4±0.1°2θ, 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3±0.1°2θ, 15.6±0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 8.7±0.1°2θ, 10.7±0.1°2θ, 15.6±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, and 24.2±0.1°2θ; (d) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 40° C. and 75% relative humidity (RH) for at least one week; (e) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 25° C. and 92% RH for at least one week; (f) having substantially the same X-ray powder diffraction (XRPD) pattern after storage in a sealed container at 60° C. and 75% RH for at least one week; (g) an infrared (IR) spectrum substantially similar to that shown in FIG. 9A ; (h) Infrared (IR) spectrum (Figure 9A) at about 3332 cm -1 、About 2853cm -1 , about 1561cm -1 、About 1524cm -1 、About 1319cm -1 、About 1258cm -1 , and about 1067cm -1 A peak appears at (i) a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG10 ; (j) a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in FIG11 ; (k) a DSC thermogram having an endothermic peak starting at about 260.5° C. and peaking at about 273° C.; (l) is basically similar to that shown in FIG. 1 H NMR (nuclear magnetic resonance) spectroscopy; (m) Hygroscopicity and absorption of approximately 2.1% water observed from 40% RH to 70% RH at 25°C; (n) an aqueous solubility of about 0.004 mg / mL observed at about pH 4.5; or (o) any combination thereof.

23. A form according to claim 22, wherein: Form D is a crystalline form.

24. The form of claim 22, wherein: Form D is a hydrate.

25. The form of claim 22, wherein: Form D has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4A.

26. The form of claim 22, wherein: Form D has an X-ray powder diffraction (XRPD) pattern substantially the same as shown below: *±0.1°。 27. The form of claim 22, wherein: Form D has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 5.3±0.1°2θ, 7±0.1°2θ, 8.7±0.1°2θ, 10.8±0.1°2θ, 12.9±0.1°2θ, 14.3±0.1°2θ, 15.6±0.1°2θ, 17±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, 21.5±0.1°2θ, and 24.2±0.1°2θ.

28. The form of claim 22, wherein: Form D has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2θ, 8.7±0.1°2θ, 10.7±0.1°2θ, 15.6±0.1°2θ, 18.5±0.1°2θ, 19.6±0.1°2θ, and 24.2±0.1°2θ.

29. The form of claim 22, wherein: Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 40°C and 75% RH for at least one week.

30. The form of claim 22, wherein: Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 25°C and 92% RH for at least one week.

31. The form of claim 22, wherein: Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in a sealed container at 60°C and 75% RH for at least one week.

32. The form of claim 22, wherein: Form D has an infrared (IR) spectrum substantially similar to that shown in Figure 9A.

33. The form of claim 22, wherein: Form D has a peak at about 3332 cm -1 、About 2853cm -1 , about 1561cm -1 、About 1524cm -1 、About 1319cm -1 、About 1258cm -1 , and about 1067cm -1 Infrared (IR) spectrum with a peak at .

34. The form of claim 22, wherein: Form D has a melting temperature of about 272-274°C.

35. The form of claim 22, wherein: Form D has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in FIG. 10 .

36. The form of claim 22, wherein: Form D has a DSC thermogram substantially similar to that shown in FIG11.

37. The form of claim 22, wherein: The DSC thermogram of Form D has an endothermic peak starting at about 260.5 °C and peaking at about 273 °C.

38. The form of claim 22, wherein: Form D has a substantially similar 1 H NMR (nuclear magnetic resonance) spectrum.

39. The form of claim 22, wherein: Form D has an aqueous solubility of about 0.004 mg / mL observed at about pH 4.

5.

40. The form of claim 23, wherein: The crystalline form is characterized by having property (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), or (o).

41. The form of claim 23, wherein: The crystalline form is characterized by having properties (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), and (o).

42. A form according to any one of claims 23 to 41, wherein: The form is a crystalline form, and the crystalline form is obtained from ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), nitromethane, methanol, ethanol, acetonitrile, dioxane, methyl tert-butyl ether (MTBE), anisole, acetone, heptane, methanol / water, or acetone / heptane mixtures.

43. The crystalline form of any one of claims 23-42, wherein The crystalline form is unsolvated.

44. The crystalline form of any one of claims 23-43, wherein The crystalline form is anhydrous.

45. The pharmaceutical preparation according to any one of claims 8 to 19, wherein N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form D.

46. ​​A pharmaceutical formulation for oral administration comprising: (a) 25 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline form D; (b) about 21 wt % pregelatinized corn starch (Starch 1500); (c) about 37% lactose (FastFlo Lactose 316); (d) about 5 wt % of crospovidone; (e) about 1 wt % fumed silica; and (f) about 0.5 wt % magnesium stearate.

47. A pharmaceutical preparation for oral administration comprising: (a) 100 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline form D; (b) about 28 wt % pregelatinized corn starch (Starch 1500); (c) about 27% lactose (FastFlo Lactose 316); (d) about 4 wt % of crospovidone; (e) about 0.8 wt % fumed silica; and (f) about 0.4 wt % magnesium stearate.

48. A pharmaceutical formulation for oral administration comprising: (a) 25 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline form D; (b) about 45 mg of pregelatinized corn starch (Starch 1500); (c) about 43 mg of lactose (FastFlo Lactose 316): (d) about 6 mg of crospovidone; (e) about 1 mg of fumed silica or colloidal silica; and (f) about 0.6 mg of magnesium stearate.

49. A pharmaceutical preparation for oral administration comprising: (a) 100 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide in crystalline form D; (b) about 331 mg of pregelatinized corn starch (Starch 1500); (c) about 174 mg of lactose (FastFlo Lactose 316); (d) about 24 mg of crospovidone; (e) about 5 mg of fumed silica or colloidal silica; and (f) about 2.4 mg of magnesium stearate.

50. The package of claim 20 or 21, wherein: N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline Form D.

51. A method of treating cancer in a mammal, comprising administering to the mammal a pharmaceutical formulation according to any one of claims 1-49.

52. The method of claim 51, wherein: The cancer is leukemia.

53. The method of claim 51, wherein: The cancer is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

54. The method of claim 51, wherein: The mammal has an MLL / KMT2A gene rearrangement.

55. The method of claim 51, wherein: The mammal has a NPM1 mutation.

56. The method according to any one of claims 51 to 55, wherein: The pharmaceutical formulation is administered in combination with a BCL-2 inhibitor.

57. The method of claim 56, wherein: The BCL-2 inhibitor is venetoclax.

58. A method for treating a KRAS mutant cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, or a pharmaceutically acceptable salt thereof.

59. The method of claim 58, wherein: The cancer is a solid tumor.

60. The method of claim 58, wherein: The KRAS mutation is a KRAS G12 mutation.

61. The method of claim 58, wherein: The KRAS mutation is a KRAS G12C, G12V, G12D, or G13D mutation.

62. The method according to any one of claims 58 to 61, wherein: The N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is in the form or pharmaceutical preparation according to any one of claims 1 to 49.

63. A method for treating diffuse large B-cell lymphoma or multiple myeloma in a mammal, comprising administering to the mammal a therapeutically effective amount of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, or a pharmaceutically acceptable salt thereof.

64. The method of claim 63, wherein: The mammal suffers from triple-hit lymphoma.

65. The method of claim 63, wherein: The mammal suffers from double expresser lymphoma.

66. The method of claim 63, wherein: The mammal suffers from multiple myeloma.

67. The method according to any one of claims 58 to 61, wherein: The N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is in the form or pharmaceutical preparation according to any one of claims 1 to 49.

68. The method of claim 51, wherein: The mammal has a TP53 mutation.

69. The method of claim 51, wherein: The mammal has a NOTCH1 mutation.

70. The method of claim 51, wherein: The mammal has a NPM1 mutation.

71. The method of claim 51, wherein: The mammal has an ATM mutation.

72. The method of claim 51, wherein: The mammal has a WT1 mutation.

73. The method of claim 51, wherein: The mammal has a KMT2A mutation.

74. The method of claim 51, wherein: The mammal has a TET2 mutation.

75. The method of claim 51, wherein: The mammal has an MLL rearrangement.

76. The method of claim 51, wherein: The mammal has a MYC amplification.

77. The method of claim 51, wherein: The mammal has a chromosome 13 deletion karyotype (del(13q) karyotype).

78. The method of claim 51, wherein: The mammal has a trisomy 12 karyotype.

79. The method according to any one of claims 51 to 78, wherein: The mammal is a human.

80. The method according to any one of claims 51 to 79, wherein: The dosage of the compound, form or pharmaceutical preparation is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 325 mg, 500 mg, and 650 mg.

81. The method according to any one of claims 51 to 79, wherein: The dosage of the compound, form or pharmaceutical preparation is administered daily.

82. The method according to any one of claims 51 to 79, wherein: Doses of the compound, form or pharmaceutical formulation are administered daily for 28 days.

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