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, an irreversible menin-MLL inhibitor for the treatment of cancer

Abstract

Menin-MLL inhibitor. [Solution] The present invention relates to 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 (formula (I)) [Formula 1] TIFF2024534014000035.tif34170 The present invention relates to a crystalline form of the compound of formula (I). The compound of formula (I) is an irreversible menin-MLL inhibitor for use in the treatment of, for example, cancer (including, for example, lymphoma and leukemia) and autoimmune diseases. The present invention discloses characterization of the crystalline form by, for example, XRPD, FTIR, DSC and TGA, as well as pharmacological data.

Description

[Technical field]

[0001] cross reference

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

[0002] Field

[0002] Described herein are covalent inhibitors of menin-MLL, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, including its stereoisomers, crystalline forms, solvates and pharma- ceutically acceptable salts, as well as pharmaceutical compositions comprising such covalent inhibitors of menin-MLL interaction and methods of using such covalent inhibitors of menin-MLL interaction in the treatment of diseases or conditions that would benefit from inhibition of menin-MLL activity. [Background technology]

[0003] background

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

[0004]

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

[0005]

[0005] KMT2A (MLL1) is often targeted cytogenetically in several types of leukemia (e.g., ALL and AML), and when balanced chromosomal translocations are found, these typically target 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 result in the formation of fusion genes that encode fusion proteins that are believed to be causally related to disease development and / or progression. Inhibition of menin may be a promising strategy for treating MLL-related diseases, including leukemia. Summary of the Invention [Means for solving the problem]

[0006] overview

[0006] Described herein are covalent inhibitors of the menin-MLL interaction, N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide, including stereoisomers, pharma- ceutically acceptable solvates (including hydrates), polymorphs and amorphous phases, and methods of use thereof. Pharmaceutically acceptable salts of the inhibitors of the menin-MLL interaction, including stereoisomers, pharma- ceutically acceptable solvates (including hydrates), polymorphs and amorphous phases, and methods of use thereof are also described. N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide and its stereoisomers and pharma- ceutically acceptable salts are used in the manufacture of medicaments for the treatment of 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-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is a covalent inhibitor of menin-MLL interaction.

[0007] Also described herein are methods for preparing crystalline forms of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide. Further described are pharmaceutical compositions comprising the crystalline forms and methods of using the covalent inhibitors of menin-MLL interaction in the treatment of diseases or conditions, including diseases or conditions in which covalent inhibition of menin-MLL interaction provides a therapeutic benefit to a mammal having the disease or condition.

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

[0009]

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

[0010]

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

[0011]

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

[0012]

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

[0013]

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

[0014]

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

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

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

[0017] Form A

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

[0018]

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

[0019]

[0019] In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 1A. In some embodiments, Form A has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown below.

[0020] [Table 1]

[0021]

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

[0022]

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

[0023]

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

[0024]

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

[0025]

[0024] In some embodiments, Form A has a DSC thermogram with an endotherm with an onset at about 234.6°C and a peak at about 245.0°C.

[0026]

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

[0027] Form B In one particular embodiment, the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 2A; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, or 8 of the following: 5.9±0.1°2-theta, 8.6±0.1°2-theta, 10.5±0.1°2-theta, 12.6±0.1°2-theta, 16.9±0.1°2-theta, 19±0.1°2-theta, 20.5±0.1°2-theta, and 24.6±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.6±0.1°2-theta, 10.5±0.1°2-theta, 12.6±0.1°2-theta, 16.9±0.1°2-theta, 19.1±0.1°2-theta, 20.5±0.1°2-theta, and 24.6±0.1°2-theta; or (d) any combination thereof Described herein is Form B of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), having at least one of:

[0028]

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

[0029]

[0028] In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 2A. In some embodiments, Form B has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown below.

[0030] [Table 2]

[0031]

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

[0032]

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

[0033]

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

[0034] In some embodiments, Form B is hygroscopic.

[0035] Form C In one particular embodiment, the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 3A; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of the following: 5.2±0.1°2-theta, 5.9±0.1°2-theta, 7.2±0.1°2-theta, 8.7±0.1°2-theta, 10.6±0.1°2-theta, 12.2±0.1°2-theta, 14.3±0.1°2-theta, 15.1±0.1°2-theta, 15.9±0.1°2-theta, 17.5±0.1°2-theta, 18.1±0.1°2-theta, and 20.1±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.2±0.1°2-theta, 5.9±0.1°2-theta, 8.7±0.1°2-theta, 12.2±0.1°2-theta, 14.3±0.1°2-theta, 15.9±0.1°2-theta, and 17.5±0.1°2-theta; (d) a DSC thermogram having an endotherm with an onset at about 150.23° C. and a peak at about 156.86° C.; or (e) any combination thereof Described herein is Form C of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), having at least one of:

[0036]

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

[0037]

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

[0038]

[0036] In some embodiments, Form C has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown below.

[0039] [Table 3]

[0040]

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

[0041]

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

[0042]

[0039] In some embodiments, Form C has a DSC thermogram with an endotherm with an onset at about 150.23°C and a peak at about 156.86°C.

[0043]

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

[0044] Form D In one particular embodiment, the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4A ; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of the following: 3.4±0.1°2-theta, 5.3±0.1°2-theta, 7±0.1°2-theta, 8.7±0.1°2-theta, 10.8±0.1°2-theta, 12.9±0.1°2-theta, 14.3±0.1°2-theta, 15.6±0.1°2-theta, 17±0.1°2-theta, 18.5±0.1°2-theta, 19.6±0.1°2-theta, 21.5±0.1°2-theta, and 24.2±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4±0.1°2-theta, 8.7±0.1°2-theta, 10.7±0.1°2-theta, 15.6±0.1°2-theta, 18.5±0.1°2-theta, 19.6±0.1°2-theta, and 24.2±0.1°2-theta; (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) Infrared (IR) spectrum substantially similar to that depicted in Figure 9A; (h) approx. 3332cm -1 , approx. 2853cm -1 , approx. 1561cm -1 , approx. 1524cm -1 , approx. 1319cm -1 , approx. 1258cm -1 and about 1067 cm -1 peaks in the infrared (IR) spectrum ( Figure 9A ); (i) A thermogravimetric analysis (TGA) thermogram substantially similar to that depicted in FIG. 10 ; (j) A DSC thermogram substantially similar to that depicted in FIG. 11 ; (k) a DSC thermogram having an endotherm with an onset at about 260.5° C. and a peak at about 273° C.; (l) Substantially similar to that shown in FIG. 1 H NMR (NMR) spectrum; (m) Hygroscopicity observed at 40% RH to 70% RH at 25°C and water absorption of approximately 2.1%; (n) an observed aqueous solubility of about 0.004 mg / mL at about pH 4.5; or (o) any combination thereof Described herein is Form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), having at least one of:

[0045]

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

[0046]

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

[0047]

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

[0048]

[0045] In some embodiments, Form D has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown below.

[0049] [Table 4]

[0050]

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

[0051]

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

[0052]

[0048] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 40° C. and 75% RH for at least 1 week.

[0053]

[0049] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 25° C. and 92% RH for at least 1 week.

[0054]

[0050] In some embodiments, Form D has substantially the same X-ray powder diffraction (XRPD) pattern after storage in a closed container at 60° C. and 75% RH for at least 1 week.

[0055]

[0051] In some embodiments, Form D has an infrared (IR) spectrum substantially similar to that set forth in Figure 9A.

[0056] In some embodiments, Form D has a molecular weight of about 3332 cm -1 , approx. 2853cm -1 , approx. 1561cm -1 , approx. 1524cm -1 , approx. 1319cm -1 , approx. 1258cm -1 and about 1067 cm -1 It has a weak peak in the infrared (IR) spectrum.

[0057]

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

[0058] In some embodiments, Form D has a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in FIG.

[0059] In some embodiments, Form D has a DSC thermogram substantially similar to that set forth in FIG.

[0060]

[0056] In some embodiments, Form D has a DSC thermogram with an endotherm with an onset at about 260.5°C and a peak at about 273°C.

[0061] In some embodiments, Form D has a structure substantially similar to that depicted in FIG. 1 It has a H NMR (NMR) spectrum.

[0062]

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

[0063]

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

[0064] Form E In one particular embodiment, the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 5A; (b) 3.4±0.1° 2-theta, 4.7±0.1° 2-theta, 6.3±0.1° 2-theta, 6.9±0.1° 2-theta, 7.1±0.1° 2-theta, 7.6±0.1° 2-theta, 8.6±0.1° 2-theta, 9.3±0.1° 2-theta, 10.8±0.1° 2-theta, 12±0.1° 2-theta, 12.5±0.1° 2-theta , 13±0.1° 2-theta, 13.8±0.1° 2-theta, 15.7±0.1° 2-theta, 16.2±0.1° 2-theta, 16.7±0.1° 2-theta, 17±0.1° 2-theta, 17.5±0.1° 2-theta, 18.4±0.1° 2-theta, 18.6±0.1° 2-theta, 19.6±0.1° 2-theta, 20.7±0.1° 2-theta .1° 2-theta, 21.4±0.1° 2-theta, 22.2±0.1° 2-theta, 23±0.1° 2-theta, 24.2±0.1° 2-theta, 25.3±0.1° 2-theta, 26±0.1° 2-theta, 28±0.1° 2-theta, 29.2±0.1° 2-theta, 30.5±0.1° 2-theta, 31.6±0.1° 2-theta, 33 an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34 of .6±0.1° 2-theta and 34.5±0.1° 2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.7±0.1°2-theta, 7.7±0.1°2-theta, 10.8±0.1°2-theta, 13.8±0.1°2-theta, 17.0±0.1°2-theta, 18.4±0.1°2-theta, and 18.6±0.1°2-theta; (d) a DSC thermogram having an endotherm with an onset at about 112.34° C. and a peak at about 137.26° C.; or (e) any combination thereof Described herein is Form E of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), having at least one of:

[0065]

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

[0066]

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

[0067]

[0063] In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown below.

[0068] [Table 5]

[0069]

[0064] In some embodiments, Form E is 4±0.1° 2-theta, 4.7±0.1° 2-theta, 6.3±0.1° 2-theta, 6.9±0.1° 2-theta, 7.1±0.1° 2-theta, 7.6±0.1° 2-theta, 8.6±0.1° 2-theta, 9.3±0.1° 2-theta, 10.8±0.1° 2-theta, 12±0.1° 2-theta, 12.5±0.1° 2-theta, 13±0.1° 2-theta, 13.8±0.1° 2-theta, 15.7±0.1° 2-theta, 16.2±0.1° 2-theta, 16.7±0.1° 2-theta, 17±0.1° 2-theta, 17.5±0.1° 2-theta , 18.4±0.1°2-theta, 18.6±0.1°2-theta, 19.6±0.1°2-theta, 20.7±0.1°2-theta, 21.4±0.1°2-theta, 22.2±0.1°2-theta, 23±0.1°2-theta, 24.2±0.1°2-theta, 25.3±0.1°2-theta, 26±0.1°2-theta, 28±0.1°2-theta, 29.2±0.1°2-theta, 30.5±0.1°2-theta, 31.6±0.1°2-theta, 33.6±0.1°2-theta, and 34.5±0.1°2-theta.

[0070]

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

[0071]

[0066] In some embodiments, Form E has a DSC thermogram with an endotherm with an onset at about 112.34°C and a peak at about 137.26°C.

[0072]

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

[0073] Form F In one particular embodiment, the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 6A; (b) 4.2±0.1° 2-theta, 6.3±0.1° 2-theta, 8.6±0.1° 2-theta, 8.8±0.1° 2-theta, 12±0.1° 2-theta, 12.2±0.1° 2-theta, 12.5±0.1° 2-theta, 14.4±0.1° 2-theta, 15±0.1° 2-theta, 16±0.1° 2-theta, 16.8 ±0.1° 2-theta, 17.2±0.1° 2-theta, 17.5±0.1° 2-theta, 17.8±0.1° 2-theta, 18.8±0.1° 2-theta, 19.2±0.1° 2-theta, 20.1±0.1° 2-theta, 20.5±0.1° 2-theta, 21.7±0.1° 2-theta, 22.1±0.1° 2-theta, 23 .4±0.1° 2-theta, 24.2±0.1° 2-theta, 25.3±0.1° 2-theta, 25.5±0.1° 2-theta, 26.3±0.1° 2-theta, 27.1±0.1° 2-theta, 29±0.1° 2-theta, 30.3±0.1° 2-theta, 31.6±0.1° 2-theta, 33.1±0.1° 2-theta, 3 an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 of 4.3±0.1°2-theta and 35.6±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.3±0.1°2-theta, 8.6±0.1°2-theta, 8.8±0.1°2-theta, 11.9±0.1°2-theta, 12.2±0.1°2-theta, 14.4±0.1°2-theta, 15.0±0.1°2-theta, and 20.5±0.1°2-theta; or (d) any combination thereof Described herein is Form F of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), having at least one of:

[0074]

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

[0075]

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

[0076]

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

[0077]

[0072] In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown below.

[0078] [Table 6]

[0079]

[0073] In some embodiments, Form F has the following peaks: 4.2±0.1° 2-theta, 6.3±0.1° 2-theta, 8.6±0.1° 2-theta, 8.8±0.1° 2-theta, 12±0.1° 2-theta, 12.2±0.1° 2-theta, 12.5±0.1° 2-theta, 14.4±0.1° 2-theta, 15±0.1° 2-theta, 16±0.1° 2-theta, 16.8±0.1° 2-theta, 17.2±0.1° 2-theta, 17.5±0.1° 2-theta, 17.8±0.1° 2-theta, 18.8±0.1° 2-theta, 19.2±0.1° 2-theta, 20.1±0.1° 2-theta

[0043] The compound has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 20.5±0.1°2-theta, 21.7±0.1°2-theta, 22.1±0.1°2-theta, 23.4±0.1°2-theta, 24.2±0.1°2-theta, 25.3±0.1°2-theta, 25.5±0.1°2-theta, 26.3±0.1°2-theta, 27.1±0.1°2-theta, 29±0.1°2-theta, 30.3±0.1°2-theta, 31.6±0.1°2-theta, 33.1±0.1°2-theta, 34.3±0.1°2-theta, and 35.6±0.1°2-theta.

[0080]

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

[0081]

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

[0082] Form G In one particular embodiment, the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 7A; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at one, two, three, four, five, or six of the following: 8±0.1° 2-theta, 10.2±0.1° 2-theta, 12.1±0.1° 2-theta, 16.8±0.1° 2-theta, 19.2±0.1° 2-theta, and 24.6±0.1° 2-theta; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1±0.1°2-theta, 10.2±0.1°2-theta, 12.1±0.1°2-theta, 16.8±0.1°2-theta, 19.2±0.1°2-theta, and 24.6±0.1°2-theta; or (d) any combination thereof Described herein is Form G of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), having at least one of:

[0083]

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

[0084]

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

[0085]

[0079] In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown below.

[0086] [Table 7]

[0087]

[0080] In some embodiments, form G has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.1±0.1° 2-theta, 10.2±0.1° 2-theta, 12.1±0.1° 2-theta, 16.8±0.1° 2-theta, 19.2±0.1° 2-theta and 24.6±0.1° 2-theta.

[0088]

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

[0089] Form J In one particular embodiment, the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 8A; (b) 3.5±0.1° 2-theta, 4.5±0.1° 2-theta, 6.4±0.1° 2-theta, 8.7±0.1° 2-theta, 10.2±0.1° 2-theta, 11.3±0.1° 2-theta, 11.8±0.1° 2-theta, 13.2±0.1° 2-theta, 13.6±0.1° 2-theta, 14±0.1° 2-theta, 14.6±0.1° 2-theta, 15.4±0.1° 2-theta, 16.1±0.1° 2-theta, 16.6±0.1° 2-theta theta, 16.9±0.1° 2-theta, 17.2±0.1° 2-theta, 18.3±0.1° 2-theta, 19.1±0.1° 2-theta, 20.5±0.1° 2-theta, 20.8±0.1° 2-theta, 21.6±0.1° 2-theta, 23.5±0.1° 2-theta, 23.8±0.1° 2-theta, 24.6±0.1° 2-theta, 24.9±0.1° 2-theta, 25.2±0.1° 2-theta, 25.8±0.1° 2-theta, 26.2± 0.1° 2-theta, 26.7±0.1° 2-theta, 26.8±0.1° 2-theta, 27.4±0.1° 2-theta, 27.7±0.1° 2-theta, 28.7±0.1° 2-theta, 29.3±0.1° 2-theta, 30.1±0.1° 2-theta, 31.2±0.1° 2-theta, 31.8±0.1° 2-theta, 34.1±0.1° 2-theta, 34.9±0.1° 2-theta, 35.6±0.1° 2-theta, 36.4±0.1° 2-theta an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44 of the following: 36.7±0.1°2-theta, 38.5±0.1°2-theta, and 38.8±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.5±0.1°2-theta, 4.5±0.1°2-theta, 19.1±0.1°2-theta, 21.6±0.1°2-theta, 22.5±0.1°2-theta, and 27.4±0.1°2-theta; (d) Hygroscopicity and water absorption of approximately 2.1% observed at 40% RH to 70% RH at 25°C; (e) an observed aqueous solubility of about 0.004 mg / mL at about pH 4.5; or (f) any combination thereof Described herein is Form J of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), having at least one of:

[0090]

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

[0091]

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

[0092]

[0085] In some embodiments, Form J is 3.5±0.1° 2-theta, 4.5±0.1° 2-theta, 6.4±0.1° 2-theta, 8.7±0.1° 2-theta, 10.2±0.1° 2-theta, 11.3±0.1° 2-theta, 11.8±0.1° 2-theta, 13.2±0.1° 2-theta, 13.6±0.1° 2-theta, 14±0.1° 2-theta, 14.6±0.1° 2-theta, 15.4±0.1°2-theta, 16.1±0.1°2-theta, 16.6±0.1°2-theta, 16.9±0.1°2-theta, 17.2±0.1°2-theta, 18.3±0.1°2-theta, 19.1±0.1°2-theta, 20.5±0.1°2-theta, 20.8±0.1°2-theta, 21.6±0.1°2-theta, 23.5±0.1°2-theta, 23.8±0.1°2-theta 24.6±0.1° 2-theta, 24.9±0.1° 2-theta, 25.2±0.1° 2-theta, 25.8±0.1° 2-theta, 26.2±0.1° 2-theta, 26.7±0.1° 2-theta, 26.8±0.1° 2-theta, 27.4±0.1° 2-theta, 27.7±0.1° 2-theta, 28.7±0.1° 2-theta, 29.3±0.1° 2-theta, 30.1±0.1° 2-theta, 31.2±0.1°2-theta, 31.8±0.1°2-theta, 34.1±0.1°2-theta, 34.9±0.1°2-theta, 35.6±0.1°2-theta, 36.4±0.1°2-theta, 36.7±0.1°2-theta, 38.5±0.1°2-theta, and 38.8±0.1°2-theta.

[0093]

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

[0094]

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

[0095] formulation In another aspect, (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 50% to about 80% by weight of one or more diluents; (c) from about 1% to about 10% by weight of one or more disintegrants; (d) from about 0.2% to about 3% by weight of one or more glidants; and (e) about 0.2% to about 1.0% by weight of one or more lubricants Provided herein is a pharmaceutical formulation for oral administration comprising:

[0096] In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is crospovidone. In some embodiments, the glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, starch, and talc. In some embodiments, the glidant is fumed silica. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments, the lubricant is magnesium stearate.

[0097] In some embodiments, (a) about 10 mg to about 500 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 20% to about 80% by weight total of pregelatinized maize starch and lactose; (c) about 3% to about 10% by weight of crospovidone; (d) about 0.1% to about 1.0% by weight of fumed silica; and (e) about 0.1% by weight to about 1.0% by weight of magnesium stearate Provided herein is a pharmaceutical formulation for oral administration comprising:

[0098] In some embodiments, (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 70% to about 80% by weight total of pregelatinized maize starch and lactose; (c) about 3% to about 10% by weight of crospovidone; (d) about 0.1% to about 1.0% by weight of fumed silica; and (e) about 0.1% by weight to about 1.0% by weight of magnesium stearate Provided herein is a pharmaceutical formulation for oral administration comprising:

[0099]

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

[0100]

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

[0101]

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

[0102] In some embodiments, (a) about 25, 50, 100, 150, 200, or 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 52% by weight pregelatinized maize starch (Starch 1500); (c) approximately 27% lactose (FastFlo Lactose 316); (d) about 4% by weight crospovidone; (e) about 0.8% by weight of fumed silica; and (f) about 0.4% by weight of magnesium stearate Provided herein is a pharmaceutical formulation for oral administration comprising:

[0103]

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

[0104]

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

[0105]

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

[0106] In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, 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 native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is crospovidone. In some embodiments, the glidant is selected from the group consisting of ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, starch, and talc. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments, the lubricant is magnesium stearate.

[0107]

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

[0108]

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

[0109]

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

[0110]

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

[0111] In some embodiments of the aforementioned pharmaceutical formulations, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form A. In some embodiments of the aforementioned pharmaceutical formulations, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form B. In some embodiments of the aforementioned pharmaceutical formulation embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form C. In some embodiments of the aforementioned pharmaceutical formulation embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form D. In some embodiments of the aforementioned pharmaceutical formulation embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form E. In some embodiments of the aforementioned pharmaceutical formulation embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form F.In some embodiments of the aforementioned pharmaceutical formulation embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form G. In some embodiments of the aforementioned pharmaceutical formulation embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is crystalline form J. In some embodiments of the foregoing pharmaceutical formulation embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, Form F, Form G, and Form J. In another embodiment of the foregoing pharmaceutical formulation embodiments, provided herein is a pharmaceutical formulation, wherein the dosage form is a hard gelatin capsule.

[0112]

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

[0113] In some embodiments, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, and talc. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the disintegrant is selected from the group consisting of native starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, crosslinked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked 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, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments, the surfactant is sodium lauryl sulfate. In some embodiments, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments, the lubricant is magnesium stearate.

[0114]

[0107] In some embodiments, (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide as crystalline form D; (b) about 70% to about 80% by weight of pregelatinized maize starch and lactose; (c) about 5% by weight crospovidone; (d) about 0.5% to 1% by weight of fumed silica; and (e) about 0.2% to 0.5% by weight of magnesium stearate Provided herein is a pharmaceutical formulation for oral administration comprising:

[0115]

[0108] In some embodiments, (a) about 10% to about 25% by weight 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 as crystalline form D; (b) about 37.2% by weight pregelatinized maize starch and about 35.6% lactose; (c) about 5% by weight crospovidone; (d) about 1% by weight of fumed silica; and (e) about 0.5% by weight of magnesium stearate Provided herein is a pharmaceutical formulation for oral administration comprising:

[0116]

[0109] In some embodiments, (a) about 10% to about 25% by weight 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 as crystalline form D; (b) about 52% by weight pregelatinized maize starch and about 27.3% lactose; (c) about 3.8% by weight crospovidone; (d) about 0.8% by weight of fumed silica; and (e) about 0.4% by weight of magnesium stearate Provided herein is a pharmaceutical formulation for oral administration comprising:

[0117]

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

[0118]

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

[0119]

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

[0120] In another embodiment, a package includes one or more separate blister pockets, each blister pocket comprising: (a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide; (b) about 50% to about 80% by weight of one or more diluents; (c) from about 1% to about 10% by weight of one or more disintegrants; (d) from about 0.2% to about 3% by weight of one or more glidants; and (e) about 0.2% to about 1.0% by weight of one or more lubricants and each blister pocket is a package comprising metal or plastic foil.

[0121]

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

[0122] In another embodiment, a package includes one or more separate blister pockets, each blister pocket comprising: a) about 10 mg to about 250 mg of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide as crystalline form A; (b) about 50% to about 80% by weight of one or more diluents; (c) from about 1% to about 10% by weight of one or more disintegrants; (d) from about 0.2% to about 3% by weight of one or more glidants; and (e) about 0.2% to about 1.0% by weight of one or more lubricants and each blister pocket is a package comprising metal or plastic foil.

[0123] In one embodiment, a kit is provided that includes a plurality of oral dosage forms, such as tablets or capsules; a package, such as a bottle, that contains the oral dosage forms; and instructions for administering the oral dosage forms according to the methods described herein. Unit dose packages, such as blister packs, provide a useful way to package oral dosage forms of the formulations described herein, and in other embodiments, in combination with instructions for use, embody the kit. In other embodiments, detailed product information is included in the kit's instructions for use. Blister packs are particularly useful for solid oral dosage forms, and in further embodiments, for example, for alternate day administration schedules. In one embodiment, a solid unit dosage form of the formulations described herein is included in a blister pack with instructions for administering one or more tablets or capsules every day so that a sufficient dose of the formulations described herein is administered. In another embodiment, the solid unit dosage form is included in a blister pack with instructions for administering one or more tablets or capsules every other day so that a sufficient dose per day is administered.

[0124] In one aspect, provided herein is a method of treating a patient by administering Compound A. In some embodiments, provided herein is a method of inhibiting menin-MLL interaction, or treating a disease, disorder, or condition that would benefit from inhibition of menin-MLL interaction, in a mammal, comprising administering a therapeutically effective amount of Compound A, or a pharma- ceutically acceptable salt, pharma- ceutically active metabolite, pharma-ceutically acceptable prodrug, or pharma-ceutically acceptable solvate, to the mammal.

[0125]

[0118] In another aspect, provided herein is the use of compound A to inhibit menin-MLL interaction or to treat a disease, disorder or condition that would benefit from inhibition of menin-MLL interaction.

[0126] In another aspect, provided herein is the use of compound A for treating a KRAS mutant cancer in a mammal. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the KRAS mutation is a KRAS G12 mutation. In certain embodiments, the KRAS mutation is a KRAS G12C, G12V, G13D or G12D mutation. In certain embodiments, the KRAS mutation is a G12C mutation. In certain embodiments, the KRAS mutation is a G12V mutation. In certain embodiments, the KRAS mutation is a G13D mutation. In certain embodiments, the KRAS mutation is a G12D mutation. In certain embodiments, compound A is in a form or pharmaceutical formulation as described elsewhere herein.

[0127] In another aspect, provided herein is the use of Compound A for treating cancer in a mammal (eg, a human patient) that does not display a KRAS mutation.

[0128] In another aspect, provided herein is the use of Compound A for treating diffuse large B-cell lymphoma in a mammal (e.g., a human patient). In certain embodiments, the mammal has a triple-hit lymphoma. In certain embodiments, the mammal has a double expresser lymphoma. In certain embodiments, the mammal has multiple myeloma. In certain embodiments, Compound A is in a form or pharmaceutical formulation as described elsewhere herein.

[0129]

[0122] In certain embodiments, compound A is in crystalline form D.

[0130] In certain embodiments, the mammal (eg, patient) has double-hit lymphoma (DHL). In certain embodiments, the mammal (eg, patient) has triple-hit lymphoma (THL).

[0131] In certain embodiments, the mammal (eg, patient) has double expressing lymphoma (DEL).

[0132]

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

[0133]

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

[0134]

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

[0135] In other embodiments, crystalline Compound A is used in the formulation of a medicament for inhibiting menin-MLL interaction. In some other embodiments, crystalline Compound A is used in the formulation of a medicament for inhibiting menin-MLL interaction.

[0136] In one aspect, provided herein is a method of treating cancer in a mammal, comprising administering to the mammal a pharmaceutical composition described herein 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 subject has an MLL / KMT2A gene rearrangement. In some embodiments, the mammal or subject has an ATM mutation. In some embodiments, the mammal or subject has an NPM1 mutation. In some embodiments, the mammal or subject has a TP53 mutation. In some embodiments, the mammal or subject has a NOTCH1 mutation. In some embodiments, the mammal or subject has a WT1 mutation. In some embodiments, the mammal or subject has a RAS mutation. In some embodiments, the mammal or subject has a KRAS mutation. In some embodiments, the mammal or subject has a KRAS G12C mutation. In some embodiments, the mammal or subject has a KRAS G12D mutation. In some embodiments, the mammal or subject has a KRAS G12V mutation. In some embodiments, the mammal or subject has a KRAS G13D mutation. In some embodiments, the mammal or subject has a TET2 mutation. In some embodiments, the mammal or subject has a MYC amplification. In some embodiments, the mammal or subject has a del(13q) karyotype. In some embodiments, the mammal or subject has a trisomy 12 karyotype. In some embodiments, the cancer is a 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 prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis. In some embodiments, if the mammal or subject suffers from cancer, an anti-cancer agent is administered to the mammal or subject in addition to one of the compounds or embodiments described above. In one embodiment, the anti-cancer agent is an inhibitor of mitogen-activated protein kinase signaling.

[0137] In one aspect, provided herein is a method of treating an inflammatory or autoimmune disease in a mammal comprising administering to the mammal a pharmaceutical composition described herein comprising Compound A. In some embodiments, the inflammatory disease is selected from the group consisting of asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, hepatitis, hidradenitis, suppuration, and the like. The following conditions are considered to be causes of infection: ulcer, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis. In some embodiments, the autoimmune disease is inflammatory bowel disease, arthritis, lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid anti-inflammatory drugs, and / or anti-inflammatory drugs. somatic syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic neuropathy, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

[0138]

[0131] An article of manufacture is provided that includes packaging material, Compound A within the packaging material, and a label indicating that Compound A is used for inhibiting the activity of menin-MLL.

[0139] In a further aspect, provided herein is a method of treating an autoimmune disease in a mammal comprising administering Compound A to the mammal.

[0140] In a further aspect, provided herein is a method of treating a heteroimmune disease or condition in a mammal comprising administering Compound A to the mammal.

[0141] In a further aspect, provided herein is a method of treating an inflammatory disease in a mammal comprising administering Compound A to the mammal.

[0142] In a further aspect, provided herein is a method of treating cancer in a mammal comprising administering Compound A to the mammal.

[0143] In a further aspect, provided herein is a method of treating a thromboembolic disorder in a mammal comprising administering to the mammal Compound A. Thromboembolic diseases include, but are not limited to, myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

[0144]

[0137] In another aspect, a method of treating inflammation is provided comprising administering to a mammal an effective amount of Compound A at least once.

[0145]

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

[0146] In another aspect, a method of treating a respiratory disease is provided, comprising administering to a mammal at least once an effective amount of Compound A. In a further embodiment of this aspect, the respiratory disease is asthma. In a further embodiment of this aspect, the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-type asthma, occupational asthma, steroid-resistant asthma, and seasonal asthma.

[0147]

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

[0148]

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

[0149]

[0142] In any of the aforementioned aspects, further embodiments are provided in which compound A is (a) administered systemically to the mammal; (b) administered orally to the mammal; (c) administered intravenously to the mammal; (d) administered by inhalation; (e) administered intranasally; (f) administered by injection to the mammal; (g) administered topically (i.e., dermally) to the mammal; (h) administered by ophthalmic administration; or (i) administered rectally to the mammal.

[0150]

[0143] In any of the aforementioned aspects, further embodiments are provided that include a single administration of Compound A, including further embodiments in which Compound A is administered (i) multiple times over the course of a day; (ii) consecutively; or (iii) continuously.

[0151]

[0144] In any of the above aspects, further embodiments include multiple administrations of Compound A, including further embodiments where: (i) Compound A is administered in a single dose; (ii) the time between the multiple administrations is every 6 hours; (iii) Compound A is administered to the mammal every 8 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of Compound A is temporarily suspended or the dose of Compound A administered is temporarily reduced. In certain embodiments, administration of Compound A is resumed at the end of the drug holiday. The length of the drug holiday can vary from 2 days to 1 year.

[0152] In some embodiments (including methods, uses, formulations, combination therapies, etc.) related to any of the embodiments disclosed herein, Compound A or a pharma- ceutically acceptable salt or solvate thereof is optically pure (i.e., greater than 99% chiral purity by HPLC). In some embodiments (including methods, uses, formulations, combination therapies, etc.) related to any of the embodiments disclosed herein, Compound A or a pharma- ceutically acceptable salt or solvate thereof may be: a) Compound A or a pharma- ceutically acceptable salt or solvate thereof of lower chiral purity; b) N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amine]-4-[ ... or c) racemic N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide or a pharma- ceutically acceptable salt or solvate thereof of any optical purity; or

[0153] In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), amorphous Compound A is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form A) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form B) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form C) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form D) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form E) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form F) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form G) is used. In any embodiment disclosed herein (including methods, uses, formulations, combination therapies, etc.), crystalline Compound A (Form J) is used.

[0154]

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

[0155] In some embodiments (including methods, uses, formulations, combination therapies, etc.) related to any of the embodiments disclosed herein, compound A or a pharma- ceutically acceptable salt thereof is replaced with an active metabolite of compound A. In some embodiments, the active metabolite is in a crystalline form. In some embodiments, the active metabolite is in an amorphous phase. In further embodiments, the metabolite is isolated. In some embodiments (including methods, uses, formulations, combination therapies, etc.) related to any of the embodiments disclosed herein, compound A or a pharma- ceutically acceptable salt thereof is replaced with a prodrug of compound A or a deuterated analog of compound A or a pharma- ceutically acceptable salt thereof. In certain embodiments, compound A is in crystalline form D.

[0156]

[0149] 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 the detailed description and specific examples, while showing specific embodiments, are given by way of illustration only, since various modifications and changes within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, papers, books, manuals and commentaries, are expressly incorporated herein by reference in their entirety for all purposes.

[0157] Incorporation by Reference

[0150] All publications and published patent applications mentioned herein are incorporated by reference herein, to the extent applicable and relevant. [Brief description of the drawings]

[0158] Brief explanation of the figure [Figure 1A]

[0151] The X-ray powder diffraction (XRPD) pattern of Form A is shown. [Figure 2A]

[0152] The X-ray powder diffraction (XRPD) pattern of Form B is shown. [Figure 3A]

[0153] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form C. [Figure 4A]

[0154] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form D. [Figure 5A]

[0155] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form E. [Figure 6A]

[0156] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form F. [Figure 7A]

[0157] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form G. [Figure 8A]

[0158] The X-ray powder diffraction (XRPD) pattern of Form J is shown. [Figure 9A]

[0159] 1 shows the infrared (IR) spectrum of free form Pattern D. [Figure 10]

[0160] 1 shows a thermogravimetric analysis (TGA) thermogram of Form D. [Figure 11]

[0161] 1 shows a DSC thermogram of Form D. [Figure 12]

[0162] 1 shows the NMR spectrum of Form D. [Figure 13]

[0163] The XRPD pattern of Pattern D is shown. [Figure 14]

[0164] 1 shows the TGA thermogram of Pattern D after drying at 50° C. for 3 hours (i.e., Pattern D-Dry). [Figure 15]

[0165] 1 shows a DSC thermogram of Pattern D after drying at 50° C. for 3 hours (i.e., Pattern D-Dry). [Figure 16]

[0166] 1H NMR spectrum of Pattern D after drying at 50° C. for 3 hours (i.e., Pattern D-Dry). [Figure 17]

[0167] A PLM photograph of free Pattern D after drying at 50° C. for 3 hours is shown (i.e., Pattern D-Dry). [Figure 18]

[0168] The XRPD pattern of Pattern D (i.e., Pattern D-THF-water-dry) is shown. [Figure 19]

[0169] 4 shows the TGA thermogram of Pattern D (i.e., Pattern D-THF-water-dry). [Figure 20]

[0170] 4 shows the DSC thermogram of Pattern D (i.e., Pattern D-THF-water-dry). [Figure 21]

[0171] The 1H NMR spectrum of pattern D (i.e., pattern D-THF-water-dry) is shown. [Figure 22]

[0172] An XRPD overlay of Pattern D (50 mg) after 10 min of simulated grinding is shown. [Diagram 23]

[0173] 1 shows the mDSC thermogram of Pattern D (50 mg) after 10 min of simulated grinding. [Figure 24]

[0174] An XRPD overlay of Pattern D (600 mg) after 10 minutes of simulated grinding is shown. [Diagram 25]

[0175] 1 shows the mDSC thermogram of Pattern D (600 mg) after 10 min of simulated grinding. [Figure 26]

[0176] An XRPD overlay of Pattern D (2g) after 10 minutes of simulated grinding is shown. [Figure 27]

[0177] 1 shows the mDSC thermogram of Pattern D (2g) after 10 minutes of simulated grinding. [Figure 28A]

[0178] Cohorts, arms, dose escalation and dose expansion strategies for Phase 1 clinical trials are shown. [Figure 28B]

[0179] Figure 1 shows the anti-proliferative effects and potent cell killing of representative DLBCL cell lines treated with Compound A or PS-341 after 4 days of treatment at eight dose concentrations ranging from 0.005 μM to 10 μM in DHL (DB, Toledo, DOHH2), THL (VAL), DEL (U2932) and GCB (SUDH8L) DLBCL subtypes. [Figure 28C]

[0180] Figure 1 shows the anti-proliferative effects and cell lethality of representative MM cell lines treated with Compound A or PS-341 after 4 days of treatment at eight dose concentrations ranging from 0.005 μM to 10 μM in MM1.R, JJN3, SKMM1 and SKMM2 cell lines. [Figure 28D]

[0181] Figure 1 shows relative survival of patient-derived DLBCL triple-hit lymphoma (THL) and MYC-amplified PDX samples treated with Compound A or a clinical reversible menin inhibitor after 6 days of treatment. [Figure 28E]

[0182] Figure 1 shows cell proliferation inhibition of bone marrow mononuclear cells (BMMCs) from newly diagnosed (A, B) and relapsed / refractory (R / R) (C, D) MM patients after 6 days of treatment with Compound A or PS-341. [Figure 28F]

[0183] FIG. 1 shows that Compound A reduces menin protein in DLBCL cells. [Figure 29A]

[0184] FIG. 1 shows that compound A induces cell death in the KRAS G12C cell line. [Figure 29B]

[0185] 1 shows changes in gene expression in KRAS and MEN1 KRAS mutant cell lines. [Figure 29C]

[0186] 1 shows that Compound A inhibits KRAS mutant cell proliferation in vitro. [Figure 30A]

[0187] Shown is the % growth inhibition of ex vivo PDX tissue. [Figure 30B]

[0188] Dose response curves of ex vivo PDX tissues are shown. [Diagram 31]

[0189] FIG. 1 shows that Compound A induces a greater than 90% reduction in BCL2 transcripts in MOLM-13 AML cells 24 hours after treatment. [Figure 32A]

[0190] FIG. 1 shows growth inhibition of patient-derived CLL PDX samples treated with Compound A or a clinical reversible menin inhibitor after 6 days of treatment, organized by genetic background. [Figure 32B]

[0190] Growth inhibition of patient-derived CLL PDX samples treated with Compound A or clinical reversible menin inhibitors after 6 days of treatment is shown, organized by Rai-Binet stage where data is available. [Figure 32C]

[0191] 1 shows dose response curves of CLL PDX samples treated with Compound A or a clinically reversible menin inhibitor that demonstrate a clinical profile of progression after prior bendamustine treatment, demonstrating high sensitivity to Compound A with >98.5% cell lethality. [Fig. 32D]

[0192] FIG. 1 shows dose response curves for CLL PDX samples treated with Compound A or a clinically reversible menin inhibitor that demonstrate a clinical profile of progression after prior ibrutinib treatment, demonstrating high sensitivity to Compound A with >98.5% cell lethality. [Figure 32E]

[0193] 1 shows dose response curves of CLL PDX samples treated with Compound A or a clinically reversible menin inhibitor that demonstrate a clinical profile of progression after prior ibrutinib and venetoclax treatment, demonstrating high sensitivity to Compound A with >98.5% cell lethality. [Diagram 33]

[0194] 1 shows compound P, a covalent inhibitor of the menin-MLL interaction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0159] Detailed Description

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

[0160]

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

[0161]

[0197] In some embodiments, Compound A can be used in the treatment of heteroimmune diseases or conditions in a mammal, including, but not limited to, graft versus host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites or cockroach calyx), Type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0162]

[0198] In some embodiments, Compound A can be used to treat inflammatory diseases in mammals, including, but not limited to, asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastroenteritis, and the like. These include, but are not limited to, inflammation, gastroenteritis, hepatitis, sweat gland abscess, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis and vulvitis.

[0163]

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

[0164]

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

[0165] Hematological malignancies

[0201] Disclosed herein, in certain embodiments, is a method of treating a hematological malignancy in an individual in need thereof, comprising administering to the individual an amount of Compound A.

[0166]

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

[0167]

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

[0168]

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

[0169]

[0205] B-cell lymphoproliferative disorders (BCLD) are hematological neoplasms, including non-Hodgkin's lymphoma, multiple myeloma, and leukemia. BCLD can arise in either lymphoid tissue (as in lymphoma) or bone marrow (as in leukemia and myeloma), all of which are associated with uncontrolled growth of lymphocytes or white blood cells. There are many subtypes of BCLD, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). The disease course and treatment of BCLD depend on the BCLD subtype. However, even within each subtype, the clinical symptoms, morphological appearance, and response to treatment are heterogeneous.

[0170]

[0206] Malignant lymphoma is the neoplastic transformation of cells that are mainly present in lymphatic tissue. There are two groups of malignant lymphoma: Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphoma infiltrate reticuloendothelial tissue. However, they differ in the neoplastic cell of origin, 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 (approved publication of the American Cancer Society, BC Decker Inc., Hamilton, Ontario, 2003)).

[0171] Non-Hodgkin lymphoma

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

[0172]

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

[0173]

[0209] Non-Hodgkin's lymphoma (NHL) is a diverse group of malignant tumors that are primarily of B-cell origin. NHL can occur in any organ associated with the lymphatic system, such as the spleen, lymph nodes, or tonsils, and can occur at any age. NHL is often characterized by enlarged lymph nodes, fever, and weight loss. NHL is classified as either B-cell NHL or T-cell NHL. Lymphomas associated with lymphoproliferative disorders after bone marrow or stem cell transplantation are usually B-cell NHL. In the Working Formulation classification scheme, NHL is classified into low-grade, intermediate-grade, and high-grade categories based on the natural history (see "The Non-Hodgkin's Lymphoma Pathologic Classification Project," Cancer 49 (1982): 2112-2135). Low-grade lymphomas are indolent, with a median survival of 5 to 10 years (Horning and Rosenberg (1984) N. Engl.J. Med.311:1471-1475). Chemotherapy can induce remission in most indolent lymphomas, but is rarely curative, and most patients eventually relapse and require further treatment. Intermediate- and high-grade lymphomas are more aggressive tumors but are more likely to be cured with chemotherapy. However, a significant proportion of these patients will relapse and require further treatment.

[0174]

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

[0175] DLBCL

[0211] Disclosed herein, in certain embodiments, is a method of treating DLCBL in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory DLCBL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0176]

[0212] As used herein, 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 proliferation index. DLBCL accounts for approximately 30% of all lymphomas and can exhibit several morphological variants, including centroblastic, immunoblastic, T-cell / histiocyte-rich, anaplastic, and plasmablastic subtypes. Genetic testing has shown that there are different subtypes of DLBCL. These subtypes appear to have different outlooks (i.e., prognosis) and responses to treatment. DLBCL affects all age groups, but occurs primarily in older adults (e.g., the average age is in the mid-60s).

[0177]

[0213] In certain embodiments, disclosed herein is a method for treating diffuse large B-cell lymphoma, activated B-cell-like subtype (ABC-DLBCL) in an individual in need thereof, comprising administering to the individual a covalent inhibitor of menin-MLL interaction in an amount of 300 mg / day to a maximum of 1000 mg / day. The ABC subtype of diffuse large B-cell lymphoma (ABC-DLBCL) is believed to arise from post-germinal center B cells arrested during plasma differentiation. The ABC subtype of DLBCL (ABC-DLBCL) accounts for approximately 30% of all DLBCL diagnoses. It is believed to be the least curable of the DLBCL molecular subtypes, and as such, patients diagnosed with ABC-DLBCL typically exhibit a significantly reduced survival rate compared to patients with other types of DLCBL. ABC-DLBCL is most commonly associated with chromosomal translocations that deregulate the germinal center master regulator BCL6 and mutations that inactivate the PRDM1 gene, which encodes a transcriptional repressor required for plasma cell differentiation.

[0178]

[0214] A signaling pathway that is particularly relevant to the development of ABC-DLBCL is that mediated by the nuclear factor (NF)-κB transcription complex. The NF-κB family contains five members (p50, p52, p65, c-rel, and RelB) that form homodimers and heterodimers as transcription factors that mediate various proliferation, apoptosis, inflammation, and immune responses, and are important for normal B-cell development and survival. NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. Therefore, NF-κB is misregulated in many different types of human tumors, and NF-κB is constitutively active. Active NF-κB turns on the expression of genes that maintain cell proliferation and protect cells from conditions that could lead to cell death by apoptosis.

[0179]

[0215] The dependence of ABC DLBCLs on NF-kB depends on a signaling pathway upstream of IkB kinase, which is composed of CARD11, BCL10, and MALT1 (i.e., the CBM complex). Interference with the CBM pathway abolishes NF-kB signaling in ABC DLBCL cells and induces apoptosis. Although the molecular basis for the constitutive activity of the NF-kB pathway is the subject of current research, several somatic alterations to the genome of ABC DLBCLs apparently trigger this pathway. For example, somatic mutations in the coiled-coil domain of CARD11 in DLBCLs enable this signaling scaffold protein to spontaneously nucleate protein-protein interactions with MALT1 and BCL10, leading to IKK activity and NF-kB activation. Constitutive activity of the B cell receptor signaling pathway is involved in the activation of NF-kB in ABC DLBCLs by wild-type CARD11, which is associated with mutations within the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activating mutations in the signaling adaptor MYD88 activate NF-κB and synergize with B cell receptor signaling in maintaining ABC DLBCL cell survival. Moreover, inactivating mutations in A20, a negative regulator of the NF-κB pathway, occur almost exclusively in ABC DLBCL.

[0180]

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

[0181]

[0217] DLBCL cells of the ABC subtype, such as OCI-Ly10, have chronically active BCR signaling and are highly sensitive to the covalent inhibitors of menin-MLL interaction described herein. The covalent inhibitors of menin-MLL interaction described herein potently and irreversibly inhibit the proliferation of OCI-Ly10 (EC 50 Continuous exposure = 10 nM, EC 50 Furthermore, induction of apoptosis is observed with OCILy10, as shown by caspase activation, annexin V flow cytometry and an increase in the sub-G0 fraction.

[0182] Follicular lymphoma

[0218] Disclosed herein, in certain embodiments, is a method of treating follicular lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory follicular lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0183]

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

[0184] CLL / SLL

[0220] Disclosed herein, in certain embodiments, is a method of treating CLL or SLL in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory CLL or SLL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0185]

[0221] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL / SLL) are commonly thought to be the same disease with slightly different symptoms. Where the cancer cells collect determines whether the disease is called CLL or SLL. If the cancer cells are found primarily in the lymph nodes, which are lima-bean shaped structures in the lymphatic system (a system made up mainly of small blood vessels in the body), the disease is called SLL. SLL accounts for about 5%-10% of all lymphomas. If most of the cancer cells are in the bloodstream and bone marrow, the disease is called CLL.

[0186]

[0222] Both CLL and SLL are slow-growing diseases, but CLL, which is by far the most common, tends to be slower. CLL and SLL are treated similarly. They are generally considered incurable with standard treatments, but most patients survive for more than 10 years, depending on the stage and growth rate of the disease. Sometimes, over time, these slow-growing lymphomas can transform into more aggressive lymphomas.

[0187]

[0223] 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 of people (>75%) newly diagnosed with CLL are over the age of 50. Currently, treatment of CLL focuses on controlling the disease and its symptoms rather than a complete cure. CLL is treated with chemotherapy, radiation therapy, biological therapy, or bone marrow transplant. Symptoms may also be treated surgically (removal of the enlarged spleen via splenectomy) or with radiation therapy ("debulking" the swollen lymph nodes). Although in most cases, CLL progresses slowly, CLL is generally considered incurable. Certain CLLs 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 with ZAP-70+ and / or CD38+; or 4) trisomy 12.

[0188]

[0224] CLL treatments are typically administered when a patient's clinical symptoms or blood counts indicate that the disease has progressed to a point that may affect the patient's quality of life.

[0189]

[0225] Small lymphocytic leukemia (SLL) is very similar to CLL above, and is also a cancer of the B cells. In SLL, abnormal lymphocytes primarily affect lymph nodes. However, in CLL, the abnormal cells primarily affect the blood and bone marrow. The spleen can be affected in either condition. SLL accounts for approximately 1 in 25 of all cases of non-Hodgkin's lymphoma. It can occur any time from young adulthood to old age, but is rare under the age of 50. SLL is considered to be an indolent lymphoma. This means that the disease progresses very slowly, and patients tend to live many years after diagnosis. However, most patients are diagnosed with advanced disease, and SLL is generally considered incurable, although it responds well to various chemotherapy drugs. Cases and deaths from SLL are split evenly between men and women, although some cancers tend to occur more frequently in one gender or the other. The average age at diagnosis is 60 years.

[0190]

[0226] SLL is slowly progressive, but persistently progressive. The usual pattern of the disease is a high response rate to radiation and / or chemotherapy, with a period of disease remission, followed by an inevitable relapse months or years later. Retreatment again results in a response, but the disease also recurs. This means that while the short-term prognosis of SLL is very good, over time many patients develop fatal complications from recurrent disease. Given the age of individuals who are typically diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment of the disease with minimal side effects that does not interfere with the patient's quality of life. The present disclosure fulfills this long-standing need in the art.

[0191] Mantle cell lymphoma

[0227] Disclosed herein, in certain embodiments, is a method of treating mantle cell lymphoma (MCL) in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory mantle cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0192]

[0228] As used herein, the term "mantle cell lymphoma" refers to a subtype of B cell lymphoma that originates from CD5 positive antigen naive pre-germinal center B cells in the mantle zone surrounding normal germinal center follicles. MCL cells generally overexpress cyclin D1 due to a t(11:14) chromosomal translocation in the DNA. More specifically, the translocation is at t(11;14)(q13;q32). This type of lymphoma accounts for only about 5% of cases. The cells are small to medium in size. Men are most frequently affected. The average age of patients is in their early 60s. When lymphoma is diagnosed, it has usually spread widely, including lymph nodes, bone marrow, and very often the spleen. Mantle cell lymphoma is not a very fast growing lymphoma, but it is difficult to treat.

[0193] Marginal zone B-cell lymphoma

[0229] Disclosed herein, in certain embodiments, is a method of treating marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0194]

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

[0195] MALT

[0231] Disclosed herein, in certain embodiments, is a method of treating MALT in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory MALT in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0196]

[0232] The term "mucosa-associated lymphoid tissue (MALT) lymphoma" as used herein refers to the extranodal manifestations of marginal zone lymphoma. The majority of MALT lymphomas are low-grade, but a small number initially present as intermediate-grade non-Hodgkin's lymphoma (NHL) or evolve from a low-grade form. The majority of MALT lymphomas arise 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 infection with bacteria or viruses. The average age of patients with MALT lymphoma is approximately 60 years.

[0197] Nodal marginal zone B-cell lymphoma

[0233] Disclosed herein, in certain embodiments, is a method of treating nodal marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory nodal marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0198]

[0234] The term "nodal marginal zone B-cell lymphoma" refers to an indolent B-cell lymphoma found primarily in lymph nodes. The disease is rare, accounting for only 1% of all non-Hodgkin's lymphomas (NHL). It is most commonly diagnosed in older patients, with women more susceptible than men. Because the mutation occurs in the marginal zone of B cells, the disease is classified as marginal zone lymphoma. Because the disease is confined to the lymph nodes, the disease is also classified as nodal.

[0199] Splenic marginal zone B-cell lymphoma

[0235] Disclosed herein, in certain embodiments, is a method of treating splenic marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory splenic marginal zone B-cell lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0200]

[0236] The term "splenic marginal zone B-cell lymphoma" refers to a specific low-grade small B-cell lymphoma that is incorporated into the World Health Organization classification. Characteristic features are splenomegaly, moderate lymphocytosis with villous morphology, intrasinusoidal patterns of involvement of various organs, especially bone marrow, and a relatively indolent course. Tumor progression and aggressive behavior with increased blast morphology is observed in a minority of patients. Molecular and cytogenetic testing has shown heterogeneous results, probably due to the lack of standardized diagnostic criteria.

[0201] Burkitt Lymphoma

[0237] Disclosed herein, in certain embodiments, is a method of treating Burkitt's lymphoma in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory Burkitt's lymphoma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0202]

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

[0203]

[0239] Endemic Burkitt lymphoma. This disease occurs much more frequently in children than adults and is associated with Epstein-Barr virus (EBV) infection in 95% of cases. It occurs mainly 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 rare and distinctive feature of sporadic Burkitt lymphoma. It also commonly involves the abdomen.

[0204]

[0240] Sporadic Burkitt lymphoma. The type of Burkitt lymphoma that affects other parts of the world, including Europe and the Americas, is the sporadic type. It is also primarily a disease of children. The association with Epstein-Barr virus (EBV) is not as strong as in the endemic type, but direct evidence of EBV infection is present in one in five patients. The abdomen is more prominently affected in over 90% of children, rather than lymph node involvement. Bone marrow involvement is more common than in the sporadic type.

[0205] Waldenström macroglobulinemia

[0241] Disclosed herein, in certain embodiments, is a method of treating Waldenstrom's Macroglobulinemia in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory Waldenstrom's Macroglobulinemia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0206]

[0242] The term "Waldenström's Macroglobulinemia", also known as lymphoplasmacytic lymphoma, is a cancer involving a subtype of white blood cells called lymphocytes. It is characterized by the uncontrolled clonal proliferation of terminally differentiated B lymphocytes. It is also characterized by lymphoma cells making an antibody called Immunoglobulin M (IgM). IgM antibodies circulate in large quantities in the blood, thickening the liquid portion of the blood to a syrup-like consistency. This reduces blood flow to many organs, which can lead to vision problems (due to poor circulation in the blood vessels behind the eyes) and neurological problems (i.e. headaches, dizziness and confusion) caused by poor blood flow in the brain. Other symptoms can include fatigue and weakness as well as a tendency to bleed easily. The underlying etiology is not fully understood, but a number of risk factors have been identified, including the gene locus 6p21.3 on chromosome 6. Individuals with a history of autoantibody-driven autoimmune diseases have a two- to three-fold increased risk of developing WM, particularly those associated with hepatitis, human immunodeficiency virus, and rickettsioses.

[0207] Multiple myeloma

[0243] Disclosed herein, in certain embodiments, is a method of treating myeloma in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory myeloma in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0208]

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

[0209] leukemia

[0245] Disclosed herein, in certain embodiments, is a method of treating leukemia in an individual in need thereof, comprising administering to the individual an amount of Compound A. Further disclosed herein, in certain embodiments, is a method of treating relapsed or refractory leukemia in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Compound A.

[0210]

[0246] Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase in blood cells, usually leukocytes (white blood cells). Leukemia is a broad term that includes a variety of diseases. The first division is acute and chronic.

[0211]

[0247] Acute leukemia is characterized by a rapid increase in immature blood cells. This crowding causes the bone marrow to be unable to produce healthy blood cells. Acute leukemia requires immediate treatment because there is rapid progression and accumulation of malignant cells that then spread to the bloodstream and other organs of the body. Acute leukemia is the most common form of leukemia in children.

[0212]

[0248] Chronic leukemia is distinguished by the excessive accumulation of relatively mature, but still abnormal, white blood cells. Typically, it takes months or years to progress, with cells being produced at a much higher rate than normal cells, resulting in a large number of abnormal white blood cells in the blood. Chronic leukemia occurs primarily in older people, but theoretically can occur at any age.

[0213]

[0249] The diseases are further subdivided according to which type of blood cells are affected. This division classifies leukemia into lymphoblastic or lymphocytic leukemia and myelocytic or myeloid leukemia: (i) lymphoblastic or lymphocytic leukemia. The cancerous changes occur in a type of bone marrow cell that usually forms lymphocytes, the immune system cells that fight infections; (ii) myelocytic or myeloid leukemia. The cancerous changes occur in a type of bone marrow cell that forms red blood cells, several other types of white blood cells, and platelets.

[0214]

[0250] 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 called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and hairy cell leukemia (HCL). Thus, in certain embodiments, disclosed herein is a method of treating acute lymphoblastic leukemia (ALL), precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hairy cell leukemia (HCL) in an individual in need thereof, comprising administering to the individual an amount of Compound A. In some embodiments, the leukemia is a relapsed or refractory leukemia. In some embodiments, the leukemia is relapsed or refractory acute lymphoblastic leukemia (ALL), relapsed or refractory precursor B-cell acute lymphoblastic leukemia (precursor B-ALL; also called precursor B-lymphoblastic leukemia), relapsed or refractory acute myeloid leukemia (AML), relapsed or refractory chronic myeloid leukemia (CML), or relapsed or refractory hairy cell leukemia (HCL). In some embodiments, the mammal or subject has a MLL / KMT2A gene rearrangement. In some embodiments, the mammal or subject has a NPM1 mutation. In some embodiments, the mammal or subject has a TP53 mutation. In some embodiments, the mammal or subject has a NOTCH1 mutation. In some embodiments, the mammal or subject has a del(13q) karyotype. In some embodiments, the mammal or subject has a trisomy 12 karyotype.

[0215]

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

[0216]

[0252] A number of animal models are useful for establishing the range of therapeutically effective doses of a compound, a covalent inhibitor of menin-MLL interaction, such as Compound A, for treating any of the aforementioned diseases.

[0217]

[0253] The therapeutic effect of Compound A on any of the aforementioned diseases can be optimized during the course of treatment. For example, a mammal or subject undergoing treatment can undergo a diagnostic evaluation to correlate the alleviation of disease symptoms or pathology with the inhibition of in vivo menin-MLL activity achieved by administering a given dose of Compound A. Thus, the amount of covalent inhibitor of menin-MLL interaction inhibitor compound administered to a mammal or subject can be increased or decreased as necessary to maintain an optimal level of inhibition to treat the disease condition in the mammal or subject.

[0218]

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

[0219]

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

[0220]

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

[0221]

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

[0222]

[0258] In some embodiments, the cancer is bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, pediatric 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, extragonadal germ cell tumor, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, Hodgkin's lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, midline carcinoma and / or non-Hodgkin's lymphoma.

[0223]

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

[0224]

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

[0225]

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

[0226]

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

[0227]

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

[0228]

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

[0229]

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

[0230]

[0266] In certain embodiments, provided herein are methods for treating the following diseases or conditions, comprising administering a compound provided herein 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), childhood medulloblastoma, glioblastoma, pancreatic tumor or cancer, liver cancer (hepatocellular carcinoma), prostate cancer (Myc), triple-negative breast cancer (Myc), AML (acute myeloid leukemia) or MDS (myelodysplastic syndrome). In some embodiments, the disease or condition is early-onset dystonia. In some embodiments, the disease or condition is Kabuki syndrome.

[0231]

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

[0232]

[0268] In some embodiments, the disease or condition is a MYC-driven tumor. MYC has been widely implicated in many cancers, and its expression is estimated to be elevated or deregulated in up to 70% of human cancers. High levels of MYC expression have been associated with aggressive human prostate and triple-negative breast cancers (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 suggest that established tumors are dependent on Myc, and when Myc expression is deregulated, they become dependent not only on Myc, but also on nutrients. These Myc-induced changes provide a unique opportunity for new therapeutic strategies. Despite the fact that normal proliferating cells (stem cell compartment and immune cells) also use MYC for regeneration, many studies have focused on targeting Myc for cancer therapy. Strategies have emerged that inhibit MYC expression, prevent Myc-Max dimerization, inhibit Myc-Max DNA binding, and interfere with key Myc target genes (Dang et al. Cell. 2012, 149(1):22-35).

[0233]

[0269] In some embodiments, compound A may 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 expressing lymphoma (DEL) and menin-dependent multiple myeloma (MM).

[0234]

[0270] In some embodiments, compound A may 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 expressing lymphoma (DEL) and menin-independent multiple myeloma (MM).

[0235]

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

[0236]

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

[0237]

[0273] In some embodiments, Compound A may be used to treat hematological malignancies involving mutations in the nucleophosmin (NMP1) gene. In some embodiments, Compound A may be used to treat hematological malignancies involving no mutations in the nucleophosmin (NMP1) gene.

[0238]

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

[0239]

[0275] In some embodiments, Compound A may 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 double expressing lymphoma (DEL), and MYC-dependent multiple myeloma (MM).

[0240]

[0276] In some embodiments, Compound A may 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 expressing lymphoma (DEL), and MYC-independent multiple myeloma (MM).

[0241]

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

[0242]

[0278] In some embodiments, compound A can be used to treat cancers with mutations in the p53 gene. In some embodiments, compound A can be used to treat cancers without mutations in the p53 gene.

[0243]

[0279] In some embodiments, compound A can be used to treat cancers with mutations in the RAS gene. In some embodiments, compound A can be used to treat cancers with mutations in the KRAS gene. In some embodiments, compound A can be used to treat cancers without mutations in the KRAS gene.

[0244]

[0280] 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 overexpress BCL2.

[0245]

[0281] In some embodiments, compound A can be used to treat cancers with ATM gene mutations. In some embodiments, compound A can be used to treat cancers without ATM gene mutations.

[0246]

[0282] In some embodiments, compound A can be used to treat cancers with mutations in the Notch1 gene. In some embodiments, compound A can be used to treat cancers without mutations in the Notch1 gene.

[0247]

[0283] In some embodiments, compound A can be used to treat cancers with mutations in the TP53 gene. In some embodiments, compound A can be used to treat cancers without mutations in the TP53 gene.

[0248]

[0284] In some embodiments, compound A can be used to treat cancers with WT1 gene mutations. In some embodiments, compound A can be used to treat cancers without WT1 gene mutations.

[0249]

[0285] In some embodiments, compound A can be used to treat cancers with mutations in the KMT2A gene. In some embodiments, compound A can be used to treat cancers without mutations in the KMT2A gene.

[0250]

[0286] In some embodiments, compound A can be used to treat cancers with mutations in the TET2 gene. In some embodiments, compound A can be used to treat cancers without mutations in the TET2 gene.

[0251]

[0287] In some embodiments, compound A can be used to treat cancers with mutations in the Del(13q) gene. In some embodiments, compound A can be used to treat cancers without mutations in the Del(13q) gene.

[0252]

[0288] In some embodiments, compound A can be used to treat cancers with mutations in the trisomy 12 gene. In some embodiments, compound A can be used to treat cancers without mutations in the trisomy 12 gene.

[0253] Compound A and its pharma- ceutically acceptable salts

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

[0254]

[0290] A variety of pharma-ceutically acceptable salts may be formed from Compound A, including the following: - acid addition salts formed by reacting compound A with organic acids (including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxylalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc.; 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, etc.); - Acid addition salts formed by reacting compound A with inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

[0255]

[0291] The term "pharmaceutically acceptable salt" with respect to Compound A refers to a salt of Compound A that does not cause significant irritation to a mammal to which it is administered and that does not substantially neutralize the biological activity and properties of the neutral compound.

[0256]

[0292] It should be understood that reference to a pharma-ceutically acceptable salt includes solvent addition forms (solvates). Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and are formed during the process of product formation or isolation with pharma-ceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, and the like. In one embodiment, solvates are formed using Class 3 solvents, but are not limited thereto. Solvent classifications are defined, for example, in 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). When the solvent is water, a hydrate is formed, and when the solvent is alcohol, an alcoholate is formed. In some embodiments, a solvate of Compound A or a pharma- ceutically acceptable salt thereof is conveniently prepared or formed during the process described herein. In some embodiments, a solvate of Compound A is anhydrous. In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is present in a nonsolvated form. In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is present in a nonsolvated form and is anhydrous.

[0257]

[0293] In yet other embodiments, Compound A or a pharma- ceutically acceptable salt thereof is prepared in various forms, including, but not limited to, amorphous phase, crystalline form, milled form, and nanoparticulate form. In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is amorphous. In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is amorphous and anhydrous. In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is crystalline. In some embodiments, Compound A or a pharma- ceutically acceptable salt thereof is crystalline and anhydrous.

[0258]

[0294] The term "substantially free" or "substantially absent" with respect to a composition refers to a composition that contains at least 50%, 60%, 70%, 75%, 80%, 85%, or 90%, and in certain embodiments, 95%, 98%, 99%, or 100%, by weight, or in certain embodiments, 95%, 98%, 99%, or 100%, of a specified enantiomer of a compound. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of one of the two enantiomers. In certain embodiments, in the methods and compounds provided herein, the compound is substantially free of the other enantiomer.

[0259]

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

[0260]

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

[0261]

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

[0262] Amorphous Compound A

[0298] 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 that indicates a lack of crystallinity.

[0263] Compound A, Form A

[0299] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is in crystalline form A. Crystalline form A of Compound A has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1A; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.5±0.1°2-theta, 10.4±0.1°2-theta, 14.7±0.1°2-theta, 17.1±0.1°2-theta, 21±0.1°2-theta, 24.9±0.1°2-theta, 29.5±0.1°2-theta, and 34.1±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.5±0.1°2-theta, 17.1±0.1°2-theta, 21.0±0.1°2-theta, 24.9±0.1°2-theta, and 29.5±0.1°2-theta; (d) a DSC thermogram having an endotherm with an onset at about 234.6° C. and a peak at about 245° C.; or (e) any combination thereof The present invention is characterized by having at least one of the following:

[0264]

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

[0265]

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

[0266]

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

[0267]

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

[0268]

[0304] In some embodiments, Form A is non-solvated. In some embodiments, Form A is anhydrous. In some embodiments, Form A is solvated. In some embodiments, Form A is hydrous or hydrated.

[0269] Compound A, Form B

[0305] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form B. Crystalline form B of compound A has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 2A; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.9±0.1°2-theta, 8.6±0.1°2-theta, 10.5±0.1°2-theta, 12.6±0.1°2-theta, 16.9±0.1°2-theta, 19±0.1°2-theta, 20.5±0.1°2-theta, and 24.6±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.6±0.1°2-theta, 10.5±0.1°2-theta, 12.6±0.1°2-theta, 16.9±0.1°2-theta, 19.1±0.1°2-theta, 20.5±0.1°2-theta, and 24.6±0.1°2-theta; or (d) any combination thereof The present invention is characterized by having at least one of the following:

[0270]

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

[0271]

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

[0272]

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

[0273]

[0309] In some embodiments, Form B is non-solvated. In some embodiments, Form B is anhydrous. In some embodiments, Form B is solvated. In some embodiments, Form B is a hydrate.

[0274] Compound A, Form C

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

[0275]

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

[0276]

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

[0277] Compound A, Form D

[0313] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form D. Crystalline form D of compound A has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 4A ; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4±0.1°2-theta, 5.3±0.1°2-theta, 7±0.1°2-theta, 8.7±0.1°2-theta, 10.8±0.1°2-theta, 12.9±0.1°2-theta, 14.3±0.1°2-theta, 15.6±0.1°2-theta, 17±0.1°2-theta, 18.5±0.1°2-theta, 19.6±0.1°2-theta, 21.5±0.1°2-theta, and 24.2±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.4±0.1°2-theta, 8.7±0.1°2-theta, 10.7±0.1°2-theta, 15.6±0.1°2-theta, 18.5±0.1°2-theta, 19.6±0.1°2-theta, and 24.2±0.1°2-theta; (d) substantially the same X-ray powder diffraction (XRPD) pattern after storage in an open container at 40° C. and 75% RH for at least one week; (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) Infrared (IR) spectrum substantially similar to that depicted in Figure 9A; (h) approx. 3332cm -1 (No sign), approx. 2853cm -1 (No sign), approx. 1561cm -1 (No sign), approx. 1523cm -1 , approx. 1438cm -1 , approx. 1257cm -1 , 1112cm -1 and about 930 cm -1 infrared (IR) spectrum peaks (Figure 9A); (i) A thermogravimetric analysis (TGA) thermogram substantially similar to that depicted in FIG. 10 ; (j) A DSC thermogram substantially similar to that depicted in FIG. 11 ; (k) a DSC thermogram having an endotherm and an exotherm with an onset at about 260.5° C. and a peak at about 273° C.; (l) Substantially similar to that shown in FIG. 1 H NMR (NMR) spectrum; (m) Hygroscopicity observed at 40% RH to 70% RH at 25°C and water absorption of approximately 2.1%; (n) an observed aqueous solubility of about 0.004 mg / mL at about pH 4.5; or (o) any combination thereof The present invention is characterized by having at least one of the following:

[0278]

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

[0279]

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

[0280]

[0316] In some embodiments, Form D has a thermogravimetric analysis (TGA) thermogram substantially similar to that set forth in FIG.

[0281]

[0317] In some embodiments, Form D has a DSC thermogram substantially similar to that set forth in FIG.

[0282]

[0318] In some embodiments, Form D has an NMR spectrum substantially similar to that set forth in FIG.

[0283]

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

[0284] Compound A, Form E

[0320] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form E. Crystalline form E of compound A has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 5A; (b) 3.4±0.1° 2-theta, 4.7±0.1° 2-theta, 6.3±0.1° 2-theta, 6.9±0.1° 2-theta, 7.1±0.1° 2-theta, 7.6±0.1° 2-theta, 8.6±0.1° 2-theta, 9.3±0.1° 2-theta, 10.8±0.1° 2-theta, 12±0.1° 2-theta, 12.5±0.1° 2-theta, 13±0.1° 2-theta, 13.8±0.1° 2-theta, 15.7±0.1° 2-theta, 16.2±0.1° 2-theta, 16.7±0.1° 2-theta, 17±0.1° 2-theta, 17.5±0.1° 2-theta, 18. an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4±0.1°2-theta, 18.6±0.1°2-theta, 19.6±0.1°2-theta, 20.7±0.1°2-theta, 21.4±0.1°2-theta, 22.2±0.1°2-theta, 23±0.1°2-theta, 24.2±0.1°2-theta, 25.3±0.1°2-theta, 26±0.1°2-theta, 28±0.1°2-theta, 29.2±0.1°2-theta, 30.5±0.1°2-theta, 31.6±0.1°2-theta, 33.6±0.1°2-theta, and 34.5±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.7±0.1°2-theta, 7.7±0.1°2-theta, 10.8±0.1°2-theta, 13.8±0.1°2-theta, 17.0±0.1°2-theta, 18.4±0.1°2-theta, and 18.6±0.1°2-theta; (d) a DSC thermogram having an endotherm with an onset at about 112.34° C. and a peak at about 137.26° C.; or (e) any combination thereof The present invention is characterized by having at least one of the following:

[0285]

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

[0286]

[0322] In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 5A. In some embodiments, Form E has the following structure: 3.4±0.1° 2-theta, 4.7±0.1° 2-theta, 6.3±0.1° 2-theta, 6.9±0.1° 2-theta, 7.1±0.1° 2-theta, 7.6±0.1° 2-theta, 8.6±0.1° 2-theta, 9.3±0.1° 2-theta, 10.8±0.1° 2-theta, 12±0.1° 2-theta, 12.5±0.1° 2-theta, 13±0.1° 2-theta, 13.8±0.1° 2-theta, 15.7±0.1° 2-theta, 16.2±0.1° 2-theta, 16.7±0.1° 2-theta, 17±0.1° 2-theta, 17.5±0.1° 2-theta

[0043] The compound has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 18.4±0.1°2-theta, 18.6±0.1°2-theta, 19.6±0.1°2-theta, 20.7±0.1°2-theta, 21.4±0.1°2-theta, 22.2±0.1°2-theta, 23±0.1°2-theta, 24.2±0.1°2-theta, 25.3±0.1°2-theta, 26±0.1°2-theta, 28±0.1°2-theta, 29.2±0.1°2-theta, 30.5±0.1°2-theta, 31.6±0.1°2-theta, 33.6±0.1°2-theta, and 34.5±0.1°2-theta. In some embodiments, Form E has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 4.7±0.1°2-theta, 7.7±0.1°2-theta, 10.8±0.1°2-theta, 13.8±0.1°2-theta, 17.0±0.1°2-theta, 18.4±0.1°2-theta, and 18.6±0.1°2-theta.

[0287] Compound A, Form F

[0323] In some embodiments, Compound A is crystalline. In some embodiments, Compound A is in crystalline form F. Crystalline form F of Compound A has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 6A; (b) 4.2±0.1° 2-theta, 6.3±0.1° 2-theta, 8.6±0.1° 2-theta, 8.8±0.1° 2-theta, 12±0.1° 2-theta, 12.2±0.1° 2-theta, 12.5±0.1° 2-theta, 14.4±0.1° 2-theta, 15±0.1° 2-theta, 16±0.1° 2-theta, 16.8±0.1° 2-theta, 17.2±0.1° 2-theta, 17.5±0.1° 2-theta, 17.8±0.1° 2-theta, 18.8±0.1° 2-theta, 19.2±0.1° 2-theta, 20.1±0.1° 2-theta, 20. an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5±0.1°2-theta, 21.7±0.1°2-theta, 22.1±0.1°2-theta, 23.4±0.1°2-theta, 24.2±0.1°2-theta, 25.3±0.1°2-theta, 25.5±0.1°2-theta, 26.3±0.1°2-theta, 27.1±0.1°2-theta, 29±0.1°2-theta, 30.3±0.1°2-theta, 31.6±0.1°2-theta, 33.1±0.1°2-theta, 34.3±0.1°2-theta, and 35.6±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.3±0.1°2-theta, 8.6±0.1°2-theta, 8.8±0.1°2-theta, 11.9±0.1°2-theta, 12.2±0.1°2-theta, 14.4±0.1°2-theta, 15.0±0.1°2-theta, and 20.5±0.1°2-theta; or (d) any combination thereof The present invention is characterized by having at least one of the following:

[0288]

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

[0289]

[0325] In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 6A. In some embodiments, Form F is 4.2±0.1° 2-theta, 6.3±0.1° 2-theta, 8.6±0.1° 2-theta, 8.8±0.1° 2-theta, 12±0.1° 2-theta, 12.2±0.1° 2-theta, 12.5±0.1° 2-theta, 14.4±0.1° 2-theta, 15±0.1° 2-theta, 16±0.1° 2-theta, 16.8±0.1° 2-theta, 17.2±0.1° 2-theta, 17.5±0.1° 2-theta, 17.8±0.1° 2-theta, 18.8±0.1° 2-theta, 19.2±0.1° 2-theta, 20.1±0.1° 2-theta

[0043] The compound has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 20.5±0.1°2-theta, 21.7±0.1°2-theta, 22.1±0.1°2-theta, 23.4±0.1°2-theta, 24.2±0.1°2-theta, 25.3±0.1°2-theta, 25.5±0.1°2-theta, 26.3±0.1°2-theta, 27.1±0.1°2-theta, 29±0.1°2-theta, 30.3±0.1°2-theta, 31.6±0.1°2-theta, 33.1±0.1°2-theta, 34.3±0.1°2-theta, and 35.6±0.1°2-theta. In some embodiments, Form F has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.3±0.1°2-theta, 8.6±0.1°2-theta, 8.8±0.1°2-theta, 11.9±0.1°2-theta, 12.2±0.1°2-theta, 14.4±0.1°2-theta, 15.0±0.1°2-theta, and 20.5±0.1°2-theta.

[0290] Compound A, Form G

[0326] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form G. Crystalline form G of compound A has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 7A; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8±0.1°2-theta, 10.2±0.1°2-theta, 12.1±0.1°2-theta, 16.8±0.1°2-theta, 19.2±0.1°2-theta, and 24.6±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1±0.1°2-theta, 10.2±0.1°2-theta, 12.1±0.1°2-theta, 16.8±0.1°2-theta, 19.2±0.1°2-theta, and 24.6±0.1°2-theta; or (d) any combination thereof The present invention is characterized by having at least one of the following:

[0291]

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

[0292]

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

[0293] Compound A, Form J

[0329] In some embodiments, compound A is crystalline. In some embodiments, compound A is in crystalline form J. Crystalline form J of compound A has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 8A; (b) 3.5±0.1° 2-theta, 4.5±0.1° 2-theta, 6.4±0.1° 2-theta, 8.7±0.1° 2-theta, 10.2±0.1° 2-theta, 11.3±0.1° 2-theta, 11.8±0.1° 2-theta, 13.2±0.1° 2-theta, 13.6±0.1° 2-theta, 14±0.1° 2-theta, 14.6±0.1° 2-theta, 15.4±0.1° 2-theta -theta, 16.1±0.1° 2-theta, 16.6±0.1° 2-theta, 16.9±0.1° 2-theta, 17.2±0.1° 2-theta, 18.3±0.1° 2-theta, 19.1±0.1° 2-theta, 20.5±0.1° 2-theta, 20.8±0.1° 2-theta, 21.6±0.1° 2-theta, 23.5±0.1° 2-theta, 23.8±0.1° 2-theta, 24 .6±0.1° 2-theta, 24.9±0.1° 2-theta, 25.2±0.1° 2-theta, 25.8±0.1° 2-theta, 26.2±0.1° 2-theta, 26.7±0.1° 2-theta, 26.8±0.1° 2-theta, 27.4±0.1° 2-theta, 27.7±0.1° 2-theta, 28.7±0.1° 2-theta, 29.3±0.1° 2-theta, 30.1±0.1° an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 31.2±0.1°2-theta, 31.8±0.1°2-theta, 34.1±0.1°2-theta, 34.9±0.1°2-theta, 35.6±0.1°2-theta, 36.4±0.1°2-theta, 36.7±0.1°2-theta, 38.5±0.1°2-theta, and 38.8±0.1°2-theta; (c) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.5±0.1°2-theta, 4.5±0.1°2-theta, 19.1±0.1°2-theta, 21.6±0.1°2-theta, 22.5±0.1°2-theta, and 27.4±0.1°2-theta; (d) hygroscopicity observed at 40% RH to 70% RH at 25°C and water absorption of approximately 2.1%; or (e) any combination thereof The present invention is characterized by having at least one of the following:

[0294]

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

[0295]

[0331] In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 8A. In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 8A. In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 8A. 5.4±0.1° 2-theta, 16.1±0.1° 2-theta, 16.6±0.1° 2-theta, 16.9±0.1° 2-theta, 17.2±0.1° 2-theta, 18.3±0.1° 2-theta, 19.1±0.1° 2-theta, 20.5±0.1° 2-theta, 20.8±0.1° 2-theta, 21.6±0.1° 2-theta, 23.5±0.1° 2-theta, 23.8±0.1° 2-theta 24.6±0.1° 2-theta, 24.9±0.1° 2-theta, 25.2±0.1° 2-theta, 25.8±0.1° 2-theta, 26.2±0.1° 2-theta, 26.7±0.1° 2-theta, 26.8±0.1° 2-theta, 27.4±0.1° 2-theta, 27.7±0.1° 2-theta, 28.7±0.1° 2-theta, 29.3±0.1° 2-theta, 30.1±0.1° 2-theta, 31.2±0.1°2-theta, 31.8±0.1°2-theta, 34.1±0.1°2-theta, 34.9±0.1°2-theta, 35.6±0.1°2-theta, 36.4±0.1°2-theta, 36.7±0.1°2-theta, 38.5±0.1°2-theta, and 38.8±0.1°2-theta. In some embodiments, Form G has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.5±0.1° 2-theta, 4.5±0.1° 2-theta, 19.1±0.1° 2-theta, 21.6±0.1° 2-theta, 22.5±0.1° 2-theta, and 27.4±0.1° 2-theta.

[0296] Preparation of crystalline forms

[0332] In some embodiments, 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 are prepared as outlined in the Examples. Note that solvents, temperatures and other reaction conditions given herein may vary.

[0297] Suitable Solvent

[0333] Therapeutic agents that can be administered to mammals, such as humans, are prepared according to regulatory guidelines. Such government-regulated guidelines are called Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic agents, e.g., the amount of residual solvents in the final product. Acceptable solvents are suitable for use in GMP facilities and consistent with industrial safety concerns. Solvent classifications are defined, for example, in 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).

[0298]

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

[0299]

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

[0300]

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

[0301]

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

[0302]

[0338] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of the APIs. In some cases, practical manufacturing techniques do not completely remove the solvent. Appropriate selection of solvents for the synthesis of APIs can enhance yields or determine characteristics such as crystal form, purity and solubility. Thus, the solvent can be an important parameter in the synthesis process.

[0303]

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

[0304] Specific Terms

[0340] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and are not intended to limit the claimed subject matter. In this disclosure, the use of the singular also includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. In this disclosure, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" and other forms such as "include", "includes" and "included" is not limiting.

[0305]

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

[0306]

[0342] The term "acceptable" or "pharmaceutical acceptable" as used herein with respect to a formulation, composition or ingredient means not causing permanent adverse effects on the general health of the subject being treated or not neutralizing the biological activity or properties of the compound, and being relatively low in toxicity.

[0307]

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

[0308]

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

[0309]

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

[0310]

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

[0311]

[0347] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered to relieve to some extent one or more symptoms of the disease or condition being treated. The result may be reduction and / or alleviation of the signs, symptoms, or causes of the disease or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms without undue adverse side effects. An appropriate "effective amount" in each case may be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement without undue adverse side effects. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject due to variations in the metabolism of the compound (e.g., Compound A), age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount may be determined by routine experimentation, including, but not limited to, a dose escalation clinical trial.

[0312]

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

[0313]

[0349] The term "identical" as used herein refers to two or more sequences or subsequences that are the same. Additionally, the term "substantially identical" refers to two or more sequences that have a percentage of sequence units that are the same when compared and aligned for maximum correspondence over a comparison window or designated region, as measured using a comparison algorithm or by manual alignment and visual inspection. By way of example only, two or more sequences can be "substantially identical" if the sequence units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a designated region. Such percentages represent the "percent identity" of two or more sequences. Sequence identity can exist over a region that is at least about 75-100 sequence units in length, over a region that is about 50 sequence units in length, or over the entire sequence if not specified. This definition also refers to the complement of a test sequence. By way of example only, two or more polypeptide sequences are identical if the amino acid residues are the same, while two or more polypeptide sequences are "substantially identical" if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. Identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, if not specified, over the entire sequence of the polypeptide sequence. Further, by way of example only, two or more polynucleotide sequences are identical if the nucleic acid residues are the same, while two or more polynucleotide sequences are "substantially identical" if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. Identity can exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, if not specified, over the entire sequence of the polynucleotide sequence.

[0314]

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

[0315]

[0351] As used herein, the term "covalent inhibitor" refers to a compound that, upon contact with a target protein (e.g., menin or menin-MLL), causes the formation of a new covalent bond with or within the protein, thereby reducing or eliminating one or more of the biological activities (e.g., phosphotransferase activity) of the target protein, regardless of the subsequent presence or absence of the covalent inhibitor. In certain embodiments, the inhibitors are irreversible.

[0316]

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

[0317]

[0353] The term "modulate" as used herein means to interact with a target, either directly or indirectly, to alter the activity of the target (including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target).

[0318]

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

[0319]

[0355] The term "prophylactically effective amount" as used herein refers to an amount of a composition applied to a patient that will relieve to some extent one or more symptoms of the disease, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's health status, weight, and the like. It is considered well within the skill of one of ordinary skill in the art to determine such prophylactically effective amounts by routine experimentation, including but not limited to dose escalation clinical trials.

[0320]

[0356] The term "subject" as used herein refers to an animal that is the object of treatment, observation or experiment. By way of example only, a subject may be, but is not limited to, a mammal, including, but not limited to, a human.

[0321]

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

[0322]

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

[0323]

[0359] The terms "treat", "treating" or "treatment" as used herein include alleviating, reducing or ameliorating the symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic cause of the symptoms, inhibiting the disease or condition, e.g., arresting the onset of the disease or condition, relieving the disease or condition, regressing the disease or condition, alleviating conditions caused by the disease or condition or halting the symptoms of the disease or condition. The terms "treat", "treating" or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatments.

[0324]

[0360] As used herein, IC 50 refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures a response, such as menin inhibition.

[0325]

[0361] As used herein, EC 50 refers to the dose, concentration or amount of a particular test compound that elicits a dose-dependent response that is 50% of the maximal expression of the particular response induced, elicited or enhanced by the particular test compound.

[0326] Pharmaceutical Compositions / Formulations

[0362] 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 active compounds into medicament-usable preparations. Appropriate formulations depend on the route of administration selected. Any of the well-known techniques, carriers and excipients can be appropriately used as understood in the art. In addition to those described herein, general information on pharmaceutical compositions can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., 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 & Wilkins1999), each of which is incorporated herein by reference in its entirety.

[0327]

[0363] As used herein, a pharmaceutical composition refers to a mixture of a compound (e.g., Compound A) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates administration of the compound to a subject (e.g., a mammal). In practicing the methods of treatment or use provided herein, a therapeutically effective amount of, for example, Compound A is administered as a pharmaceutical composition to a subject (e.g., a mammal) having a disease, disorder, or condition to be treated. In one embodiment, the subject 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 age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0328]

[0364] The term "pharmaceutical combination" as used herein refers to a product resulting from the mixing or combination of multiple active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., Compound A and co-drug, are administered to a subject simultaneously, both in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., Compound A and co-drug, are administered to a subject simultaneously, in parallel or sequentially, as separate entities, without any specific intervening time period, such administration providing an effective level of the two compounds in the subject's body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0329]

[0365] In some embodiments, crystalline Compound A is incorporated into a pharmaceutical composition to provide a solid oral dosage form. In other embodiments, crystalline Compound A is used to prepare a pharmaceutical composition other than an oral solid dosage form. The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations and mixed immediate and controlled release formulations.

[0330]

[0366] Pharmaceutical compositions containing a compound described herein can be manufactured in a conventional manner, such as by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0331] Dosage form

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

[0332]

[0368] Furthermore, the pharmaceutical compositions described herein, including Compound A, may be formulated into any suitable dosage form, including, but not limited to, solid oral dosage forms, sustained release formulations, fast dissolve formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0333]

[0369] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, adding suitable auxiliaries as necessary, and then processing the granulated mixture to obtain tablets or dragee 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, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate, can be added.

[0334]

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

[0335]

[0371] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet (including suspension tablets, fast dissolving tablets, bite-disintegrating tablets, rapid disintegrating tablets, effervescent tablets or caplets), a pill, a powder (including sterile packaged powders, dispensable powders or effervescent powders), a capsule (including soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC or "sprinkle capsules"), a solid dispersion, a solid solution, a bioerodible dosage form, a controlled release formulation, a pulsed release dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a fast melt tablet. Additionally, the pharmaceutical formulations described herein may be administered as a single capsule or in a multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, or four capsules or tablets.

[0336]

[0372] In some embodiments, solid dosage forms, such as tablets, effervescent tablets and capsules, are prepared by mixing Compound A particles with one or more pharmaceutical excipients to form bulk blend compositions.When referring to these bulk blend compositions as homogeneous, it means that Compound A particles are evenly distributed throughout the composition, so that the composition can be easily divided into similarly effective unit dosage forms, such as tablets, pills and capsules.The individual unit dosage forms can also include a film coating that disintegrates when taken orally or when contacted with a diluent.These formulations can be manufactured by conventional pharmacological techniques.

[0337]

[0373] Conventional pharmaceutical techniques include, for example, one or a combination of the following methods: (1) dry blending; (2) direct compression; (3) milling; (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., Worcester coating), tangential coating, top spray, tabletting, extrusion, and the like.

[0338]

[0374] The pharmaceutical solid dosage forms described herein may comprise Compound A and one or more pharma- ceutically acceptable excipients, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. In yet other embodiments, a film coating is provided around the formulation of Compound A using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). 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 not coated.

[0339]

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

[0340]

[0376] Fillers suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0341]

[0377] In order to release the compound (e.g., Compound A) from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage form is compressed with a binder. Disintegrants promote the breakdown of the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Disintegrants suitable for use in the solid dosage forms described herein include natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline celluloses such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable crosslinking agents include, but are not limited to, Tia® and Solka-Floc®, methylcellulose, croscarmellose or crosslinked cellulose (e.g., crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose or crosslinked croscarmellose), crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked 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, locust bean, karaya, pectin, tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.In some embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clays or gums. In some embodiments provided herein, the disintegrant is croscarmellose sodium.

[0342]

[0378] Binders provide cohesiveness to solid oral dosage form formulations. For powder filled capsule formulations, they facilitate the formation of a plug that can be filled into a soft or hard shell capsule, and for tablet formulations, they help ensure that the tablet remains intact after compression and ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, Hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, acid polysaccharides, bentonite, gelatin, polyvinylpyrrolidone:vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac®), glucose, dextrose, These include, but are not limited to, sugars such as molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as acacia, tragacanth, ghatti gum, mucilage of isapol husk, 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.

[0343]

[0379] Generally, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage levels in tablet formulations vary with either direct compression, wet granulation, roller compaction, or the use of other excipients such as fillers that may themselves act as moderate binders. Those skilled in the art of formulation can determine the binder level for their formulation, but binder usage levels of up to 70% are common in tablet formulations.

[0344]

[0380] Suitable lubricants or glidants suitable for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts (e.g., aluminum, calcium, magnesium and zinc), stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearone®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol (such as Carbowax™, PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate. In some embodiments provided herein, 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 provided herein, the lubricant is magnesium stearate.

[0345]

[0381] Diluents suitable for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrins, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0346]

[0382] The term "water-insoluble diluent" includes calcium phosphate, calcium sulfate, starch, modified starch, and microcrystalline and microfine cellulose (e.g., less than about 0.45 g / cm 3 and represents compounds typically used in pharmaceutical formulations, such as Avicel, powdered cellulose) and talc.

[0347]

[0383] Wetting agents suitable for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, Vitamin E TPGS, and the like.

[0348]

[0384] Surfactants suitable for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF). In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0349]

[0385] Suspending agents suitable for use in the solid dosage forms described herein include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., the polyethylene glycol can 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 carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate 60, polysorbate 65, polysorbate 67, polysorbate 68, polysorbate 69, polysorbate 70 ... Examples of suitable cellulose acetate hydrochloride include, but are not limited to, sorbitan-based cellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums (e.g., gum tragacanth and gum acacia, guar gum, xanthans including xanthan gum), sugars, cellulosics (e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose), hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0350]

[0386] Antioxidants suitable for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0351]

[0387] It should be understood that there is considerable overlap between the additives used in the solid dosage forms described herein.Therefore, the additives listed above should be considered as merely illustrative, but not limiting, of the types of additives that can be included in the solid dosage forms described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0352]

[0388] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high boiling solids or liquids. Suitable plasticizers can be added at about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0353]

[0389] Compressed tablets are solid dosage forms prepared by compressing bulk blends of the above formulations. In various embodiments, compressed tablets designed to dissolve in the mouth include one or more flavoring agents. In other embodiments, compressed tablets include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of the compound (e.g., Compound A) from the formulation. In other embodiments, the film coating promotes patient compliance (e.g., Opadry® coating or sugar coating). Film coatings including Opadry® typically range from about 1% to about 3% of the tablet weight. In other embodiments, compressed tablets include one or more excipients.

[0354]

[0390] Capsules can be prepared, for example, by placing a bulk blend of the compound (e.g., Compound A) formulation into a capsule. In some embodiments, the formulation (non-aqueous suspension and solution) is placed into a soft gelatin capsule. In other embodiments, the formulation is placed into a non-gelatin capsule, such as a standard gelatin capsule or a capsule containing HPMC. In other embodiments, the formulation is placed into a sprinkle capsule, which can be swallowed whole or the capsule can be opened and the contents sprinkled on food before eating. In some embodiments, the therapeutic dose is divided into multiple (e.g., 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0355]

[0391] In various embodiments, particles of Compound A and one or more excipients are dry blended and compressed into a mass, such as a tablet, that has 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 gastrointestinal fluids.

[0356]

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

[0357]

[0393] Materials useful for microencapsulation as described herein include materials that are compatible with a compound (e.g., Compound A) and that sufficiently isolate the compound (e.g., Compound A) from other incompatible excipients. Materials that are compatible with a compound (e.g., Compound A) are those that delay the release of the compound (e.g., Compound A) in vivo.

[0358]

[0394] Exemplary microencapsulation materials useful for delaying the release of formulations comprising the compounds described herein 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®, Metolose 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 Metolose®), ethylcellulose (EC) and mixtures thereof (such as E461, Ethocel®, Aqualon®-EC, Surelease®, etc.), polyvinyl alcohol (PVA) (such as Opadry®), and mixtures thereof (such as Methocel®-A, Methocel®-B, Methocel®-C, Methocel®-D, Methocel®-E, Methocel®-F, Methocel®-H ... AMB), hydroxyethylcellulose (such as Natrosol®), carboxymethylcellulose and salts of carboxymethylcellulose (CMC) (such as Aqualon®-CMC), polyvinyl alcohol and polyethylene glycol copolymers (such as Kollicoat IR®), monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers (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 (such as a mixture of HPMC and stearic acid), cyclodextrins and mixtures of these materials.

[0359]

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

[0360]

[0396] Microencapsulated compounds (e.g., Compound A) can be formulated by methods known to those skilled in the art. Such known methods include, for example, spray drying process, spinning disk-solvent process, hot melt process, spray cooling, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at the interface of liquid-gas or solid-gas, pressure extrusion or spray solvent extraction bath. In addition to these, some chemical techniques can also be used, such as complex coacervation, dissolution evaporation, incompatibility between polymers, interfacial polymerization in liquid medium, in situ polymerization, drying in liquid and desolvation in liquid medium. Furthermore, other methods such as roller compaction, extrusion / spheronization, coacervation or nanoparticle coating can be used.

[0361]

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

[0362]

[0398] In another embodiment, the solid dosage form of Compound A is plasticized (coated) with one or more layers. It should be remembered that plasticizers are generally high boiling point solids or liquids. Suitable plasticizers can be added at about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0363]

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

[0364]

[0400] In yet another embodiment, effervescent powders are also prepared according to the present disclosure. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders containing drugs in a dry mixture, usually composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salt of the compositions described herein is added to water, the acid and base react to release carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any combination of acid and base that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0365]

[0401] In some embodiments, the solid dosage forms described herein can be formulated as enterically coated delayed release oral dosage forms (i.e., oral dosage forms of the pharmaceutical compositions described herein that utilize an enteric coating to affect release in the small intestine of the gastrointestinal tract). The enterically coated dosage forms can be compressed, molded or extruded tablets / forms (coated or uncoated) containing granules, powders, pellets, beads or particles (themselves coated or uncoated) of the active ingredient and / or other compositional ingredients. The enterically coated oral dosage forms can be capsules (coated or uncoated) containing pellets, beads or granules of the solid carrier or composition (themselves coated or uncoated).

[0366]

[0402] The term "delayed release" as used herein refers to delivery where release can be achieved at some generally predictable location in the intestinal tract distal to the location that would be achieved if there was no delayed release change. In some embodiments, the method of delayed release is a coating. Any coating should be applied to a sufficient thickness such that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, but dissolves at a pH of about 5 or greater. It is expected that any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and their compatible mixtures and some of their properties include, but are not limited to, the following: Shellac (also called refined lac), a refined product obtained from the resinous secretions of insects. This coating dissolves in media with a pH > 7. Acrylic polymers. The performance of acrylic polymers (mainly solubility in body fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available solubilized in organic solvents, as aqueous dispersions or as dry powders. Eudragit series RL, NE, RS are insoluble but permeable in the gastrointestinal tract and are primarily used for colonic targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach and dissolve in the intestine; and Cellulose derivatives. Examples of suitable cellulose derivatives include ethyl cellulose; and reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. Performance may vary with the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH above 6. Aquateric (FMC) is an aqueous-based system, a spray-dried CAP pseudolatex with particles less than 1 μm. Other components of Aquateric may include Pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin-Etsu Chemical Co., Ltd.)). Performance may vary with the degree and type of substitution. For example, HPMCP such as HP-50, HP-55, HP-55S, and HP-55F grades are suitable. Performance may vary with the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pHs. These polymers are offered as granules or as fine powders for aqueous dispersion; and polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH>5 and is much less permeable to water vapor and gastric juices.

[0367]

[0403] In some embodiments, the coating can and typically does include plasticizers known in the art and optionally other coating excipients such as colorants, talc and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers typically contain 10-25% by weight of plasticizers, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spray coating or pan coating are used to apply the coating. A coating thickness sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is recommended.

[0368]

[0404] Colorants, antiblocking agents, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG) may be added to the coating instead of plasticizers to solubilize or disperse the coating materials and improve coating performance and the coated product.

[0369]

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

[0370]

[0406] In some embodiments, a pharmaceutical formulation is provided comprising particles of Compound A and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, which upon mixing with water results in a substantially uniform suspension.

[0371]

[0407] It should be understood that there is overlap between the additives listed above that are used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by different experts in the art or is commonly used for any of several different functions.Therefore, the additives listed above should be considered merely as examples, but not as limitations, of the types of additives that can be included in the formulations described herein.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0372] Dosage and Treatment Regimens

[0408] In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is from 300 mg / day to a maximum of 1000 mg / day. In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is from 420 mg / day to a maximum of 840 mg / day. In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is about 420 mg / day, about 560 mg / day, or about 840 mg / day. In some embodiments, the amount of Compound A administered to a subject (e.g., a mammal) is about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 425 mg / day, about 450 mg / day, about 475 mg / day, about 500 mg / day, about 525 mg / day, about 550 mg / day, about 560 mg / day, about 575 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1500 mg / day, about 1600 mg / day, about 1700 mg / day, about 1800 mg / day, about 1900 mg / day, about 2000 mg / day, about 2100 mg / day, about 2200 mg / day, about 2300 mg / day, about 2400 mg / day, about 2500 mg / day, about 2600 mg / day, about 2700 mg / day, about 2800 mg / day, about 2900 mg / day, about 3000 mg / day, about 3100 mg / day, about 3200 mg / day, about 3300 mg In some embodiments, the amount of Compound A administered to the mammal is about 420 mg / day. In some embodiments, the amount of Compound A administered to the mammal is about 560 mg / day. In some embodiments, the AUC 0-24 In some embodiments, the AUC of Compound A is about 150 to about 3500 ng*h / mL. 0-24is about 500 to about 1100 ng*h / mL. In some embodiments, Compound A is administered orally. In some embodiments, Compound A is administered once a day, twice a day, or three times a day. In some embodiments, Compound A is administered daily. In some embodiments, Compound A is administered once a day. In some embodiments, Compound A is administered every other day. In some embodiments, Compound A is a maintenance therapy.

[0373]

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

[0374]

[0410] In certain embodiments, compound A is administered daily. In certain embodiments, compound A is administered twice daily. In certain embodiments, compound A is administered three times daily. In certain embodiments, compound A is administered four times daily. In certain embodiments, compound A is administered daily in divided doses. In certain embodiments, compound A is administered daily in a 28 day cycle.

[0375]

[0411] Compound A can be used in the preparation of a medicament for inhibiting menin or a homolog thereof or for the treatment of a disease or condition that would benefit, at least in part, from the inhibition of menin or a homolog thereof, including a subject diagnosed with a hematological malignancy. Additionally, a method of treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to said subject a therapeutically effective amount of a pharmaceutical composition containing Compound A or a pharma- ceutically acceptable salt, pharma-ceutically acceptable N-oxide, pharma-ceutically active metabolite, pharma-ceutically acceptable prodrug, or pharma-ceutically acceptable solvate thereof.

[0376]

[0412] The composition containing Compound A can be administered for prophylactic, therapeutic or maintenance treatment. In some embodiments, the composition containing Compound A is administered for therapeutic use (e.g., administered to a subject diagnosed with a hematological malignancy). In some embodiments, the composition containing Compound A is administered for therapeutic use (e.g., administered to a subject predisposed to or at risk of developing a hematological malignancy). In some embodiments, the composition containing Compound A is administered to a patient in remission as a maintenance therapy.

[0377]

[0413] The amount of Compound A depends on the application (e.g., treatment, prevention, or maintenance). The amount of Compound A depends on the severity and course of the disease or condition, previous treatments, the patient's health, weight, response to the drug, and the judgment of the treating physician. It is considered well within the skill of the art to determine such therapeutically effective amounts by routine experimentation (including, but not limited to, dose escalation clinical trials). In some embodiments, the amount of Compound A is 10 mg / day to a maximum of 250 mg / day. In some embodiments, the amount of Compound A is 25 mg / day to a maximum of 300 mg / day. In some embodiments, the amount of Compound A is 25 mg / day to a maximum of 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 from 2 mg / kg / day to a maximum of 13 mg / kg / day. In some embodiments, the amount of Compound A is from 2.5 mg / kg / day to a maximum of 8 mg / kg / day. In some embodiments, the amount of Compound A is from 2.5 mg / kg / day to a maximum of 6 mg / kg / day. In some embodiments, the amount of Compound A is from 2.5 mg / kg / day to a maximum of 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.

[0378]

[0414] In some embodiments, the pharmaceutical compositions described herein contain about 25 mg of Compound A. In some embodiments, a capsule formulation is prepared containing about 100 mg of Compound A. In some embodiments, 1, 2, 3, 4, or 5 capsule formulations are administered daily. In some embodiments, 3 or 4 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, the capsules are administered once daily. In other embodiments, the capsules are administered multiple times daily.

[0379]

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

[0380]

[0416] 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.

[0381]

[0417] If the patient's condition improves, at the discretion of the physician, administration of the compound (e.g., Compound A) may continue, or the dose of the administered drug may be temporarily reduced or temporarily discontinued for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary from 2 days to 1 year (by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days). Dose reductions during drug holidays can be from 10% to 100% (including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%).

[0382]

[0418] Once the patient's condition has improved, a maintenance dose is administered as needed. Depending on the symptoms, the dosage or frequency of administration, or both, may then be reduced to a level at which the improved disease, disorder, or condition is maintained. However, if symptoms recur, intermittent treatment may be required on a long-term basis.

[0383]

[0419] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the identity (e.g., body weight) of the subject or host requiring treatment, but can nevertheless be routinely determined in a manner known in the art depending on the particular circumstances surrounding the case, including, for example, the particular agent administered, the route of administration, and the subject or host being treated. In general, however, doses employed for the treatment of adult humans will typically be in the range of 0.02 to 5000 mg per day, or about 1 to 1500 mg per day. The desired dose may be conveniently provided in a single dose or as divided doses administered simultaneously (or closely spaced), or at appropriate intervals, e.g., as two, three, four or more divided doses per day.

[0384]

[0420] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosage amounts. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds (e.g., Compound A). The unit dosage form may be in the form of a package 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-resealable containers. Alternatively, multi-dose resealable containers may be used, in which case it is common to include a preservative in the composition. By way of example only, formulations for parenteral injection may be provided in unit dosage form, 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, an individual is administered one unit dosage form per day. In some embodiments, an individual is administered two unit dosage forms per day. In some embodiments, an individual is administered three unit dosage forms per day. In some embodiments, an individual is administered four unit dosage forms per day.

[0385]

[0421] The foregoing ranges are merely suggestions, since there are many variables for each individual treatment regimen, and significant deviations from these recommendations are common. Such dosages may vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the method of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0386]

[0422] The toxicity and therapeutic efficacy of such treatment regimens are 50 (lethal dose for 50% of the population) and ED 50 These can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is known as the therapeutic index, and the LD 50 and ED 50Compounds that exhibit large therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used, for example, in formulating a range of dosages for use in humans. The dosage of such compounds can be adjusted to achieve the ED with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0387] Combination therapy

[0423] In certain cases it may be appropriate to administer Compound A in combination with another therapeutic agent.

[0388]

[0424] In one embodiment, the compositions and methods described herein are combined with other therapeutic agents selected for their particular usefulness against the condition being treated. Generally, in embodiments in which the compositions and combination therapies described herein are used, the other agents do not need to be administered in the same pharmaceutical composition, but rather are administered by a different route due to different physical and chemical characteristics. In one embodiment, initial administration is performed according to an established protocol, after which further modifications in dosage, mode of administration, and frequency of administration can be made based on the observed effects.

[0389]

[0425] In various embodiments, the compounds are administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, the condition of the patient, and the actual choice of compounds used. In certain embodiments, the determination of the order of administration and the number of repetitions of administration of each therapeutic agent during a treatment protocol is based on an evaluation of the disease being treated and the condition of the patient.

[0390]

[0426] For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, and the like.

[0391]

[0427] The individual compounds of such combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds are administered simultaneously in a combined pharmaceutical formulation. Appropriate doses of known therapeutic agents will be appreciated by those of skill in the art.

[0392]

[0428] The combinations referred to herein are conveniently presented for use in the form of a pharmaceutical composition, together with a pharma- ceutically acceptable diluent or carrier.

[0393]

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

[0394]

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

[0395]

[0431] In some embodiments, the second cancer treatment regimen comprises a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises a B cell receptor pathway inhibitor. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCγ inhibitor, a PKCβ inhibitor, or a combination thereof. In some embodiments, the second cancer treatment regimen comprises an antibody, a B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapeutic 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.

[0396]

[0432] In some embodiments, the second cancer treatment regimen is a BCL-2 inhibitor. In some embodiments, the second cancer treatment regimen is selected from the group consisting of oblimersen (G3139), ABT-737 (CAS Registry 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 Registry Number 1257044-40-8 or 4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide). In some embodiments, the second cancer treatment regimen is ABT-199 (venetoclax) and the treatment is synergistic.

[0397]

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

[0398]

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

[0399]

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

[0400]

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

[0401]

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

[0402]

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

[0403]

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

[0404]

[0440] In some embodiments, the second cancer treatment comprises a proteasome inhibitor. In some embodiments, the second treatment comprises bortezomib. In some embodiments, the second cancer treatment comprises an epoxyketone. In some embodiments, the second cancer treatment comprises epoxomicin. In some embodiments, the second cancer treatment comprises a tetrapeptide epoxyketone. In some embodiments, the second cancer treatment comprises carfilzomib. In some embodiments, the second cancer treatment comprises disulfuram, epigallocatechin-3-gallate, salinosporamide A, ONX 0912m, CEP-18770, MLN9708, or MG132.

[0405]

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

[0406]

[0442] In some embodiments, the second cancer treatment comprises a Janus kinase (JAK) inhibitor. In some embodiments, the second treatment comprises lestaurtinib, tofacitinib, ruxolitinib, CYT387, baricitinib, or pacritinib.

[0407]

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

[0408]

[0444] Additional cancer treatment regimens include nitrogen mustards such as bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, prednimustine, and tofosfamide; alkyl sulfonates such as busulfan, mannosulfan, and treosulfan; ethylenimines such as carboquone, thiotepa, and triaziquone; nitrosoureas such as carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, and streptozocin; epoxides such as etoglucide; other alkylating agents such as benzodiazepine, mitobronitol, pipobroman, and temozolomide; folic acid analogues such as methotrexate, pemetrexed, pralatrexate, and raltitrexed; purine analogues such as cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, and thioguanine; pyrimidine analogues such as azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, and tegafur; vinblastine, vincristine, vindesine, vinflunine, and vinorelbine. Vinca alkaloids such as vinca alkaloids, podophyllotoxin derivatives such as etoposide and teniposide; colchicine derivatives such as demecolcine; taxanes such as docetaxel, paclitaxel and paclitaxel poliglumex; other plant alkaloids and natural products such as trabectedin; actinomycins such as dactinomycin; anthracyclines such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin and zorubicin; bleomycin, ixabepirin, other cytotoxic antibiotics such as cyclosporine, mitomycin and plicamycin; platinum compounds such as carboplatin, cisplatin, oxaliplatin and satraplatin; methylhydrazines such as procarbazine; sensitizers such as aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium and temoporfin; protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib and temsirolimus;Other antineoplastic agents such as alitretinoin, altretamine, amsacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxycarbamide, irinotecan, lonidamine, masoprocol, miltefosine, mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, citigene seradenovec, tiazofurin, topotecan, tretinoin and vorinostat; estrogens such as diethylstilbeno1, ethinyl estradiol, fosfestrol and polyestradiol phosphate; progestogens such as gestnorone, medroxyprogesterone and megestrol; gonadotropes such as buserelin, goserelin, leuprorelin and triptorelin. These include: tropin releasing hormone analogues; antiestrogens such as fulvestrant, tamoxifen and toremifene; antiandrogens such as bicalutamide, flutamide and nilutamide; enzyme inhibitors such as aminoglutethimide, anastrozole, exemestane, formestane, letrozole and vorozole; other antihormones such as abarelix 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 cyclosporine and tacrolimus; other immunosuppressants such as azathioprine, lenalidomide, methotrexate and thalidomide; and radiopharmaceuticals such as iobenguane.

[0409]

[0445] Additional cancer treatment regimens include interferons, interleukins, tumor necrosis factors, growth factors, and the like.

[0410]

[0446] Additional cancer treatment regimens include immunostimulants such as ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, and sargramostim; interferons such as natural interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon alfacon-1, interferon alpha-n1, natural interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, peginterferon alpha-2a, and peginterferon alpha-2b; interleukins such as aldesleukin and oprelvekin; BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I:C, poly I Other immunostimulants such as CLC, rokinimex, tasonermin and thymopentin; immunosuppressants such as abatacept, avetimus, alefacept, antilymphatic immunoglobulin (horse), antithymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muromab-CD3, mycophenolate, natalizumab and sirolimus; adalimumab, afelimomab, certolizumab TNF-alpha inhibitors such as mab pegol, etanercept, golimumab and infliximab; interleukin inhibitors such as anakinra, basiliximab, canakinumab, daclizumab, mepolizumab, rilonacept, tocilizumab and ustekinumab; calcineurin inhibitors such as cyclosporine and tacrolimus; other immunosuppressants such as azathioprine, lenalidomide, methotrexate and thalidomide.

[0411]

[0447] Additional cancer treatment regimens include adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3, natalizumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab, or combinations thereof.

[0412]

[0448] Additional cancer treatment regimens include monoclonal antibodies such as alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, ofatumumab, panitumumab, rituximab, trastuzumab, immunosuppressants, eculizumab, efalizumab, muromab-CD3 and natalizumab; TNF-alpha inhibitors such as adalimumab, afelimomab, certolizumab pegol, golimumab and infliximab; basiliximab; interleukin inhibitors such as ibritumomab tiuxetan and tositumomab; radiopharmaceuticals such as abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, blennam, brenne Tuximab vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamicin, glevatumumab, ibritumomab, ibritumomab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab Other monoclonal antibodies such as mab, lucatumumab, pamatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, ofatumumab, oregovomab, pertuzumab, ramaclimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab, tucotuzumab, celmoleukin, veltuzumab, visilizumab, volociximab, and zalutumumab.

[0413]

[0449] The additional cancer treatment regimen includes agents that affect the tumor microenvironment, such as cellular signaling networks (e.g., signaling from the phosphatidylinositol 3-kinase (PI3K) signaling pathway, 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 syk inhibitor is R788. In another embodiment, the second agent is a PKCγ inhibitor, such as enzastaurin.

[0414]

[0450] Examples of drugs that affect the tumor microenvironment include PI3K signaling inhibitors, syc kinase inhibitors, protein kinase inhibitors such as dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pasonanib, sorafenib, sunitinib, and temsirolimus; other vascular inhibitors such as GT-111, JI-101, and R1530. Formation inhibitors: AC220, AC480, ACE-041, AMG900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY73-4506, BGJ398, BGT226, BI811283, BI6727, BIBF 1120, BIBW2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinaciclib, dovitinib lactate, E7050, EMD1214063, ENMD-2076, fostamatinib disodium, GSK22 56098, GSK690693, INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, Linifarnib, LY260361 8, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON01919 .Na, OSI-027, OSI-930, Btk inhibitors, PF-00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF-3758309, PHA-739358, PLC3397, progenipoietin, R547, R763, ramucirumab , regorafenib, RO5185426, SAR103168, SCH727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN-232, TTP607, XL147, XL228, XL281RO5126766, XL418 and XL765.

[0415]

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

[0416]

[0452] Other anticancer drugs that may be used in combination with the menin-MLL interaction covalent inhibitor compounds (e.g., Compound A) include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, and acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; bevacizumab; and the like. Nzodepa;Bicalutamide;Bisantrene hydrochloride;Visnafide dimesylate;Bizelesin;Bleomycin sulfate;Brequinar sodium;Bropirimine;Busulfan;Cactinomycin;Calsterone;Caracemide;Carbetimer;Carboplatin;Carmustine;Carbicin hydrochloride;Carzelesin;Cedefingol;Chlorambucil;Ciloremycin;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Daunorubicin hydrochloride;Decitabine;Dexormaplatin;Desaguanine;Desaguanine mesylate ;Diaziquone;Doxorubicin;Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Empromate;Epipropizine;Epirubicin hydrochloride;Elburozole;Esorubicin hydrochloride;Estramustine;Estramustine phosphate sodium;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine; Fludarabine phosphate; Fluorouracil; Flurocitabine; Foskidone; Fostriestine sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Imofosine; Interleukin Il (including recombinant interleukin II or rlL2), interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-la; interferon gamma-lb; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole;Leuprolide acetate;Liarozole hydrochloride;Lometrexol sodium;Lomustine;Losoxantrone hydrochloride;Masoprocol;Maytansine;Mechlorethamine hydrochloride;Megestrol acetate;Melengestrol acetate;Melphalan;Menogaril;Mercaptopurine;Methotrexate;Methotrexate sodium;Metoprine;Meturedepa;Mitindomide;Mitocalcine;Mitochromine;Mitogillin;Mitomarcin;Mitomycin;Mitosper;Mitotane;Mitoxantrone Hydrochloride;Mycophenolic acid;Nocodazole;Nogalamycin;Ormaplatin;Oxisuran;Pegaspargase;Periomycin;Pentamustine;Peplomycin sulfate;Perfosfamide;Pipobroman;Piposulfan;Piroxantrone hydrochloride;Plicamycin;Promestane;Porfimer sodium;Porfiromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pirazofurin;Riboprin;Rogletimide;Safingol safingol hydrochloride;semustine;simtrazene;sparphosate sodium;sparsomycin;spirogermanium hydrochloride;spiromustine;spiroplatin;streptonigrin;streptozocin;sulofenur;tallysomycin;tecogalan sodium;tegafur;teloxantrone hydrochloride;temoporfin;teniposide;teroxylon;testolactone;thiamiprine;thioguanine;thiotepa;tiazofurin;tirapazamine;toremifene citrate;thoracetate These include: Restrone; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleucine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0417]

[0453] Other anti-cancer agents that may be used in combination with a covalent inhibitor of menin-MLL interacting compounds (e.g., Compound A) include 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; anti-androgen, prostate cancer; anti-estrogen; anti-neoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurin Acid;ara-CDP-DL-PTBA;Arginine deaminase;Aslacrin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxin;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists;Benzochlorins;Benzoylstaurosporine;β-lactam derivatives;β-Aretin;Betacuramina Syn B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistraten A;Bizelesin;Brefurate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcipotriol;Calfostin C;Camptothecin derivatives;Canarypox IL-2;Capecitabine;Carboxamide-amino-triazole;Carboxamide aminotriazole;CaRest M3;CARN 700;cartilage-derived inhibitor;carzelesin;casein kinase inhibitor (ICOS);castanospermine;cecropin B;cetrorelix;chlorambucil;chloroquinoxaline sulfonamide;cicaprost;cis-porphyrin;cladribine;clomiphene analogues;clotrimazole;collismycin A;collismycin B;combretastatin A4;combretastatin analogues;conagenin;crambesidin 816;crisnatol;cryptophycin 8;cryptophycin A derivatives;curacin A;cyclopentathraquinone;Cycloplatin;Sipemycin;Cytarabine ocphosphate;Cytolytic factors;Cytostatin;Dacliximab;Decitabine;Dehydrodidemnin B;Deslorelin;Dexamethasone;Dexyphosphamide;Dexrazoxane;Dexverapamil;Diaziquone;Didemnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;9-dioxamycin;Diphenylspiromustine;Docosanol;Dolasetron;Doxifluridine;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;E Delfosine;Edrecolomab;Eflornithine;Elemene;Emiteflu;Epirubicin;Epristeride;Estramustine analogs;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flezelastine;Fluasterone;Fludarabine;Fluorodaunornithine hydrochloride;Forfenimex;Formestane;Fostriesi;Fotemustine;Gadolinium texaphyrin;Galiu nitrate ;Galocitabine;Ganirelix;Gelatinase inhibitors;Gemcitabine;Glutathione inhibitors;Hepsulfame;Heregulin;Hexamethylene bisacetamide;Hypericin;Ibandronic acid;Idarubicin;Idoxifene;Idramantone;Ilmofosine;Ilomastat;Imidazoacridone;Imiquimod;Immunostimulating peptides;Insulin such as growth factor-1 receptor inhibitors;Interferon agonists;Interferon;Interleukin;Iobenguane;Iododoxorubicin;Ipomeanol, 4-;Ilopract;Irsogladine;I Sobengazole; Isohomohalichondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprorelin; Levamisole; Liarozole; Linear polyamine analogues; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lysoclinamide 7; Lobaplatin; Lombricin; Lometrexol; Lonidamine; Rosoxantrone;Lovastatin; Loxoribine; Raltotecan; Lutetium texaphyrin; Lysofylline; Lytic peptides; Maytansine; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrilysin inhibitors; Matrix metalloproteinase inhibitors; Menogaril; Melbarone; Meterelin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Millimostim; Mismatched double-stranded RNA; Mitoguazone; Mitolactol; Mitomycin analogs; Mitonafide; Mitotoxin Fibroblast growth factor-support Phosphorus; Mitoxantrone; Mofalotene; Molgramostim; Monoclonal antibodies, human chorionic gonadotropin; Monophosphoryl lipid A + Mycobacterium cell wall sk; Mopidamol; Multidrug resistance gene inhibitors; Multiple tumor suppressor 1-based therapy; Mustard anticancer drugs; Mycaperoxide; Mycobacterial cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamides; Nafarelin; Nagressip; Naloxone + Pentazocine; Napavine; Nafterpine; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Neutral endo Peptidases;Nilutamide;Nisamycin;Nitric oxide modulators;Nitroxide antioxidants;Nitrulline;O6-benzylguanine;Octreotide;Oxenone;Oligonucleotides;Onapristone;Ondansetron;Ondansetron;Oracin;Oral cytokine inducers;Ormaplatin;Osateron;Oxaliplatin;Oxaunomycin;Palauamine;Palmitoyl rhizoxin;Pamidronic acid;Panaxytriol;Panomyphen;Parabactin;Pazeliptin;Pegaspargase;Perdecin;Pentosan polysulfate sodium;Pe antostatin;pentrozole;perflubron;perphosphamide;perillyl alcohol;phenazinomycin;phenyl acetate;phosphatase inhibitors;picibanil;pilocarpine hydrochloride;pirarubicin;piritrexim;prasetin A;prasetin B;plasminogen activator inhibitors;platinum complexes;platinum compounds;platinum-triamine complexes;porfimer sodium;porfiromycin;prednisone;propyl bis-acridone;prostaglandin J2;proteasome inhibitors;protein A-based immunomodulators;protein kinase C inhibitors;Protein kinase C inhibitors, microalgae;protein tyrosine phosphatase inhibitors;purine nucleoside phosphorylase inhibitors;purpurins;pyrazoloacridines;pyridoxylated hemoglobin polyoxyethylene conjugates;raf antagonists;raltitrexed;ramosetron;ras farnesyl protein transferase inhibitors;ras inhibitors;ras-GAP inhibitors;demethylated reteriptin;rhenium Re186 etidronate;rhizoxin;ribozymes;RII retinamide;logretimide;rohitkin;romultide;rokinin Mex;Rubiginone B1;Ruboxyl;Safingol;Saintopine;SarCNU;Sarcophytol A;Sargramostim;Sdi1 mimetic;Semustine;Senescence derived inhibitor 1;Sense oligonucleotide;Signal transduction inhibitor;Signal transduction regulator;Single-chain antigen binding protein;Sizofiran;Sobuzoxane;Sodium borocaptate;Sodium phenylacetate;Sorberol;Somatomedin binding protein;Sonermin;Sparfosic acid;Spicamycin D;Spiromustine;Splenopentin;Spongistatin 1;Squalamine;Stem cell Cell inhibitors;Stem cell division inhibitors;Stypiamides;Stromelysin inhibitors;Sulfinosines;Superactive vasoactive intestinal peptide antagonists;Thragista;Suramin;Swainsonine;Synthetic glycosaminoglycans;Talimustine;Tamoxifen methiodide;Tauromustine;Tazarotene;Tecogalan sodium;Tegafur;Terlapyrylium;Telomerase inhibitors;Temoporfin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Taliblastine;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin; Thymopoietin receptor agonists;Thymotrinan;Thyroid stimulating hormone;Tin ethyl etiopurpurin;Tirapazamine;Titanocene dichloride;Topsentin;Toremifene;Totipotent stem cell factor;Translation inhibitors;Tretinoin;Triacetyluridine;Triciribine;Trimetrexate;Triptorelin;Tropisetron;Turosteride;Tyrosine kinase inhibitors;Tyrphostin;UBC inhibitors;Ubenimex;Uroginal sinus-derived growth inhibitor;Urokinase receptor antagonists;Vapreotide;Variolin B;Vector systems, red blood cell gene therapy;Veraresol;Veramine;These include verudine, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorub, and zinostatin stimalamer.

[0418]

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

[0419]

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

[0420]

[0456] Examples of anti-cancer drugs that act by arresting cells in the G2-M phase by stabilized microtubules and that may be used in combination with the covalent inhibitor compound of menin-MLL interaction (Compound A) include, but are not limited to, the following marketed and investigational drugs: elbrozole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mibobulin 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), and other drugs in development. ), altriltin (such as altriltin A and altriltin C), spongistatins (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (epothilone A, epothilone B, epothilone C (also known as desoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as desoxyepothilone F and dEpoF), 26-fluoroepothilone, etc.), auristatin PE (also known as NSC-654663), sobridotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), (Pharmacia), 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 (also known as Ajinomoto, AVE-8063A and CS-39.HCI), AC-7700 (also known as Ajinomoto, AVE-8062, AVE-8062A, CS-39-L-Ser.HCI and RPR-258062A), bitilebuamide, tubulysin A, canadensol, centaureydin (also known as NSC-106969), T-138067 (also known as Tularik, 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 StateUniversity), oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), physianolide B, laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), narcosine (also known as NSC-5366), nascapine, D-24851 (Asta Medica), A-105972 (Abbott), hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, inanosin (also known as NSC-698666), 3-lAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), eleutherobin (including desmethyleleutherobin, desacetyleleutherobin, isoeleutherobin A and Z-eleutherobin), caribeoside, caribeolin, halichondrin 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, (-)-phenylahistine (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (AstaMedica), myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resbellastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes) and SSR-250411 (Sanofi).

[0421]

[0457] In certain embodiments, if an individual suffers from or is at risk of suffering from an autoimmune, inflammatory or allergic disease, Compound A may be used with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolic acid or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), nonsteroidal anti-inflammatory drugs (e.g., For example, salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulfonanilides), Cox-2-specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, aurothioglucose, aurothiomalate, aurophin, sulfasalazine, hydroxychloroquine, minocycline, TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, anti-leukotrienes, β-agonists, theophylline, or anticholinergics.

[0422] Kit or Product

[0458] Also described herein are kits and products for use in the therapeutic methods of use described herein.Such kits include carriers, packages or containers that are compartmentalized to receive one or more containers, such as vials, tubes, etc., each container containing one of the separate 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 from a variety of materials, such as glass or plastic.

[0423]

[0459] The products provided herein include packaging materials.Packaging materials for use in 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, bottles, and any packaging material suitable for the selected formulation and intended administration and treatment mode.

[0424]

[0460] In some embodiments, the compounds or compositions described herein are provided in a package or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The compounds or compositions described herein are packaged alone or together with another compound or another ingredient or additive. In some embodiments, the package contains one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein. In some embodiments, the package contains a metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser device is accompanied by instructions for administration, such as instructions for administering the compound or composition to treat a neoplastic disease. In some embodiments, the package or dispenser is accompanied by a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the form of the drug for administration to humans or animals. In some embodiments, such notice 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 compositions comprise a compound described herein (e.g., Compound A) formulated in a compatible pharmaceutical carrier, prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0425]

[0461] For example, a container contains Compound A, optionally in a composition or in combination with another agent described herein. Such kits optionally include an identifying description or label or instructions for its use in the methods described herein.

[0426]

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

[0427]

[0463] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container if the writing, numbers, or other characters forming the label are attached, molded, or etched onto the container itself; the label is associated with the container if the label is present within the container or carrier that holds the container (e.g., as a package insert). In one embodiment, the label is used to indicate that the contents are to be used for a particular therapeutic application. The label also indicates how to use the contents, such as in the methods described herein.

[0428]

[0464] In certain embodiments, the pharmaceutical compositions are provided in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein (e.g., Compound A). The pack comprises, for example, metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser also bears a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the drug form for administration to humans or animals. Such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In one embodiment, compositions containing a compound provided herein (e.g., Compound A) formulated in a compatible pharmaceutical carrier are also prepared, placed in a suitable container, and labeled for treatment of an indicated condition.

[0429]

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

[0430]

[0466] In certain embodiments, the deuterium analog of compound A is [ka] It is.

[0431]

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

[0432]

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

[0433]

[0469] In certain embodiments, the deuterium analog of compound A is [ka] It is.

[0434]

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

[0435]

[0471] In another aspect, described herein is Compound P, a covalent inhibitor of menin-MLL interaction, including stereoisomers, pharma- ceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases, and methods of use thereof. In certain embodiments, only one hydrogen of Compound P is replaced with deuterium. [ka]

[0436]

[0472] In another aspect, described herein are deuterium analogs of compound P and methods of use thereof as covalent inhibitors of menin-MLL interaction, including stereoisomers, pharma- ceutically acceptable solvates (including hydrates), polymorphs, and amorphous phases. In certain embodiments, only one hydrogen of compound P is replaced with deuterium. In certain embodiments, one or more hydrogens of compound P are replaced with deuterium.

[0437]

[0473] In certain embodiments, the deuterium analog of compound P is [ka] It is.

[0438]

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

[0439]

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

[0440]

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

[0441]

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

[0442]

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

[0443]

[0479] In certain embodiments, deuterium is attached at position 27, as shown above.

[0444]

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

[0445]

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

[0446]

[0482] In certain embodiments, the deuterium analog of compound P is [ka] It is. EXAMPLES

[0447] Working Example

[0483] The following ingredients, formulations, processes, and procedures for making the compounds and practicing the methods disclosed herein correspond to the compounds and methods disclosed above.

[0448] Preparation of Compound A

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

[0449]

[0485] Alternatively, compound A may be prepared according to the synthetic scheme shown below. [ka]

[0450] Example 1: Preparation of a crystalline form of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) Preparation of polymorphic pattern A

[0486] Compound A as the HCl salt was dissolved in deionized water (3.00 vol) and saturated aqueous NaHCO3 was added slowly 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 MeOH (2.00 vol). The filter cake was dried in an oven at 45° C. for 24 hours to give compound A as the free base.

[0451] Preparation of Pattern B

[0487] Compound A was dissolved in DCM:MeOH (1:1, 150 vol.) and resin (SMA-905, 50 wt.%) was added. The mixture was then stirred at 65° C. for 12 h. The mixture was then cooled to 25° C. and filtered. The filtrate was concentrated under vacuum to give compound A.

[0452] Preparation of polymorphic pattern C

[0488] Pattern C was successfully prepared using the following procedure. Approximately 200 mg of Compound A was weighed into a 4 mL glass vial. TFE (2.2 mL) was then added to the vial. The resulting suspension was kept as a slurry at 50°C for about 2 hours; the slurry was then kept stirring for about 3 days in the dark. The solids were isolated by filtration and the wet cake was examined by XRPD. The medium crystalline pattern C was obtained as a pale yellow solid. The solid was analyzed by XRPD, TGA, DSC and 1 It was further characterized by 1 H NMR.

[0453] [Table 8]

[0454] Preparation of polymorphic pattern E

[0489] Pattern E (DMSO solvate): Approximately 50 mg of compound A was equilibrated in DMSO (0.4 mL) with stirring at 25° C. After 1 day, additional DMSO (0.4 mL) was added to maintain the suspension. After equilibration for 2 weeks, the solid was isolated by centrifugal filtration to obtain Pattern E.

[0455] Preparation of polymorphic pattern G

[0490] Pattern 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 allowed to evaporate slowly at ambient temperature. After 8 days, the residual solid was analyzed by XRPD to give Pattern G.

[0456] Preparation of polymorphic pattern F

[0491] Pattern E was successfully prepared using the following procedure. Approximately 250 mg of compound A was weighed into an 8 mL glass vial. MeOH:DCM (1:1 v / v, 4 mL) was added to the vial. 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. The solids were isolated by filtration and the wet cake was examined by XRPD. Highly crystalline pattern F was obtained as a pale yellow solid. 1 It was further characterized by 1 H NMR.

[0457] [Table 9]

[0458] Preparation of Pattern Polymorph D

[0492] Pattern D, Compound A, Pattern D-Dry were successfully prepared using the following procedure. Approximately 500 mg of compound A was weighed into an 8 mL glass vial. THF:water (80:20 v / v, 8 mL) was added to the vial. The resulting suspension was stored as a slurry at 50°C for approximately 4 days in the dark. The solid was isolated by filtration and the wet cake was dried under vacuum at 50°C for approximately 3 hours. Highly crystalline pattern D was obtained as a pale yellow solid (54% yield). The dried solid was analyzed by XRPD, TGA, DSC, 1 It was further characterized by 1 H NMR, KF and DVS.

[0459] Preparation of polymorphic pattern D-1

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

[0460]

[0494] Preparation of amorphous free form by manual grinding

[0495] Amorphous free form, Pattern D-Milled-Amorphous free form was successfully prepared using the following procedure. 2 g of free form Pattern D was manually ground using a mortar and pestle for 10 minutes. 1.83 g of the amorphous free form was obtained as a pale yellow solid (yield 91.5%). The yellow powder was examined by XRPD and mDSC.

[0461] [Table 10]

[0462]

[0496] Characterization of the amorphous free form of Compound A, sample pattern D-milled-amorphous free form is reported in the table below.

[0463]

[0497] Characterization of compound A form pattern D, sample scale-up-Pattern D-THF-water-dried is reported in the table below.

[0464] [Table 11]

[0465] Preparation of polymorphic pattern J

[0498] Compound A as the HCl salt was dissolved in deionized water (3.00 vol), and saturated aqueous NaHCO3 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 vol). The filter cake was dried in an oven at 45° C. for 24 hours to give compound A as pattern J.

[0466] Example 2: X-ray Powder Diffraction (XRPD)

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

[0467] Bruker AXS C2 GADDS

[0500] Powder X-ray diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a HiStar 2D area detector. The X-ray optics consisted of a single Goebel multilayer mirror combined with a 0.3 mm pinhole collimator. Weekly performance checks were performed using certified standard NIST 1976 corundum (flat plate). The beam divergence (i.e. the effective size of the X-ray beam on the sample) was approximately 4 mm. The θ-θ continuous scan mode was used with a sample-to-detector distance of 20 cm, resulting in an effective 2θ range of 3.2° to 29.7°. Typically, samples could be exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for WNT 4.1.16, and data were analyzed and displayed using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2.

[0468]

[0501] Ambient conditions

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

[0469]

[0503] Non-ambient conditions

[0504] Samples run under non-ambient conditions were mounted on a silicon wafer with a thermally conductive compound, then heated at 10°C / min to the appropriate temperature (unless otherwise noted) and then held isothermal for 1 min before data collection began.

[0470] Bruker AXS D8 Advance

[0505] Powder X-ray diffraction patterns were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), theta-2theta goniometer and receiving slit divergence of V4, and a Ge monochromator and Lynxeye detector. The instrument is performance checked using certified corundum standards (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.5.0 and data was analyzed and displayed using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2. Samples were run under ambient conditions as flat specimens using as-received powder. Samples were gently packed into spaces cut into polished zero-background (510) silicon wafers. Samples were rotated in-plane during analysis. Details of data collection are as follows: Angle range: 2~42°2θ Step width: 0.05°2θ Acquisition time: 0.5 seconds / step

[0471] XRPD of Form A

[0506] The powder X-ray diffraction pattern of Form A is shown in Figure 1 A. Characteristic peaks include 3.5±0.1° 2-theta, 10.4±0.1° 2-theta, 14.7±0.1° 2-theta, 17.1±0.1° 2-theta, 21±0.1° 2-theta, 24.9±0.1° 2-theta, 29.5±0.1° 2-theta, and 34.1±0.1° 2-theta.

[0472] XRPD of Form B

[0507] The powder X-ray diffraction of Form B is shown in Figure 2A. Characteristic peaks include 5.9±0.1° 2-theta, 8.6±0.1° 2-theta, 10.5±0.1° 2-theta, 12.6±0.1° 2-theta, 16.9±0.1° 2-theta, 19±0.1° 2-theta, 20.5±0.1° 2-theta, and 24.6±0.1° 2-theta.

[0473] XRPD of Form C

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

[0474] XRPD of Form D

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

[0475]

[0510] After storage at 40° C. / 75% RH for 1 week or at 25° C. / 92% RH for 1 week, the crystallinity was unaffected.

[0476] XRPD of Form E

[0511] The powder X-ray diffraction pattern of Form E is shown in Figure 5A. Characteristic peaks include 3.4 ± 0.1° 2-theta, 4.7 ± 0.1° 2-theta, 6.3 ± 0.1° 2-theta, 6.9 ± 0.1° 2-theta, 7.1 ± 0.1° 2-theta, 7.6 ± 0.1° 2-theta, 8.6 ± 0.1° 2-theta, 9.3 ± 0.1° 2-theta, 10.8 ± 0.1° 2-theta, 12 ± 0.1° 2-theta, 12.5 ± 0.1° 2-theta, 13 ± 0.1° 2-theta, 13.8 ± 0.1° 2-theta, 15.7 ± 0.1° 2-theta, 16.2 ± 0.1° 2-theta, 16.7 ± 0.1° 2-theta, 17 ± 0.1° 2-theta, 1 These include 7.5±0.1° 2-theta, 18.4±0.1° 2-theta, 18.6±0.1° 2-theta, 19.6±0.1° 2-theta, 20.7±0.1° 2-theta, 21.4±0.1° 2-theta, 22.2±0.1° 2-theta, 23±0.1° 2-theta, 24.2±0.1° 2-theta, 25.3±0.1° 2-theta, 26±0.1° 2-theta, 28±0.1° 2-theta, 29.2±0.1° 2-theta, 30.5±0.1° 2-theta, 31.6±0.1° 2-theta, 33.6±0.1° 2-theta, and 34.5±0.1° 2-theta.

[0477] XRPD of Form F

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

[0478] XRPD of Form G

[0513] The powder X-ray diffraction of Form G is shown in Figure 7A. Characteristic peaks include 8±0.1° 2-theta, 10.2±0.1° 2-theta, 12.1±0.1° 2-theta, 16.8±0.1° 2-theta, 19.2±0.1° 2-theta, and 24.6±0.1° 2-theta.

[0479] XRPD of Form J

[0514] The powder X-ray diffraction of Form J is shown in Figure 8A. Characteristic peaks include 3.5 ± 0.1° 2-theta, 4.5 ± 0.1° 2-theta, 6.4 ± 0.1° 2-theta, 8.7 ± 0.1° 2-theta, 10.2 ± 0.1° 2-theta, 11.3 ± 0.1° 2-theta, 11.8 ± 0.1° 2-theta, 13.2 ± 0.1° 2-theta, 13.6 ± 0.1° 2-theta, 14 ± 0.1° 2-theta, and 14.6 ± 0.1° 2-theta. , 15.4±0.1° 2-theta, 16.1±0.1° 2-theta, 16.6±0.1° 2-theta, 16.9±0.1° 2-theta, 17.2±0.1° 2-theta, 18.3±0.1° 2-theta, 19.1±0.1° 2-theta, 20.5±0.1° 2-theta, 20.8±0.1° 2-theta, 21.6±0.1° 2-theta, 23.5±0.1° 2-theta, 23.8±0.1° 2-theta, 24.6±0.1° 2-theta, 24.9±0.1° 2-theta, 25.2±0.1° 2-theta, 25.8±0.1° 2-theta, 26.2±0.1° 2-theta, 26.7±0.1° 2-theta, 26.8±0.1° 2-theta, 27.4±0.1° 2-theta, 27.7±0.1° 2-theta, 28.7±0.1° 2-theta, 29. 3±0.1° 2-theta, 30.1±0.1° 2-theta, 31.2±0.1° 2-theta, 31.8±0.1° 2-theta, 34.1±0.1° 2-theta, 34.9±0.1° 2-theta, 35.6±0.1° 2-theta, 36.4±0.1° 2-theta, 36.7±0.1° 2-theta, 38.5±0.1° 2-theta and 38.8±0.1° 2-theta.

[0480] Simulated XRPD for Form D

[0515] A simulated XRPD pattern was generated for Form D. The simulated powder X-ray diffraction pattern for Form D is shown in Figure 4A. Characteristic peaks include 5.3 ± 0.1° 2-theta, 7 ± 0.1° 2-theta, 8.7 ± 0.1° 2-theta, 10.8 ± 0.1° 2-theta, 12.9 ± 0.1° 2-theta, 14.3 ± 0.1° 2-theta, 15.6 ± 0.1° 2-theta, 17 ± 0.1° 2-theta, 18.5 ± 0.1° 2-theta, 19.6 ± 0.1° 2-theta, 21.5 ± 0.1° 2-theta, and 24.2 ± 0.1° 2-theta.

[0481] Example 4: Fourier Transform-Infrared (FTIR)

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

[0482]

[0517] The infrared spectrum of Form D is shown in Figure 9A. Characteristic peaks observed in the infrared spectrum of Form D include at about 3332 cm -1 (No sign), approx. 2853cm -1 (No sign), approx. 1561cm -1 (No sign), approx. 1523cm -1 , approx. 1438cm -1 , approx. 1257cm -1 , 1112cm -1 and about 930 cm -1 Includes:

[0483] Example 5: Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

[0518] DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Heat capacity calibration was performed using sapphire, and energy and temperature calibrations were performed using certified indium. Typically, 0.5–3 mg of each sample was heated from 25°C to 300°C at 10°C / min in pinhole-equipped aluminum pans. A purge of dry nitrogen at 50 mL / min was maintained throughout the sample unless otherwise noted. Temperature-modulated DSC was performed using a base heating rate of 2°C / min and temperature modulation parameters 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 data were analyzed using Universal Analysis v4.4A.

[0484]

[0519] TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. The instrument was temperature calibrated using certified alumel and nickel. Typically, 3-10 mg of each sample was placed into a pre-tared aluminum DSC pan and heated at 10 °C / min from ambient to 350 °C. A nitrogen purge at 60 mL / min was maintained throughout the sample unless otherwise noted. 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.

[0485] Form A

[0520] In DSC (heating rate: 10°C / min or 20°C / min), an endotherm was observed with an onset at about 234.6°C and a peak at about 245°C.

[0486] Form C

[0521] In DSC (heating rate: 10°C / min or 20°C / min), an endotherm was observed with an onset at about 150-151°C and a peak at about 156-157°C.

[0487] Form D

[0522] In DSC (heating rate: 10°C / min or 20°C / min), an endotherm with an onset at about 260-261°C and a peak at about 273°C was observed.

[0488] Form E

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

[0489]

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

[0490]

[0525] In some embodiments, form B is greater than 95% pure by HPLC analysis. In some embodiments, form B is greater than 96% pure by HPLC analysis. In some embodiments, form B is greater than 97% pure by HPLC analysis. In some embodiments, form B is greater than 98% pure by HPLC analysis. In some embodiments, form B is greater than 99% pure by HPLC analysis. In some embodiments, form B is 97.8% pure by HPLC analysis. In some embodiments, form B is 99.8% pure by HPLC analysis.

[0491]

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

[0492]

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

[0493]

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

[0494]

[0529] In some embodiments, form F is greater than 95% pure by HPLC analysis. In some embodiments, form F is greater than 96% pure by HPLC analysis. In some embodiments, form F is greater than 97% pure by HPLC analysis. In some embodiments, form F is greater than 98% pure by HPLC analysis. In some embodiments, form F is greater than 99% pure by HPLC analysis. In some embodiments, form F is 99.4% pure by HPLC analysis.

[0495]

[0530] In some embodiments, form G is greater than 95% pure by HPLC analysis. In some embodiments, form G is greater than 96% pure by HPLC analysis. In some embodiments, form G is greater than 97% pure by HPLC analysis. In some embodiments, form G is greater than 98% pure by HPLC analysis. In some embodiments, form G is greater than 99% pure by HPLC analysis. In some embodiments, form G is 99.4% pure by HPLC analysis.

[0496] Solid Oral Dosage Forms

[0531] In some embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into a solid oral dosage form. In some embodiments, the crystallinity of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is maintained in the solid oral dosage form. In some embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into a tablet. In some embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into a pill. In some embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is formulated into a capsule. In some embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is placed in a capsule with or without excipients. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form A.In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form B. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form C. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is form 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-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is form E. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is Form F. In any of these embodiments, the crystalline N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide is a mixture of two or more crystalline forms selected from the group consisting of Form A, Form B, Form C, Form D, Form E, and Form F.

[0497] Example 6: Capsule Formulation

[0532] In one embodiment, a capsule formulation of Compound A for administration to a human is prepared using the following ingredients:

[0498] [Table 12]

[0499]

[0533] In some embodiments, the manufacturing process includes the steps of: weighing out the specified amounts of ingredients, mixing them together, adding them to an appropriate size capsule, and closing the capsule. In some embodiments, the capsules are stored at room temperature for an extended period of time until they are used.

[0500] Example 7: Compound A

[0534] The process steps for manufacturing Compound A capsules (25 mg and 100 mg) are described below (Tables 2 and 3). The API is blended with pregelatinized starch, lactose, crospovidone and colloidal silicon dioxide in a tumble blender. The blend is milled using a conical mill (to eliminate lumps). The milled blend is blended again in a tumble blender. Magnesium stearate is added and the powders are blended. The blend is roller compacted. For 100 mg capsules, extragranular pregelatinized starch is added to the granules and blended. The final blend is filled into capsules using a semi-manual process. The capsules are de-dusted / polished, inspected for metal and screened by weight.

[0501] [Table 13]

[0502] [Table 14]

[0503] Example 8: Safety and tolerability study of Compound A in chronic lymphocytic leukemia

[0535] The open-label dose escalation study of Compound A will determine the safety, tolerability, PK / PD and clinical activity of escalating doses of Compound A. When administered to adult patients (i.e., individuals aged 18 years or older) with R / R acute leukemia, including ALL, AML and acute mixed phenotype leukemia (AMPL), the compound will be administered daily in 28-day cycles using an accelerated titration design (ATD) with dose escalation according to a modified Fibonacci sequence (i.e., using increment ratios of 2.00 for the first titration, 1.67 for the second titration, 1.50 for the third titration, and 1.33 for all dose levels thereafter).

[0504]

[0536] Two separate dose escalations will be run in parallel, with the dose escalation arms (Arm A, Arm B) selectively enrolling patients not receiving (Arm A) or receiving (Arm B) drugs that inhibit cytochrome P450 3A4 (CYP3A4) activity. Following determination of the optimal biological dose (OBD), two expansion cohorts (differentiated based on whether the patient is receiving a CYP3A4 inhibitor) of approximately 12 patients each with R / R acute leukemia will be conducted in the second half of Phase 1 to further evaluate the safety and tolerability of the drug when administered at the OBD and to identify early efficacy signals. If a single OBD can be identified, a single expansion cohort of approximately 24 patients with R / R acute leukemia will be conducted.

[0505]

[0537] Compound A will be administered as an oral dose once daily on consecutive 28-day cycles. Dose will be escalated and / or expanded to the potential maximum tolerated dose to determine the optimal biological dose and recommended Phase 2 dose.

[0506]

[0538] In the second phase, patients with acute leukemia will be enrolled. Patients include those with R / R AML, ALL or AMPL, including mixed lineage leukemia gene rearrangements (MLL, also known as lysine methyltransferase 2A, KMT2A), MLL / KMT2A partial tandem duplications (MLL-PTD), PICALM-AF10 (also known as CALM-AF10) rearrangements, nucleophosmin 1 (NPM1) mutations, translocations in meningioma-1 (MN1) or CCAAT enhancer binding protein alpha (CEBP / A) mutations. Patients will receive treatment in consecutive cycles for 28 days starting on day 1. Patients will be evaluated for pharmacokinetics and pharmacodynamics throughout the study. Endpoints include complete remission, complete remission with partial hematologic recovery, overall survival and event-free survival.

[0507] Example 9: Safety and tolerability study of Compound A in chronic lymphocytic leukemia

[0539] Objective: The objective of this study was to establish 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 endpoint: Safety and tolerability of Compound A (frequency, severity and relevance of adverse events). Secondary endpoints: Pharmacokinetic / pharmacodynamic evaluation. Tumor response: Overall response rate and duration of response as defined by current guidelines for CLL and SLL (B-cell lymphoma). Eligibility: Ages 18 and older; both genders are eligible.

[0508]

[0540] Inclusion Criteria: 1. Treatment-naive group only: Men and women aged 65 years or older with a confirmed diagnosis of CLL / SLL and requiring treatment according to NCI or International Working Group guidelines 11-14. 2. Relapsed / Refractory group only: Men and women aged 18 years or older with a confirmed diagnosis of relapsed / refractory CLL / SLL that is not responding to treatment (i.e., failed 2 or more prior treatments for CLL / SLL and for CLL subjects at least one regimen must have had a purine analogue [e.g., fludarabine]). 3. Weight 40 kg or more. 4. ECOG performance status 2 or less. 5. Agreement to contraception during the study and for 30 days after the last dose of study drug if sexually active and capable of bearing children. 6. Willing and able to participate in all evaluations and procedures required by this study protocol, including swallowing capsules without difficulty. 7. Ability to understand the purpose and risks of the study and to provide signed and dated informed consent and permission to use protected health information (in accordance with state and local subject privacy regulations).

[0509]

[0541] Exclusion Criteria: 1. Life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, may compromise the subject's safety, interfere with absorption and metabolism of Compound A PO, or unduly jeopardize study outcomes. 2. Any immunotherapy, chemotherapy, radiation therapy, or experimental treatment within 4 weeks prior to first dose of study drug (corticosteroids for disease-related symptoms are permitted but require a 1-week washout prior to administration of study drug). 3. Central nervous system (CNS) involvement due to lymphoma. 4. Major surgery within 4 weeks prior to first dose of study drug. 5. Creatinine >1.5×histologic upper limit of normal (ULN); total bilirubin >1.5×ULN (unless due to Gilbert's disease); and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5×ULN unless disease-related. 6. Concomitant use of medications known to cause QT prolongation or torsades de pointes. 7. Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, second degree AV block type II, third degree block, bradycardia, and QTc > 470 msec. 8. Breast-feeding or pregnancy.

[0510] Example 10: Safety and Efficacy of Compound A in Patients with Relapsed / Refractory (R / R) Mantle Cell Lymphoma (MCL)

[0542] The primary objective of this study is to evaluate the efficacy of Compound A in relapsed / refractory (R / R) subjects with mantle cell lymphoma (MCL). A secondary objective is to evaluate the safety of a daily fixed dosing regimen of Compound A (25 or 100 mg / day in capsule form) in this population. Primary endpoint: To determine the number of participants having a response to Compound A. Secondary endpoints: Measuring the number of participants with adverse events as a measure of safety and tolerability. Measuring pharmacokinetics to help determine how the body responds to the study drug. Patient-reported outcomes (measuring the number of participants who reported outcomes in determining health-related quality of life). Eligibility: Ages 18 and older; both genders are eligible. Inclusion Criteria: Males and females aged 18 years or older. ECOG performance status ≥2. Pathologically confirmed MCL with documented overexpression of either cyclin D1 or t(11;14) and measurable disease on cross-sectional imaging ≥2 cm in longest diameter and measurable in two perpendicular dimensions. Confirmed failure to achieve at least a partial response (PR) on the most recent treatment regimen or subsequent disease progression. At least one but no more than five prior treatment regimens for MCL (Note: subjects who have received ≥2 cycles of prior treatment with bortezomib as part of a monotherapy or combination therapy regimen are considered bortezomib exposed). Willing and able to participate in all evaluations and procedures required by this study protocol, including swallowing capsules without difficulty. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and permission to use protected health information (in accordance with national and local subject privacy regulations). Major Exclusion Criteria: Chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic anticancer antibodies within 4 weeks, radioimmunoconjugates or toxin immunoconjugates within 10 ...

Claims

1. Formula (I): 【Chemical 1】 Crystalline Form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A), Crystalline Form D, having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at angles (°2-theta) selected from the group consisting of 18.5±0.1°2-theta, 19.6±0.1°2-theta, and 24.2±0.1°2-theta.

2. 10. The crystalline form D of claim 1 in a therapeutically effective amount for the treatment of cancer or diabetes in a mammal.

3. the cancer is a solid tumor, leukemia, KRAS-mutated cancer, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma, or multiple myeloma; The diabetes is type 1 or type 2 diabetes. Crystalline form D according to claim 2.

4. 3. The crystalline form D of claim 2, wherein a therapeutically effective amount of the crystalline form D 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, and 650 mg is administered to the mammal in need thereof.

5. 2. The crystalline form D of claim 1, having one, two, three, or four additional characteristic peaks at angles (°2-theta) selected from the group consisting of 3.4±0.1°2-theta, 8.7±0.1°2-theta, 10.7±0.1°2-theta, and 15.6±0.1°2-theta.

6. 2. The crystalline form D of claim 1, having four, five, or six additional characteristic peaks at angles (°2-theta) selected from the group consisting of 3.4±0.1°2-theta, 5.3±0.1°2-theta, 7±0.1°2-theta, 8.7±0.1°2-theta, 10.8±0.1°2-theta, 12.9±0.1°2-theta, 14.3±0.1°2-theta, 15.6±0.1°2-theta, and 17±0.1°2-theta.

7. 2. The crystalline form D of claim 1, having 7, 8, or 9 additional characteristic peaks at angles (°2-theta) selected from the group consisting of 3.4±0.1°2-theta, 5.3±0.1°2-theta, 6.9±0.1°2-theta, 7±0.1°2-theta, 8.7±0.1°2-theta, 10.8±0.1°2-theta, 12.9±0.1°2-theta, 14.3±0.1°2-theta, 15.6±0.1°2-theta, 17±0.1°2-theta, and 21.5±0.1°2-theta.

8. 2. The crystalline form D of claim 1, having the X-ray powder diffraction (XRPD) pattern shown in FIG. 4A.

9. Formula (I): 【Chemistry 2】 1. A method for preparing crystalline form D of N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-[[3(R)-[(1-oxo-2-propen-1-yl)amino]-1-piperidinyl]methyl]-2-pyridinecarboxamide (Compound A) of the formula: the crystalline form D has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at angles (°2-theta) selected from the group consisting of 18.5±0.1°2-theta, 19.6±0.1°2-theta, and 24.2±0.1°2-theta; The method comprises: (1) adding compound A of formula (I) to a vial containing a tetrahydrofuran:water mixture to obtain a suspension; (2) A step of forming a slurry from the suspension obtained in the step (1) at 50°C for 4 days in the dark; (3) filtering the suspension obtained in step (2) to obtain a wet cake containing crystalline form D of compound A of formula (I); and (4) drying the wet cake obtained in step (3) under vacuum at 50°C for 3 hours to obtain crystalline form D of compound A of formula (I); A method comprising:

10. 10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or diluent and crystalline form D of claim 1.

11. 11. The pharmaceutical composition of claim 10, for the treatment of cancer or diabetes in a mammal, comprising a therapeutically effective amount of said crystalline form D.

12. the cancer is a solid tumor, leukemia, KRAS-mutated cancer, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma, or multiple myeloma; The diabetes is type 1 or type 2 diabetes. The pharmaceutical composition of claim 11.

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