Crystalline forms 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, methods for preparing the same, pharmaceutical compositions comprising the same, and uses thereof

Abstract

This invention provides N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, comprising its crystalline form, solvate, and pharmaceutically acceptable salt. Pharmaceutical compositions comprising this compound are also disclosed, as well as methods of using the compound alone or in combination with other therapeutic agents for the treatment of autoimmune diseases or conditions, xenoimmune diseases or conditions, cancers (including lymphoma), and inflammatory diseases or conditions.

Description

[Technical Field]

[0001] This invention describes a covalent inhibitor of menin-MLL, N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, including its stereoisomers, crystalline forms, solvates and pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising the above-described covalent inhibitor of menin-MLL interaction and methods of treating diseases or conditions that would benefit from inhibition of menin-MLL activity using the above-described covalent inhibitor of menin-MLL interaction. [Previous Technology]

[0002] The histone-lysine N-methyltransferase 2 (KMT2) protein family, consisting of at least five members, 4-methylates lysine on the tail of histone H3 in important regulatory regions of the genome, thereby conferring key functions by regulating chromatin structure and DNA openness (Morera, Lübbert, and Jung., Clin. Epigenetics 8, 57- (2016)). These enzymes are known to play important roles in the regulation of gene expression during early development and hematopoiesis (Rao & Dou., Nat. Rev. Cancer 15, 334-346 (2015)).

[0003] The human KMT2 family was originally named the mixed-lineage leukemia (MLL) family because of the role of the first member discovered in the disease, KMT2A, which is still commonly referred to as MLL1 or MLL in routine clinical practice.

[0004] KMT2A (MLL1) is frequently identified as a cytogenetic target in several types of leukemia, such as ALL and AML. In cases where balanced chromosomal translocations are found, these are typically targeted at KMT2A (MLL1) and one of the more than 80 translocation partner genes described to date (Winters and Bernt, Front. Pediatr. 5, 4 (2017)). These chromosomal abnormalities often lead to the formation of fusion genes encoding fusion proteins that are thought to be causally related to the onset and / or progression of the disease. Inhibition of menin may be a promising strategy for treating MLL-related diseases, including leukemia. [Summary of the Invention]

[0005] This invention describes a covalent inhibitor of menin-MLL interaction, N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, comprising stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases, and methods of use thereof. It also describes a pharmaceutically acceptable salt of a menin-MLL interaction inhibitor, comprising stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases, and methods of use thereof. N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinecarboxamide, its stereoisomers, and its pharmaceutically acceptable salts are used to prepare remedies for diseases or conditions associated with menin-MLL activity. N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinecarboxamide is a covalent inhibitor of menin-MLL interaction.

[0006] A method is also provided for preparing the following crystalline form: N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine. A pharmaceutical composition comprising this crystalline form and a method for treating a disease or condition (including diseases or conditions where the covalent inhibition of the menin-MLL interaction provides a therapeutic benefit to a mammal suffering from said disease or condition) using a covalent inhibitor of the menin-MLL interaction are also provided.

[0007] In one embodiment, the covalent inhibitor of the menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, is an (R)-isomer. In another embodiment, the covalent inhibitor of the menin-MLL interaction is an (S)-isomer.

[0008] In a specific embodiment, the covalent inhibitor of the menin-MLL interaction is N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine.

[0009] In one embodiment, the covalent inhibitor of the menin-MLL interaction is anhydrous N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine.

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

[0011] In another embodiment, the covalent inhibitor of the menin-MLL interaction is amorphous and anhydrous N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine.

[0012] In another 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine.

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

[0014] In one embodiment, the covalent inhibitor of the menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, is an (R)-isomer, designated as compound A. In some embodiments, compound A is substantially free of the other mirror-image isomer. In some embodiments, compound A is isolated. In some embodiments, compound A is enantiomeric excess.

[0015] In one embodiment, the covalent inhibitor of the menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, is an (S)-isomer, designated as compound B. In some embodiments, compound B is substantially free of the other mirror-image isomer. In some embodiments, compound B is isolated. In some embodiments, compound B is in excess of the mirror-image isomer. Form A

[0016] In a specific state sample, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form A, having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1A; (b) (c) The X-ray powder diffraction (XRPD) pattern exhibits characteristic peaks at 3.5±0.1°2-θ, 10.4±0.1°2-θ, 14.7±0.1°2-θ, 17.1±0.1°2-θ, 21±0.1°2-θ, 24.9±0.1°2-θ, 29.5±0.1°2-θ, and 34.1±0.1°2-θ; (d) The X-ray powder diffraction (XRPD) pattern exhibits characteristic peaks at 3.5±0.1°2-θ, 17.1±0.1°2-θ, 21.0±0.1°2-θ, 24.9±0.1°2-θ, and 29.5±0.1°2-θ; (d) Differential scanning calorimetry (DSC) shows an endothermic peak starting at approximately 234.6°C and peaking at approximately 245°C. (e) calorimetry (DSC) thermal analysis diagram; or (e) a combination thereof.

[0017] In some embodiments, form A is a crystalline form. In some embodiments, form A is a hydrate.

[0018] In some embodiments, form A has a substantially identical X-ray powder diffraction (XRPD) pattern to that shown in FIG. 1A. In some embodiments, form A has a substantially identical X-ray powder diffraction (XRPD) pattern to that shown below. XRPD Table A: XRPD pattern of free form mode A (compound A, form A) serial number angle* d value Net strength Total strength relative strength 1 3.472° 25.42665 A 817.224 988.968 100.0% 2 10.395° 8.50313 A 59.0212 198.748 7.2% 3 14.717° 6.01444 A 65.3863 347.962 8.0% 4 17.137° 5.17011 A 546.417 915.709 66.9% 5 21.029° 4.22120 A 309.975 720.606 37.9% 6 24.866° 3.57780 A 405.254 738.189 49.6% 7 29.485° 3.02703 A 125.412 381.519 15.3% 8 34.050° 2.63088 A 49.0499 244.102 6.0% *±0.1°

[0019] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form A has characteristic peaks at one, two, three, four, five, six, seven or eight locations at 3.5±0.1°2-θ, 10.4±0.1°2-θ, 14.7±0.1°2-θ, 17.1±0.1°2-θ, 21±0.1°2-θ, 24.9±0.1°2-θ, 29.5±0.1°2-θ and 34.1±0.1°2-θ.

[0020] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form A has characteristic peaks at 3.5±0.1°2-θ, 17.1±0.1°2-θ, 21.0±0.1°2-θ, 24.9±0.1°2-θ and 29.5±0.1°2-θ.

[0021] In some embodiments, form A has a melting temperature of about 245°C.

[0022] In some embodiments, Form A has a thermogravimetric analysis (TGA) thermal analysis plot showing a weight loss of up to about 1.80% at about 200°C.

[0023] In some embodiments, Form A has a DSC thermal analysis plot with an endothermic peak starting at about 234.6°C and peaking at about 245.0°C.

[0024] In some embodiments, form A is hygroscopic. Form B

[0025] In a specific state sample, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form B, having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 2A; (b) The X-ray powder diffraction (XRPD) pattern exhibits characteristic peaks at one, two, three, four, five, six, seven, or eight locations within the ranges of 5.9±0.1°2-θ, 8.6±0.1°2-θ, 10.5±0.1°2-θ, 12.6±0.1°2-θ, 16.9±0.1°2-θ, 19±0.1°2-θ, 20.5±0.1°2-θ, and 24.6±0.1°2-θ; (c) The X-ray powder diffraction (XRPD) pattern has characteristic peaks at 8.6±0.1°2-θ, 10.5±0.1°2-θ, 12.6±0.1°2-θ, 16.9±0.1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ and 24.6±0.1°2-θ; or (d) combinations thereof.

[0026] In some embodiments, form B is a crystalline form. In some embodiments, form B is a hydrate.

[0027] In some embodiments, form B has a substantially identical X-ray powder diffraction (XRPD) pattern to that shown in FIG. 2A. In some embodiments, form B has a substantially identical X-ray powder diffraction (XRPD) pattern to that shown below. XRPD Table B: XRPD pattern of free form mode B (compound A, form B) serial number angle* d value Net strength Total strength relative strength 1 5.925° 14.90443 A 40.3324 148.819 7.6% 2 8.587° 10.28913 A 58.2126 208.167 11.0% 3 10.522° 8.40127 A 58.0415 236.296 10.9% 4 12.611° 7.01369 A 188.498 390.785 35.5% 5 16.854° 5.25634 A 132.691 407.283 25.0% 6 19.039° 4.65756 A 198.523 520.924 37.4% 7 20.454° 4.33858 A 334.602 672.713 63.1% 8 24.632° 3.61124 A 530.528 845.184 100.0% *±0.1°

[0028] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form B has characteristic peaks at 5.9±0.1°2-θ, 8.6±0.1°2-θ, 10.5±0.1°2-θ, 12.6±0.1°2-θ, 16.9±0.1°2-θ, 19±0.1°2-θ, 20.5±0.1°2-θ and 24.6±0.1°2-θ.

[0029] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form B has characteristic peaks at 8.6±0.1°2-θ, 10.5±0.1°2-θ, 12.6±0.1°2-θ, 16.9±0.1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ and 24.6±0.1°2-θ.

[0030] In some embodiments, Form B has a thermogravimetric analysis (TGA) thermal analysis plot showing a weight loss of up to about 1.350% at about 100°C.

[0031] In some embodiments, form B is hygroscopic. Form C

[0032] In a specific state sample, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form C, having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 3A; (b) The X-ray powder diffraction (XRPD) pattern exhibits characteristic peaks at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve locations at 5.2±0.1°2-θ, 5.9±0.1°2-θ, 7.2±0.1°2-θ, 8.7±0.1°2-θ, 10.6±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.1±0.1°2-θ, 15.9±0.1°2-θ, 17.5±0.1°2-θ, 18.1±0.1°2-θ, and 20.1±0.1°2-θ; (c) The X-ray powder diffraction (XRPD) pattern has characteristic peaks at 5.2±0.1°2-θ, 5.9±0.1°2-θ, 8.7±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.9±0.1°2-θ, and 17.5±0.1°2-θ; (d) the DSC thermal analysis pattern has an endothermic peak that begins at about 150.23°C and peaks at about 156.86°C; or (e) a combination thereof.

[0033] 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.

[0034] In some embodiments, form C has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG3A.

[0035] In some embodiments, form C has substantially the same X-ray powder diffraction (XRPD) pattern as shown below. XRPD Table C: XRPD pattern of free form mode C (compound A, form C) serial number angle* d value Net strength Total strength relative strength 1 5.186° 17.02747 A 133.727 225.336 58.9% 2 5.861° 15.06777 A 130.303 222.034 57.4% 3 7.211° 12.24949 A 55.5581 144.593 24..5% 4 8.657° 10.20582 A 139.726 224.000 61.6% 5 10.554° 8.37575 A 54.3884 141.714 24.0% 6 12.161° 7.27219 A 226.948 332.463 100.0% 7 14.347° 6.16879 A 117.349 238.66"1 51.7% 8 15.054° 5.88057 A 115.107 239.909 50.7% 9 15.857° 5.58433 A 155.055 281.563 68.3% 10 17.464° 5.07388 A 125.43·1 248.'146 55.3% 11 18.107° 4.89517 A 110.474 228.981 48.7% 12 20.068° 4.42109 A 105.704 209.415 46.6% *±0.1°

[0036] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form C has characteristic peaks at 5.2±0.1°2-θ, 5.9±0.1°2-θ, 7.2±0.1°2-θ, 8.7±0.1°2-θ, 10.6±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.1±0.1°2-θ, 15.9±0.1°2-θ, 17.5±0.1°2-θ, 18.1±0.1°2-θ, and 20.1±0.1°2-θ.

[0037] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form C has characteristic peaks at 5.2±0.1°2-θ, 5.9±0.1°2-θ, 8.7±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.9±0.1°2-θ and 17.5±0.1°2-θ.

[0038] In some embodiments, Form C has a DSC thermal analysis plot with an endothermic peak starting at about 150.23°C and peaking at about 156.86°C.

[0039] In some embodiments, form C is hygroscopic. Form D

[0040] In a specific state sample, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form D, 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) The X-ray powder diffraction (XRPD) pattern exhibits characteristic peaks at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen of the following: 3.4±0.1°2-θ, 5.3±0.1°2-θ, 7±0.1°2-θ, 8.7±0.1°2-θ, 10.8±0.1°2-θ, 12.9±0.1°2-θ, 14.3±0.1°2-θ, 15.6±0.1°2-θ, 17±0.1°2-θ, 18.5±0.1°2-θ, 19.6±0.1°2-θ, 21.5±0.1°2-θ, and 24.2±0.1°2-θ. (c) The X-ray powder diffraction (XRPD) pattern exhibits characteristic peaks at 3.4 ± 0.1°2-θ, 8.7 ± 0.1°2-θ, 10.7 ± 0.1°2-θ, 15.6 ± 0.1°2-θ, 18.5 ± 0.1°2-θ, 19.6 ± 0.1°2-θ, and 24.2 ± 0.1°2-θ; (d) 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) 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) substantially the same X-ray powder diffraction (XRPD) pattern after storage in a closed container at 60°C and 75% RH for at least one week; (g) substantially similar to the infrared (IR) spectrum shown in Figure 9A; (h) The infrared (IR) spectrum (Figure 9A) shows peaks at approximately 3332 cm⁻¹, approximately 2853 cm⁻¹, approximately 1561 cm⁻¹, approximately 1524 cm⁻¹, approximately 1319 cm⁻¹, approximately 1258 cm⁻¹, and approximately 1067 cm⁻¹; (i) substantially similar to the thermogravimetric analysis (TGA) thermal analysis plot shown in Figure 10; (j) substantially similar to the DSC thermal analysis plot shown in Figure 11; (k) the DSC thermal analysis plot has peaks starting at approximately 260 cm⁻¹.An endothermic peak at 5°C and peaking at approximately 273°C; (l) a 1H NMR (nuclear magnetic resonance) spectrum substantially similar to the spectrum shown in Figure 12; (m) hygroscopicity and absorbency of approximately 2.1% water observed at 25°C from 40% RH to 70% RH; (n) water solubility of approximately 0.004 mg / mL observed at approximately pH 4.5; or (o) a combination thereof.

[0041] In some embodiments, form D is a crystalline form.

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

[0043] In some embodiments, form D has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG4A;

[0044] In some embodiments, form D has substantially the same X-ray powder diffraction (XRPD) pattern as shown below. XRPD Table D: XRPD pattern of free form mode D (compound A, form D) serial number angle* d value Net strength Total strength relative strength 1 3.354° 26.32488 A 123.441 290.6 42.8% 2 5.314° 16.61580 A 32.3960 129.144 11.2% 3 6.986° 12.64352 A 59.6702 163.276 20.7% 4 8.689° 10.16814 A 145.824 261.449 50.6% 5 10.747° 8.22587 A 139.539 268.016 48.4% 6 12.900° 6.85704 A 27.2461 166.544 9.4% 7 14.250° 6.21032 A 54.4465 202.156 18.9% 8 15.632° 566419 A 130.038 299.722 45.1% 9 16.982° 5.21684 A 81.8461 276.600 28.4% 10 18.461° 4.80220 A 228.372 444.437 79.2% 11 19.618° 4.52148 A 193.879 421.715 67.2% 12 21.514° 4.12702 A 55.4205 289.294 19.2% 13 24.150° 3..68223 A 288.350 503.268 100.0% *±0.1°

[0045] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form D has characteristic peaks at 3.4±0.1°2-θ, 5.3±0.1°2-θ, 7±0.1°2-θ, 8.7±0.1°2-θ, 10.8±0.1°2-θ, 12.9±0.1°2-θ, 14.3±0.1°2-θ, 15.6±0.1°2-θ, 17±0.1°2-θ, 18.5±0.1°2-θ, 19.6±0.1°2-θ, 21.5±0.1°2-θ, and 24.2±0.1°2-θ.

[0046] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form D has characteristic peaks at 3.4±0.1°2-θ, 8.7±0.1°2-θ, 10.7±0.1°2-θ, 15.6±0.1°2-θ, 18.5±0.1°2-θ, 19.6±0.1°2-θ and 24.2±0.1°2-θ.

[0047] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after being stored in an open container at 40°C and 75% RH for at least one week.

[0048] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after being stored in an open container at 25°C and 92% RH for at least one week.

[0049] In some embodiments, Form D exhibits substantially the same X-ray powder diffraction (XRPD) after being stored in a sealed container at 60°C and 75% RH for at least one week.

[0050] In some embodiments, form D has an infrared (IR) spectrum that is substantially similar to that shown in FIG9A.

[0051] In some embodiments, the infrared (IR) spectrum of form D has weak peaks at about 3332 cm-1, about 2853 cm-1, about 1561 cm-1, about 1524 cm-1, about 1319 cm-1, about 1258 cm-1 and about 1067 cm-1.

[0052] In some embodiments, form D has a melting temperature of about 272-274°C.

[0053] In some embodiments, form D has a thermogravimetric analysis (TGA) thermal analysis diagram that is substantially similar to that shown in FIG10.

[0054] In some embodiments, form D has a DSC thermal analysis map that is substantially similar to that shown in FIG11.

[0055] In some embodiments, form D has a DSC thermal analysis plot with an endothermic peak starting at about 260.5°C and peaking at about 273°C.

[0056] In some embodiments, form D has a 1H NMR (nuclear magnetic resonance) spectrum that is substantially similar to that shown in Figure 12.

[0057] In some embodiments, form D is hygroscopic.

[0058] In some embodiments, form D has an observed water solubility of about 0.004 mg / mL at about pH 4.5. Form E

[0059] In a specific state sample, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form E, having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 5A; (b) X-ray powder diffraction (XRPD) pattern at 3.4±0.1°2-θ, 4.7±0.1°2-θ, 6.3±0.1°2-θ, 6.9±0.1°2-θ, 7.1±0.1°2 -θ, 7.6±0.1°2-θ, 8.6±0.1°2-θ, 9.3±0.1°2-θ, 10.8±0.1°2-θ, 12±0.1°2-θ, 12.5±0.1°2 -θ, 13±0.1°2-θ, 13.8±0.1°2-θ, 15.7±0.1°2-θ, 16.2±0.1°2-θ, 16.7±0.1°2-θ, 17±0.1° 2-θ, 17.5±0.1°2-θ, 18.4±0.1°2-θ, 18.6±0.1°2-θ, 19.6±0.1°2-θ, 20.7±0.1°2-θ, 21.4 ±0.1°2-θ, 22.2±0.1°2-θ, 23±0.1°2-θ, 24.2±0.1°2-θ, 25.3±0.1°2-θ, 26±0.1°2-θ, 28± 0.1°2-θ, 29.2±0.1°2-θ, 30.5±0.1°2-θ, 31.6±0.1°2-θ, 33.6±0.1°2-θ and 34.5±0.1°2-θ Characteristic peaks are present at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, or thirty-four locations; (c) The X-ray powder diffraction (XRPD) pattern has characteristic peaks at 4.7±0.1°2-θ, 7.7±0.1°2-θ, 10.8±0.1°2-θ, 13.8±0.1°2-θ, 17.0±0.1°2-θ, 18.4±0.1°2-θ and 18.6±0.1°2-θ; (d) The DSC thermal analysis plot has an endothermic peak that begins at about 112.34°C and peaks at about 137.26°C; or (e) a combination thereof.

[0060] In some embodiments, form E is a crystalline form. In some embodiments, form E is a DMSO solvate.

[0061] In some embodiments, form E has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG5A;

[0062] In some embodiments, form E has substantially the same X-ray powder diffraction (XRPD) pattern as shown below. XRPD Table E: XRPD pattern of free form E (compound A, form E) serial number angle* d value Net strength Total strength relative strength 1 3.354° 26.32488 A 123.441 290.6 42.8% 1 3.406° 25.91845 A 30.3536 129.000 4.1% 2 4.663° 18.93379 A 498.089 574.667 67.8% 3 6259° 14.10883 A 57.5069 137.733 7.8% 4 6.902° 12.79648 A l13.808 202.012 15.5% 5 7.138° 12.37390 A 102.194 192.583 13.9% 6 7.574° 11.66253 A 638.030 731.400 86.8% 7 8.627° 10.24171 A 69.9785 170.785 9.5% 8 9.299° 9.50315 A 72.5036 180.093 9.9% 9 10.790° 8.19307 A 436.276 549.567 59.4% 10 11.968° 7.38895 A 22.2062 138.035 3.0% 11 12.480° 7.08703 A l12.097 234.224 15.3% 12 12.947° 6.83238 A 280.661 406.890 38.2% 13 13.779° 6.42140 A 596.81 725.831 81.1% 14 15.690° 5.64346 A 56.4454 209.584 7.7% 15 16.188° 5.47110 A 122.791 286.384 16.7% 16 16.663° 5.31622 A 85.8718 257.783 11.7% 17 16.982° 5.21684 A 103.238 279.836 14.0% 18 17.512° 5.06020 A 175.880 358.624 23.9% 19 18.397° 4.81884 A 586.508 775.013 79.8% 20 18.616° 4.76266 A 735.061 924.123 100.0% 21 19..616° 4.52185 A 208.661 395.877 28..4% 22 20.11° 4.28409 A 69.4470 252.011 9.4% 23 21.435° 4.14210 A 155.825 336.360 21.2% 24 22.175° 4.00564 A 76.9573 251.528 10.5% 25 22.956° 3.87107 A 61.4421 232.682 8.4% 26 24.226° 3.67091 A 77.6650 242.971 10.6% 27 25.300° 3.51748 A 53.0406 204.275 7.2% 28 25.964° 3.42896 A 67.3128 205.687 9.2% 29 27.961° 3.18845 A 65.3500 178.917 8.9% 30 29.229° 3.05295 A 30.9502 139.437 4.2% 31 30.52° 2.92615 A 26.0676 128.990 3.5% 32 31.640° 2.82562 A 17.2880 121.439 2.4% 33 33.632° 2.66261 A 43.3283 145.288 5.9% 34 34.500° 2.59759 A 30.0408 129.000 4.1% *±0.1°

[0063] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form E is at 4±0.1°2-θ, 4.7±0.1°2-θ, 6.3±0.1°2-θ, 6.9±0.1°2-θ, 7.1±0.1°2-θ, 7.6±0.1°2-θ, 8.6±0.1°2-θ, 9.3±0.1°2-θ, 10.8±0.1°2-θ, 12±0.1°2-θ, 12.5±0.1°2-θ, 13±0.1°2-θ, 13.8±0.1°2-θ, 15.7±0.1°2-θ, 16.2±0.1°2-θ, 16.7±0.1°2-θ, 17±0.1°2-θ, 17.5±0.1°2-θ, 18.4±0.1°2-θ, 18.6±0.1°2-θ, 19.6±0.1°2-θ, 20.7±0.1°2-θ, 21.4±0.1°2-θ, 22.2±0.1°2-θ, 23±0.1°2-θ, 24.2±0.1°2-θ, There are characteristic peaks at 25.3±0.1°2-θ, 26±0.1°2-θ, 28±0.1°2-θ, 29.2±0.1°2-θ, 30.5±0.1°2-θ, 31.6±0.1°2-θ, 33.6±0.1°2-θ and 34.5±0.1°2-θ.

[0064] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form E has characteristic peaks at 4.7±0.1°2-θ, 7.7±0.1°2-θ, 10.8±0.1°2-θ, 13.8±0.1°2-θ, 17.0±0.1°2-θ, 18.4±0.1°2-θ and 18.6±0.1°2-θ.

[0065] In some embodiments, Form E has a DSC thermal analysis plot with an endothermic peak starting at about 112.34°C and peaking at about 137.26°C.

[0066] In some embodiments, form E is hygroscopic. Form F

[0067] In a specific state sample, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form F, having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 6A; (b) The X-ray powder diffraction (XRPD) pattern is at 4.2±0.1°2-θ, 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 12±0. 1°2-θ, 12.2±0.1°2-θ, 12.5±0.1°2-θ, 14.4±0.1°2-θ, 15±0.1°2-θ, 16±0.1°2-θ, 16. 8±0.1°2-θ, 17.2±0.1°2-θ, 17.5±0.1°2-θ, 17.8±0.1°2-θ, 18.8±0.1°2-θ, 19.2±0. 1°2-θ, 20.1±0.1°2-θ, 20.5±0.1°2-θ, 21.7±0.1°2-θ, 22.1±0.1°2-θ, 23.4±0.1°2-θ Characteristic peaks are present at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty, thirty-one, or thirty-two locations at 24.2±0.1°2-θ, 25.3±0.1°2-θ, 25.5±0.1°2-θ, 26.3±0.1°2-θ, 27.1±0.1°2-θ, 29±0.1°2-θ, 30.3±0.1°2-θ, 31.6±0.1°2-θ, 33.1±0.1°2-θ, 34.3±0.1°2-θ, and 35.6±0.1°2-θ. (c) An X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 11.9±0.1°2-θ, 12.2±0.1°2-θ, 14.4±0.1°2-θ, 15.0±0.1°2-θ and 20.5±0.1°2-θ; or (d) a combination thereof.

[0068] In some embodiments, form F is a crystalline form.

[0069] In some embodiments, form F is a solvate. In some embodiments, form F is a heteo solvate. In some embodiments, form F is a disolvate. In some embodiments, form F is a heteo solvate or a disolvate of methanol and DCM (1:1).

[0070] In some embodiments, form F has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG6A.

[0071] In some embodiments, form F has substantially the same X-ray powder diffraction (XRPD) pattern as shown below. XRPD Table F: XRPD pattern of free form mode F (compound A, form F) serial number angle* d value Net strength Total strength relative strength 1 4.221° 20.91462 A 116.3237 87.3639 1.8% 2 6.281° 14.05959 A 405.346 477.688 43.7% 3 8.561° 10.32057 A 372.008 460.190 40.1% 4 8.786° 10.05676 A 368.812 457.922 39.7% 5 11.904° 7.42871 A 927.836 1043.85 100.0% 6 12.161° 7.27219 A 623.900 741.888 67.2% 7 12.482° 7.08564 A 350.836 470.673 37.8% 8 14.411° 6.1442 A 530.623 668.184 57.2% 9 15.022° 5.89308 A 510.988 653.688 55.1% 10 15_954° 5.55079 A 180.999 326.786 19.5% 11 16.774° 5.28110 A 40.0577 183.806 4.3% 12 17.171° 5.15999 A 57.5230 201.798 6.2% 13 17.529° 5,.05542 A 1169.685 317.535 18.3% 14 17.786° 4.98290 A 1143.213 293.107 15.4% 15 18.792° 4.71841 A 1153.791 307.481 16.6l% 16 19.1168° 4.62660 A 91.9137 245.305 9.9% 17 20.068° 4.42109 A 199.462 355.009 21.5% 18 20.486° 4.331185 A 393.366 549.624 42.4l% 19 21.692° 4.09361 A 186.510 338.341 20.1% 20 22.061° 4.02601 A 80.6176 229.174 8.7% 21 23.411° 3.79681 A 240.104 394.409 25.9% 22 24.182° 3.67741 A 228.495 390.682 24.6% 23 25.275° 3.52082 A 220.009 386.624 23.7% 24 25.532° 3.48594 A 1182.510 349.021 19.7% 25 26.334° 3.38157 A 53.8584 217.224 5.8% 26 27.107° 3.28687 A 68.0545 224.365 7.3% 27 27.429° 3.24908 A 95.1971 247.410 10.3% 28 27.686° 3.21948 A 122.467 270.911 13.2% 29 28.972° 3.07946 A 84.0006 209.058 9.1% 30 30.322° 2.94536 A 41.0037 156.840 4.4% 31 31.64° 2.82562 A 18.3329 126.702 2.0% 32 33.067° 2.70680 A 37.5462 150.489 4.0% 33 34.275° 2.61412 A 25.5112 140.543 2.7% 34 35.561° 2.52250 A 112.6371 120.689 1.4% *±0.1°

[0072] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form F is at 4.2±0.1°2-θ, 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 12±0.1°2-θ, 12.2±0.1°2-θ, 12.5±0.1°2-θ, 14.4±0.1°2-θ, 15±0.1°2-θ, 16±0.1°2-θ, 16.8±0.1°2-θ, 17.2±0.1°2-θ, 17.5±0.1°2-θ, 17.8±0.1°2-θ, 18.8±0.1°2-θ, 19.2±0.1°2-θ, 20.1±0.1°2-θ, 20.5±0.1°2-θ, 21.7±0.1°2-θ, 22.1±0.1°2-θ, 23.4±0.1°2-θ, 24.2±0.1°2-θ , 25.3±0.1°2-θ, 25.5±0.1°2-θ, 26.3±0.1°2-θ, 27.1±0.1°2-θ, 29±0.1°2-θ, 30.3±0.1°2-θ, 31.6±0.1°2-θ, 33.1±0.1°2-θ, There are characteristic peaks at 34.3±0.1°2-θ and 35.6±0.1°2-θ.

[0073] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form F has characteristic peaks at 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 11.9±0.1°2-θ, 12.2±0.1°2-θ, 14.4±0.1°2-θ, 15±0.1°2-θ and 20.5±0.1°2-θ.

[0074] In some embodiments, form F is hygroscopic. Form G

[0075] In a specific state sample, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form G, having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 7A; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at one, two, three, four, five, or six of 8±0.1°2-θ, 10.2±0.1°2-θ, 12.1±0.1°2-θ, 16.8±0.1°2-θ, 19.2±0.1°2-θ, and 24.6±0.1°2-θ; (c) An X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.1±0.1°2-θ, 10.2±0.1°2-θ, 12.1±0.1°2-θ, 16.8±0.1°2-θ, 19.2±0.1°2-θ and 24.6±0.1°2-θ; or (d) a combination thereof.

[0076] In some embodiments, form G is a crystalline form. In some embodiments, form G is a TFE solvate.

[0077] In some embodiments, form G has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG7A.

[0078] In some embodiments, form G has substantially the same X-ray powder diffraction (XRPD) pattern as shown below. XRPD Table G: XRPD pattern of free form mode G (compound A, form G) serial number angle* d value Net strength Total strength relative strength 1 8.046° 10.97902 A 76.8302 160.625 39.9% 2 10.200° 8.66528 A 36.4001 137.004 18.9% 3 12.097° 7.31070 A 40.5158 152.039 21.0% 4 16.789° 5.27632 A 58.8715 208.042 30.6% 5 19.168° 4.62660 A 94.3343 269.130 49.0% 6 24.568° 3.62054 A 192.545 347.027 100.0% *±0.1°

[0079] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form G has characteristic peaks at 8.1±0.1°2-θ, 10.2±0.1°2-θ, 12.1±0.1°2-θ, 16.8±0.1°2-θ, 19.2±0.1°2-θ and 24.6±0.1°2-θ.

[0080] In some embodiments, form G is hygroscopic. Form J

[0081] In a specific state, the present invention describes an N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of form J, having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 8A; (b) X-ray powder diffraction (XRPD) pattern at 3.5±0.1°2-θ, 4.5±0.1°2-θ, 6.4±0.1°2-θ, 8.7±0.1°2-θ, 10.2±0.1°2-θ, 11.3±0.1°2-θ, 11.8± 0.1°2-θ, 13.2±0.1°2-θ, 13.6±0.1°2-θ, 14±0.1°2-θ, 14.6±0.1°2-θ, 15.4±0.1°2-θ, 16.1±0.1°2-θ, 16.6±0.1°2-θ , 16.9±0.1°2-θ, 17.2±0.1°2-θ, 18.3±0.1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ, 20.8±0.1°2-θ, 21.6±0.1°2-θ, 23.5 ±0.1°2-θ, 23.8±0.1°2-θ, 24.6±0.1°2-θ, 24.9±0.1°2-θ, 25.2±0.1°2-θ, 25.8±0.1°2-θ, 26.2±0.1°2-θ, 26.7±0.1° 2-θ, 26.8±0.1°2-θ, 27.4±0.1°2-θ, 27.7±0.1°2-θ, 28.7±0.1°2-θ, 29.3±0.1°2-θ, 30.1±0.1°2-θ, 31.2±0.1°2-θ, 31.8±0.1°2-θ, 34.1±0.1°2-θ, 34.9±0.1°2-θ, 35.6±0.1°2-θ, 36.4±0.1°2-θ, 36.7±0.1°2-θ, 38.5±0.1°2-θ and 38.8± Characteristic peaks at 0.1°2-θ: one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two, forty-three, or forty-four; (c) X-ray powder diffraction (XRPD) patterns at 3.5±0.1°2-θ, 4.5±0.1°2-θ, 19.1±0.1°2-θ, 21.Characteristic peaks are observed at 6 ± 0.1°²⁻θ, 22.5 ± 0.1°²⁻θ, and 27.4 ± 0.1°²⁻θ; (d) hygroscopicity and absorbency of approximately 2.1% water observed at 25°C from 40% RH to 70% RH; (e) water solubility observed at approximately 0.004 mg / mL at approximately pH 4.5; or (f) combinations thereof.

[0082] In some embodiments, form J is a crystalline form. In some embodiments, form J is anhydrous.

[0083] In some embodiments, form J has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG8A.

[0084] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form J is at 3.5±0.1°2-θ, 4.5±0.1°2-θ, 6.4±0.1°2-θ, 8.7±0.1°2-θ, 10.2±0.1°2-θ, 11.3±0.1°2-θ, 11.8±0.1°2-θ, 13.2±0.1°2-θ, and 13.6±0.1°2-θ. -θ, 14±0.1°2-θ, 14.6±0.1°2-θ, 15.4±0.1°2-θ, 16.1±0.1°2-θ, 16.6±0.1°2-θ, 16.9±0 .1°2-θ, 17.2±0.1°2-θ, 18.3±0.1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ, 20.8±0.1°2-θ, 21.6±0.1°2-θ, 23.5±0.1°2-θ, 23.8±0.1°2-θ, 24.6±0.1°2-θ, 24.9±0.1°2-θ, 25.2±0.1°2-θ, 25.8±0.1°2-θ, 26.2±0.1°2-θ, 26.7±0.1°2-θ, 26.8±0.1°2-θ, 27.4±0.1°2-θ, 27.7±0.1°2-θ, 28.7±0.1°2-θ, 29.3±0.1°2-θ, 30.1±0.1°2-θ, 31.2±0.1°2-θ, 31.8±0.1° There are characteristic peaks at 2-θ, 34.1±0.1°2-θ, 34.9±0.1°2-θ, 35.6±0.1°2-θ, 36.4±0.1°2-θ, 36.7±0.1°2-θ, 38.5±0.1°2-θ and 38.8±0.1°2-θ.

[0085] In some embodiments, the X-ray powder diffraction (XRPD) pattern of form J has characteristic peaks at 3.5±0.1°2-θ, 4.5±0.1°2-θ, 19.1±0.1°2-θ, 21.6±0.1°2-θ, 22.5±0.1°2-θ and 27.4±0.1°2-θ.

[0086] In some embodiments, form F is hygroscopic. Formulation

[0087] In another embodiment, the present invention provides a pharmaceutical preparation 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 50 wt% to about 80 wt% of one or more diluents; (c) about 1 wt% to about 10 wt% of one or more disintegrating agents; (d) about 0.2 wt% to about 3 wt% of one or more glidants; and (e) about 0.2 wt% to about 1.0 wt% of one or more lubricants.

[0088] In some embodiments, the diluent is selected from the group consisting of: lactose, sucrose, glucose, glucose dextrorates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is pregelatinized maize starch and lactose. In some embodiments, the disintegrant is selected from the group consisting of: natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is crospovidone. In some embodiments, the flow aid is selected from the group consisting of: ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, starch, and talc. In some embodiments, the flow aid 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 wax. In some embodiments, the lubricant is magnesium stearate.

[0089] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 20 wt% to about 80 wt% of total pregelatinized corn starch and lactose; (c) about 3 wt% to about 10 wt% of crospovidone; (d) about 0.1 wt% to about 1.0 wt% of fumed silica; and (e) about 0.1 wt% to about 1.0 wt% of magnesium stearate.

[0090] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 70 wt% to about 80 wt% of total pregelatinized corn starch and lactose; (c) about 3 wt% to about 10 wt% of crospovidone; (d) about 0.1 wt% to about 1.0 wt% of fumed silica; and (e) about 0.1 wt% to about 1.0 wt% of magnesium stearate.

[0091] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 25 wt% to about 65 wt% of pregelatinized corn starch and about 25 wt% to about 40 wt% of lactose; (c) about 1 wt% to about 10 wt% of crospovidone; (d) about 0.1 wt% to about 1.0 wt% of fumed silica; and (e) about 0.1 wt% to about 1.0 wt% of magnesium stearate.

[0092] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 25 wt% to about 60 wt% of pregelatinized corn starch and about 25 wt% to about 40 wt% of lactose; (c) about 1 wt% to about 10 wt% of crospovidone; (d) about 0.1 wt% to about 1.0 wt% of fumed silica; and (e) about 0.1 wt% to about 1.0 wt% of magnesium stearate.

[0093] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 37 wt% of pregelatinized corn starch (Starch 1500); (c) about 36% of lactose (fastfloLactose 316); (d) about 5 wt% of crospovidone; (e) about 1 wt% of fumed silica; and (f) about 0.5 wt% of 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 52 wt% of pregelatinized corn starch (Starch 1500); (c) about 27% of lactose (fastflo Lactose 316); (d) about 4 wt% of crospovidone; (e) about 0.8 wt% of fumed silica; and (f) about 0.4 wt% of 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 21 wt% of pregelatinized corn starch (Starch 1500); (c) about 37% of lactose (fastflo Lactose 316); (d) about 5 wt% of crospovidone; (e) about 1 wt% of fumed silica; and (f) about 0.5 wt% of 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 28 wt% of pregelatinized corn starch (Starch 1500); (c) about 27% of lactose (fastflo Lactose 316); (d) about 4 wt% of crospovidone; (e) about 0.8 wt% of fumed silica; and (f) about 0.4 wt% of magnesium stearate.

[0097] In some embodiments, the pharmaceutical preparations are substantially homogeneous. In some embodiments, the pharmaceutical preparations are granular. In some embodiments, the intragranular composition is one of the embodiments described above. In some embodiments, the extragranular composition comprises pregelatinized corn starch, such as starch 1500.

[0098] In some embodiments, the diluent is selected from the group consisting of: lactose, sucrose, glucose, glucose dextrorates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, 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, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is crospovidone. In some embodiments, the flow aid 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 wax. In some embodiments, the lubricant is magnesium stearate.

[0099] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 70 wt% to about 80 wt% of total pregelatinized corn starch and lactose; (c) about 5 wt% of crospovidone; (d) about 0.5 wt% to 1 wt% of fumed silica; and (e) about 0.2 wt% to 0.5 wt% of magnesium stearate.

[0100] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 70 wt% to about 80 wt% of total pregelatinized corn starch and lactose; (c) about 5 wt% of crospovidone; (d) about 0.5 wt% to 1 wt% of fumed silica; and (e) about 0.2 wt% to 0.5 wt% of magnesium stearate.

[0101] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 70 wt% to about 80 wt% of pregelatinized corn starch and lactose; (c) about 5 wt% of crospovidone; (d) about 0.5 wt% to 1 wt% of fumed silica; and (e) about 0.2 wt% to about 0.5 wt% of magnesium stearate.

[0102] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 70 wt% to about 80 wt% of pregelatinized corn starch and lactose; (c) about 5 wt% of crospovidone; (d) about 0.5 wt% to 1 wt% of fumed silica; and (e) about 0.2 wt% to 0.5 wt% of magnesium stearate.

[0103] In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is crystalline form A. In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is crystalline form B. In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is in crystalline form C. In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is in crystalline form D. In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is in crystalline form E. In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is in form F. In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is in crystalline form G. In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is in crystalline form J.In some embodiments of the above pharmaceutical formulation examples, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine 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.

[0104] In another embodiment, the present invention provides a pharmaceutical preparation 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, in crystalline form A; (b) about 50 wt% to about 80 wt% of one or more diluents; (c) about 1 wt% to about 10 wt% of one or more disintegrating agents; (d) about 0.2 wt% to about 3 wt% of one or more glidants; and (e) about 0.2 wt% to about 1.0 wt% of one or more lubricants.

[0105] In some embodiments, the diluent is selected from the group consisting of: lactose, sucrose, glucose, glucose dextrorates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, 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, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, and 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 wax. In some embodiments, the lubricant is magnesium stearate.

[0106] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, in crystalline form D; (b) about 70 wt% to about 80 wt% of pregelatinized corn starch and lactose; (c) about 5 wt% of crospovidone; (d) about 0.5 wt% to 1 wt% of fumed silica; and (e) about 0.2 wt% to 0.5 wt% of magnesium stearate.

[0107] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, in crystalline form D; (b) about 37.2 wt% of pregelatinized corn starch and about 35.6 wt% of lactose; (c) about 5 wt% of crospovidone; (d) about 1 wt% of fumed silica; and (e) about 0.5 wt% of 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, in crystalline form D; (b) about 52 wt% of pregelatinized corn starch and about 27.3% of lactose; (c) about 3.8 wt% of crospovidone; (d) about 0.8 wt% of fumed silica; and (e) about 0.4 wt% of magnesium stearate.

[0109] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, 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.

[0110] 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, 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.

[0111] In another embodiment provided by the present invention, a pharmaceutical preparation is provided, 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; 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 flow aid; and e) about 0.2 wt% to about 1.0 wt% of a lubricant; wherein the preparation is a unit dosage form in a bottle or blister pack. In some 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 37.2 wt% of pregelatinized corn starch and about 35.6% of lactose; (c) about 5 wt% of crospovidone; (d) about 1 wt% of fumed silica; and (e) about 0.5 wt% of magnesium stearate. The formulation is a unit dosage form in a bottle or blister pack. In some 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (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. The formulation is a unit dosage form in a bottle or blister pack. In some embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil.

[0112] In another embodiment, the package comprises one or more discrete blister pockets, each blister pocket containing 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 50 wt% to about 80 wt% of one or more diluents; (c) about 1 wt% to about 10 wt% of one or more disintegrating agents; (d) about 0.2 wt% to about 3 wt% of one or more glidants; and (e) about 0.2 wt% to about 1.0 wt% of one or more lubricants. Each blister pack contains either metal or plastic foil.

[0113] In another embodiment provided by the present invention, a pharmaceutical preparation is provided, 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, in crystalline form A; (b) about 50 wt% to about 80 wt% of one or more diluents; (c) about 1 wt% to about 10 wt% of one or more disintegrants; (d) about 0.2 wt% to about 3 wt% of one or more glidants; and (e) about 0.2 wt% to about 1.0 wt% of one or more lubricants. The preparation is a unit dosage form in a bottle or blister pack. In some 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 37.2 wt% of pregelatinized corn starch and about 35.6% of lactose; (c) about 5 wt% of crospovidone; (d) about 1 wt% of fumed silica; and (e) about 0.5 wt% of magnesium stearate; wherein the formulation is a unit dosage form in a bottle or blister pack. In some 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine; (b) about 52 wt% pregelatinized corn starch and about 27.3% lactose; (c) about 3.8 wt% crospovidone; (d) about 0.8 wt% fumed silica; and (e) about 0.4 wt% magnesium stearate. The formulation is a unit dosage form in a bottle or blister pack. In some embodiments, the dosage form is in a blister pack, and the blister pack comprises metal or plastic foil.

[0114] In another embodiment, the package comprises one or more discrete blister pockets, each blister pocket containing 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, in crystalline form A; (b) about 50 wt% to about 80 wt% of one or more diluents; (c) about 1 wt% to about 10 wt% of one or more disintegrating agents; (d) about 0.2 wt% to about 3 wt% of one or more glidants; and (e) One or more lubricants, ranging from about 0.2 wt% to about 1.0 wt%. Each blister pack includes metal or plastic foil.

[0115] In one embodiment, a kit is provided comprising various oral dosage forms, such as tablets or capsules; packaging containing the oral dosage forms, such as a jar; and instructions for use to administer the oral dosage forms according to the method of the invention. Unit-dose packaging, such as blister packaging, provides a useful way of packaging oral dosage forms of the formulations of the present invention, and in other embodiments, when used in conjunction with instructions for use, is embodied as a kit. In other embodiments, detailed product information is included in the instructions for use of the kit. Blister packaging is particularly useful for solid oral dosage forms, and in other embodiments, for example, for every-other-day dosing regimens. In one embodiment, a solid unit dosage form of the formulation of the present invention is contained in a blister package having instructions for administering one or more tablets or capsules on a daily basis, such that the dose of the formulation of the present invention is adequately administered. In another embodiment, a solid unit dosage form is contained in a blister package having instructions for administering one or more tablets or capsules on an every-other-day basis, such that the daily dose is adequately administered.

[0116] In one embodiment, the present invention provides a method of treating a patient by administering compound A. In some embodiments, the present invention provides a method for inhibiting menin-MLL interaction in mammals or a method for treating a disease, condition, or symptom that would benefit from inhibiting menin-MLL interaction, comprising administering to said mammal a therapeutically effective amount of compound A or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate.

[0117] In another embodiment, the present invention provides the use of compound A for inhibiting menin-MLL interaction or for treating diseases, conditions or symptoms that would benefit from inhibition of menin-MLL interaction.

[0118] In another embodiment, the present invention provides the use of compound A for treating KRAS-mutant cancers in mammals. In some embodiments, the cancer is a solid tumor. In some embodiments, the KRAS mutation is a KRASG12 mutation. In some embodiments, the KRAS mutation is a KRASG12C, G12V, G13D, or G12D mutation. In some embodiments, the KRAS mutation is a G12C mutation. In some embodiments, the KRAS mutation is a G12V mutation. In some embodiments, the KRAS mutation is a G13D mutation. In some embodiments, the KRAS mutation is a G12D mutation. In some embodiments, compound A is in the form or pharmaceutical preparation described elsewhere in the present invention.

[0119] In another embodiment, the present invention provides the use of compound A for treating cancers in mammals (e.g., human patients) that do not exhibit KRAS mutations.

[0120] In another embodiment, the present invention provides the use of compound A for treating diffuse large B-cell lymphoma in mammals (e.g., human patients). In some embodiments, the mammal has triple-hit lymphoma. In some embodiments, the mammal has double-expresser lymphoma. In some embodiments, the mammal has multiple myeloma. In some embodiments, compound A is in the form or pharmaceutical preparation described elsewhere in the present invention.

[0121] In some embodiments, compound A is in crystalline form D.

[0122] In some embodiments, the mammal (e.g., a patient) has double-hit lymphoma (DHL). In some embodiments, the mammal (e.g., a patient) has triple-hit lymphoma (THL).

[0123] In some embodiments, the mammal (e.g., a patient) has a double expressor lymphoma (DEL).

[0124] In another embodiment, the present invention provides the use of compound A for the treatment of diffuse multiple myeloma in mammals (e.g., human patients). In some embodiments, compound A is in the form or pharmaceutical preparation described elsewhere in the present invention.

[0125] In some embodiments, crystalline compound A is administered to a person.

[0126] In some embodiments, crystalline compound A is administered orally.

[0127] In other embodiments, crystalline compound A is used to formulate a drug that inhibits menin-MLL interaction.

[0128] In one embodiment, the present invention provides a method for treating cancer in mammals, comprising administering to the mammal the 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 lymphoblastic leukemia (ALL). In some embodiments, the mammal or individual has MLL / KMT2A gene recombination. In some embodiments, the mammal or individual has an ATM mutation. In some embodiments, the mammal or individual has an NPM1 mutation. In some embodiments, the mammal or individual has a TP53 mutation. In some embodiments, the mammal or individual has a NOTCH1 mutation. In some embodiments, the mammal or individual has a WT1 mutation. In some embodiments, the mammal or individual has a RAS mutation. In some embodiments, the mammal or individual has a KRAS mutation. In some embodiments, the mammal or individual has a KRA G12C mutation. In some embodiments, the mammal or individual has a KRAS G12D mutation. In some embodiments, the mammal or individual has a KRAS G12V mutation. In some embodiments, the mammal or individual has a KRA G13D mutation. In some embodiments, the mammal or individual has a TET2 mutation. In some embodiments, the mammal or individual has a MYC mutation. In some embodiments, the mammal or individual has a 13q deletion (del(13q)). In some embodiments, the mammal or individual has a trisomy 12 karyotype. In some embodiments, the cancer is lymphoma, 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 prelymphocytic leukemia, plasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytic 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 exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis. In some embodiments, when a mammal or individual has cancer, an anticancer agent is administered to the mammal or individual in addition to one of the compounds or embodiments described above. In one embodiment, the anticancer agent is an inhibitor of mitogen-activated protein kinase signaling.

[0129] In one embodiment, the present invention provides a method for treating inflammatory or autoimmune diseases in mammals, comprising administering to the mammal the pharmaceutical composition comprising compound A described in the present invention. In some embodiments, the inflammatory diseases include, for example, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epididymitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, and meningitis. Myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. In some implementation schemes, autoimmune diseases include, for example, 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, Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute diffuse encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, and Goodpasture's syndrome. 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, Behçet's disease, chronic fatigue, autonomic dysfunction, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, or vulvar pain syndrome.

[0130] An article comprising packaging material, compound A within the packaging material, and a label indicating compound A for inhibiting menin-MLL activity.

[0131] In another embodiment, the present invention provides a method for treating an autoimmune disease in a mammal, comprising administering compound A to said mammal.

[0132] In another embodiment, the present invention provides a method for treating a heteroimmune disease or condition in a mammal, comprising administering compound A to said mammal.

[0133] In another embodiment, the present invention provides a method for treating an inflammatory disease in mammals, comprising administering compound A to the mammal.

[0134] In another embodiment, the present invention provides a method for treating cancer in mammals, comprising administering compound A to said mammals.

[0135] In another embodiment, the present invention provides a method for treating thromboembolic disorders in mammals, comprising administering compound A to the mammal. Thromboembolic disorders include, but are not limited to, myocardial infarction, angina pectoris, reocclusion after arterial surgery, restenosis after arterial surgery, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemic attack, peripheral arterial obstruction, pulmonary embolism, or deep vein thrombosis.

[0136] Another approach is a method of treating inflammation, which involves administering a mammal at least once an effective amount of compound A.

[0137] Another aspect of the present invention is a method for treating cancer, comprising administering at least one effective amount of compound A to a mammal. The types of cancer may include, but are not limited to, pancreatic cancer, colorectal cancer, non-small cell lung cancer, and other solid tumors or hematologic malignancies.

[0138] In another embodiment, a method for treating a respiratory disease is provided, comprising administering at least one effective amount of compound A to a mammal. In another embodiment of this embodiment, the respiratory disease is asthma. In another embodiment of this embodiment, the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (exogenous) 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.

[0139] In another embodiment, a method for preventing rheumatoid arthritis and / or osteoarthritis is provided, comprising administering an effective amount of compound A to a mammal at least once.

[0140] In another embodiment, a method for treating an inflammatory response of the skin is provided, comprising administering at least one effective amount of compound A to a mammal. Such inflammatory responses of the skin include, for example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring. In another embodiment, a method for reducing psoriatic lesions in the skin, joints, or other tissues or organs is provided, comprising administering an effective amount of compound A to a mammal.

[0141] In any of the foregoing embodiments, further embodiments are provided, wherein compound A is (a) administered systemically to a mammal; (b) administered orally to a mammal; (c) administered intravenously to a mammal; (d) administered by inhalation; (e) administered by nasal administration; (f) administered to the mammal by injection; (g) administered topically (i.e., by skin) to a mammal; (h) administered by ocular administration; or (i) administered rectally to a mammal.

[0142] In any of the above embodiments, additional embodiments comprising a single application of compound A are provided, including additional embodiments wherein compound A is (i) applied multiple times a day; (ii) applied frequently; or (iii) applied continuously.

[0143] A further embodiment of the foregoing embodiments comprising multiple administrations of compound A includes wherein (i) compound A is administered in a single dose; (ii) compound A is administered every 6 hours between multiple administrations; and (iii) compound A is administered to a mammal every 8 hours. Further, in other or alternative embodiments, the method includes a drug holiday, wherein administration of compound A is temporarily suspended or the dose of administered compound A is temporarily reduced. In some embodiments, administration of compound A is restarted at the end of the drug holiday. The length of the drug holiday can be from 2 days to 1 year.

[0144] In some embodiments related to any of the embodiments disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), compound A or a pharmaceutically acceptable salt or solvation thereof is optically pure (i.e., greater than 99% chiral purity as determined by HPLC). In some embodiments related to any of the embodiments disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), compound A or a pharmaceutically acceptable salt or solvation thereof is replaced with: a) compound A having lower chiral purity, or a pharmaceutically acceptable salt or solvation thereof; b) N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[ (1-Side-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide or a pharmaceutically acceptable salt or solvation thereof; or c) racemic N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-Side-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide or a pharmaceutically acceptable salt or solvation thereof.

[0145] In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), amorphous compound A is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form A) is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form B) is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form C) is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form D) is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form E) is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form F) is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form G) is used. In any embodiment disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), crystalline compound A (form J) is used.

[0146] In any specific embodiment (including methods, uses, formulations, combination therapies, etc.) disclosed in this invention, crystalline compound A (form D) is used.

[0147] In some embodiments related to any of the embodiments disclosed in this 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 crystalline form. In some embodiments, the active metabolite is in an amorphous phase. In further embodiments, the metabolite is isolated. In some embodiments related to any of the embodiments disclosed in this invention (including methods, uses, formulations, combination therapies, etc.), compound A or a pharmaceutically acceptable salt thereof is replaced by a precursor 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.

[0148] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific examples indicate particular embodiments, they are given by way of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. The section headings used in this invention are for organizational purposes only and should not be construed as limiting the described subject matter. All documents or portions thereof cited in this application (including, but not limited to, patents, patent applications, articles, books, manuals, and papers) are expressly incorporated herein by reference in their entirety for any purpose.

[0149] All publications and patent application publications mentioned in this specification are incorporated herein by reference to the extent applicable and relevant.

Implementation Method

[0151] The different 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 used to reduce the risk of or treat a variety of diseases that are affected by or influence many cell types of the hematopoietic lineage, including, for example, autoimmune diseases, xenoimmune diseases, inflammatory diseases, cancers (e.g., B-cell proliferative disorders), and thromboembolic diseases.

[0152] In some embodiments, compound A can be used to treat autoimmune diseases in mammals, including but not limited to 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, Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute diffuse encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, and celiac disease. Diseases including: 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, Behçet's disease, chronic fatigue, autonomic nervous system disorders, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, or vulvar pain.

[0153] In some embodiments, compound A may be used to treat xenoimmune diseases or conditions in mammals, including but not limited to graft-versus-host disease, transplantation, blood transfusion, systemic allergic reactions, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, dust mites or cockroach calyxes), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.

[0154] 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, epididymitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, and hepatitis. Inflammation, suppurative hidradenitis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonia, proctitis, pyelonephritis, rhinitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0155] In other embodiments, the method described in this invention can be used to treat cancers, 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 prelymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström'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 exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatoid granulomatosis.

[0156] In other embodiments, the method of the present invention can be used to treat thromboembolic conditions, including (but not limited to) myocardial infarction, angina pectoris (including unstable angina), restenosis or re-occlusion after angioplasty or aortocoronary shunt surgery, stroke, transient ischemic attack, peripheral artery occlusive disease, pulmonary embolism, and deep vein thrombosis. Hematologic malignancies

[0157] In some embodiments, the present invention discloses a method for treating hematologic malignancies in an individual in need, comprising administering a certain amount of compound A to the individual.

[0158] In some embodiments, the hematologic malignancy is non-Hodgkin's lymphoma (NHL). In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, the hematologic 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, non-Burkitt high grade B cell lymphoma, or extranodal marginal zone B cell lymphoma. In some embodiments, the hematologic malignancy is an acute or chronic myeloid (or bone marrow) leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, or precursor B-cell acute lymphoblastic leukemia. In some embodiments, the hematologic malignancy is acute myelogenous leukemia (AML). In some embodiments, the hematologic malignancy is acute promyelogenous leukemia (AMPL). In some embodiments, the hematologic malignancy is acute lymphoblastic leukemia (ALL). In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia (CLL). In some embodiments, the hematologic malignancy is mantle cell lymphoma (MCL).In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL), ABC subtype. In some embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL), GCB subtype. In some embodiments, the hematologic malignancy is double-hit lymphoma (DHL). In some embodiments, the hematologic malignancy is triple-hit lymphoma (THL). In some embodiments, the hematologic malignancy is double-hit / triple-hit lymphoma (DHL / THL). In some embodiments, the hematologic malignancy is double-expresser lymphoma (DEL). In some embodiments, the hematologic malignancy is Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematologic malignancy is multiple myeloma (MM). In some embodiments, the hematologic malignancy is Burkitt's lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma (FL). In some embodiments, the hematologic malignancy is transformed follicular lymphoma. In some embodiments, the hematologic malignancy is marginal zone lymphoma.

[0159] In some embodiments, the hematologic malignancy is relapsed or refractory non-Hodgkin's lymphoma (NHL). In some embodiments, the hematologic 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 Waldenström macroglobulinemia, relapsed or refractory multiple myeloma (MM), relapsed or refractory marginal zone lymphoma, relapsed or refractory Burkitt's lymphoma, relapsed or refractory non-Burkkitt high-grade B-cell lymphoma, or relapsed or refractory extranodal marginal zone B-cell lymphoma. In some embodiments, the hematologic malignancy is relapsed or refractory acute or chronic myeloid (or bone marrow) leukemia, relapsed or refractory myelodysplastic syndrome, relapsed or refractory acute lymphoblastic leukemia, or relapsed or refractory precursor B-cell acute lymphoblastic leukemia. In some embodiments, the hematologic malignancy is relapsed or refractory acute myeloid leukemia (AML). In some embodiments, the hematologic malignancy is relapsed or refractory acute promyeloid leukemia (AMPL). In some embodiments, the hematologic malignancy is relapsed or refractory acute lymphoblastic leukemia (ALL). In some embodiments, the hematologic malignancy is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the hematologic malignancy is relapsed or refractory mantle cell lymphoma (MCL). In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), subtype ABC. In some embodiments, the hematologic malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), subtype GCB. In some embodiments, the hematologic malignancy is relapsed or refractory double-hit lymphoma (DHL).In some embodiments, the hematologic malignancy is relapsed or refractory triple-hit lymphoma (THL). In some embodiments, the hematologic malignancy is relapsed or refractory double-hit / triple-hit lymphoma (DHL / THL). In some embodiments, the hematologic malignancy is relapsed or refractory double-expresser lymphoma (DEL). In some embodiments, the hematologic malignancy is relapsed or refractory Waldenstrom's macroglobulinemia (WM). In some embodiments, the hematologic malignancy is relapsed or refractory multiple myeloma (MM). In some embodiments, the hematologic malignancy is relapsed or refractory Burkitt's lymphoma. In some embodiments, the hematologic malignancy is relapsed or refractory follicular lymphoma (FL).

[0160] In some embodiments, the hematologic malignancy is a hematologic malignancy classified as high-risk. In some embodiments, the hematologic malignancy is high-risk CLL or high-risk SLL.

[0161] B-cell lymphoproliferative disorders (BCLDs) are hematologic malignancies, particularly including non-Hodgkin lymphoma, multiple myeloma, and leukemia. BCLDs can originate from lymphoid tissue (as in the case of lymphoma) or bone marrow (as in the case of leukemia and myeloma), and both are associated with the uncontrolled growth of lymphocytes or white blood cells. There are many subtypes of BCLD, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). The course and treatment of BCLD depend on the BCLD subtype; however, even within each subtype, clinical presentation, morphological appearance, and response to treatment vary.

[0162] Malignant lymphomas are tumor transformations of cells primarily located within lymphoid tissue. Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphoma infiltrate reticuloendothelial tissue. However, they differ in the origin of the neoplasmic cells, the site of disease, the presence of systemic symptoms, and the response to treatment. (Freedman et al., "Non-Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (American Cancer Society approved publication, B. C. Decker Inc., Hamilton, Ontario, 2003)). Non-Hodgkin's lymphoma

[0163] In some embodiments, the present invention discloses a method for treating non-Hodgkin's lymphoma in an individual in need, the method comprising administering a certain amount of compound A to the individual.

[0164] In some embodiments, the present invention further discloses a method for treating relapsed or refractory non-Hodgkin lymphoma in an individual of need, comprising administering a therapeutically effective amount of compound A to said individual. In some embodiments, non-Hodgkin 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.

[0165] Non-Hodgkin's lymphoma (NHL) is a variety of malignant tumors primarily originating from B cells. NHL can develop in any organ related to the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur at any age. NHL typically presents with enlarged lymph nodes, fever, and weight loss. NHL is classified as B-cell or T-cell NHL. Lymphomas associated with lymphoproliferative disorders following bone marrow or stem cell transplantation are usually B-cell NHL. In the Working Formulation classification scheme, NHL is divided into low-grade, intermediate-grade, and high-grade categories based on its natural history (see The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49(1982):2112-2135). Low-grade lymphoma is a slowly progressing lymphoma with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl. J. Med.311: 1471-1475). Although chemotherapy can induce remission in most indolent lymphomas, a cure is rare, and most patients eventually relapse, requiring further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors, but they have a greater chance of being cured with chemotherapy. However, a large proportion of these patients relapse and require further treatment.

[0166] The non-restricted list of B-cell NHL includes Burkitt's lymphoma (e.g., endemic Burkitt's lymphoma and incidental Burkitt's lymphoma), cutaneous B-cell lymphoma, cutaneous marginal zone lymphoma (MZL), diffuse large cell lymphoma (DLBCL), diffuse mixed small cell and large cell lymphoma, diffuse small cleavage cell lymphoma, diffuse small lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, follicular lymphoma, follicular small cleavage cell (grade 1), follicular mixed small cleavage cell and large cell (grade 2), follicular large cell (grade 3), intravascular large B-cell lymphoma, intravascular lymphomatosis, large cell immunoblastic lymphoma, and large cell lymphoma. This includes lymphoblastic lymphoma (LCL), lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma (MCL), immunoblastic large cell lymphoma, precursor B-cell 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, intranodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, Waldenström's macroglobulinemia, and primary central nervous system (CNS) lymphoma. Other non-Hodgkin's lymphomas are also included within the scope of this invention and will be apparent to those skilled in the art. DLBCL

[0167] In some embodiments, the present invention discloses a method for treating DLCBL in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory DLCBL in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0168] As used in this invention, the term "diffuse large B-cell lymphoma (DLBCL)" refers to a neoplasm of germinal center B lymphocytes with a diffuse growth pattern and a high intermediate proliferative index. DLBCLs account for approximately 30% of all lymphomas and can exist in several morphological variants, including centroblast-rich, immunoblast-rich, T-cell / histocyte-rich, anaplastic, and plasmablast-rich subtypes. Genetic testing has revealed different subtypes of DLBCL. These subtypes appear to have different appearances (i.e., prognoses) and responses to treatment. DLBCL can affect any age group, but it primarily occurs in older adults (e.g., with a mean age of around 65 years).

[0169] In some embodiments, the present invention discloses a method for treating diffuse large B-cell lymphoma, activated B-cell subtype (ABC-DLBCL), in individuals in need, the method comprising administering to the individual a covalent inhibitor of menin-MLL interaction at a dose of 300 mg / day to 1000 mg / day (inclusive). The ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is believed to arise from germinal center post-B cells that have arrested during plasma differentiation. The ABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. The DLBCL molecular subtype is considered to have the lowest cure rate; therefore, patients diagnosed with ABC-DLBCL typically show significantly lower survival rates compared to individuals with other types of DLBCL. ABC-DLBCL is most commonly associated with chromosomal translocations that cause loss of regulation of the germinal center master regulator BCL6 and mutations that deactivate the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation.

[0170] A particularly relevant signaling pathway in the pathogenesis of ABC-DLBCL is the signaling pathway mediated by the nuclear factor (NF)-κB transcriptional complex. The NF-κB family comprises five members (p50, p52, p65, c-rel, and RelB), which form homodimers and heterodimers and act as transcription factors to mediate various proliferation, apoptosis, inflammatory, and immune responses, and are crucial for normal B cell development and survival. NF-κB is widely used in eukaryotic cells as a regulator of genes controlling cell proliferation and cell survival. Consequently, many different types of human tumors exhibit dysregulated NF-κB: that is, NF-κB is constitutively active. Active NF-κB activates the expression of genes that maintain cell proliferation and protect cells from pathological conditions that would otherwise lead to cell death via apoptosis.

[0171] The dependence of ABC DLBCL on NF-κB depends on the signaling pathway upstream of the ikb kinase composed of CARD11, BCL10, and MALT1 (i.e., the CBM complex). Interference with the CBM pathway suppresses NF-κB signaling in ABC DLBCL cells and induces apoptosis. The molecular basis of the constitutive activity of the NF-κB pathway is the subject of current research, but some somatic alterations in the ABC DLBCL genome clearly cause this pathway. For example, somatic mutations in the coil-coil domain of CARD11 in DLBCL enable this signaling cytoskeleton protein to spontaneously nucleate protein-protein interactions with MALT1 and BCL10, leading to IKK activity and NF-κB activation. Constitutive activity of the B cell receptor signaling pathway has been associated with NF-κB activation in ABC DLBCL with wild-type CARD11, and this is associated with mutations in the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activation mutations in the signaling adaptor MYD88 activate NF-κB and synergistically maintain ABC DLBCL cell survival in conjunction with B cell receptor signaling. Furthermore, inactivation mutations in the negative regulator A20 of the NF-κB pathway occur almost entirely in ABC DLBCLs.

[0172] In fact, genetic alterations affecting multiple components of the NF-κB signaling pathway have recently been identified in over 50% of ABC-DLBCL patients. These alterations promote constitutive NF-κB activation, thereby contributing to lymphoma growth. These include CARD11 mutations (approximately 10% of cases). CARD11 is a lymphocyte-specific cytoskeletal protein that, along with MALT1 and BCL10, forms the BCR signaling body, which translocates signals from antigen receptors to downstream mediators of NF-κB activation. Even a larger proportion of cases (approximately 30%) carry dual-pair gene alterations that inactivate the negative NF-κB regulator A20. Furthermore, high levels of NF-κB target genes have been observed in ABC-DLBCL tumor samples. See, for example, 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.

[0173] ABC subtype DLBCL cells, such as OCI-Ly10, possess chronically active BCR signaling and are highly sensitive to the covalent inhibitor of menin-MLL interaction described in this invention. The covalent inhibitor of menin-MLL interaction described in this invention effectively and irreversibly inhibits the growth of OCI-Ly10 (continuous EC50 exposure = 10 nM, EC50 one-hour pulse = 50 nM). Furthermore, apoptosis-inducing activity was observed in OCI-Ly10 cells, as indicated by caspasin activation, phospholipid-binding protein-V flow cytometry, and increased denominator-G0 fraction. Follicular lymphoma

[0174] In some embodiments, the present invention discloses a method for treating follicular lymphoma in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory follicular lymphoma in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0175] As used in this invention, 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 within lymph nodes. The average age of people with this type of lymphoma is approximately 60 years. CLL / SLL

[0176] In some embodiments, the present invention discloses a method for treating CLL or SLL in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention also discloses a method for treating relapsed or refractory CLL or SLL in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0177] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are often considered the same disease with slightly different presentations. The location where the cancer cells accumulate determines whether it is called CLL or SLL. When the cancer cells are mainly located in the lymph nodes, the lima bean-shaped structures of the lymphatic system (a system mainly formed by tiny blood vessels in the body), the disease is called SLL. SLL accounts for about 5% to 10% of all lymphomas. When most of the cancer cells are in the bloodstream and bone marrow, the disease is called CLL.

[0178] Both CLL and SLL are slow-growing diseases, but CLL, being much more common, tends to develop more slowly. CLL and SLL are treated in the same way. They are not usually considered curable with standard treatments, but depending on the stage and growth rate of the disease, most patients survive for more than ten years. Sometimes, over time, these slow-growing lymphomas may transform into more aggressive lymphomas.

[0179] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. It is estimated that 100,760 people in the United States have CLL or are in remission. The majority (>75%) of newly diagnosed CLL patients are over 50 years of age. Current treatment for CLL focuses on controlling the disease and its symptoms, rather than a complete cure. CLL is treated with chemotherapy, radiation therapy, biotherapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy to remove an enlarged spleen) or with radiation therapy ("swollen lymph nodes" to remove swelling). Although CLL progresses slowly in most cases, it is generally considered incurable. Some types of CLL are classified as high-risk. As used herein, "high-risk CLL" means CLL characterized by at least one of the following: 1) 17p13-; 2) 11q22-; 3) unmutated IgVH and ZAP-70+ and / or CD38+; or 4) trisomy 12.

[0180] CLL treatment is usually administered when a patient’s clinical symptoms or blood cell counts indicate that the disease has progressed to a point where it can affect the patient’s quality of life.

[0181] Small lymphocytic leukemia (SLL) is very similar to CLL described above, and is also a B-cell cancer. In SLL, the abnormal lymphocytes primarily affect the lymph nodes. However, in CLL, the abnormal cells primarily affect the blood and bone marrow. The spleen can be affected in both conditions. SLL accounts for approximately 1 in 25 of all non-Hodgkin's lymphoma cases. It can occur at any time from young adulthood to old age, but is rare in those under 50. SLL is considered an indolent lymphoma. This means that the disease progresses very slowly, and patients often survive for many 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. While some cancers tend to occur more frequently in one sex or the other, cases and deaths caused by SLL are evenly distributed between men and women. The average age at diagnosis is 60 years.

[0182] Although SLL is indolent, it is progressive. A common pattern of this disease is one of the high response rates to radiotherapy and / or chemotherapy, with periods of remission. Relapse inevitably occurs after months or years. Retreatment again leads to a response, but the disease will relapse again. This means that although the short-term prognosis of SLL is fairly good, many patients experience fatal complications from recurrent disease over time. Considering the age of individuals typically diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment with minimal side effects that does not affect the patient's quality of life. This invention addresses a long-standing need in the art. Mantle cell lymphoma

[0183] In some embodiments, the present invention discloses a method for treating mantle cell lymphoma (MCL) in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory mantle cell lymphoma in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0184] As used in this invention, the term "mantle cell lymphoma" refers to a subtype of B-cell lymphoma arising from untreated CD5-positive B cells in the mantle zone surrounding normal germinal center follicles. MCL cells typically overexpress cyclin D1 due to a 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. Cells are small to medium in size. Men are most commonly affected. The average age of patients is in their early sixties. Lymphomas are usually widespread at diagnosis, involving lymph nodes, bone marrow, and frequently the spleen. Mantle cell lymphoma is not a very rapidly progressing lymphoma, but it is difficult to treat. Marginal zone B-cell lymphoma

[0185] In some embodiments, the present invention discloses a method for treating marginal zone B-cell lymphoma in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0186] As used in this invention, the term "marginal zone B-cell lymphoma" refers to a group of associated B-cell neoplasms involving lymphoid tissue in the marginal zone (the flocculent area outside the follicular mantle). Marginal zone lymphomas account for approximately 5% to 10% of lymphomas. The cells in these lymphomas appear very small under a microscope. There are three main types of marginal zone lymphomas, including extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma. MALT

[0187] In some embodiments, the present invention discloses a method for treating MALT in an individual in need, comprising administering a certain amount of compound A to said individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory MALT in an individual in need, comprising administering a therapeutically effective amount of compound A to said individual.

[0188] As used in this invention, the term "mucosa-associated lymphoid tissue (MALT) lymphoma" refers to the extranodal manifestation of marginal zone lymphoma. Most MALT lymphomas are low-grade, although a minority initially present as intermediate-grade non-Hodgkin's lymphoma (NHL) or evolve from a low-grade form. 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 identified, the most common being trisomy 3 or t(11;18). Many of these other MALT lymphomas are also associated with bacterial or viral infections. The average age of patients with MALT lymphoma is approximately 60 years. Nodal marginal zone B-cell lymphoma

[0189] In some embodiments, the present invention discloses a method for treating nodal marginal zone B-cell lymphoma in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory nodal marginal zone B-cell lymphoma in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0190] The term "marginal zone B-cell lymphoma" refers to an indolent B-cell lymphoma primarily found in lymph nodes. This disease is rare, accounting for only 1% of all non-Hodgkin lymphomas (NHL). It is most commonly diagnosed in older patients, and women are more susceptible than men. The disease is classified as marginal zone lymphoma because the mutation occurs in the marginal zone of B cells. Because the disease is confined to lymph nodes, it is also classified as intranodal. Splenic marginal zone B-cell lymphoma

[0191] In some embodiments, the present invention discloses a method for treating splenic marginal zone B-cell lymphoma in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0192] The term "marginal zone B-cell lymphoma of the spleen" refers to a specific low-grade small B-cell lymphoma included in the World Health Organization classification. It is characterized by splenomegaly, moderate lymphocytosis with a villous morphology, a sinusoidal luminal pattern involving various organs, particularly the bone marrow, and a relatively indolent process. Increased blastic morphology and aggressive tumor progression have been observed in a minority of patients. Molecular and cytogenetic studies have shown heterogeneous results, likely due to the lack of standardized diagnostic criteria. Burkitt lymphoma

[0193] In some embodiments, the present invention discloses a method for treating Burkitt lymphoma in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory Burkitt lymphoma in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0194] The term "Burkitt lymphoma" refers to a type of non-Hodgkin's lymphoma (NHL) that typically affects children. It is a highly aggressive type of B-cell lymphoma that usually begins and affects sites of the body outside the lymph nodes. Despite its rapid-growing nature, Burkitt lymphoma is often curable with modern intensive therapies. There are two broad types of Burkitt lymphoma—ephemeral and specific types.

[0195] Endemic Burkitt lymphoma: This disease affects far more children than adults, and in 95% of cases, it is associated with Epstein-Barr virus (EBV) infection. It occurs primarily in equatorial Africa, where approximately half of all childhood cancers are Burkitt lymphoma. It is characterized by a high probability of involvement of the jawbone, a rather unique feature that is very rare in sporadic Burkitt disease. It also often includes the abdomen.

[0196] Incidental Burkitt lymphoma: This type of Burkitt lymphoma affects other parts of the world, including Europe and the Americas. It is also a leading cause of death in children. The link between Epstein-Barr virus (EBV) and the lymphoma is not as strong as in the endemic type, although direct evidence of EBV infection is present in one-fifth of patients. The abdomen is significantly affected in over 90% of children compared to lymph node involvement. Bone marrow involvement is more common than in the incidental type. Waldenström macroglobulinemia

[0197] In some embodiments, the present invention discloses a method for treating Waldenström macroglobulinemia in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory Waldenström macroglobulinemia in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0198] The term "Waldenström macroglobulinemia," also known as lymphoplasmacytic lymphoma, is a cancer involving a subtype of white blood cells called lymphocytes. It is characterized by the uncontrolled, pure-lineage proliferation of terminally differentiated B lymphocytes. It is also characterized by lymphoma cells forming antibodies called immunoglobulin M (IgM). IgM antibodies circulate extensively in the blood, causing the fluid portion of the blood to thicken, like syrup. This can lead to reduced blood flow to many organs, resulting in visual problems (due to poor circulation in the blood vessels behind the eyes) and neurological problems caused by poor blood flow in the brain (i.e., headaches, dizziness, and confusion). Other symptoms may include feeling tired and weak, and easy bleeding. The underlying cause is not fully understood, but several risk factors have been identified, including locus 6p21.3 on chromosome 6. Individuals with a personal history of autoimmune diseases involving autoantibodies have a 2 to 3 times increased risk of developing WM, with particularly elevated risks associated with hepatitis, human immunodeficiency virus (HIV), and rickettsial diseases. Multiple myeloma

[0199] In some embodiments, the present invention discloses a method for treating multiple myeloma in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory multiple myeloma in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0200] 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. A type of B cell, plasma cells are a key part of the immune system responsible for producing antibodies in humans and other vertebrates. They are produced in the bone marrow and transported via the lymphatic system. Leukemia

[0201] In some embodiments, the present invention discloses a method for treating leukemia in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the present invention further discloses a method for treating relapsed or refractory leukemia in an individual in need, comprising administering a therapeutically effective amount of compound A to the individual.

[0202] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually white blood cells (leukocytes). Leukemia is a broad term encompassing a range of diseases. It was initially classified between its acute and chronic forms.

[0203] Acute leukemia is characterized by a rapid increase in immature blood cells. This overcrowding prevents the bone marrow from producing healthy blood cells. Due to the rapid development and accumulation of malignant cells, these cells then leak into the bloodstream and spread to other organs of the body, thus acute leukemia requires immediate treatment. Acute leukemia is the most common form of leukemia in children.

[0204] Chronic leukemia is characterized by an excessive accumulation of relatively mature but still abnormal white blood cells. This process typically takes months or years, with cells being produced at a much higher rate than normal, resulting in numerous abnormal white blood cells in the blood. Chronic leukemia primarily occurs in the elderly, but theoretically it can occur in any age group.

[0205] Furthermore, the disease is further subdivided according to the types of blood cells affected. This subdivision divides leukemia into lymphoblastic or lymphocytic leukemia and myeloid or myeloid leukemia: (i) lymphoblastic or lymphocytic leukemia, in which cancerous changes occur in a type of bone marrow cell that normally forms lymphocytes, which are immune system cells that fight infection; and (ii) myeloid or myeloid leukemia, in which cancerous changes occur in a type of bone marrow cell that normally forms red blood cells, some other types of white blood cells, and platelets.

[0206] Within these main 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). Therefore, in some embodiments, the present invention discloses a method for 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 of need, comprising administering a certain amount of compound A to said individual. In some embodiments, the leukemia is 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 individual has MLL / KMT2A gene recombination. In some embodiments, the mammal or individual has an NPM1 mutation. In some embodiments, the mammal or individual has a TP53 mutation. In some embodiments, the mammal or individual has a NOTCH1 mutation. In some embodiments, the mammal or individual has a 13q deletion (del(13q)). In some embodiments, the mammal or individual has a trisomy 12 karyotype.

[0207] The symptoms, diagnostic tests, and prognostic tests for each of the above conditions are known. See, for example, Harrison's Principles of Internal Medicine©, 16th edition, 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojournal 3(24), and the Revised European American Lymphoma (REAL) classification system (see, for example, the website maintained by the National Cancer Institute).

[0208] Many animal models can be used to establish a series of therapeutically effective doses of menin-MLL interacting compounds, such as covalent inhibitors of compound A for the treatment of any of the aforementioned diseases.

[0209] The therapeutic efficacy of compound A against any of the aforementioned diseases can be optimized during treatment. For example, the treated mammal or individual may undergo diagnostic evaluation to correlate the reduction of disease symptoms or pathology with the inhibition of Menin-MLL activity in vivo achieved by administering a given dose of compound A. Therefore, the amount of covalent inhibitor of the menin-MLL interaction inhibitor compound administered to the mammal or individual can be increased or decreased as needed to maintain the optimal level of inhibition for the treatment of the disease state in the mammal or individual.

[0210] 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 shown efficacy in a variety of diseases and conditions described in this invention.

[0211] In some embodiments, compound A is used to prepare a medicament for treating any of the aforementioned conditions (e.g., autoimmune diseases, inflammatory diseases, allergic conditions, B-cell proliferative disorders, or thromboembolic disorders).

[0212] In some embodiments, cancer is a B-cell proliferation disorder.

[0213] In some embodiments, the B-cell proliferation disorder is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, lymphocytic leukemia, ALL, soft tissue tumor, glioblastoma, pancreatic tumor, or renal cell carcinoma.

[0214] In some embodiments, the cancer is cancer in adolescents, childhood adrenocortical carcinoma, AIDS-related cancer (such as lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, or bladder cancer.

[0215] In some embodiments, cancer is bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma or cardiac tumor, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, Ewing's sarcoma, extracranial germ cell tumor, gonadal 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 carcinoma and / or non-Hodgkin lymphoma.

[0216] In some embodiments, the cancer is multiple endocrine adenoma syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, spinal dysplasia syndrome, myelodysplastic dysplasia / myeloma and / or multiple myeloma.

[0217] In some embodiments, the cancer is Merkel cell carcinoma, mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity carcinoma, parathyroid cancer, penile cancer, pharyngeal cancer, pleural pulmonary blastoma, or primary central nervous system (CNS).

[0218] 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, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer or oral cancer with occult primary origin.

[0219] In some embodiments, the cancer is multiple endocrine adenoma syndrome, multiple myeloma / plasma cell tumor, granulomatous granulomatosis, spinal dysplasia syndrome, myelodysplastic syndrome / myeloma, multiple myeloma, lymphoma, prostate cancer, rectal cancer, or transitional cell carcinoma.

[0220] In some embodiments, the cancer is retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer (gastric cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood abnormal cancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, the method relates to treating non-cancerous hyperplastic conditions such as benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate conditions (e.g., benign prostatic hyperplasia (BPH)).

[0221] In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, and / or colorectal cancer.

[0222] In some embodiments, the cancer is CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesia-sensitive neuroblastoma, eye cancer, bone fibrous histiocytoma, gallbladder cancer, and / or gastric cancer.

[0223] In some embodiments, the present invention provides a method for treating the following diseases or conditions, comprising administering the compounds provided by the present invention to a mammal. In some embodiments, the disease or condition is ALL (acute lymphoblastic lymphoma), DLBCL (diffuse large B-cell lymphoma), FL (follicular lymphoma), RCC (renal cell carcinoma), pediatric neuroblastoma, 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 condition is early-onset dystonia. In still other embodiments, the disease or condition is Kabuki syndrome.

[0224] In some embodiments, the disease or symptom is a p53-driven tumor.

[0225] In some embodiments, the disease or condition is MYC-driven tumor. MYC is documented to be widely involved in many cancers, with its expression estimated to be 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 highly attractive to Myc, and that dysregulated Myc expression leads to a strong attraction not only to Myc but also to nutrient C. These Myc-induced alterations offer unique opportunities for novel therapeutic strategies. Although normal proliferating cells (stem cell compartments and immune cells) also use MYC for renewal, much research has focused on targeting Myc for cancer therapy. Strategies have emerged to inhibit MYC expression, interrupt Myc-Max dimerization, inhibit Myc-Max DNA binding, and interfere with key Myc target genes. (Dang et al. Cell. 2012, 149(1): 22–35).

[0226] 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 / triple hit lymphoma (DHL / THL), menin-dependent dual-expression lymphoma (DEL), and menin-dependent multiple myeloma (MM).

[0227] 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 / triple hit lymphoma (DHL / THL), menin-independent dual-expression lymphoma (DEL), and menin-independent multiple myeloma (MM).

[0228] 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.

[0229] In some embodiments, compound A can be used to treat menin-dependent hematologic malignancies. In some embodiments, compound A can be used to treat menin-independent hematologic malignancies.

[0230] In some embodiments, compound A can be used to treat hematologic malignancies involving mutations in the nucleophosphorus protein (NMP1) gene. In some embodiments, compound A can be used to treat hematologic malignancies not involving mutations in the nucleophosphorus protein (NMP1) gene.

[0231] In some embodiments, compound A can be used to treat hematologic malignancies involving MLL recombination. In some embodiments, compound A can be used to treat hematologic malignancies without MLL recombination.

[0232] 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 / triple hit lymphoma (DHL / THL), MYC-dependent dual-expression lymphoma (DEL), and MYC-dependent multiple myeloma (MM).

[0233] 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 / triple hit lymphoma (DHL / THL), MYC-independent dual-expression lymphoma (DEL), and MYC-independent multiple myeloma (MM).

[0234] In some embodiments, compound A can be used to treat relapsed / refractory (R / R) acute leukemia (AL), DLBCL and MM.

[0235] 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 not involving p53 gene mutations.

[0236] 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 not involving KRAS gene mutations.

[0237] In some embodiments, compound A can be used to treat CLL patients who have overexpressed BCL2. In some embodiments, compound A can be used to treat CLL patients who do not have overexpressed BCL2.

[0238] In some embodiments, compound A can be used to treat cancers involving mutations in the ATM gene. In some embodiments, compound A can be used to treat cancers not involving mutations in the ATM gene.

[0239] 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 not involving Notch1 gene mutations.

[0240] 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 not involving TP53 gene mutations.

[0241] In some embodiments, compound A can be used to treat cancers involving mutations in the WT1 gene. In some embodiments, compound A can be used to treat cancers that do not involve mutations in the WT1 gene.

[0242] 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 not involving KMT2A gene mutations.

[0243] In some embodiments, compound A can be used to treat cancers involving mutations in the TET2 gene. In some embodiments, compound A can be used to treat cancers not involving mutations in the TET2 gene.

[0244] In some embodiments, compound A can be used to treat cancers involving gene mutations in chromosome Del(13q). In some embodiments, compound A can be used to treat cancers not involving gene mutations in chromosome Del(13q).

[0245] In some embodiments, compound A can be used to treat cancers involving gene mutations related to trisomy 12. In some embodiments, compound A can be used to treat cancers not involving gene mutations related to trisomy 12. Compound A and its pharmaceutically acceptable salts.

[0246] "Compound A" or "N-[4-[4-(4-morpholino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine" or any other suitable name refers to a compound having the following structure:

[0247] A variety of pharmaceutically acceptable salts are formed from compound A and include: - acid addition salts formed by reacting compound A with an organic acid, said organic acid including aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl alkanoates, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., and including, 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 analogues; - acid addition salts formed by reacting compound A with an inorganic acid, said inorganic acid including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0248] The term “pharmaceutically acceptable salt” for compound A means a salt of compound A that does not cause significant irritation to mammals to which it is administered and substantially does not eliminate the biological activity and properties of the neutral compound.

[0249] It should be understood that references to pharmaceutically acceptable salts include solvation forms (solvents). Solvents contain stoichiometric or non-stoichiometric amounts of solvent and are formed in the course of product formation or separation with pharmaceutically acceptable solvents 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, etc. In one instance, solvates are formed using, but not limited to, Class 3 solvents. The types of solvents are defined, for example, by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005)". A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is an alcohol. In some embodiments, a solvate of compound A or a pharmaceutically acceptable salt thereof is conveniently prepared or formed in the process described herein. In some embodiments, the solvate of compound A is anhydrous. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in a non-solvate form. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in a non-solvate form and is anhydrous.

[0250] In other embodiments, compound A or a pharmaceutically acceptable salt thereof is prepared in various forms, including but not limited to amorphous phase, crystalline form, milled form, and nanoparticle form. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is amorphous and anhydrous. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is crystalline. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is crystalline and anhydrous.

[0251] The terms "substantially free of" or "substantially absent" in relation to a composition mean that the composition contains at least 50 wt%, 60 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, or 90 wt%, and in some embodiments 95 wt%, 98 wt%, 99 wt%, or 100 wt% of a specified mirror-image isomer of the compound; or in some embodiments, 95 wt%, 98 wt%, 99 wt%, or 100 wt% of a specified mirror-image isomer of the compound. In some embodiments, in the methods and compounds provided by the present invention, the compound is substantially free of one of the two mirror-image isomers. In some embodiments, in the methods and compounds provided by the present invention, the compound is substantially free of the other mirror-image isomer.

[0252] Similarly, the term "isolated" in relation to a composition means a composition comprising 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 a compound, with the remainder comprising other mirror isomers.

[0253] As used in this invention, "excess of mirror isomers (ee)" refers to a dimensionless mole ratio describing the purity of a chiral substance containing, for example, a single stereoisomeric center. For example, a zero excess of mirror isomers indicates racemization (e.g., a 50:50 mixture of mirror isomers, or one mirror isomer being in no excess relative to another). As another example, a 99% excess of mirror isomers indicates a nearly stereopure mirror isomer compound (i.e., one mirror isomer being in significant excess relative to another). Excess percentage of mirror isomers: ee (%) = ([(R)-compound] - [(S)-compound]) / ([(R)-compound] + [(S)-compound]) x 100, where (R)-compound > (S)-compound; or ee (%) = ([(S)-compound] - [(R)-compound]) / ([(S)-compound] + [(R)-compound]) x 100, where (S)-compound > (R)-compound.

[0254] In some embodiments, compound A is prepared as outlined in U.S. Patent No. 11,084,825. Amorphous compound A

[0255] In some embodiments, compound A is amorphous and anhydrous. In some embodiments, compound A is amorphous. In some embodiments, amorphous compound A has an X-ray powder diffraction (XRPD) pattern showing a lack of crystallinity. Compound A, form A

[0256] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form A. The crystalline form A of compound A is characterized by having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 1A; (b) characteristic peaks in the X-ray powder diffraction (XRPD) pattern at 3.5 ± 0.1°²⁻θ, 10.4 ± 0.1°²⁻θ, 14.7 ± 0.1°²⁻θ, 17.1 ± 0.1°²⁻θ, 21 ± 0.1°²⁻θ, 24.9 ± 0.1°²⁻θ, 29.5 ± 0.1°²⁻θ, and 34.1 ± 0.1°²⁻θ; (c) characteristic peaks in the X-ray powder diffraction (XRPD) pattern at 3.5 ± 0.1°²⁻θ, 17.1 ± 0.1°²⁻θ, 21.0 ± 0.1°²⁻θ, 24.9 ± 0.1°²⁻θ, and 29.5 ± 0.1°²⁻θ; (d) characteristic peaks in the X-ray powder diffraction (XRPD) pattern at 3.5 ± 0.1°²⁻θ, 17.1 ± 0.1°²⁻θ, 21.0 ± 0.1°²⁻θ, 24.9 ± 0.1°²⁻θ, and 29.5 ± 0.1°²⁻θ; The DSC thermal analysis plot has an endothermic peak that begins at about 234.6°C and peaks at about 245°C; or (e) a combination thereof.

[0257] In some embodiments, form A of compound A is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, form A of compound A is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, form A of compound A is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, form A of compound A is characterized by having all five of the properties selected from (a) to (e).

[0258] In some embodiments, form A has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG. 1A. In some embodiments, form A has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.5±0.1°2-θ, 10.4±0.1°2-θ, 14.7±0.1°2-θ, 17.1±0.1°2-θ, 21.0±0.1°2-θ, 24.9±0.1°2-θ, 29.5±0.1°2-θ, and 30.0±0.1°2-θ.

[0259] In some embodiments, form A is non-hygroscopic. In some embodiments, form A is hygroscopic.

[0260] 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.

[0261] In some embodiments, form A is non-solventized. In some embodiments, form A is anhydrous. In some embodiments, form A is dissolved. In some embodiments, form A is aqueous or a hydrate. Compound A, form B

[0262] 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) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 2A; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.9±0.1°2-θ, 8.6±0.1°2-θ, 10.5±0.1°2-θ, 12.6±0.1°2-θ, 16.9±0.1°2-θ, 19±0.1°2-θ, 20.5±0.1°2-θ, and 24.6±0.1°2-θ; (c) The X-ray powder diffraction (XRPD) pattern has characteristic peaks at 8.6±0.1°2-θ, 10.5±0.1°2-θ, 12.6±0.1°2-θ, 16.9±0.1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ and 24.6±0.1°2-θ; or (d) combinations thereof.

[0263] In some embodiments, form B of compound A is characterized by having at least two of the properties selected from (a) to (d). In some embodiments, form B of compound A is characterized by having at least three of the properties selected from (a) to (d). In some embodiments, form B of compound A is characterized by having all four of the properties selected from (a) to (d).

[0264] In some embodiments, Form B has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG. 2A. In some embodiments, the X-ray powder diffraction (XRPD) pattern of Form B has characteristic peaks at 8.6±0.1°2-θ, 10.5±0.1°2-θ, 12.6±0.1°2-θ, 16.9±0.1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ, and 24.6±0.1°2-θ.

[0265] In some embodiments, form B is obtained from a mixture of methanol and water.

[0266] In some embodiments, form B is non-solventized. In some embodiments, form B is anhydrous. In some embodiments, form B is dissolved. In some embodiments, form B is a hydrate. Compound A, form C

[0267] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form C. Crystalline form C of compound A is characterized by having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 3A; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.2±0.1°2-θ, 5.9±0.1°2-θ, 7.2±0.1°2-θ, 8.7±0.1°2-θ, 10.6±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.1±0.1°2-θ, 15.9±0.1°2-θ, 17.5±0.1°2-θ, 18.1±0.1°2-θ, and 20.1±0.1°2-θ. (c) The X-ray powder diffraction (XRPD) pattern has characteristic peaks at 5.2±0.1°2-θ, 5.9±0.1°2-θ, 8.7±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.9±0.1°2-θ and 17.5±0.1°2-θ; (d) The DSC thermal analysis plot has an endothermic peak that begins at about 150.23°C and peaks at about 156.86°C; or (e) a combination thereof.

[0268] In some embodiments, form C of compound A is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, form C of compound A is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, form C of compound A is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, form C of compound A is characterized by having all five of the properties selected from (a) to (e).

[0269] In some embodiments, form C has a substantially identical X-ray powder diffraction (XRPD) pattern to that shown in FIG. 3A. In some embodiments, the X-ray powder diffraction (XRPD) pattern of form C has characteristic peaks at 5.2±0.1°2-θ, 5.9±0.1°2-θ, 7.2±0.1°2-θ, 8.7±0.1°2-θ, 10.6±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.1±0.1°2-θ, 15.9±0.1°2-θ, 17.5±0.1°2-θ, 18.1±0.1°2-θ, and 20.1±0.1°2-θ. In some embodiments, the X-ray powder diffraction (XRPD) pattern of form C has characteristic peaks at 5.2 ± 0.1°2-θ, 5.9 ± 0.1°2-θ, 8.7 ± 0.1°2-θ, 12.2 ± 0.1°2-θ, 14.3 ± 0.1°2-θ, 15.9 ± 0.1°2-θ, and 17.5 ± 0.1°2-θ. Compound A, form D

[0270] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form D. Crystalline form D of compound A is characterized by 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) the X-ray powder diffraction (XRPD) pattern having characteristic peaks at 3.4±0.1°2-θ, 5.3±0.1°2-θ, 7±0.1°2-θ, 8.7±0.1°2-θ, 10.8±0.1°2-θ, 12.9±0.1°2-θ, 14.3±0.1°2-θ, 15.6±0.1°2-θ, 17±0.1°2-θ, 18.5±0.1°2-θ, 19.6±0.1°2-θ, 21.5±0.1°2-θ, and 24.2±0.1°2-θ; (c) The X-ray powder diffraction (XRPD) pattern exhibits characteristic peaks at 3.4 ± 0.1°2-θ, 8.7 ± 0.1°2-θ, 10.7 ± 0.1°2-θ, 15.6 ± 0.1°2-θ, 18.5 ± 0.1°2-θ, 19.6 ± 0.1°2-θ, and 24.2 ± 0.1°2-θ; (d) after storage in an open container at 40°C and 75% RH for at least one week, it exhibits substantially the same X-ray powder diffraction (XRPD) pattern; (e) after storage in an open container at 25°C and 92% RH for at least one week, it exhibits substantially the same X-ray powder diffraction (XRPD) pattern; (f) after storage in a closed container at 60°C and 75% RH for at least one week, it exhibits substantially the same X-ray powder diffraction (XRPD) pattern; (g) substantially similar to the infrared (IR) spectrum shown in Figure 9A; (h) The infrared (IR) spectrum (Figure 9A) shows peaks at approximately 3332 cm⁻¹ (unlabeled), approximately 2853 cm⁻¹ (unlabeled), approximately 1561 cm⁻¹ (unlabeled), approximately 1523 cm⁻¹, approximately 1438 cm⁻¹, approximately 1257 cm⁻¹, 1112 cm⁻¹, and approximately 930 cm⁻¹; (i) substantially similar to the thermogravimetric analysis (TGA) thermal analysis plot shown in Figure 10; (j) substantially similar to the DSC thermal analysis plot shown in Figure 11; (k) the DSC thermal analysis plot exhibits endothermic and exothermic characteristics starting at approximately 260.5°C and peaking at approximately 273°C; (l) the 1H NMR (nuclear magnetic resonance) spectrum is substantially similar to the spectrum shown in Figure 12; (m) hygroscopicity and absorbency of approximately 2.1% water observed at 25°C from 40% RH to 70% RH; (n) Water solubility of approximately 0.004 mg / mL observed at approximately pH 4.5; or (o) combinations thereof.

[0271] In some embodiments, form D of compound A is characterized by having at least two of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least three of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least four of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least five of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least six of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least seven of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least eight of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least nine of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having at least ten of the properties selected from (a) to (n). In some embodiments, form D of compound A is characterized by having properties (a) to (n).

[0272] In some embodiments, form D has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG. 4A; in some embodiments, the X-ray powder diffraction (XRPD) pattern of form D has 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, the X-ray powder diffraction (XRPD) pattern of form D has characteristic peaks at 3.4±0.1°2-θ, 8.7±0.1°2-θ, 10.7±0.1°2-θ, 15.6±0.1°2-θ, 18.5±0.1°2-θ, 19.6±0.1°2-θ, and 24.2±0.1°2-θ.

[0273] In some embodiments, form D has a thermogravimetric analysis (TGA) thermal analysis map that is substantially similar to that shown in FIG10.

[0274] In some embodiments, form D has a DSC thermal analysis map that is substantially similar to that shown in FIG11.

[0275] In some embodiments, form D has an NMR spectrum that is substantially similar to that shown in FIG12.

[0276] In some embodiments, form D is obtained from methyl isobutyl ketone (MIBK). In some embodiments, form D is dissolved. In some embodiments, form D is dissolved in methyl isobutyl ketone (MIBK). Compound A, form E

[0277] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form E. Crystalline form E of compound A is characterized by having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 5A; (b) X-ray powder diffraction (XRPD) pattern at 3.4±0.1°2-θ, 4.7±0.1°2-θ, 6.3±0.1°2-θ, 6.9±0.1°2-θ, 7.1±0.1°2-θ, 7.6±0.1°2-θ, 8.6±0.1°2-θ, 9.3±0.1°2-θ , 10.8±0.1°2-θ, 12±0.1°2-θ, 12.5±0.1°2-θ, 13±0.1°2-θ, 13.8±0.1°2-θ, 15.7±0.1°2-θ, 16.2±0.1°2-θ, 16.7±0.1°2-θ, 17±0.1°2-θ , 17.5±0.1°2-θ, 18.4±0.1°2-θ, 18.6±0.1°2-θ, 19.6±0.1°2-θ, 20.7±0.1°2-θ, 21.4±0.1°2-θ, 22.2±0.1°2-θ, 23±0.1°2-θ, 24.2±0.1 There are characteristic peaks at °2-θ, 25.3±0.1°2-θ, 26±0.1°2-θ, 28±0.1°2-θ, 29.2±0.1°2-θ, 30.5±0.1°2-θ, 31.6±0.1°2-θ, 33.6±0.1°2-θ and 34.5±0.1°2-θ; (c) The X-ray powder diffraction (XRPD) pattern has characteristic peaks at 4.7±0.1°2-θ, 7.7±0.1°2-θ, 10.8±0.1°2-θ, 13.8±0.1°2-θ, 17.0±0.1°2-θ, 18.4±0.1°2-θ and 18.6±0.1°2-θ; (d) The DSC thermal analysis plot has an endothermic peak that begins at about 112.34°C and peaks at about 137.26°C; or (e) a combination thereof.

[0278] In some embodiments, form E of compound A is characterized by having at least two of the properties selected from (a) to (d). In some embodiments, form E of compound A is characterized by having at least three of the properties selected from (a) to (d). In some embodiments, form E of compound A is characterized by having all four of the properties selected from (a) to (d).

[0279] In some embodiments, form E has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG. 5A; in some embodiments, the X-ray powder diffraction (XRPD) pattern of form E is at 3.4 ± 0.1°2-θ. 4.7±0.1°2-θ, 6.3±0.1°2-θ, 6.9±0.1°2-θ, 7.1±0.1°2-θ, 7.6±0.1°2- θ, 8.6±0.1°2-θ, 9.3±0.1°2-θ, 10.8±0.1°2-θ, 12±0.1°2-θ, 12.5±0.1° 2-θ, 13±0.1°2-θ, 13.8±0.1°2-θ, 15.7±0.1°2-θ, 16.2±0.1°2-θ, 16.7 ±0.1°2-θ, 17±0.1°2-θ, 17.5±0.1°2-θ, 18.4±0.1°2-θ, 18.6±0.1°2-θ, 19.6±0.1°2-θ, 20.7±0.1°2-θ, 21.4±0.1°2-θ, 22.2±0.1°2-θ, 23±0.1°2-θ, 24.2±0.1°2-θ, 25.3±0.1°2-θ, 26±0.1°2-θ, 28±0.1°2-θ, 29.2±0.1°2-θ, There are characteristic peaks at 30.5±0.1°2-θ, 31.6±0.1°2-θ, 33.6±0.1°2-θ and 34.5±0.1°2-θ. In some embodiments, the X-ray powder diffraction (XRPD) pattern of form E has characteristic peaks at 4.7 ± 0.1°2-θ, 7.7 ± 0.1°2-θ, 10.8 ± 0.1°2-θ, 13.8 ± 0.1°2-θ, 17.0 ± 0.1°2-θ, 18.4 ± 0.1°2-θ, and 18.6 ± 0.1°2-θ. Compound A, form F

[0280] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form F. Crystalline form F of compound A is characterized by having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 6A; (b) an X-ray powder diffraction (XRPD) pattern at 4.2±0.1°2-θ, 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 12±0.1°2-θ, 12.2±0.1°2-θ, 12.5±0.1°2-θ, 14.4±0.1°2-θ, 15±0.1°2-θ, 16±0.1°2-θ, 16.8±0.1 °2-θ, 17.2±0.1°2-θ, 17.5±0.1°2-θ, 17.8±0.1°2-θ, 18.8±0.1°2-θ, 19.2±0.1°2-θ, 20.1±0.1°2-θ, 20.5±0.1°2-θ, 21.7±0.1°2-θ, 22.1±0.1°2-θ, 23.4±0.1°2-θ, 24.2±0.1°2-θ , 25.3±0.1°2-θ, 25.5±0.1°2-θ, 26.3±0.1°2-θ, 27.1±0.1°2-θ, 29±0.1°2-θ, 30.3±0.1°2-θ, There are characteristic peaks at 31.6±0.1°2-θ, 33.1±0.1°2-θ, 34.3±0.1°2-θ and 35.6±0.1°2-θ; (c) The X-ray powder diffraction (XRPD) pattern has characteristic peaks at 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 11.9±0.1°2-θ, 12.2±0.1°2-θ, 14.4±0.1°2-θ, 15.0±0.1°2-θ, and 20.5±0.1°2-θ; or (d) combinations thereof.

[0281] In some embodiments, form F of compound A is characterized by having at least two of the properties selected from (a) to (d). In some embodiments, form F of compound A is characterized by having at least three of the properties selected from (a) to (d). In some embodiments, form F of compound A is characterized by having all four of the properties selected from (a) to (d).

[0282] In some embodiments, form F has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG. 6A. In some embodiments, the X-ray powder diffraction (XRPD) pattern of form F is at 4.2±0.1°2-θ, 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 12±0.1°2-θ, 12.2±0.1°2-θ, 12.5±0.1°2-θ, 14.4±0.1°2-θ, 15±0.1°2-θ, 16±0.1°2-θ, and 16.8±0.1°2-θ. -θ, 17.2±0.1°2-θ, 17.5±0.1°2-θ, 17.8±0.1°2-θ, 18.8±0.1°2-θ, 19.2±0.1°2-θ, 20.1±0.1°2- θ, 20.5±0.1°2-θ, 21.7±0.1°2-θ, 22.1±0.1°2-θ, 23.4±0.1°2-θ, 24.2±0.1°2-θ, 25.3±0.1°2-θ, Characteristic peaks are observed at 25.5±0.1°2-θ, 26.3±0.1°2-θ, 27.1±0.1°2-θ, 29±0.1°2-θ, 30.3±0.1°2-θ, 31.6±0.1°2-θ, 33.1±0.1°2-θ, 34.3±0.1°2-θ, and 35.6±0.1°2-θ. In some embodiments, the X-ray powder diffraction (XRPD) pattern of form F has characteristic peaks at 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 11.9±0.1°2-θ, 12.2±0.1°2-θ, 14.4±0.1°2-θ, 15±0.1°2-θ, and 20.5±0.1°2-θ. Compound A, form G

[0283] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form G. The crystalline form G of compound A is characterized by having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 7A; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8±0.1°2-θ, 10.2±0.1°2-θ, 12.1±0.1°2-θ, 16.8±0.1°2-θ, 19.2±0.1°2-θ and 24.6±0.1°2-θ; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1±0.1°2-θ, 10.2±0.1°2-θ, 12.1±0.1°2-θ, 16.8±0.1°2-θ, 19.2±0.1°2-θ and 24.6±0.1°2-θ; or (d) a combination thereof.

[0284] In some embodiments, the form G of compound A is characterized by having at least two of the properties selected from (a) to (d). In some embodiments, the form G of compound A is characterized by having at least three of the properties selected from (a) to (d). In some embodiments, the form G of compound A is characterized by having all four of the properties selected from (a) to (d).

[0285] In some embodiments, form G has a substantially identical X-ray powder diffraction (XRPD) pattern to that shown in FIG. 7A. In some embodiments, the XRPD pattern of form G has characteristic peaks at 8 ± 0.1°2-θ, 10.2 ± 0.1°2-θ, 12.1 ± 0.1°2-θ, 16.8 ± 0.1°2-θ, 19.2 ± 0.1°2-θ, and 24.6 ± 0.1°2-θ. In some embodiments, the XRPD pattern of form G has characteristic peaks at 8.1 ± 0.1°2-θ, 10.2 ± 0.1°2-θ, 12.1 ± 0.1°2-θ, 16.8 ± 0.1°2-θ, 19.2 ± 0.1°2-θ, and 24.6 ± 0.1°2-θ. Compound A, form J

[0286] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form J. Crystalline form J of compound A is characterized by having at least one of the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 8A; (b) an X-ray powder diffraction (XRPD) pattern at 3.5±0.1°2-θ, 4.5±0.1°2-θ, 6.4±0.1°2-θ, 8.7±0.1°2-θ, 10.2±0.1°2-θ, 11.3±0.1°2-θ, 11.8±0.1°2-θ, 13.2±0.1°2-θ, and 13.6±0.1°2-θ. , 14±0.1°2-θ, 14.6±0.1°2-θ, 15.4±0.1°2-θ, 16.1±0.1°2-θ, 16.6±0.1°2-θ, 16.9±0.1°2-θ, 17.2±0.1°2-θ, 18.3±0.1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ, 20.8±0.1°2-θ, 21.6±0.1°2-θ, 23.5±0.1°2-θ, 23.8±0.1°2-θ, 24.6±0.1°2-θ, 24.9±0.1°2-θ, 25.2±0.1°2-θ, 25.8±0.1°2-θ, 26.2±0.1°2-θ, 26.7±0.1°2-θ, 26.8±0.1°2-θ, 27.4±0.1°2-θ, 27.7±0.1°2-θ, 28.7±0.1°2-θ, 29.3±0.1°2-θ, 30.1±0.1°2-θ, 31.2±0.1°2-θ, 31.8±0.1°2-θ, 34.1±0.1° There are characteristic peaks at 2-θ, 34.9±0.1°2-θ, 35.6±0.1°2-θ, 36.4±0.1°2-θ, 36.7±0.1°2-θ, 38.5±0.1°2-θ and 38.8±0.1°2-θ; (c) X-ray powder diffraction (XRPD) patterns with characteristic peaks at 3.5 ± 0.1°2-θ, 4.5 ± 0.1°2-θ, 19.1 ± 0.1°2-θ, 21.6 ± 0.1°2-θ, 22.5 ± 0.1°2-θ, and 27.4 ± 0.1°2-θ; (d) hygroscopicity and absorbency of approximately 2.1% water observed at 25°C from 40% RH to 70% RH; or (e) combinations thereof.

[0287] In some embodiments, form J of compound A is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, form J of compound A is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, form J of compound A is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, form J of compound A is characterized by having all five of the properties selected from (a) to (e).

[0288] In some embodiments, form G has substantially the same X-ray powder diffraction (XRPD) pattern as shown in FIG. 8A. In some embodiments, the X-ray powder diffraction (XRPD) pattern of form G is at 0.5±0.1°2-θ, 4.5±0.1°2-θ, 6.4±0.1°2-θ, 8.7±0.1°2-θ, 10.2±0.1°2-θ, 11.3±0.1°2-θ, 11.8±0.1°2-θ, 13.2±0.1°2-θ, 13.6±0.1°2-θ, 14±0.1°2-θ, 14.6±0.1°2-θ, 15 .4±0.1°2-θ, 16.1±0.1°2-θ, 16.6±0.1°2-θ, 16.9±0.1°2-θ, 17.2±0.1°2-θ, 18.3±0.1°2-θ, 19.1±0. 1°2-θ, 20.5±0.1°2-θ, 20.8±0.1°2-θ, 21.6±0.1°2-θ, 23.5±0.1°2-θ, 23.8±0.1°2-θ, 24.6±0.1°2-θ, 24.9±0.1°2-θ, 25.2±0.1°2-θ, 25.8±0.1°2-θ, 26.2±0.1°2-θ, 26.7±0.1°2-θ, 26.8±0.1°2-θ, 27.4±0.1°2-θ, 27.7±0.1°2-θ, 28.7±0.1°2-2-θ, θ, 29.3±0.1°2-θ, 30.1±0.1°2-θ, 31.2±0.1°2-θ, 31.8±0.1°2-θ, 3 There are characteristic peaks at 4.1±0.1°2-θ, 34.9±0.1°2-θ, 35.6±0.1°2-θ, 36.4±0.1°2-θ,, 36.7±0.1°2-θ, 38.5±0.1°2-θ and 38.8±0.1°2-θ. In some embodiments, the X-ray powder diffraction (XRPD) pattern of form G has characteristic peaks at 3.5 ± 0.1°2-θ, 4.5 ± 0.1°2-θ, 19.1 ± 0.1°2-θ, 21.6 ± 0.1°2-θ, 22.5 ± 0.1°2-θ, and 27.4 ± 0.1°2-θ. Preparation of the crystalline form.

[0289] In some embodiments, as outlined in the examples, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine was prepared in crystalline form. It should be noted that the solvents, temperatures, and other reaction conditions presented in this invention can be varied. Suitable solvents

[0290] Therapeutic agents that can be administered to mammals (e.g., humans) are prepared in accordance with regulatory guidelines. These government-mandated guidelines are known as Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination for active therapeutic agents, such as the amount of residual solvents in the final product. Acceptable solvents are those suitable for GMP facilities and that meet industrial safety considerations. The types of solvents are defined, for example, by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005)".

[0291] Solvents are classified into three categories. Category 1 solvents are toxic and should be avoided. Category 2 solvents are those whose use is restricted in the preparation of therapeutic agents. Category 3 solvents are those with low toxicity potential and a low risk to human health. Data on Category 3 solvents indicate that they have low toxicity in acute or short-term studies and are negative in genotoxicity studies.

[0292] Class 1 solvents to be avoided include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethane; and 1,1,1-trichloroethane.

[0293] Examples of Class 2 solvents are acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,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, cyclobutane, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, and xylene.

[0294] 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, diethyl 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.

[0295] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacturing process of the API. In some cases, the solvent cannot be completely removed by actual manufacturing techniques. Appropriate selection of the solvent used to synthesize the API can improve the yield or determine properties such as crystal form, purity, and solubility. Therefore, the solvent can be a critical parameter in the synthesis process.

[0296] In some embodiments, the composition comprising compound A includes an organic solvent. In some embodiments, the composition comprising compound A includes a residual amount of an organic solvent. In some embodiments, the composition comprising compound A includes a residual amount of a third-class solvent. In some embodiments, the organic solvent is a third-class solvent. In some embodiments, the third-class solvent is selected from acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl 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 third-class solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol. In one embodiment, the third-class solvent is ethyl acetate. In one embodiment, the third type of solvent is isopropyl acetate. In one embodiment, the third type of solvent is tert-butylmethyl ether. In one embodiment, the third type of solvent is heptane. In one embodiment, the third type of solvent is isopropanol. In one embodiment, the third type of solvent is ethanol. Specific terminology

[0297] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that the foregoing general description and the following detailed description are merely exemplary and illustrative, and not intended to limit any of the claimed subject matter. In this invention, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural indicators unless the context clearly indicates otherwise. In this invention, the use of "or" means "and / or" unless otherwise stated. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not restrictive.

[0298] The chapter headings used in this invention are for organizational purposes only and should not be construed as limiting the subject matter described. All references or portions thereof (including but not limited to patents, patent application publications, articles, books, manuals, and papers) cited in this invention are expressly incorporated herein by reference in their entirety for any purpose.

[0299] As used in this invention, the terms "acceptable" or "pharmaceutically acceptable" in relation to formulations, compositions or ingredients mean that the compound does not have a lasting harmful effect on the general health of the individual being treated or does not eliminate the biological activity or properties of the compound, and is relatively non-toxic.

[0300] As used in this invention, “improvement” of a particular disease, symptom or condition by applying a particular compound or pharmaceutical composition means any reduction, delay of onset, slowing of progression or shortening of duration of severity attributable to or related to the application of the compound or composition, whether permanent or temporary, continuous or transient.

[0301] "Bioavailability" refers to the percentage of a administered compound (e.g., compound A) delivered into the systemic circulation of the animal or human studied. When administered intravenously, the total exposure of the drug (AUC(0-∞)) is typically defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which a compound (e.g., compound A) is absorbed into the systemic circulation when the pharmaceutical composition is administered orally compared to intravenous administration.

[0302] "Plasma concentration" refers to the concentration of a compound (e.g., compound A) in the plasma components of an individual's blood. It should be understood that the plasma concentration of a compound (e.g., compound A) can vary significantly between individuals due to variability in metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed in the present invention, the plasma concentration of a compound (e.g., compound A) can vary between individuals. Similarly, values ​​such as the maximum plasma concentration (Cmax) or the time to reach the maximum plasma concentration (Tmax), or the total area under the plasma concentration-time curve (AUC(0-∞)), can vary from individual to individual. Due to this variability, the amount required to constitute a "therapeuticly effective amount" of the compound (e.g., compound A) can vary from individual to individual.

[0303] As used in this invention, the terms "co-administration" are intended to cover the administration of a selected therapeutic agent to a single individual and are intended to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times.

[0304] As used in this invention, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of an administered agent or compound that will alleviate, to a certain extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed in this invention required to provide a clinically significant reduction in disease symptoms without excessive adverse side effects. A suitable "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutic effective amount" includes, for example, a prophylactic effective amount. An "effective amount" of a compound disclosed in this invention is an amount that effectively achieves the desired pharmacological effect or therapeutic improvement without excessive adverse side effects. It should be understood that the "effective amount" or "therapeutic effective amount" may vary from person to person due to variations in the metabolism of the compound (e.g., compound A), the individual's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the prescribing physician's judgment. By way of example only, the effective therapeutic dose can be determined through routine experiments, including but not limited to dose-escalation clinical trials.

[0305] The term "enhance" or "enhancing" refers to increasing or prolonging the potency or duration of a desired effect. For example, "enhancing" the effect of a therapeutic agent means increasing or prolonging the effect of the therapeutic agent in terms of potency or duration during the treatment of a disease, condition, or symptom. As used in this invention, "enhancing effective amount" refers to an amount sufficient to enhance the effect of the therapeutic agent in the treatment of a disease, condition, or symptom. When used on an individual, the effective amount for that purpose will depend on the severity and course of the disease, condition, or symptom, prior treatment, the patient's health status and response to the drug, and the judgment of the treating physician.

[0306] As used in this invention, the term "identical" refers to two or more identical sequences or subsequences. Furthermore, as used in this invention, the term "substantially identical" means that two or more sequences have a certain percentage of sequence units that are identical when compared and aligned over a comparison window or specified region to obtain maximum consistency, such as when measured using a comparison algorithm or by manual alignment and visual inspection. By way of example only, two or more sequences may be considered "substantially identical" if consecutive units have approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% similarity over a specified region. These percentages describe the "percent identity" of the two or more sequences. Sequence similarity may exist over a region of at least approximately 75-100 sequence units, over a region of approximately 50 sequence units, or, if not specified, over the entire sequence. This definition also refers to complementary sequences of the test sequences. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are the same, and are "substantially identical" if the amino acid residues are approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identical in a specific region. This similarity can be present in regions of at least about 75-100 amino acids, in regions of about 50 amino acids, or, if not specified, throughout the entire sequence of the polypeptide. Furthermore, by way of example only, two or more polynucleotide sequences are identical when the nucleic acid residues are the same, and are "substantially identical" if the nucleic acid residues are approximately 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% identical in a specific region. The similarity can exist in regions of at least about 75-100 nucleotides in length, in regions of about 50 nucleotides in length, or, if not specified, throughout the entire sequence of a polynucleotide sequence.

[0307] The terms "inhibits, inhibiting" or "inhibitors" as used herein refer to inhibition of menin activity, such as menin-MLL interactions and activity.

[0308] The term "covalent inhibitor" as used herein refers to a compound that after 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, whereby the biological activity of one or more target proteins (e.g., phosphotransferase activity) is reduced or disappeared despite the subsequent presence or absence of covalent inhibitors. In certain embodiments, the inhibitor is irreversible.

[0309] 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.

[0310] The term "modulation" as used herein means to interact directly or indirectly with a target to alter the activity of the target, including (as an 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.

[0311] As used in the present invention, the term "modulator" refers to a compound that alters the activity of a molecule. For example, modulators can cause an increase or decrease in certain activity sizes of the molecule compared to the size of activity in the absence of the modulator. In certain embodiments, the modulator is an inhibitor that reduces the magnitude of one or more activities of the molecule. In certain embodiments, the inhibitor completely blocks one or more activities of the molecule. In certain embodiments, the modulator is an activator that increases the size of at least one activity of the molecule. In certain embodiments, the presence of the modulator results in activity that does not occur in the absence of the modulator.

[0312] The term "preventive effective amount" as used herein refers to an amount of a composition administered to a patient that will alleviate to a certain extent one or more symptoms of the disease, disorder or condition being treated. In such preventive applications, such amounts can depend on the patient's health status, weight, and so on. By routine experiments, including, but not limited to, dose-increasing clinical trials, it is determined that such an effective amount of prophylaxis is considered fully within the technical scope of the art.

[0313] The term "individual" as used in the present invention refers to an animal that is the subject of treatment, observation or experiment. By way of example only, an individual may be, but is not limited to, a mammal, including, but not limited to, a human.

[0314] As used in this invention, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Some 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.

[0315] As used in this invention, the term "target protein" refers to a molecule or portion of a protein that can be selectively bound by a binding compound. In some embodiments, the target protein is a menin.

[0316] As used in this invention, the terms "treat," "treating," or "treatment" include relieving, reducing, or improving symptoms of a disease or condition; preventing other symptoms; improving or preventing underlying metabolic causes of symptoms; inhibiting a disease or condition, such as preventing its progression; alleviating a disease or condition; causing a disease or condition to subside; relieving symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, preventative and / or therapeutic treatments.

[0317] As used in this invention, IC50 refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum response (such as inhibition of menin) in a determination measuring such a response.

[0318] As used in this invention, EC50 refers to the dose, concentration, or amount of a specific test compound that elicits a dose-dependent response at 50% of the maximum expression of a specific response induced, caused, or enhanced by the specific test compound. Pharmaceutical Composition / Formulation

[0319] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers (including excipients and adjuvants) that facilitate the processing of the active compound into a pharmaceutically usable formulation. A suitable formulation depends on the chosen route of administration. Any well-known techniques, carriers, and excipients may be suitably used and are understood in the art. In addition to those described herein, an overview of pharmaceutical compositions can be found, for example, in 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., Easton, 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.

[0320] The pharmaceutical composition used in this invention refers to a mixture of a compound (e.g., compound A) and other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). The pharmaceutical composition facilitates the administration of the compound to an individual (e.g., a mammal). In carrying out the treatment methods or uses provided by this invention, a therapeutically effective amount, such as compound A, is administered in the form of a pharmaceutical composition to an individual (e.g., a mammal) suffering from a disease, condition, or symptom to be treated. In one embodiment, the individual is a mammal. In one embodiment, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the individual's age and relative health condition, the potency of the compound used, and other factors. The compound can be used alone or as a component of a mixture in combination with one or more therapeutic agents.

[0321] As used in this invention, the term "drug combination" refers to a product resulting from a mixture or combination of more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredient (e.g., compound A and a co-active agent) is administered simultaneously to an individual in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredient, such as compound A, and the co-active agent are administered to an individual simultaneously, in parallel, or sequentially without a specific time interval, as separate entities, wherein such administration provides an effective level of both compounds in the individual. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0322] In some embodiments, crystalline compound A is incorporated into the 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 preparations of the present invention can be administered to an individual via a variety of routes of administration, including but not limited to oral, injectable (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. The pharmaceutical preparations of the present invention include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, instantaneous formulations, tablets, capsules, pills, delayed-release formulations, sustained-release formulations, pulsed-release formulations, multi-particle formulations, and mixtures of immediate-release and controlled-release formulations.

[0323] Pharmaceutical compositions comprising the compounds described in this invention can be prepared in a conventional manner, such as by conventional methods of mixing, dissolving, granulation, forming sugar-coated pellets, grinding, emulsifying, encapsulating, embedding, or compressing. Dosage Form

[0324] The pharmaceutical compositions of the present invention can be formulated for administration to an individual (e.g., a mammal) by any conventional means, including but not limited to oral, injectable (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal administration. As used herein, the term "individual" is used to mean an animal, such as a mammal, including humans or non-humans. The terms patient and individual are used interchangeably.

[0325] Furthermore, the pharmaceutical composition comprising compound A described in this invention can be formulated into any suitable dosage form, including but not limited to solid oral dosage forms, controlled-release formulations, fast-dissolving formulations, effervescent formulations, tablets, powders, pills, capsules, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations.

[0326] Pharmaceutical formulations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described in this invention, optionally grinding the resulting mixture, and, if necessary, processing the mixture into granules after adding suitable adjuvants to obtain tablets or sugar-coated pellet cores. 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 gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts such as sodium alginate can be added.

[0327] Orally administered pharmaceutical preparations include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-fit capsules may contain an active ingredient mixed with a filler (e.g., lactose), a binder (e.g., starch), and / or a lubricant (e.g., 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 fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. All preparations intended for oral administration should be at a dosage suitable for such administration.

[0328] In some embodiments, the solid dosage forms disclosed in this invention may be tablets (including suspension tablets, fast-dissolving tablets, chewable disintegrating tablets, rapidly disintegrating tablets, foaming tablets, or capsules), pills, powders (including aseptically packaged powders, dispensable powders, or foaming powders), capsules (including soft capsules or hard capsules, such as capsules made from animal-derived gelatin or plant-derived HPMC, or "spray capsules"), solid dispersions, solid solutions, biodissolving formulations, controlled-release formulations, pulsed-release formulations, multi-particle formulations, pills, granules, or aerosols. In other embodiments, the pharmaceutical preparation is in powder form. In other embodiments, the pharmaceutical preparation is in tablet form, including but not limited to fast-melt tablets. Additionally, the pharmaceutical preparations described in this invention may be administered as a single capsule or multiple capsule dosage forms. In some embodiments, the pharmaceutical preparation is administered as two, three, or four capsules or tablets.

[0329] 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 these bulk blend compositions are referred to as homogeneous, it means that the particles of compound A are uniformly dispersed throughout the composition, such that the composition can be readily further divided 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 contact with a diluent. These formulations can be prepared using conventional pharmacological techniques.

[0330] Common 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) fusion. 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., Worst coating), tangential coating, top spraying, tableting, extrusion, etc.

[0331] The pharmaceutical solid dosage form of the present invention may comprise compound A and one or more pharmaceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, defoamers, antioxidants, preservatives, or one or more combinations thereof. In other embodiments, standard coating methods, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), are used to provide a film coating around the formulation of compound A. In one embodiment, some or all of the particles of compound A are coated. In another embodiment, some or all of the particles of compound A are microencapsulated. In yet another embodiment, the particles of compound A are not microencapsulated and are uncoated.

[0332] The carriers suitable for the solid dosage forms described in this invention include, but are not limited to, gum arabic, gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soybean lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearate lactate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, etc.

[0333] The fillers applicable to the solid dosage form of the present invention include (but are not limited to) lactose, calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, glucose binder, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, etc.

[0334] To release compounds (e.g., compound A) from a solid dosage form matrix as efficiently as possible, disintegrants are typically used in formulations, especially when the dosage form is compressed with a binder. When moisture is absorbed into the dosage form, the disintegrant helps the dosage form matrix break down through swelling or capillary action. Suitable disintegrants for the solid dosage forms described in this invention include, but are not limited to, natural starches such as corn starch or potato starch; pregelatinized starches such as National 1551 or Amijel®; or sodium glycolate starch such as Promogel® or Explotab®; cellulose, such as wood products; methyl crystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia® and Solka-Floc®, methylcellulose, croscarmellose cellulose; or cross-linked cellulose, such as sodium croscarmellose cellulose (Ac-Di-Sol®), croscarmellose cellulose or cross-linked croscarmellose cellulose; cross-linked starches, such as sodium glycolate starch; cross-linked polymers, such as croscarmellose ketone, croscarmellose polyvinylpyrrolidone; alginates, such as alginic acid or salts of alginic acid, such as sodium alginate; clays, such as Veegum® HV (Magnesium aluminum silicate); gums, such as agar, guar gum, locust bean gum, galatian gum, pectin, or tragacanth gum; sodium glycolate starch; bentonite; natural sponges; surfactants; resins, such as cation exchange resins; citrus pomace; sodium lauryl sulfate; combinations of sodium lauryl sulfate and starch; and the like. In some embodiments provided by the present invention, the disintegrant is selected from natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose cellulose, croscarmellose cellulose sodium, croscarmellose cellulose sodium, croscarmellose cellulose, cross-linked croscarmellose cellulose, cross-linked starch (such as sodium glycolate starch), cross-linked polymers (such as croscarmellose), croscarmellose polyvinylpyrrolidone, sodium alginate, clay, and gums. In some embodiments provided by the present invention, the disintegrant is croscarmellose cellulose sodium.

[0335] Binders impart adhesiveness to solid oral dosage forms. For powder-filled capsule formulations, they facilitate stopper formation that can be filled into soft-shell or hard-shell capsules; for tablet formulations, they ensure that the tablets remain intact after compression and help ensure blending homogeneity prior to the compression or filling step. Materials suitable as binders in the solid dosage forms described in this invention include, but are not limited to, carboxymethyl cellulose, methyl cellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose USP Pharmacoat-603), and hydroxypropyl methylcellulose acetate stearate (Aqoate). HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crosslinked povidone, povidone, starch, pregelatinized starch, tragacanth gum, dextrin; sugars, such as sucrose (e.g., Dipac®), glucose, dextrose, sugar Honey, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose; natural or synthetic gums, such as gum arabic, tragacanth, gum, escarpone mucus, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10 and Povidone® K-12), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate and the like.

[0336] Typically, 20-70% binder levels are used in powder-filled gelatin capsule formulations. The amount of binder in tablet formulations varies depending on the use of direct compression, wet granulation, rolling, or other excipients, such as fillers that can themselves act as moderate binders. Those skilled in the art can determine the amount of binder in a formulation, but it is common for tablet formulations to use up to 70% binder.

[0337] Suitable lubricants or flow aids for the solid dosage forms described in this invention include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearate fumarate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium and zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Stearoet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxy polyethylene glycol such as Carbowax™, PEG4000, PEG5000, PEG6000, propylene glycol, sodium oleate, glyceryl dodecanoate, palmityl stearate, glyceryl benzoate, magnesium laurate or sodium lauryl sulfate and the like. In some embodiments provided in this invention, the lubricant is selected from the group consisting of: stearic acid, calcium hydroxide, talc, corn starch, sodium stearate fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate and waxes. In some embodiments provided by the present invention, the lubricant is magnesium stearate.

[0338] Diluents suitable for the solid dosage forms described in this invention include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including glucose binders and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrin, etc. In some embodiments provided by this invention, the diluent is selected from lactose, sucrose, dextrose, glucose binders, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, and talc. In some embodiments provided by this invention, the diluent is microcrystalline cellulose.

[0339] The term "non-water-soluble diluent" refers to compounds commonly used in pharmaceutical preparations, such as calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline cellulose, as well as microcellulose (e.g., having a density of about 0.45 g / cm3; e.g., Avicel, powdered cellulose) and talc.

[0340] Suitable wetting agents for the solid dosage forms described in this 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., Polyquat10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, glyceryl triacetate, vitamin E TPGS, etc.

[0341] Surfactants suitable for the solid dosage forms described in this invention include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF). In some embodiments provided in this invention, the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided in this invention, the surfactant is sodium lauryl sulfate.

[0342] Suitable suspending agents for the solid dosage forms described in this invention include, but are not limited to, polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; polyethylene glycol, for example, polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000; vinylpyrrolidone / vinyl acetate copolymer (S630); sodium carboxymethyl cellulose (sodium... Carboxymethylcellulose; methylcellulose; hydroxypropylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium alginate; gums, such as gum arabic and gum arabic; guar gum; xanthan gum; sugar; cellulose products, such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitol monolaurate, polyethoxylated sorbitol monolaurate, povidone, etc.

[0343] Antioxidants suitable for the solid dosage form described in this invention include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and vitamin E (tocopherol).

[0344] It should be understood that there is considerable overlap among the additives used in the solid dosage forms described in this invention. Therefore, the additives listed above should be considered merely exemplary and not a limitation on the types of additives that may be included in the solid dosage forms described in this invention. The amounts of these additives can be readily determined by those skilled in the art based on the specific properties required.

[0345] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, the plasticizer is typically a high-boiling-point solid or liquid. Suitable plasticizers may be added to the coating composition from about 0.01% by weight to about 50% by weight (w / w). Plasticizers include, but are not limited to, diethyl phthalate, citrate, polyethylene glycol, glycerin, acetylated glyceryl ester, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0346] Compressed tablets are solid dosage forms prepared by compressing a bulk blend of the above-described formulation. In various embodiments, compressed tablets designed to dissolve in the mouth will contain one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, film coating may provide delayed release of a compound (e.g., compound A) from the formulation. In other embodiments, film coating may contribute to patient compliance (e.g., Opadry® coating or sugar coating). Film coatings containing Opadry® are typically from about 1% to about 3% of the tablet weight. In other embodiments, compressed tablets include one or more excipients.

[0347] For example, preparation is carried out by placing a bulk blend of a formulation of a compound (e.g., compound A) into a capsule. In some embodiments, the formulation (a non-aqueous suspension and solution) is placed in a soft gelatin capsule. In other embodiments, the formulation is placed in a standard gelatin capsule or a non-gelatin capsule, such as a capsule containing HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule can be swallowed whole or the contents can be opened and sprinkled onto food before eating. 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 formulation is provided in capsule form.

[0348] In various embodiments, particles of compound A and one or more excipients are dry-mixed and compressed into blocks, such as tablets, having sufficient hardness to provide a pharmaceutical composition that substantially disintegrates within 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.

[0349] In another embodiment, 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, solubilizers, defoamers, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0350] Materials that can be used for microencapsulation according to the present invention include materials compatible with the compound (e.g., compound A) that adequately separate the compound (e.g., compound A) from other incompatible excipients. Materials compatible with the compound (e.g., compound A) are those that can delay the in vivo release of the compound (e.g., compound A).

[0351] Exemplary microencapsulation materials that can be used to delay the release of formulations containing compounds described in this invention include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as Klucel® or Nisso HPC; low-substituted hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm-LC, Pharmacoat®, Metalose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843; methylcellulose polymers, such as Methocel®-A; hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Metalose®; ethyl cellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, and Surelease®; and polyvinyl alcohol (PVA), such as Opadry. AMB; hydroxyethyl cellulose, such as Natrosol®; carboxymethyl cellulose and its salts (CMC), such as Aqualon®-CMC; polyvinyl alcohol and polyethylene glycol copolymers, such as Kollicoat IR®; monoglycerides (Myverol); triglycerides (KLX); polyethylene glycol; modified food starch; acrylic polymers and mixtures of acrylic polymers and cellulose ethers, such as Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D, Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D; cellulose acetate phthalate, sepifilm, mixtures such as HPMC with stearic acid and cyclodextrin; and mixtures of these substances.

[0352] In other embodiments, plasticizers such as polyethylene glycol, for example PEG300, PEG400, PEG600, PEG800, PEG1450 and PEG3350, stearic acid, propylene glycol, oleic acid and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulation material that can be used to delay the release of the pharmaceutical composition is derived from the USP or the National Formulary (NF). In other embodiments, the microencapsulation material is Klucel. In other embodiments, the microencapsulation material is methylcellulose.

[0353] Microencapsulated compounds (e.g., compound A) can be formulated using methods known to those skilled in the art. These known methods include, for example, spray drying processes, rotary solvent processes, thermal melting processes, spray cooling, fluidized bed polymerization, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at liquid-gas or solid-gas interfaces, pressurized extrusion, or spray solvent extraction baths. In addition to these, several chemical techniques can be used, such as composite coagulation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in-situ polymerization, drying in liquids, and desolvation in liquid media. Furthermore, other methods can be used, such as rolling, extrusion / spheronization, coagulation, or nanoparticle coating.

[0354] In one embodiment, the particles of compound A are microencapsulated prior to formulation into one of the above-described forms. In another embodiment, some or most of the particles are coated using a standard coating procedure prior to further formulation, such as the procedure described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0355] In other embodiments, the solid dosage form of compound A is coated with one or more layers of plasticizer. Illustratively, the plasticizer is typically a high-boiling-point solid or liquid. Suitable plasticizers may be added from about 0.01% by weight to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate, polyethylene glycol, glycerin, acetylated glyceryl ester, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[0356] In other embodiments, the powder comprising the formulation having compound A may be formulated to include one or more pharmaceutical excipients and flavoring agents. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Further embodiments also include suspending agents and / or wetting agents. The bulk blend is uniformly subdivided into single-dose packages or multi-dose packages.

[0357] In other embodiments, effervescent powder is also prepared according to the invention. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders containing a pharmaceutical agent in a dry mixture, typically composed of sodium bicarbonate, citric acid, and / or tartaric acid. When a salt of the composition described in this invention is added to water, the acid and base react to release carbon dioxide gas, thereby causing "foaming". Examples of effervescent salts include, for example, sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the release of carbon dioxide is used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, provided that these components are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0358] In some embodiments, the solid dosage form of the present invention can be formulated as an enteric-coated delayed-release oral dosage form (i.e., an oral dosage form of the pharmaceutical composition of the present invention, which utilizes enteric coating to influence release in the small intestine of the gastrointestinal tract). The enteric-coated dosage form can be a tablet / mold (coated or uncoated) containing an active ingredient and / or extruded granules, powders, pellets, beads, or granules containing an active ingredient and / or other compositional components, which are themselves coated or uncoated. Enteric-coated oral dosage forms can also be capsules (coated or uncoated) containing pellets, beads, or granules containing a solid carrier or composition, which are themselves coated or uncoated.

[0359] As used in this invention, the term "delayed release" refers to delivery in which the release occurs at a generally predictable location in the gut, a location further than would have been achieved without the delay-release alteration. In some embodiments, the delayed release method is coating. Any coating should be applied to a sufficient thickness such that the entire coating is insoluble in gastrointestinal fluids at pH below about 5, but soluble at pH about 5 and above. Any anionic polymer that exhibits a pH-dependent solubility distribution is intended to be used as an enteric coating in the methods and compositions of this invention to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described in this invention are anionic carboxylic polymers. In other embodiments, polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to: shellac, also known as purified lac, a refined product obtained from the resinous secretions of insects. This coating is soluble in the medium at pH > 7; acrylic polymers. The effectiveness 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 methacrylic acid copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available in forms dissolved in organic solvents, aqueous dispersions, or dried powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and primarily targeted to the colon. Eudragit series E is soluble in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach but soluble in the intestine; as well as cellulose derivatives. Examples of suitable cellulose derivatives include ethyl cellulose; and reaction mixtures of partial acetates of cellulose with phthalic anhydride. Properties can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) is soluble at pH > 6. Aquateric (FMC) is an aqueous solution-based system and a spray-dried CAP pseudo-latex 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)). Potency can vary based on the degree and type of substitution. For example, HPMCS grades such as HP-50, HP-55, HP-55S, and HP-55F are suitable.For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which is soluble at pH 5; AS-MG (MF), which is soluble at pH 5.5; and AS-HG (HF), which is soluble at higher pH. These polymers are provided as granules or as fine powders in aqueous dispersions; and polyvinyl acetate phthalate (PVAP). PVAP is soluble at pH > 5 and has much lower permeability to water vapor and gastric juice.

[0360] In some embodiments, the coating may contain, and generally does contain, a plasticizer and may contain other coating excipients well known in the art, such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (triacetic acid glyceride), acetylated 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 carboxyacrylate polymers typically contain 10-25% by weight of plasticizers, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetic acid glycerides. The coating is applied using conventional coating techniques such as spray or pan coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired local delivery site in the intestine.

[0361] Colorants, anti-sticking agents, surfactants, defoamers, and lubricants (e.g., carnauba wax or PEG) can be added to the coating instead of plasticizers to dissolve or disperse the coating material and improve the coating performance and the coated product.

[0362] In other embodiments, a pulsatile dosage form is used to deliver the formulation comprising compound A described in this invention. The pulsatile dosage form is capable of providing one or more immediate release pulses at a predetermined time point after a controlled lag time or at a specific site. Many other types of controlled release systems are known to those skilled in the art and are suitable for use with the formulations described in this invention. Examples of such delivery systems include, for example, polymer-based systems, such as polylactic acid and polyglycolic acid, polyanhydride and polycaprolactone; porous matrices; non-polymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids; or neutral fats, such as monoanhydride esters, dianhydride esters and trianhydride esters; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings; biosoluble formulations; compression tablets using conventional adhesives and the like. References include, for example, Liberman et al., Pharmaceutical Dosage Forms, 2nd edition, Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd edition, pp. 751-753 (2002); U.S. Patents 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.

[0363] In some embodiments, a pharmaceutical formulation is provided comprising particles of compound A, at least one dispersant or suspending agent, for oral administration to an individual. The formulation may be a powder and / or particles for suspension, and when mixed with water, yields a substantially homogeneous suspension.

[0364] It should be understood that there is overlap among the additives listed above used in the aqueous dispersions or suspensions described in this invention, because a given additive is often classified differently by different practitioners in the art, or is generally used for any of several different functions. Therefore, the additives listed above should be considered merely exemplary and not a limitation on the types of additives that may be included in the formulations described in this invention. The amounts of these additives can be readily determined by those skilled in the art based on the specific properties required. Dosing and Treatment Regimens

[0365] In some embodiments, the amount of compound A administered to an individual (e.g., a mammal) is 300 mg / day up to and including 1000 mg / day. In some embodiments, the amount of compound A administered to an individual (e.g., a mammal) is 420 mg / day up to and including 840 mg / day. In some embodiments, the amount of compound A administered to an individual (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 an individual (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, or about 600 mg / day. The amounts administered to mammals are approximately 625 mg / day, 650 mg / day, 675 mg / day, 700 mg / day, 725 mg / day, 750 mg / day, 775 mg / day, 800 mg / day, 825 mg / day, 840 mg / day, 850 mg / day, 875 mg / day, 900 mg / day, 925 mg / day, 950 mg / day, 975 mg / day, or 1000 mg / day. In some embodiments, the amount of compound A administered to a mammal is approximately 420 mg / day. In some embodiments, the amount of compound A administered to a mammal is approximately 560 mg / day. In some embodiments, the AUC0-24 of compound A is between approximately 150 ng*h / mL and approximately 3500 ng*h / mL. In some embodiments, the AUC0-24 of compound A is between about 500 ng*h / mL and about 1100 ng*h / mL. In some embodiments, compound A is administered orally. In some embodiments, compound A is administered once daily, twice daily, or three times daily. In some embodiments, compound A is administered daily. In some embodiments, compound A is administered once daily. In some embodiments, compound A is administered every other day. In some embodiments, compound A is used as maintenance therapy.

[0366] In some embodiments, the dose of compound A is selected from 25 mg to 1000 mg. In some embodiments, the dose of compound A is selected from 25 mg to 750 mg. In some embodiments, the dose of compound A is selected from 25 mg to 650 mg. In some embodiments, the dose of compound A is selected from 25 mg to 500 mg. In some embodiments, the dose of compound A 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. In some embodiments, the dose of compound A is 25 mg. In some embodiments, the dose of compound A is 50 mg. In some embodiments, the dose of compound A is 75 mg. In some embodiments, the dose of compound A is 100 mg. In some embodiments, the dose of compound A is 125 mg. In some embodiments, the dose of compound A is 150 mg. In some embodiments, the dose of compound A is 175 mg. In some embodiments, the dose of compound A is 200 mg. In some embodiments, the dose of compound A is 325 mg. In some embodiments, the dose of compound A is 500 mg. In some embodiments, the dose of compound A is 650 mg.

[0367] In some embodiments, compound A is administered 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. In some embodiments, compound A is administered daily in divided doses. In some embodiments, compound A is administered daily for a period of 28 days.

[0368] Compound A can be used to prepare a medicament for inhibiting menin or its homologs, or for treating a disease or condition that at least partially benefits from the inhibition of menin or its homologs, including an individual diagnosed with a hematologic malignancy. Furthermore, a method of treating any disease or condition described herein in an individual requiring such treatment comprises administering to the individual a therapeutically effective amount of a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate.

[0369] Compositions containing compound A can be used for preventative, therapeutic, or maintenance treatment. In some embodiments, the composition containing compound A is administered for therapeutic use (e.g., to an individual diagnosed with a hematologic malignancy). In some embodiments, the composition containing compound A is administered for therapeutic use (e.g., to an individual susceptible to or at risk of developing a hematologic malignancy). In some embodiments, the composition containing compound A is administered as maintenance therapy to a patient in remission.

[0370] The amount of compound A will depend on the intended use (e.g., treatment, prevention, or maintenance). The amount of compound A will depend on the severity and duration of the disease or symptom, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. It is considered perfectly within the scope of the art to determine such a therapeutically effective amount through routine experiments (including, but not limited to, dose-escalation clinical trials). In some embodiments, the dosage of compound A ranges from 10 mg / day up to 250 mg / day. In some embodiments, the dosage of compound A ranges from 25 mg / day up to 300 mg / day. In some embodiments, the dosage of compound A ranges from 25 mg / day up to 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 up to and including 13 mg / kg / day. In some embodiments, the amount of compound A is 2.5 mg / kg / day up to and including 8 mg / kg / day. In some embodiments, the amount of compound A is 2.5 mg / kg / day up to and including 6 mg / kg / day. In some embodiments, the amount of compound A is 2.5 mg / kg / day 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.

[0371] 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, one, two, three, four, or five capsule formulations are administered daily. In some embodiments, three or four capsules are administered daily. In some embodiments, three 140 mg capsules are administered once daily. In some embodiments, four 140 mg capsules are administered once daily. In some embodiments, capsules are administered once daily. In other embodiments, capsules are administered multiple times daily.

[0372] 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.

[0373] In some embodiments, compound A is administered until disease progression, unacceptable toxicity, or based on personal choice. In some embodiments, compound A is administered daily until disease progression, unacceptable toxicity, or based on personal choice. In some embodiments, compound A is administered every other day until disease progression, unacceptable toxicity, or based on personal choice.

[0374] Where the patient’s condition has indeed improved, the compound (e.g., compound A) may be administered continuously, at the physician’s discretion; or the dosage of the drug may be temporarily reduced or temporarily discontinued for a certain period of time (i.e., a “drug holiday”). The length of a drug holiday may vary between 2 days and 1 year, and includes, for example, 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, or 365 days. Dosage reductions during medication holidays can range from 10% to 100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0375] Once the patient's condition improves, a maintenance dose will be given if necessary. Subsequently, depending on the symptoms, the dose or frequency of administration, or both, may be reduced to the level required to maintain improvement in the disease, symptom, or condition. However, if symptoms recur, the patient may require long-term intermittent treatment.

[0376] The amount of a given agent corresponding to such a quantity will vary depending on factors such as the specific compound, the severity of the disease, the identity of the individual or host requiring treatment (e.g., weight), but can still be routinely determined in a manner known in the art based on the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, and the individual or host being treated. However, generally, the dose for adult treatment is typically 0.02–5000 mg / day or about 1–1500 mg / day. The required dose may be conveniently presented as a single dose or as separate doses administered simultaneously (or over a short period of time) or at appropriate intervals, such as as two, three, four, or more sub-dose administrations per day.

[0377] The pharmaceutical compositions of the present invention may be unit dosage forms suitable for single-dose administration of precise dosage. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds (e.g., compound A). The unit dose may be a packaged form containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-reclosable containers. Alternatively, multi-dose, reclosable containers may be used, in which case the composition typically contains a preservative. By way of example only, formulations for parenteral injection may be present in unit dosage forms, including but not limited to ampoules, or in multi-dose containers with added preservatives. 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 daily. In some embodiments, two unit dosage forms are administered to an individual daily. In some embodiments, three unit dosage forms are administered to an individual daily. In some embodiments, four unit dosage forms are administered to an individual daily.

[0378] The aforementioned ranges are merely recommendations, as the number of variables relating to individual treatment regimens is large, and considerable deviations from these recommendations are common. Such dosages can 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, individual requirements, the severity of the disease or condition to be treated, and the judgment of the physician.

[0379] The toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determining the LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is called the therapeutic index, which can be expressed as the ratio between LD50 and ED50. Compounds showing a high therapeutic index are recommended. Data obtained from cell culture assays and animal studies can be used to formulate dosage ranges for, for example, humans. The dosage of such compounds is within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage can vary within this range, depending on the dosage form and route of administration used. Combination therapy

[0380] In some cases, it is appropriate to administer compound A in combination with another therapeutic agent.

[0381] In one embodiment, the compositions and methods of the present invention are also used in combination with other therapeutic agents selected for their specific usefulness to the condition being treated. Typically, in the compositions of the present invention and in embodiments using combination therapy, other agents need not be administered in the same pharmaceutical composition and are administered via different routes due to their different physical and chemical properties. In one embodiment, an initial administration is performed according to an established protocol, and then, based on observed effects, the dosage, administration pattern, and timing can be further adjusted.

[0382] In various embodiments, compounds are administered simultaneously (e.g., concurrently, substantially concurrently, or within the same treatment regimen) or sequentially, depending on the nature of the disease, the patient's condition, and the actual selection of the compounds used. In some embodiments, the determination of the order of administration and the number of repetitions of each therapeutic agent during the treatment regimen is based on an evaluation of the disease being treated and the patient's condition.

[0383] For the combination therapy described in this invention, the dosage of the commonly administered compounds varies depending on the type of common drug used, the specific drug used, the disease or condition being treated, etc.

[0384] The compounds in this combination are administered sequentially or simultaneously in pharmaceutical preparations, either individually or in combination. In one embodiment, the compounds will be administered simultaneously in the combined pharmaceutical preparation. Those skilled in the art will understand the appropriate dosage of known therapeutic agents.

[0385] The combinations mentioned in this invention can be conveniently used in the form of pharmaceutical compositions with pharmaceutically acceptable diluents or carriers.

[0386] In some embodiments, the present invention discloses a method for treating cancer in an individual in need, comprising administering a certain amount of compound A to the individual. In some embodiments, the method further comprises administering a second cancer treatment regimen.

[0387] In some embodiments, administration of a covalent inhibitor of the menin-MLL interaction prior to a second cancer treatment regimen reduces the immune-mediated response to the second cancer treatment regimen. In some embodiments, administration of compound A prior to administration of atumumab reduces the immune-mediated response to atumumab.

[0388] In some embodiments, the second cancer treatment regimen comprises a chemotherapy agent, a steroid, an immunotherapy agent, 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 proteosome 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.

[0389] 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 registration number 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... Registration 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)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.

[0390] In some embodiments, the second cancer treatment regimen includes chlorambucil, ifosphamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, and everolimus. Fludarabine, fostamatinib, paclitaxel, docetaxel, ofracitabine, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or combinations thereof.

[0391] In some embodiments, the second cancer treatment regimen includes cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally rituximab.

[0392] In some embodiments, the second cancer treatment regimen includes bendamustine and rituximab.

[0393] In some embodiments, the second cancer treatment regimen includes fludarabine, cyclophosphamide, and rituximab.

[0394] In some embodiments, the second cancer treatment regimen includes cyclophosphamide, vincristine and prednisone, and optionally rituximab.

[0395] In some embodiments, the second cancer treatment regimen includes etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and optionally rituximab.

[0396] In some embodiments, the second cancer treatment regimen includes dexamethasone and lenalidomide.

[0397] In some embodiments, the second cancer treatment regimen includes a proteasome inhibitor. In some embodiments, the second cancer treatment regimen includes bortezomib. In some embodiments, the second cancer treatment regimen includes epoxyketone. In some embodiments, the second cancer treatment regimen includes epoxomicin. In some embodiments, the second cancer treatment regimen includes tetrapeptide epoxyketone. In some embodiments, the second cancer treatment regimen includes carfilzomib. In some embodiments, the second cancer treatment includes disulfiram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m, CEP-18770, MLN9708, or MG132.

[0398] In some embodiments, the second cancer treatment regimen includes a Cyp3A4 inhibitor. In some embodiments, the second cancer treatment includes indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, and / or efazodone. In some embodiments, the second cancer treatment regimen includes ketoconazole.

[0399] In some embodiments, the second cancer treatment regimen includes a Janus kinase (JAK) inhibitor. In some embodiments, the second cancer treatment regimen includes lettaurtinib, tofacitinib, ruxolitinib, CYT387, baricitinib, or parcritinib.

[0400] In some embodiments, the second cancer treatment includes a histone deacetylasase inhibitor (HDAC inhibitor, HDI). In some embodiments, the second cancer treatment agent comprises isohydroxamic acid (or isohydroxamic ester), such as trichostatin A, vorinostat (SAHA), belistat (PXD101), LAQ824, and pabistat (LBH589), cyclic tetrapeptides, such as trapoxin B, pentapeptides, benzoylamine, such as entinostat (MS-275), CI994, and mocetinostat (MGCD0103), phenylbutyrate, electrophilic ketones, or aliphatic acid compounds, such as valproic acid.

[0401] Other cancer treatment options include nitrogen mustards, such as bendamustine, chlormethicone, cyclophosphamide, ifosfamide, melphalan, prednimustine, and trofosfamide; alkyl sulfonates, such as busulfan, mannosulfan, and treosulfan; ethyleneimines, such as carboquone, thiotepa, and triaziquone; and nitrosoureas, such as carmustine and formosine. ne), lomustine, nimustine, ranimustine, semustine, streptozocin; epoxides, such as etoglucid; other alkylating agents, such as dacarbazine, mitobronitol, pipebroman, temozolomide; folic acid analogs, such as methotrexate, permetrexed, pralatrexat e) Raltitrexed; purine analogs, such as cladribine, clofarabine, fludarabine, mecaptopurine, nelarabine, and tioguanine; pyrimidine analogs, such as azacitidine, capecitabine, carmofur, cytarabine, decitabine, and fluorouracil. acil, gemcitabine, tegafur; vinca alkaloids, such as vinblastine, vincristine, vindesine, influnine, vinorelbine; podophyllotoxin derivatives, such as etoposide, teniposide; colchicine derivatives, such as demecolcine; taxanes, such as docetaxel, paclitaxel, paclitaxel poliglumex;Other plant alkaloids and natural products, such as trabectedin; actinomycins, such as dactinomycin D; anthracyclines, such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, and zorubincin; and other cytotoxic antibiotics, such as bleomycin. ycin), ixabepilone, mitomycin, plicamycin; platinum compounds such as carboplatin, cisplatin, oxaliplatin, and satraplatin; methylhydrazine, such as procarbazine; sensitizers such as aminoacetylpropionic acid, efaproxiral, methyl aminoacetylpropionic acid, and porfimer. Sodium, temoporfin; protein kinase inhibitors, such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, temsirolimus;Other antitumor agents include alitretinoin, altretamine, amzacrine, anagrelide, arsenic trioxide, aspartate aminotransferase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxycarbamide, irinotecan, lonidamine, masoprocol, miltefosein, mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, and sitimagene. Ceradenovec, tiazofurine, topotecan, tretinoin, vorinostat; estrogens, such as diethylstilbenol, ethinylestradiol, fosfestrol, polyestradiol Phosphate); progestins, such as gestonorone, medroxyprogesterone, and megestrol; gonadotropin-releasing hormone analogs, such as buserelin, goserelin, leuprorelin, 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; and other hormone antagonists, such as abarrelix and degarelix.Immunostimulants, such as histamine dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex, and thymopentin; immunosuppressants, such as everolimus, gusperimus, leflunomide, mycophenolic acid, and sirolimus; calcineurin inhibitors, such as cyclosporin and tacrolimus; other immunosuppressants, such as azathioprine, lenalidomide, methotrexate, and thalidomide; and radiopharmaceuticals, such as iobenguane.

[0402] Other cancer treatment options include interferons, interleukins, tumor necrosis factors, and growth factors.

[0403] Other cancer treatment options include immunostimulants such as ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, and sargramostim; interferons such as natural interferon α, interferon α-2a, interferon α-2b, interferon alfacon-1, interferon α-n1, natural interferon β, interferon β-1a, interferon β-1b, interferon γ, pegylated interferon α-2a, and pegylated interferon α-2b; interleukins such as aldesleukin and oprelvekin; and other immunostimulants such as BCG vaccine, glatiramer acetate, and histamine dihydrochloride. dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly-I:C, poly-ICLC, roquinimex, tasonermin, thymopentin; immunosuppressants such as abatacept, abetimus, alefacept, anti-lymphocyte immunoglobulin (horse), anti-thymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muroximab-CD3 (muromab-CD3), mycophenolic acid, natalizumab, and sirolimus; TNFα inhibitors, such as adalimumab, afelimomab, pegylated certolizumab pegol, etanercept, golimumab, and infliximab.Interleukin inhibitors, such as anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab, and ustekinumab; calcineurin inhibitors, such as cyclosporin and tacrolimus; and other immunosuppressants, such as azathioprine, lenalidomide, methotrexate, and thalidomide.

[0404] Other cancer treatment options include adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, pegylated certocilizumab, daclizumab, eculizumab, efalizumab, gemtuzumab, and buprofen (tezzetan). tiuxetan), infliximab, muromonab-CD3, natalizumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab, or combinations thereof.

[0405] Other cancer treatment options include monoclonal antibodies, such as alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ovarumumab, panitumumab, rituximab, and trastuzumab; immunosuppressants, such as ecuizumab, fazilumab, muroximab-CD3, and natezumab; TNFα inhibitors, such as adalimumab, afelimomab, pegylated cetuzumab, golimumab, and infliximab; interleukin inhibitors, such as baliximab, konnabumab, dalizumab, mepolilimumab, tosilimumab, and ustekinumab; radiopharmaceuticals, such as butumerumab (tezazan) and tosilimumab; and other monoclonal antibodies.Examples of antibodies include abagovomab, adalimumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apotomab, arcitumomab, baliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, and capromab. Pendetide, Cixutumumab, Claudiximab, Conatumumab, Dacetuzumab, Denosumab, Icuzumab, Epratuzumab, Epratuzumab, Ertumaxomab, Etaracizumab, Figitumumab, Fresolimumab, Galiximab, Ganitumab, Gemtuzumab ozogamicin, Glembatumumab, Ibritumomab, Inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, CC49 monoclonal antibody, necitumumab, nimotuzumab The following are listed: uzumab, ovovanumab, oregovomab, pertuzumab, ramacurimab, rambizumab, siplizumab, sonepcizumab, tanezumab, tosimozumab, trastuzumab, tremelimumab, tucotuzumab celmoleukin, veltuzumab, visilizumab, volociximab, and zalutumumab.

[0406] Other cancer treatment options include agents that affect the tumor microenvironment, such as cellular signaling networks (e.g., the phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from B cell receptors and IgE receptors). In some embodiments, the second agent is a PI3K signaling inhibitor or a syc kinase inhibitor. In one embodiment, the syc inhibitor is R788. In another embodiment, it is a PKCγ inhibitor, such as enzastaurin.

[0407] Examples of drugs that affect the tumor microenvironment include PI3K signaling inhibitors, syc kinase inhibitors, and protein kinase inhibitors, such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and tamsulosinib; other angiogenesis inhibitors, such as GT-111, JI-101, and R1530; and other kinase inhibitors, such as AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, and BAY. 73-4506, BGJ398, BGT226, BI 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinaciclib, dovitinib lactate, E7050, EMD 1214063, ENMD-2076, fostamatinib disodium disodium), GSK2256098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, lini fanib), LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON 01919.Na, OSI-027, OSI-930, Btk inhibitor, PF-00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenitor cell cytokinin, 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. .

[0408] Other examples of anticancer agents used in combination with covalent inhibitors of menin-MLL interacting compounds (e.g., compound A) include mitogen-activated protein kinase signaling inhibitors such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies such as rituxana.

[0409] Other anticancer agents that can be used in combination with covalent inhibitors of menin-MLL interacting compounds (e.g., compound A) include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, and acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; interleukin; hexamethylmelamine; ambomycin; and ametantrone acetate. acetate); aminoglutethimide; amsacrine; anastrozole; anhramycin; aspartate; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequina sodium. sodium); bropirimine; busulfan; cactinomycin C; calusterone; caracemide; carbetimer; carplatin; carmustine; carrubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; cristatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; cranberry;Doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; nloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride hydrochloride); fazarabine; fenretinide; fluxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II or rlL2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-la; interferon γ-lb; iproplatin; irinotecan hydrochloride; lanreotide. acetate); letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride.Masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; mefarin; menogaril; mercaptopurine; methamidophos; methamidophos sodium; metoprine; meturedepa; itindomide; itocarcin; mitochorimin; mitogillin; itomacin; itosper; mitotane; mitoxantrone hydrochloride hydrochloride); mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposesulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride hydrochloride); pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin;Streptozocin; sulfofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tuboozole hydrochloride; uracil Mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozolidine; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0410] Other anticancer agents that can be used in combination with covalent inhibitors of menin-MLL interacting compounds (e.g., compound A) include 20-epi-1, 25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenypenol; adozelesin; interleukin; ALL-TK antagonists; hexamethylmelamine; ambamustine; amidox; amifostine; aminolevulinic acid. acid); amrubicin; acridine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogen; prostatic carcinoma; antiestrogen; anti-antineoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; depurine nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 1; Azasetron; 2; Azasetron; 3; Azasetron; Azatoxin; Azatyrosine; Baccatin III derivative; Balanol; Bamastamine; BCR / ABL antagonist; Benzochlorins; Benzoylstaurosporine; β-lactam derivative; Beta-alethine; Beta-clarithromycin B; Betulinic acid; bFGF inhibitor; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnafide; Bistratene A; Bizelexin;Breflate; budotitane; butyronine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; methamidotriazole; carboxyamidotriazole; CaRest M3; CARN 700; chondroderm-derived inhibitors; carzolinone; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorambucil; chloroquinoxaline sulfonamide); cicaprost; cis-porphyrin; cladribine; cromifene analogues; clotrimazole; cristomycin A; cristomycin B; compretastatin A4; compretastatin analogue; conagenin; crambexetine 816; cristatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor Factor); cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxan; dexverapamil; diaquinone; didenin B; didox; diethylnorspermine;Dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonist; estrogen antagonist. Antagonist); Etadazole; Etoposide phosphate; Exemestane; Faldazole; Fazalabin; Feritinide; Filgrasting; Finaxone; Flavoprin; Flezelastine; Fluasterone; Fludarabine; Fludaunorunicin hydrochloride; Forfenimex; Formex; Fostriecin; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitor Inhibitors); Gemcitabine; Glutathione inhibitors; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idamycin; Idoxifene; Idramantone; Ilmofosine; Ilomastat; Imidazolidinones; Imiquimod; Immunostimulating peptides;Insulin, such as growth factor-1 receptor inhibitors; interferon agonists; interferon; interleukin; iodobenzylguanidine; iododoxorubicin; 4-sweet potato alcohol; iroplact; isogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon. Interferon); Leuprolide + Estrogen + Progesterone; Leuprolide; Levamisole; Liarozole; Linear polyamine analogs; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lissoclinamide 7; Lobaplatin; Lombricine; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Lutetium texaphyrin; Lysofylline; Dissolving peptides; Maitansine; Mannostatin A A); marimastat; masoprocol; maspin; matrixlysin inhibitor; matrix metalloproteinase inhibitor; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; mitolactone.Mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibodies; human chorionic gonadotropin; monophosphatidyllipid A+ mycobacterial cell wall SK; mopidamol; multidrug-resistant gene inhibitors; multi-tumor-suppressive therapy; nitrogen mustard anticancer agents; Indian Ocean sponge B (mycaperoxide) B); Mycobacterium cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzylamine; nafarelin; nagrestip; naloxone + tebuconazole; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid acid); neutral endopeptidase; nilutamide; nisamycin; nitric oxide regulator; nitrogen oxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotide; onapristone; ondansetron; oracin; oral cytokine inducer; omaliplatin; osaterone; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid acid); panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;Fenazinomycin; phenylacetate; phosphatase inhibitor; picibanil; pirocarpine hydrochloride; pirarubicin; pirritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compound; platinum-triamine complex; porphyrin sodium; pofiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitor; protein A-based immunomodulator; protein kinase C inhibitor; protein kinase C inhibitor; microalgal; protein tyrosine phosphatase inhibitor; purine nucleoside phosphorylase inhibitor; purpurin; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyl Conjugate); RAF antagonist; Raltitrexed; Ramosetron; RAS farnesyl proteotransferase inhibitor; RAS inhibitor; RAS-GAP inhibitor; Retriptine demethylated; Rhenium etradicate Re 186; Rhizoxin; Ribozyme; RII retelliptine; Rogletimide; Rohitukine; Romurtide; Roquinimex; Rubiginone B1; Ruboxyl; Safingol; Saintopin; SarCNU; Sarcophytol A; Sargramostim; Sdi 1. Analog; Semustine; Aging-derived inhibitor; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction modulator; Single-chain antigen-binding protein; Sizofiran; Sobuzoxane; Sodium borocaptate; Sodium phenylacetate; Solvrol; Growth factor-binding protein; Sonermin; Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin;Spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; matrix lysin inhibitor; sulfinosine; super-active vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glucosamine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogallan sodium); tegafur; tellurapyrylium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimic; thymalfasin; thymosin receptor agonist; thymotrinan; thyroid-stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors Inhibitors); tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitors; urokinase receptor antagonists; vapreotide; variolin B; vector systems, erythrocyte gene therapy; velaresol; veramine; verdins.Verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[0411] Other anticancer agents that can be used in combination with covalent inhibitors of menin-MLL interacting compounds (e.g., compound A) include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustard (e.g., chloroethylamine, cyclophosphamide, and chlorambucil), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine and lomestine), or triazines (e.g., dacarbazine). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, and pentostatin).

[0412] Examples of alkylating agents that can be used in combination with covalent inhibitors of menin-MLL interacting compounds (e.g., compound A) include, but are not limited to, nitrogen mustard (e.g., dichloromethyldiethylamine, cyclophosphamide, chlorambucil, and melphalan), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, and streptozotocin), or triazine (e.g., dacarbazine). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, fluorouracil, and cytarabine) and purine analogs (e.g., mercaptopurine, thioguanine, and pentostatin).

[0413] Examples of anticancer agents that work by arresting cells in the G2-M phase due to stable microtubules and can be used in combination with covalent inhibitors of menin-MLL-interacting compounds (e.g., compound A) include, but are not limited to, the following commercially available and developing drugs: irbuproazole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mivobulin 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 altorhyrtin A and altorhyrtin C), and spongin (such as sponginstatin 1, sponginstatin 2, and sponginstatin 3). Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cimadolicin Hydrochloride (also known as LU-103793 and NSC-D-669356), 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, Epomycin A, N-oxide, 16-aza-epomycin B, 21-aminoepomycin B (also known as BMS-310705), 21-hydroxyepomycin D (also known as deoxyepomycin F and dEpoF), 26-fluoroepomycin), Aprestatin PE (also known as NSC-654663), Solidocin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, 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), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), Vitilelevuamide, Tobrexon A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes 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) 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), Vanadox acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (also known as NSC-698666), 3-lAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-115781 (Aventis), Eleutherobin (such as demethyleleutherobin, deacetylatedeleutherobin, isoeleutherobin A and Z-eleutherobin), Caribaeolin, Caribaeolin B, D-64131 (Asta Medica), D-68144 (Asta Medica), 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 (Asta Medica), D-68836 (Asta Medica), 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 phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0414] In some embodiments, when an individual has an autoimmune disease, inflammatory disease, or allergic disease, or is at risk of developing an autoimmune disease, inflammatory disease, or allergic disease, compound A may be used in any combination with one or more of the following therapeutic agents: immunosuppressants (e.g., tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate mofetil, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone). Acetate, aldosterone, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., salicylates, arylalkyl acids, 2-arylpropionic acid, N-aryl-o-aminobenzoic acid, oxicam, coxib, or sulphonanilide), Cox-2 specific inhibitors (e.g., valdecoxib, senecoxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate. Thiomalate, aurofin, sulfasalazine, hydroxychloroquine, minocycline, TNF-α binding protein (e.g., infliximab, etanercept, or adalimumab), abatacept, anaerobicin, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotriene, β-agonists, theophylline, or anticholinergic agents. Kits or products.

[0415] For use in the therapeutic application methods described herein, kits and articles are also described. Such kits include carriers, packages, or containers that are divided to accommodate one or more containers, such as vials, tubes, etc., each container comprising one of the individual elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is formed of various materials such as glass or plastic.

[0416] The articles provided by this invention comprise packaging materials. Packaging materials for packaging pharmaceutical products include, for example, those described in U.S. Patent No. 5,323,907. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, vials, and any packaging materials suitable for the selected formulation and the intended mode of administration and treatment.

[0417] In some embodiments, the compounds or compositions of the present invention are present in a packaging or dispenser device, which may contain a unit dosage form of the active ingredient. The compounds or compositions of the present invention are packaged individually or together with another compound or another ingredient or additive. In some embodiments, the packaging contains one or more containers filled with one or more components of the pharmaceutical composition of the present invention. In some embodiments, the packaging comprises metal or plastic foil, such as blister packs. In some embodiments, the packaging or dispenser device is accompanied by instructions for use, such as instructions for use of a compound or composition for the treatment of oncological diseases. In some embodiments, the packaging or dispenser is accompanied by a notification related to the container, the form of which is prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting the form of the drug approved by that agency for human or veterinary administration. In some embodiments, such a notification is, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. In some embodiments, the composition comprises a compound of the present invention (e.g., compound A) formulated in a compatible pharmaceutical carrier and prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0418] For example, the container includes compound A, which may be used in a composition or in combination with another pharmaceutical agent described in this invention. Such a kit may optionally include an identification description or label or instruction manual regarding its use in the methods described in this invention.

[0419] The set typically includes a label listing the contents and / or instructions for use, as well as a packaging insert with the instructions for use. A set of instruction manuals is also usually included.

[0420] In one embodiment, the label is located on or associated with the container. In one embodiment, the label may be located on the container when the letters, numbers, or other features forming the label are attached, molded, or etched into the container itself; the label may be associated with the container, for example, as a packaging instruction, when the label is present in the container or within a carrier that also holds the container. In one embodiment, the label is used to indicate the amount intended for a specific therapeutic application. The label may also indicate the amount, such as usage instructions in the methods described in this invention.

[0421] In some embodiments, the pharmaceutical composition is contained in a packaging or dispenser device containing one or more unit dosage forms of compounds provided by the present invention (e.g., compound A). The packaging may contain, for example, metal or plastic foil, such as blister packs. In one embodiment, the packaging or dispenser device is accompanied by instructions for use. In one embodiment, the packaging or dispenser is also accompanied by a notification related to the container, the form of which is prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting the form of the drug approved by that agency for human or veterinary administration. For example, such a notification is a label or approved product insert approved by the U.S. Food and Drug Administration for prescription drugs. In one embodiment, a composition containing compounds provided by the present invention (e.g., compound A) formulated in a compatible pharmaceutical carrier is also prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0422] In another embodiment, the present invention describes a deuterium analog of compound A, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine, a deuterium analog, as a covalent inhibitor of the menin-MLL interaction, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases, and methods of use thereof. In some embodiments, only one hydrogen atom is substituted with deuterium. In some embodiments, one or more hydrogen atoms are substituted with deuterium.

[0423] In some embodiments, the deuterium analogue of compound A is:

[0424] wherein the deuterium is connected to any one or more of the 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.

[0425] In some embodiments, deuterium is connected to any one or more positions selected from 2, 3, 5, and 6 shown above. In some embodiments, deuterium is connected to any one or more positions selected from 13 and 15 shown above. In some embodiments, deuterium is connected to any one or more positions selected from 19, 20, 22, and 23 shown above. In some embodiments, deuterium is connected to any one or more positions selected from 26, 28, and 29 shown above. In some embodiments, deuterium is connected to position 31 shown above. In some embodiments, deuterium is connected to any one or more positions selected from 33-36 shown above. In some embodiments, deuterium is connected to any one or more positions selected from 40-42 shown above.

[0426] In some embodiments, the deuterium analogue of compound A is:

[0427] In some embodiments, one or more hydrogen atoms of the central pyridine ring are replaced by deuterium.

[0428] In another embodiment, the present invention describes a covalent inhibitor of the menin-MLL interaction, compound P, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases, and methods of using thereof. In some embodiments, only one hydrogen atom of compound P is replaced by deuterium.

[0429] In another embodiment, the present invention describes deuterium analogues of compound P as covalent inhibitors of the menin-MLL interaction, including stereoisomers, pharmaceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases, and methods of use thereof. In some embodiments, only one hydrogen atom of compound P is substituted with deuterium. In some embodiments, one or more hydrogen atoms of compound P are substituted with deuterium.

[0430] In some embodiments, the deuterium analogue of compound P is:

[0431] wherein the deuterium is connected to any one or more of the positions selected from 1, 3, 4, 6, 13, 14, 16, 18-20, 23, 24, 27, 33, 36, 37, 39 and 40 as shown above.

[0432] In some embodiments, deuterium is connected to any one or more of the locations selected from 1, 3, 4 and 6 as shown above.

[0433] In some embodiments, deuterium is connected to any one or more of the locations selected from 13, 14 and 16 as shown above.

[0434] In some embodiments, deuterium is connected to any one or more locations selected from 18-20 as shown above.

[0435] In some embodiments, deuterium is connected to any one or more of the locations selected from 23 and 24 as shown above.

[0436] In some embodiments, deuterium is connected to position 27 as shown above.

[0437] In some embodiments, deuterium is connected to any one or more locations selected from 33 as shown above.

[0438] In some embodiments, deuterium is connected to any one or more of the locations selected from 36, 37, 39 and 40 as shown above.

[0439] In some embodiments, the deuterium analogue of compound P is: Example

[0440] The following components, formulations, methods, and procedures for preparing the compounds disclosed in this invention and for carrying out the methods disclosed in this invention correspond to the compounds and methods described above. Preparation of Compound A

[0441] Compound A was prepared according to the method described in U.S. Patent No. 11,084,825 (incorporated in its entirety by reference).

[0442] Alternatively, compound A can be prepared according to the synthetic scheme described below: Example 1: Preparation of crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) Preparation of polymorphic form A

[0443] Compound A, as an HCl salt, was dissolved in deionized water (3.00 v / v), and a saturated aqueous solution of NaHCO3 was slowly added to the mixture until the solution was neutral (pH=7). A solid precipitated during the addition. The solid was collected by filtration and washed with methanol (2.00 v / v). The filter cake was dried in an oven at 45°C for 24 hours to obtain compound A in its free base form.

[0444] Preparation of Pattern B

[0445] Compound A was dissolved in DCM:MeOH (1:1, 150 volumes) 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 under vacuum to obtain compound A. Preparation of polymorphic mode C

[0446] Mode C was successfully prepared using the following procedure.

[0447] Weigh approximately 200 mg of compound A into a 4 mL glass vial. Then add 2.2 mL of TFE to the vial.

[0448] The resulting suspension was kept at 50°C for about 2 hours as a slurry; then the slurry was kept stirred for about 3 days in the dark.

[0449] Solids were separated by filtration and the wet filter cake was studied by XRPD.

[0450] A medium-crystallization model C was obtained as a pale yellow solid. The solid was further characterized by XRPD, TGA, DSC, and 1H NMR. Characterization of Model C Sample ID Mode C parameter method result Yield / / purity HPLC / / DSC melt initiation DSC, 10 °C / min After drying in a fume hood: No obvious melting point of 150.2°C (53 J / g) Wet cake: No obvious melting point; 69.4°C (17 J / g); 154.0°C (7 J / g) X-ray diffraction 3-40(2 Theta) Medium crystallinity Pattern C, Figure 3A Thermogravimetric method TGA, 10°C / min After drying in a fume hood: 18.3% @ 200°C Residual solvent 1 H NMR (DMSO-d6) After drying in a fume hood: 19.2% TFE by weight (1.35 equivalent in molar ratio) Note “ / / ”: Preparation of polymorphic mode E was not performed.

[0451] Model E (DMSO solvate): Approximately 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 suspension. After two weeks of equilibration, the solid was separated by centrifugation and filtration to obtain Model E. Preparation of polymorphic Model G

[0452] Model G (TFE solvate): Approximately 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 solids were analyzed by XRPD to obtain Model G. Preparation of polymorphic Model F

[0453] Model F was successfully prepared using the following method.

[0454] 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.

[0455] The resulting suspension was kept as a slurry at 25°C for about 2 hours, and then stirred in the dark for about 5 days.

[0456] Solids were separated by filtration and the wet filter cake was studied by XRPD.

[0457] Highly crystalline model F was obtained, which was a light yellow solid. The solid was further characterized by XRPD and 1H NMR. Characterization of model F Sample ID Mode F parameter method result Yield / / purity HPLC / / DSC melt initiation DSC, 10°C / min / / X-ray diffraction 3-40(2 Theta) Figure 6A shows the high crystallinity mode F. Thermogravimetric method TGA, 10°C / min / / Note “ / / ”: Preparation of polymorphic mode D was not performed.

[0458] The following procedure was used to successfully prepare pattern D, compound A, and pattern D-drying.

[0459] Weigh approximately 500 mg of compound A into an 8 mL glass vial. Add THF:water (80:20 v / v, 8 mL) to the vial.

[0460] The resulting suspension was kept as a slurry at 50°C in the dark for about four days.

[0461] The solids are separated by filtration, and the wet filter cake is vacuum dried at 50°C for about 3 hours.

[0462] Highly crystalline form D was obtained as a pale yellow solid (54% yield). The dried solid was further characterized by XRPD, TGA, DSC, 1H NMR, KF, and DVS. Preparation of polymorphic form D-1

[0463] The following procedure was used to successfully prepare pattern D, compound A, and pattern D-THF-water-drying.

[0464] Weigh approximately 8 g of compound A into a 120 mL glass vial. Add THF:water (80:20 v / v, 80 mL) to the vial to maintain the suspension.

[0465] The resulting suspension was kept as a slurry at 50°C in the dark for about two days.

[0466] Add THF:water (80:20 v / v, 20 mL) to maintain suspension.

[0467] The solids are separated by filtration, and the wet filter cake is vacuum dried at 50°C for about 12 hours.

[0468] 6.66 g of medium crystallization pattern D as a pale yellow solid was obtained (82.5% yield).

[0469] The dry solids were further characterized by XRPD, TGA, DSC, 1H NMR and KF.

[0470] Amorphous free form was prepared by artificial grinding.

[0471] The following procedure was used to successfully prepare the amorphous free form, mode D-grinding-amorphous free form.

[0472] Grind 2g of free form in mode D manually for 10 minutes using a mortar and pestle.

[0473] 1.83 g of amorphous free form was obtained as a pale yellow solid (91.5% yield).

[0474] Yellow powder was studied by XRPD and mDSC. Amorphous free form was prepared by hand grinding. Exp. ID XRPD mDSC GSE1 (50mg) (trial) Amorphous form diagram 22 Glass transition temperature: Midpoint 137.1°C, ΔCp 0.3 / (g.°C) Figure 23 GSE1 (600mg) (trial) Amorphous form diagram 24 Glass transition temperature: Midpoint 137.1°C, ΔCp 0.2 / (g.°C) Figure 25 GSE3 (2g) Amorphous form diagram 26 Glass transition temperature: Midpoint 137°C, ΔCp 0.2 / (g.°C) Figure 27

[0475] The characterization report of compound A in amorphous free form and sample mode D-grinding-amorphous free form is shown in the table below.

[0476] The characterization of compound A in form mode D and sample scale-up mode D-THF-water-drying is reported in the table below. Homogeneous polymorph Free form pattern D Free form pattern D amorphous free form batch number Mode D - Drying Mode D-THF-water-dry Mode D - Grinding - Amorphous Free Form parameter method result Yield 54% 82.5% 91.5% purity HPLC 96.9% 97.8% 97.9% X-ray diffraction 3-40° (2 Theta) High crystallinity mode D Figure 13 Medium crystallinity Pattern D Figure 18 amorphous form Figure 26 Melt initiation and enthalpy DSC, 10°C / min Endothermic onset: 31.5°C (47 J / g) Figure 15 Endothermic: 31.6°C (18 J / g); Melting initiation: 268.6°C (68 J / g) Figure 20 mDSC: Glass transition temperature: Midpoint 137°C, ΔCp 0.2 / (g.°C) Figure 27 Thermogravimetric method TGA, 10°C / min 2.7% @ 160°C Figure 14 1.4% @ 100°C Figure 19 / / Residual solvent 1 H-NMR (DMSO-d6) No residual solvent Figure 16 No residual solvent Figure 21 / / Water content Karl Fisher 2.9% water by weight (0.9 mole equivalents) 1.4% water by weight (0.5 mole equivalents) 4.5% water by weight (1.5 mole equivalents) morphology PLM / SEM Figure 17 of aggregated crystals / / / / Note: " / / ": Preparation of polymorphic mode J was not performed.

[0477] Compound A, as an HCl salt, was dissolved in deionized water (3.00 volume), and a saturated NaHCO3 aqueous solution was slowly added to the mixture until pH=7. A solid precipitated during the addition. The solid was then collected by filtration and washed with MeOH (2.00 volume). The filter cake was dried in an oven at 45°C for 24 hours to provide compound A as pattern J. Example 2: X-ray powder diffraction (XRPD)

[0478] Collect X-ray powder diffraction patterns on a Bruker AXS C2 GADDS or Bruker AXS D8 diffractometer. (Bruker AXS C2 GADDS)

[0479] X-ray powder diffraction patterns were collected using CuK radiation (40 kV, 40 mA) on a Bruker AXS C2 GADDS diffractometer, with an automated XYZ stage, a laser imaging microscope for automated sample positioning, and a Histal 2D area detector. The X-ray optics consisted of a single Göbel multilayer mirror coupled to a 0.3 mm pinhole collimator. Weekly performance checks were performed using a certified standard NIST 1976 corundum (plate). The beam divergence (i.e., the effective size of the X-ray beam on the sample) was approximately 4 mm. A continuous θ-θ scan mode was used with a sample-detector distance of 20 cm, yielding 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 collection was GADDS WNT 4.1.16, and data were analyzed and presented using diffracplusEVA v11.0.0.2 or v13.0.0.2. Environmental conditions

[0480] Samples operated under ambient conditions were prepared as flat specimens using unground virgin powder. Approximately 1-2 mg of sample was gently pressed onto a glass slide to obtain a flat surface. Non-ambient conditions

[0481] Samples to be operated under non-ambient conditions are mounted on a silicon wafer with a thermally conductive compound. The samples are then heated to a suitable temperature at 10°C / min (unless otherwise specified), followed by isothermal holding for 1 minute, and then data acquisition begins. Bruker AXS D8 Advance

[0482] X-ray powder diffraction patterns were collected using Cu K radiation (40 kV, 40 mA) on a Bruker D8 diffractometer, with an θ-2θ goniometer and a V4 diverging and receiving slit, a Ge monochromator, and a Lynxeye detector. Instrument performance was checked using the certified corundum standard (NIST 1976). The software used for data collection was diffracplusXRD Commander v2.5.0, and data were analyzed and presented using diffracplusEVA v11.0.0.2 or v13.0.0.2. Samples were prepared as flat samples using the received powder under ambient conditions. The samples were gently loaded into cavities cut into polished zero-background (510) silicon wafers. The samples were rotated through their own plane during analysis. Data collection details are as follows: • Angle range: 2 to 42 °2θ • Step size: 0.05 °2θ • Collection time: 0.5 s / step. XRPD of Form A

[0483] X-ray powder diffraction of form A is shown in Figure 1A. Characteristic peaks include 3.5 ± 0.1°2-θ, 10.4 ± 0.1°2-θ, 14.7 ± 0.1°2-θ, 17.1 ± 0.1°2-θ, 21 ± 0.1°2-θ, 24.9 ± 0.1°2-θ, 29.5 ± 0.1°2-θ, and 34.1 ± 0.1°2-θ. XRPD of form B

[0484] X-ray powder diffraction of form B is shown in Figure 2A. Characteristic peaks include 5.9 ± 0.1°2-θ, 8.6 ± 0.1°2-θ, 10.5 ± 0.1°2-θ, 12.6 ± 0.1°2-θ, 16.9 ± 0.1°2-θ, 19 ± 0.1°2-θ, 20.5 ± 0.1°2-θ, and 24.6 ± 0.1°2-θ. XRPD of form C

[0485] X-ray powder diffraction of form C is shown in Figure 3A. Characteristic peaks include 5.2±0.1°2-θ, 5.9±0.1°2-θ, 7.2±0.1°2-θ, 8.7±0.1°2-θ, 10.6±0.1°2-θ, 12.2±0.1°2-θ, 14.3±0.1°2-θ, 15.1±0.1°2-θ, 15.9±0.1°2-θ, 17.5±0.1°2-θ, 18.1±0.1°2-θ, and 20.1±0.1°2-θ. XRPD of form D

[0486] X-ray powder diffraction of form D is shown in Figure 4A. Characteristic peaks include 3.4±0.1°2-θ, 5.3±0.1°2-θ, 7±0.1°2-θ, 8.7±0.1°2-θ, 10.8±0.1°2-θ, 12.9±0.1°2-θ, 14.3±0.1°2-θ, 15.6±0.1°2-θ, 17±0.1°2-θ, 18.5±0.1°2-θ, 19.6±0.1°2-θ, 21.5±0.1°2-θ, and 24.2±0.1°2-θ.

[0487] Crystallinity is unaffected after one week of storage at 40°C / 75% RH or at 25°C / 92% RH. XRPD in form E

[0488] The X-ray powder diffraction of form E is shown in Figure 5A. Characteristic peaks include 3.4±0.1°2-θ, 4.7±0.1°2-θ, 6.3±0.1°2-θ, 6.9±0.1°2-θ, 7.1±0.1°2-θ, 7.6±0.1°2-θ, 8.6±0.1°2-θ, 9.3±0.1°2-θ, 10.8±0.1°2-θ, 12±0.1°2-θ, 12.5±0.1°2-θ, 13±0.1°2-θ, 13.8±0.1°2-θ, 15.7±0.1°2-θ, 16.2±0.1°2-θ, 16.7±0.1°2-θ, 17±0.1°2-θ, 1 7.5±0.1°2-θ, 18.4±0.1°2-θ, 18.6±0.1°2-θ, 19.6±0.1°2-θ, 20.7±0.1°2-θ, 21.4±0.1°2-θ, 22.2±0.1°2-θ, 23±0.1°2-θ, 24.2±0 .1°2-θ, 25.3±0.1°2-θ, 26±0.1°2-θ, 28±0.1°2-θ, 29.2±0.1°2-θ, 30.5±0.1°2-θ, 31.6±0.1°2-θ, 33.6±0.1°2-θ, and 34.5±0.1°2-θ. XRPD of Form F

[0489] The X-ray powder diffraction of form F is shown in Figure 6A. Characteristic peaks include 4.2±0.1°2-θ, 6.3±0.1°2-θ, 8.6±0.1°2-θ, 8.8±0.1°2-θ, 12±0.1°2-θ, 12.2±0.1°2-θ, 12.5±0.1°2-θ, 14.4±0.1°2-θ, 15±0.1°2-θ, 16±0.1°2-θ, 16.8±0.1°2-θ, 17.2±0.1°2-θ, 17.5±0.1°2-θ, 17.8±0.1°2-θ, 18.8±0.1°2-θ, 19.2±0.1°2-θ, 2 0.1±0.1°2-θ, 20.5±0.1°2-θ, 21.7±0.1°2-θ, 22.1±0.1°2-θ, 23.4±0.1°2-θ, 24.2±0.1°2-θ, 25.3±0.1°2-θ, 25.5±0.1°2-θ , 26.3±0.1°2-θ, 27.1±0.1°2-θ, 29±0.1°2-θ, 30.3±0.1°2-θ, 31.6±0.1°2-θ, 33.1±0.1°2-θ, 34.3±0.1°2-θ and 35.6±0.1°2-θ. XRPD of form G

[0490] X-ray powder diffraction of form G is shown in Figure 7A. Characteristic peaks include 8 ± 0.1°2-θ, 10.2 ± 0.1°2-θ, 12.1 ± 0.1°2-θ, 16.8 ± 0.1°2-θ, 19.2 ± 0.1°2-θ, and 24.6 ± 0.1°2-θ. XRPD of form J

[0491] X-ray powder diffraction of form J is shown in Figure 8A. Characteristic peaks include 3.5±0.1°2-θ, 4.5±0.1°2-θ, 6.4±0.1°2-θ, 8.7±0.1°2-θ, 10.2±0.1°2-θ, 11.3±0.1°2-θ, 11.8±0.1°2-θ, 13.2±0.1°2-θ, 13.6±0.1°2-θ, 14±0.1°2-θ, 14.6±0.1°2-θ. 15.4±0.1°2-θ, 16.1±0.1°2-θ, 16.6±0.1°2-θ, 16.9±0.1°2-θ, 17.2±0.1°2-θ, 18.3±0 .1°2-θ, 19.1±0.1°2-θ, 20.5±0.1°2-θ, 20.8±0.1°2-θ, 21.6±0.1°2-θ, 23.5±0.1°2-θ, 23.8±0.1°2-θ, 24.6±0.1°2-θ, 24.9±0.1°2-θ, 25.2±0.1°2-θ, 25.8±0.1°2-θ, 26.2±0 .1°2-θ, 26.7±0.1°2-θ, 26.8±0.1°2-θ, 27.4±0.1°2-θ, 27.7±0.1°2-θ, 28.7±0.1°2-θ, 29.3±0.1°2-θ, 30.1±0.1°2-θ, 31.2±0.1°2-θ, 31.8±0.1°2-θ, 34.1±0.1°2-θ, 34.9±0 .1°2-θ, 35.6±0.1°2-θ, 36.4±0.1°2-θ, 36.7±0.1°2-θ, 38.5±0.1°2-θ, and 38.8±0.1°2-θ. Simulated XRPD of Form D

[0492] A simulated XRPD pattern of form D was generated. The simulated X-ray powder diffraction pattern of form D is shown in Figure 4A. Characteristic peaks include 5.3±0.1°2-θ, 7±0.1°2-θ, 8.7±0.1°2-θ, 10.8±0.1°2-θ, 12.9±0.1°2-θ, 14.3±0.1°2-θ, 15.6±0.1°2-θ, 17±0.1°2-θ, 18.5±0.1°2-θ, 19.6±0.1°2-θ, 21.5±0.1°2-θ, and 24.2±0.1°2-θ. Example 4: Fourier Transform-Infrared (FTIR)

[0493] Data were collected on a Perkin-Elmer spectrometer equipped with a universal attenuated total reflection (ATR) sampling attachment. Data were collected and analyzed using Spectrum v5.0.1 software.

[0494] The infrared spectrum of Form D is shown in Figure 9A. Characteristic peaks observed in the infrared spectrum of Form D include those at approximately 3332 cm⁻¹ (unlabeled), 2853 cm⁻¹ (unlabeled), approximately 1561 cm⁻¹ (unlabeled), approximately 1523 cm⁻¹, approximately 1438 cm⁻¹, approximately 1257 cm⁻¹, 1112 cm⁻¹, and approximately 930 cm⁻¹. Example 5: Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

[0495] 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 were performed using certified indium. Typically, 0.5–3 mg samples were heated from 25°C to 300°C at 10°C / min in a pinhole aluminum disk. The samples were maintained under 50 mL / min purging with dry nitrogen, unless otherwise specified. Temperature-modulated DSC was performed using a base heating rate of 2°C / min and a temperature modulation parameter of ±0.318°C (amplitude) every 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.

[0496] TGA data were collected on a TA Instruments Q500TGA equipped with a 16-position autosampler. The instrument was calibrated for temperature using certified Alumel and Nickel instruments. Samples were typically loaded in the range of 3–10 mg onto pre-prepared aluminum DSC trays and heated from ambient temperature to 350°C at a rate of 10°C / min. Unless otherwise specified, nitrogen was maintained at a rate of 60 mL / min on the samples. The instrument control software was Advantage for Q Series v2.8.0.392 and thermal advantage v4.8.3, and data were analyzed using Universal Analysis v4.4A. Form A

[0497] In DSC (heating rate: 10°C / min or 20°C / min), endothermic reaction was observed, starting at approximately 234.6°C and peaking at approximately 245°C. Form C

[0498] In DSC (heating rate: 10°C / min or 20°C / min), endothermic reaction was observed, starting at approximately 150-151°C and peaking at approximately 156-157°C. Form D

[0499] In DSC (heating rate: 10°C / min or 20°C / min), endothermic reaction was observed, starting at approximately 260-261°C and peaking at approximately 273°C. Form E

[0500] In DSC (heating rate: 10°C / min or 20°C / min), endothermic reaction was observed, which started at about 112-113°C and peaked at about 137-138°C.

[0501] 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.

[0502] 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.

[0503] 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.

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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

[0508] In some embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is formulated into 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-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine 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-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is formulated into capsules. In some embodiments, crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine is placed in capsules without excipients or with 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-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine 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-sideoxy-2-propen-1-yl)amino]-1-guanidinyl]methyl]-2-pyridinemethylamine 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine is in form C.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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine is in form D. 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine is in 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine 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-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine is a mixture of two or more crystalline forms selected from the group consisting of forms A, B, C, D, E, and F. Example 6: Capsule formulation.

[0509] In one embodiment, the capsule formulation of compound A for administration to humans is prepared from the following ingredients. Table 1 Capsule Formulation Components 25 mg capsules 100 mg capsules 25 mg capsules 200 mg capsules w / w % mg / capsule w / w % mg / capsule w / w % mg / capsule w / w % mg / capsule Crystalline compound A 20.6 25.0 15.7 100.0 20.6 25 15.7 100 Starch 1500 37.2 45.16 52.0 330.6 37.2 45.2 28.4 180.6 Lactose 316 35.6 43.44 27.3 173.8 35.8 43.4 27.3 173.8 Cross-linked polyvinylpyrrolidone 5.0 6.08 3.8 24.3 5.0 6.1 3.8 24.3 Fumed silicon dioxide 1.0 1.22 0.8 4.9 1.0 1.2 0.8 4.86 magnesium stearate 0.5 0.61 0.4 2.4 0.5 0.6 0.4 2.43 Within all particles NA NA NA NA 76.4 121.5 76.4 485.9 Starch 1500 (excluding granules) NA NA NA NA 23.6 37.5 23.6 150

[0510] In some embodiments, the manufacturing method includes the following steps: weighing a specified amount of components, mixing them together, adding them into capsules of appropriate size, and sealing the capsules. In some embodiments, the capsules are stored at room temperature for an extended period until use. Example 7: Compound A

[0511] The method for preparing 25 mg and 100 mg capsules of Compound A is described below (Tables 2 and 3). API was mixed with pregelatinized starch, lactose, crospovidone, and colloidal silica in a tumble blender. The mixture was ground (de-agglomerated) using a conical mill. The ground mixture was then mixed again in the tumble blender. Magnesium stearate was added, and the powder was mixed. The mixture was then compacted. For the 100 mg capsules, the pregelatinized starch was added to the granules and mixed. The final mixture was filled into the capsules using a semi-manual method. The capsules were dusted / polished, inspected for metal, and sorted by weight. Table 2: Composition of Compound A capsules, 25 mg Components effect Dosage per capsule (mg) Compound A* Active ingredients 25.0 Pregelatinized starch** diluent 45.2 lactose monohydrate diluent 43.4 Cross-linked polyvinylpyrrolidone Disintegrant 6.1 colloidal silicon dioxide Flow aid 1.2 magnesium stearate lubricant 0.6 Swedish orange gelatin capsules Capsule shell 1 capsule (Nominal weight: 39) Table 3. Composition of Compound A capsules, 100 mg Components effect Dosage per capsule (mg) Compound A * Active ingredients 100.0 Pregelatinized starch** diluent 330.6 lactose monohydrate Diluent, adhesive 173.7 Cross-linked polyvinylpyrrolidone Disintegrant 24.3 colloidal silicon dioxide Flow aid 4.9 magnesium stearate lubricant 2.4 White opaque gelatin capsules Capsule shell 1 capsule (Nominal weight: 117) *A correction factor can be applied to illustrate API potency. **Adjust pregelatinized starch to accommodate the API correction factor. Example 8: Safety and tolerability study of compound A in chronic lymphocytic leukemia.

[0512] In the open-label, dose-escalation study of compound A, the safety, tolerability, PK / PD, and clinical activity of dose escalation of compound A were determined. When administered to adult patients with relapsed / relapsed acute leukemia (including ALL, AML, and acute mixed phenotype leukemia (AMPL)) (i.e., individuals aged ≥18 years), the compound was administered daily over a 28-day period using an accelerated titration design (ATD), in which the dose was escalated according to a modified Fibonacci sequence (i.e., using an escalation ratio of: initial escalation 2.00, second escalation 1.67, third escalation 1.50, and then all subsequent dose levels escalated by 1.33).

[0513] Two separate dose escalation trials were conducted in parallel, with selective recruitment of patients who were not receiving (Group A) or were receiving (Group B) a drug that inhibited cytochrome P450 3A4 (CYP3A4) activity. After determining the optimal biological dose (OBD), during the latter part of Phase 1, two extended cohorts of approximately 12 patients with relapsed / relapsed acute leukemia (R / R) were conducted (distinguished based on whether patients were receiving / not receiving a CYP3A4 inhibitor) to further evaluate the safety and tolerability of the agent when administered via OBDs and to identify initial efficacy signals. If a single OBD could be identified, approximately 24 R / R acute leukemia patients were placed in a single extended cohort.

[0514] Compound A was administered once daily as an oral dose over a continuous 28-day cycle. The dose was gradually increased and / or expanded to the potential maximum tolerated dose to determine the optimal biological dose and the recommended Phase 2 dose.

[0515] In the second phase, patients with acute leukemia were recruited. Patients included individuals with R / R AML, ALL, or AMPL who had mixed lineage leukemia gene rearrangements (MLL, also known as lysine methyltransferase 2A, KMT2A), MLL / KMT2A partial tandem repeat (MLL-PTD), PICALM-Af10 (also known as CALM-AF10) rearrangement, nucleophosphoprotein 1 (NPM1) mutations, meningioma-1 (MN1) translocations, or CCAAT enhancer-binding protein α (CEBP / A) mutations. Treatment began on day 1 and continued in consecutive 28-day cycles. Pharmacokinetics and pharmacodynamics were evaluated throughout the study. Endpoints included complete remission, complete remission with partial hematologic recovery, overall survival, and event-free survival. Example 9: Safety and Tolerability Study of Compound A in Chronic Lymphocytic Leukemia

[0516] Objective: The objective of this study was to determine the safety and optimal dose of orally administered compound A (25 or 100 mg / day) in patients with B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma / diffuse well-differentiated lymphocytic lymphoma. Primary outcome measure: Safety and tolerability of compound A (frequency, severity, and relevance of adverse events). Secondary outcome measure: Pharmacokinetic / pharmacodynamic assessment. Tumor response: Overall response rate as defined by current guidelines for CLL and SLL (B-cell lymphoma) and duration of response. Eligibility: 18 years of age or older; both sexes must be eligible.

[0517] Inclusion Criteria: 1. For the untreated group only: Men and women diagnosed with CLL / SLL, ≥65 years of age, requiring treatment according to NCI or International Working Group guidelines 11-14. 2. For the relapsed / refractory group only: Men and women diagnosed with relapsed / refractory CLL / SLL unresponsive to treatment, ≥18 years of age (i.e., ≥2 previous treatment failures for CLL / SLL, and for the CLL individual, at least one regimen must use a purine analog [e.g., fludarabine]). 3. Weight ≥40 kg. 4. ECOG efficacy status ≤2. 5. If sexually active and fertile, consent to use contraception during the study and for up to 30 days after the last dose of the study drug. 6. Willing and able to participate without difficulty in all required evaluations and procedures in this study protocol, including swallowing capsules without difficulty. 7. Be able to understand the purpose and risks of the research, and provide a signed and dated informed consent form and authorize the use of protected health information (in accordance with national and local privacy regulations).

[0518] Exclusion Criteria: 1. Life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's view, may jeopardize individual safety, interfere with the absorption or metabolism of compound APO, or place the study results at undue risk. 2. Any immunotherapy, chemotherapy, radiation therapy, or experimental therapy administered within 4 weeks prior to the first administration of the study drug (corticosteroids for disease-related symptoms are permitted but must be cleared 1 week prior to administration of the study drug). 3. Lymphoma involving the central nervous system (CNS). 4. Major surgery performed within 4 weeks prior to the first administration of the study drug. 5. Creatinine > 1.5 times the facility's upper limit of normal (ULN); total bilirubin > 1.5 times the ULN (unless due to Gilbert's disease); and aspartate transaminase (AST) or alanine transaminase (ALT) > 2.5 times the ULN, unless related to disease. 6. Concomitant use of drugs known to cause QT prolongation or torsion point. 7. Severe screening for ECG abnormalities, including left bundle branch block, second-degree type II AV block, third-degree block, bradycardia, and QTc > 470 msec. 8. Breastfeeding or pregnancy. Example 10: Safety and efficacy of compound A in individuals with relapsed / refractory (R / R) mantle cell lymphoma (MCL).

[0519] The primary objective of this study was to evaluate the efficacy of compound A in individuals with relapsed / refractory (R / R) mantle cell lymphoma (MCL). A secondary objective was to evaluate the safety of a fixed daily dosing regimen of compound A (25 or 100 mg / day, in capsule form) in this population.

[0520] Main outcome measure: The number of participants who responded to compound A.

[0521] Secondary outcome measures: Measure the number of participants experiencing adverse events as a measure of safety and tolerability. Measure pharmacokinetics to help determine the body's response to the investigational drug. Patient-reported outcomes (measure the number of participants reporting outcomes to determine health-related quality of life).

[0522] Eligibility: 18 years of age or older; both sexes must meet the requirements.

[0523] Inclusion criteria: Males and females ≥18 years of age. ECOG efficacy status ≤2. Pathologically confirmed MCL, demonstrating cyclin D1 or t(11;14) overexpression, and measurable disease on cross-sectional imaging with a longest diameter ≥2 cm, measurable in two vertical directions. Failure to achieve at least a partial response (PR) or disease progression in a recent treatment regimen. At least one, but no more than five, prior MCL treatment regimens (Note: Individuals who have received ≥2 cycles of bortezomib as a single agent or as part of a combin...

Claims

1. A crystalline form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A): wherein the X-ray powder diffraction (XRPD) pattern of the crystalline form D contains characteristic peaks at angles (°2θ) selected from the following groups: 18.5°±0.1° 2θ, 19.6°±0.1° 2θ and 24.2°±0.1° 2θ.

2. A use of the crystalline form D according to claim 1 for preparing a medicament for treating diabetes or cancer in mammals at a therapeutically effective dose.

3. The use as described in claim 2, wherein the cancer is leukemia, acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), KRAS-mutant cancer, solid tumor, diffuse large B-cell lymphoma or multiple myeloma.

4. The use as described in claim 2, wherein the diabetes is type 1 diabetes or type 2 diabetes.

5. The use as claimed in claim 2, wherein the crystalline form D of the N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine is a therapeutically effective dose selected from the group consisting of: 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 325 mg, 500 mg or 650 mg.

6. The crystalline form D according to claim 1, wherein the further X-ray powder diffraction (XRPD) pattern of the crystalline form D includes additional characteristic peaks at one, two, three, or four angles (°2θ) selected from the group consisting of: 3.4°±0.1° 2θ, 8.7°±0.1° 2θ, 10.7°±0.1° 2θ, and 15.6°±0.1° 2θ.

7. The crystalline form D according to claim 1, wherein the further X-ray powder diffraction (XRPD) pattern of the crystalline form D includes four, five, or six additional characteristic peaks at angles (°2θ) selected from the following group: 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, and 17°±0.1° 2θ.

8. The crystalline form D according to claim 1, wherein the further X-ray powder diffraction (XRPD) pattern of the crystalline form D includes seven, eight, or nine additional characteristic peaks at angles (°2θ) selected from the following group: 3.4°±0.1° 2θ, 5.3°±0.1° 2θ, 6.9°±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, and 21.5°±0.1° 2θ.

9. The crystalline form D according to claim 1, wherein a further X-ray powder diffraction (XRPD) pattern of the crystalline form D is shown in Figure 4A.

10. The crystalline form D according to claim 1, wherein the crystalline form D further has any one of the following properties (a), (b) or (c): (a) the crystalline form D has the same X-ray powder diffraction (XRPD) pattern after being stored in an open container at 40°C and 75% relative humidity (RH) for at least one week; or (b) the crystalline form D has the same X-ray powder diffraction (XRPD) pattern after being stored in an open container at 25°C and 92% relative humidity (RH) for at least one week; or (c) the crystalline form D has the same X-ray powder diffraction (XRPD) pattern after being stored in a closed container at 60°C and 75% relative humidity (RH) for at least one week.

11. A method for preparing the crystalline form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A), wherein, The X-ray powder diffraction (XRPD) pattern of the crystalline form D contains characteristic peaks at angles (°2θ) selected from the following groups: 18.5°±0.1° 2θ, 19.6°±0.1° 2θ, and 24.2°±0.1° 2θ; and wherein the method comprises the following steps: (1) adding N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of formula (I) to a vial containing a mixture of tetrahydrofuran and water to form a suspension; (2) subjecting the suspension formed in step (1) to a slurry treatment at 50°C for four days, avoiding light exposure; (3) The suspension formed in step (2) is filtered to obtain a wet filter cake containing N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of formula (I) in crystalline form D; and (4) The wet filter cake obtained in step (3) was dried in a vacuum at 50°C for three hours to obtain the crystalline form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-sideoxy-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinemethylamine (compound A) of the above formula (I).

12. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or diluent, and the crystalline form D as described in claim 1.

13. A pharmaceutical composition for preparing a medicament for treating diabetes, cancer, KRAS-mutant cancer, diffuse large B-cell lymphoma, or multiple myeloma, the composition comprising a pharmaceutically acceptable excipient, carrier, or diluent, and the crystalline form D as described in claim 1.

14. Use of the pharmaceutical composition according to claim 13 for preparing a medicament for treating diabetes in mammals at a therapeutically effective dose.

15. The use as described in claim 14, wherein the diabetes is type 1 diabetes or type 2 diabetes.

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