CRYSTALLINE FORMS OF A PYRROLOPYRIDINE COMPOUND

FIELD OF THE INVENTION

Disclosed herein are crystalline forms of a pyrrolopyridine compound, and salts solvates, and hydrates thereof, with therapeutic activity, against diseases such as cancer, and processes for making the same.

BACKGROUND OF INVENTION

CHK1 is a serine/threonine kinase that regulates cell-cycle progression and is a main factor in DNA-damage response within a cell. CHK1 inhibitors have been shown to sensitize tumor cells to a variety of genotoxic agents, such as chemotherapy and radiation. U.S. Pat. No. 8,178,131 discusses a number of inhibitors of CHK1, including the compound (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (Compound 1), which is being investigated in clinical trials for the treatment of various cancers.

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What is needed are forms of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide and its salts, solvates, and hydrates that have improved pharmaceutical properties.

SUMMARY OF INVENTION

One aspect includes crystalline forms of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, and pharmaceutical compositions, formulations and a process of manufacturing thereof.

Another aspect includes use of a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, or pharmaceutical formulation thereof in therapy.

Another aspect includes a method of treating a cancer comprising administering a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, or pharmaceutical formulation thereof to a patient in need thereof.

One aspect includes crystalline forms of an acetic acid, ethanedisulfonic acid or fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof, pharmaceutical compositions, formulations and a process of manufacturing thereof.

Another aspect includes use of a crystalline form of an acetic acid, ethanedisulfonic acid or fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof, or pharmaceutical formulation thereof in therapy.

Another aspect includes a method of treating a cancer comprising administering a crystalline form of an acetic acid, ethanedisulfonic acid or fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof, or pharmaceutical formulation thereof to a patient in need thereof.

DESCRIPTION OF FIGURES

FIG. 1 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide acetic acid salt.

FIG. 2 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid hydrate.

FIG. 3 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide fumaric acid hydrate.

FIG. 4 shows Xray physical characterization of a crystalline form (Form A) of the non-solvated free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide.

FIG. 5 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of a crystalline form (Form A) of the non-solvated free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide.

FIG. 6 shows Xray physical characterization of a crystalline form (Form B) of the non-solvated free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide.

FIG. 7 shows DSC of a crystalline form (Form B) of the non-solvated free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide.

FIG. 8 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base cyclopropyl methyl ether solvate.

FIG. 9 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base cyclopropyl methyl ether solvate.

FIG. 10 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 1,2-dichloroethane solvate.

FIG. 11 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 1,2-dichloroethane solvate.

FIG. 12 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 2-methyltetrahydrofuran solvate.

FIG. 13 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 2-methyltetrahydrofuran solvate.

FIG. 14 shows the crystal structure of the asymmetric unit of the 2-methyltetrahydrofuran solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, as determined by single crystal X-ray diffraction (SCXRD).

FIG. 15 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 1-pentanol solvate.

FIG. 16 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 1-pentanol solvate.

FIG. 17 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base pyridine solvate.

FIG. 18 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base pyridine solvate.

FIG. 19 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 1,4-dioxane solvate.

FIG. 20 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 1,4-dioxane solvate.

FIG. 21 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 2-butanol solvate.

FIG. 22 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 2-butanol solvate.

FIG. 23 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base anisole solvate.

FIG. 24 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base anisole solvate.

FIG. 25 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base 1-propanol solvate.

FIG. 26 shows the crystal structure of the asymmetric unit of the bis-ethanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, as determined by SCXRD.

FIG. 27 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base bis-ethanol solvate calculated from the SCXRD data at 100 K.

FIG. 28 shows the crystal structure of the asymmetric unit of the bis-methanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide along the crystallographic b axis, as determined by SCXRD.

FIG. 29 shows an XRPD pattern of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base bis-methanol solvate calculated from the SCXRD data at 100 K.

FIG. 30 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base methyl tert-butyl ether solvate.

FIG. 31 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base methyl tert-butyl ether solvate.

FIG. 32 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base toluene solvate.

FIG. 33 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base toluene solvate.

FIG. 34 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base butyronitrile solvate.

FIG. 35 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base butyronitrile solvate.

FIG. 36 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate.

FIG. 37 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate.

FIG. 38 shows TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate.

FIG. 39 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate.

FIG. 40 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate.

FIG. 41 shows TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate.

FIG. 42 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt.

FIG. 43 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt.

FIG. 44 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt.

FIG. 45 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt.

FIG. 46 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-benzenesulfonic acid salt.

FIG. 47 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt.

FIG. 48 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt.

FIG. 49 shows Xray physical characterization of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt anhydrate.

FIG. 50 shows DSC of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt anhydrate.

FIG. 51 shows TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt anhydrate.

FIG. 52 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide acetic acid salt.

FIG. 53 shows DSC and TGA of a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid hydrate.

FIG. 54 shows the oral absorption of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base Form A and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide maleic acid salt in PiC formulations, versus (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base in solution, in a preclinical pharmacokinetic study conducted in canines.

DETAILED DESCRIPTION OF INVENTION

The term “a” as used herein means one or more.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se and in one embodiment plus or minus 20% of the given value. For example, description referring to “about X” includes description of “X”.

A “hydrate” refers to an association or complex of one or more water molecules and a compound of the invention.

Compounds of the present invention, unless otherwise indicated, include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of the present invention, wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by a ¹³C or ¹⁴C carbon atom, or one or more nitrogen atoms are replaced by a ¹⁵N nitrogen atom, or one or more sulfur atoms are replaced by a ³³S, ³⁴S or ³⁶S sulfur atom, or one or more oxygen atoms are replaced by a ¹⁷O or ¹⁸O oxygen atom are within the scope of this invention.

It has been unexpectedly discovered that isolating (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and salts, solvates, and hydrates thereof, from particular solvents produces different physical forms of the compound, and that the different forms have different pharmaceutical properties. It has been found that certain forms have improved properties useful for formulating the compound into stable drug forms for treating diseases such as cancer.

Therefore, one aspect includes crystalline forms of an acetic acid, ethanedisulfonic acid or fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof, pharmaceutical compositions, formulations and a process of manufacturing thereof.

Another aspect includes crystalline form of an acetic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, pharmaceutical compositions, formulations and a process of manufacturing thereof.

Another aspect includes crystalline form of an ethanedisulfonic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof, pharmaceutical compositions, formulations and a process of manufacturing thereof.

Another aspect includes crystalline form of a fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof, pharmaceutical compositions, formulations and a process of manufacturing thereof.

Another aspect includes a tablet formulation, comprising a crystalline form of an acetic acid, ethanedisulfonic acid or fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof and a process of manufacturing thereof.

Another aspect includes crystalline forms of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide acetic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide fumaric acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide cyclopropyl methyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,2-dichloroethane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-methyltetrahydrofuran solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-pentanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide pyridine solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,4-dioxane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-butanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide anisole solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-propanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-ethanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide methyl tert-butyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide toluene solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-benzenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide maleic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide HBr salt methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HCl salt; and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HBr salt; and pharmaceutical compositions, formulations and a process of manufacturing thereof.

Another aspect includes a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; and pharmaceutical compositions, formulations and a process of manufacturing thereof. In some embodiments, the crystalline form is Form A. In some embodiments, the crystalline form is Form B.

Another aspect includes a composition comprising a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, and a solvent selected from: cyclopropyl methyl ether, 1-pentanol, 2-butanol, anisole, 1-propanol, ethanol, methanol, and methyl tert-butyl ether.

Another aspect includes a tablet formulation, comprising a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide acetic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide fumaric acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide cyclopropyl methyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,2-dichloroethane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-methyltetrahydrofuran solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-pentanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide pyridine solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,4-dioxane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-butanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide anisole solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-propanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-ethanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide methyl tert-butyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide toluene solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-benzenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide maleic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide HBr salt methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HCl salt; and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HBr salt; and a process of manufacturing thereof.

Another aspect includes a tablet formulation, comprising a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; and a process of manufacturing thereof. In some embodiments, the crystalline form is Form A. In some embodiments, the crystalline form is Form B.

Methods of Treatment with Crystalline Form of the Present Invention

The compounds described herein can be used as therapeutic agents for treating diseases.

In one embodiment, compounds of the present invention can be used for the treatment of hyperproliferative disorders, including cancers of the following categories: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung, small cell lung; (3) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); (4) Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); (5) Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; (7) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme. oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8) Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (9) Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin: advanced melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; (11) Adrenal glands: neuroblastoma; (12) Breast: metastatic breast; breast adenocarcinoma; (13) Colon; (14) Oral cavity; (15) Hairy cell leukemia; (16) Head and neck; (17) and others including refractory metastatic disease; Kaposi's sarcoma; Bannayan-Zonana syndrome; and Cowden disease or Lhermitte-Duclos disease, among other kinds of hyperproliferative disorders. In one example, the disease is triple negative breast cancer.

Accordingly, another aspect of this invention provides a method of treating diseases or medical conditions in a mammal, comprising administering to said mammal one or more crystalline forms of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide acetic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide fumaric acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide cyclopropyl methyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,2-dichloroethane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-methyltetrahydrofuran solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-pentanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide pyridine solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,4-dioxane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-butanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide anisole solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-propanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-ethanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide methyl tert-butyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide toluene solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-benzenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide maleic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide HBr salt methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HCl salt; and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HBr salt; in an amount effective to treat or prevent said disorder.

Accordingly, another aspect of this invention provides a method of treating diseases or medical conditions in a mammal, comprising administering to said mammal a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; in an amount effective to treat or prevent said disorder. In some embodiments, the crystalline form is Form A. In some embodiments, the crystalline form is Form B.

The phrase “effective amount” means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, an effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR).

The amount of a compound of the present invention that will correspond to such an effective amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

The terms “treat” and “treatment” refer to therapeutic treatment, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as having been diagnosed as having it by a licensed medical doctor.

As used herein, the term “mammal” refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

This invention also provides crystalline forms of the present invention for use in the treatment of CHK1 protein kinase-mediated conditions.

An additional aspect of the invention is the use of a crystalline form of the present invention in the preparation of a medicament for therapy, such as for the treatment or prevention of CHK1 protein kinase-mediated conditions.

One aspect of the present invention relates to a method of treating a disease or disorder modulated by CHK1, comprising administering a crystalline form of the present invention, or pharmaceutical formulation thereof, to a patient in need thereof. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma.

Another aspect of the present invention relates to a use of a crystalline form of the present invention, in the manufacture of a medicament for treating a disease or disorder modulated by CHK1. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma.

Another aspect of the present invention relates to a crystalline form of the present invention, or pharmaceutical formulation thereof, for use in a method of treatment of the human or animal body by therapy.

Combination Therapy

The compounds of the present invention can be used in combination with one or more additional drugs such as described below. The dose of the second drug can be appropriately selected based on a clinically employed dose. The proportion of the compound of the present invention and the second drug can be appropriately determined according to the administration subject, the administration route, the target disease, the clinical condition, the combination, and other factors. In cases where the administration subject is a human, for instance, the second drug may be used in an amount of 0.01 to 100 parts by weight per part by weight of the compound of the present invention.

The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other. Such drugs are suitably present in combination in amounts that are effective for the purpose intended. Accordingly, another aspect of the present invention provides a composition comprising a compound of this invention in combination with a second drug, such as described herein.

A compound of this invention and the additional pharmaceutically active drug(s) may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time. The amounts of the compound of this invention and the second drug(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

The combination therapy may provide “synergy” and prove “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

A “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include compounds used in “targeted therapy” and conventional chemotherapy.

Examples of chemotherapeutic agents include gemcitabine, Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNEO, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), Irinotecan (CAMPTOSAR®, Pfizer) and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASINO (exemestane; Pfizer), formestanie, fadrozole, RIVISORO (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTINO, LEUVECTINO, and VAXID®; PROLEUKINO rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTINO, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTINO, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTINO, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the PI3K inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

Accordingly one aspect of the present invention relates to a pharmaceutical formulation comprising a crystalline form of the present invention and a DNA damaging agent. In some embodiments, the DNA damaging agent is selected from: gemcitabine, irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5-FU. In some embodiments, the formulation further comprises an excipient. In some embodiments, the formulation is a tablet for oral delivery.

Another aspect of the present invention relates to a method of treating a disease or disorder modulated by CHK1, comprising administering a crystalline form of the present invention, or pharmaceutical formulation thereof, to a patient in need thereof, wherein a DNA damaging agent is also administered. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma. In some embodiments, the DNA damaging agent is selected from: gemcitabine, irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5-FU.

Another aspect of the present invention relates to a use of a crystalline form of the present invention, in the manufacture of a medicament for treating a disease or disorder modulated by CHK1, wherein the medicament further comprises a DNA damaging agent. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma. In some embodiments, the DNA damaging agent is selected from: gemcitabine, irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5-FU.

Another aspect of the present invention relates to a crystalline form of the present invention, or pharmaceutical formulation thereof, for use in a method of treating a disease or disorder modulated by CHK1, in combination with a DNA damaging agent. In some embodiments, the disease is cancer. In some embodiments, the cancer is selected from: leukemia, pancreatic cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, a refractory solid tumor, and lymphoma. In some embodiments, the DNA damaging agent is selected from: gemcitabine, irinotecan, temozolomide, capecitabine, camptothecin, cisplatin, ara-C, and 5-FU.

Routes of Administration

The compounds of the invention may be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. It will be appreciated that the preferred route may vary with for example the condition of the recipient. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.

Pharmaceutical Formulations

In order to use a compound of this invention for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition that comprises a compound of this invention. In certain embodiments, the pharmaceutical composition comprises a crystalline form of an acetic acid, ethanedisulfonic acid or fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof in association with a pharmaceutically acceptable diluent or carrier.

In certain embodiments, the pharmaceutical composition comprises a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof; in association with a pharmaceutically acceptable diluent or carrier.

In certain embodiments, the pharmaceutical composition comprises a composition comprising a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, and a solvent selected from: cyclopropyl methyl ether, 1-pentanol, 2-butanol, anisole, 1-propanol, ethanol, methanol, and methyl tert-butyl ether; in association with a pharmaceutically acceptable diluent or carrier.

In certain embodiments, the pharmaceutical composition comprises a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide acetic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide fumaric acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide cyclopropyl methyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,2-dichloroethane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-methyltetrahydrofuran solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-pentanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide pyridine solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,4-dioxane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-butanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide anisole solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-propanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-ethanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide methyl tert-butyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide toluene solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-benzenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide maleic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide HBr salt methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HCl salt; and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HBr salt; in association with a pharmaceutically acceptable diluent or carrier.

In certain embodiments, the pharmaceutical composition comprises a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; in association with a pharmaceutically acceptable diluent or carrier. In some embodiments, the crystalline form is Form A. In some embodiments, the crystalline form is Form B.

The pharmaceutical compositions of the invention are formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the disorder. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

The composition for use herein is preferably sterile. In particular, formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished, for example, by filtration through sterile filtration membranes. The compound ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.

Pharmaceutical formulations of the compounds of the present invention may be prepared for various routes and types of administration. For example, a compound of this invention having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation, a milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. The formulations may be prepared using conventional dissolution and mixing procedures.

The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The formulations may also include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of compounds of this invention may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a crystalline form of the present invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The compositions of the invention may also be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder).

Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. For example, an article for distribution can include a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The formulations may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

The amount of a compound of this invention that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. In one embodiment, a suitable amount of a compound of this invention is administered to a mammal in need thereof. Administration in one embodiment occurs in an amount between about 0.001 mg/kg of body weight to about 60 mg/kg of body weight per day. In another embodiment, administration occurs in an amount between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosage regimes, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or “kit”, containing materials useful for the treatment of the disorders described above is provided. In one embodiment, the kit comprises a container comprising a compound of this invention. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of this invention or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).

The kit may further comprise a label or package insert on or associated with the container. The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. In one embodiment, the label or package inserts indicates that the composition comprising a compound of this invention can be used to treat a disorder such as cancer. The label or package insert may also indicate that the composition can be used to treat other disorders.

In certain embodiments, the kits are suitable for the delivery of solid oral forms of a compound of this invention, such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a “blister pack”. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.

According to another embodiment, a kit may comprise (a) a first container with a compound of this invention contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound useful for treating a disorder such as cancer. Alternatively, or additionally, the kit may further comprise a third container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of the compound of this invention and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of this invention and a second pharmaceutical formulation, the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.

In certain other embodiments wherein the kit comprises a composition of this invention and a second therapeutic agent, the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container. In certain embodiments, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

Accordingly, a further aspect of this invention provides a kit for treating a disorder, wherein said kit comprises a) a first pharmaceutical composition comprising a crystalline form of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide acetic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide fumaric acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide cyclopropyl methyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,2-dichloroethane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-methyltetrahydrofuran solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-pentanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide pyridine solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,4-dioxane solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-butanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide anisole solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-propanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-ethanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide methyl tert-butyl ether solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide toluene solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-benzenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide maleic acid salt; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide HBr salt methanol solvate; (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HCl salt; and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HBr salt; and b) instructions for use.

In certain embodiments, the kit further comprises (c) a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a second compound suitable for treating the disease. In certain embodiments comprising a second pharmaceutical composition, the kit further comprises instructions for the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof. In certain embodiments, said first and second pharmaceutical compositions are contained in separate containers. In other embodiments, said first and second pharmaceutical compositions are contained in the same container.

Although the crystalline forms of an acetic acid, ethanedisulfonic acid or fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide or hydrates thereof, are primarily of value as therapeutic agents for use in mammals, they are also useful whenever it is required to control CHK1 protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents and pharmaceutical forms thereof.

Although the crystalline forms of a compound selected from: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, and pharmaceutically acceptable salts, solvates, and hydrates thereof, are primarily of value as therapeutic agents for use in mammals, they are also useful whenever it is required to control CHK1 protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents and pharmaceutical forms thereof.

Hydrates and Solvates

It is understood that when the phrase “pharmaceutically acceptable salts, solvates, and hydrates” or the phrase “pharmaceutically acceptable salt, solvate, or hydrate” is used when referring to compounds described herein, it embraces pharmaceutically acceptable solvates and/or hydrates of the compounds, pharmaceutically acceptable salts of the compounds, as well as pharmaceutically acceptable solvates and/or hydrates of pharmaceutically acceptable salts of the compounds. It is also understood that when the phrase “pharmaceutically acceptable solvates and hydrates” or the phrase “pharmaceutically acceptable solvate or hydrate” is used when referring to compounds described herein that are salts, it embraces pharmaceutically acceptable solvates and/or hydrates of such salts. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999.

Crystalline Forms

Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphs show the same properties in the liquid or gaseous state but they may behave differently in the solid state.

Besides single-component polymorphs, drugs can also exist as salts and other multicomponent crystalline phases. For example, solvates and hydrates may contain an active pharmaceutical ingredient (API) host and either solvent or water molecules, respectively, as guests. Analogously, when the guest compound is a solid at room temperature, the resulting form is often called a cocrystal. Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as pseudopolymorphs of one another.

Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.

Recently, polymorph screens of 245 compounds revealed that about 90% of them exhibited multiple solid forms. Overall, approximately half the compounds were polymorphic, often having one to three forms. About one-third of the compounds formed hydrates, and about one-third formed solvates. Data from cocrystal screens of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates. (G. P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026.)

The present invention is directed, inter alia, to crystalline forms of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide and salts, hydrates, and solvates thereof. The crystalline forms of the present invention can be identified by unique solid state signatures with respect to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and other solid state methods. Further characterization with respect to water or solvent content of the crystalline forms of the present invention can be gauged by any of the following methods for example, thermogravimetric analysis (TGA), DSC and the like. For DSC, it is known that the temperatures observed will depend upon sample purity, the rate of temperature change, as well as sample preparation technique and the particular instrument employed. Thus, the values reported herein relating to DSC thermograms can vary by about ±6° C. For desolvation events, DSC thermograms may vary by more than ±6° C. depending on instrument configuration and/or sample quantity. The values reported herein relating to DSC thermograms can also vary by about ±20 joules per gram. For XRPD, the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can often affect the 2θ values. Therefore, the peak assignments of diffraction patterns can vary by about ±0.2 °2θ. The relative intensities of the reported peaks can also vary. For TGA, the features reported herein can vary by about ±5° C. The TGA features reported herein can also vary by about ±2% weight change due to, for example, sample variation. Further characterization with respect to hygroscopicity of the crystalline form can be gauged by, for example, dynamic vapor sorption (DVS). The DVS features reported herein can vary by about ±5% relative humidity. The DVS features reported herein can also vary by about ±5% weight change.

Crystalline Form A of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

One aspect of the present invention is directed to a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide having an X-ray powder diffraction pattern comprising a peak, in terms of °2θ, at about 12.1. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 12.1, 19.9, and 19.5. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 12.1, 19.9, 19.5, 23.4, and 24.4. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 12.1, 19.9, 19.5, 23.4, 24.4, 9.7, and 29.4. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 9.7, 12.1, 16.1, 19.5, 19.9, 21.7, 23.4, 24.4, 27.0, 29.4, and 32.2. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising one or more peaks listed in Table 7. In some embodiments, the salt has an X-ray powder diffraction pattern substantially as shown in FIG. 4, wherein by “substantially” is meant that the reported peaks can vary by about ±0.2 °2θ and also that the relative intensities of the reported peaks can vary.

In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 258° C. and about 278° C. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 268° C. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 95 joules per gram. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a differential scanning calorimetry thermogram substantially as shown in FIG. 5, wherein by “substantially” is meant that the reported DSC features can vary by about ±6° C. and by about ±20 joules per gram.

In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a thermogravimetric analysis profile substantially as shown in FIG. 5, wherein by “substantially” is meant that the reported TGA features can vary by about ±5° C. and by about ±2% weight change.

Form A of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form A of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide salt can be prepared as described in Example 4. In some embodiments, Form A of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide can be prepared by heating (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide containing one or more crystalline forms other than Form A. In some embodiments, Form A of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide can be prepared by recrystallizing crystalline (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide containing one or more crystalline forms other than Form A.

Crystalline Form B of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

One aspect of the present invention is directed to a crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide having an X-ray powder diffraction pattern comprising a peak, in terms of °2θ, at about 24.3. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 24.3, 20.0, and 13.6. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 24.3, 20.0, 13.6, 23.1, and 18.4. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 24.3, 20.0, 13.6, 23.1, 18.4, 31.8, and 27.3. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising peaks, in terms of °2θ, at about 9.1, 13.6, 18.4, 18.8, 20.0, 20.9, 23.1, 24.3, 27.3, 28.8, and 31.8. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has an X-ray powder diffraction pattern comprising one or more peaks listed in Table 9. In some embodiments, the salt has an X-ray powder diffraction pattern substantially as shown in FIG. 6, wherein by “substantially” is meant that the reported peaks can vary by about ±0.2 °2θ and also that the relative intensities of the reported peaks can vary.

In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a differential scanning calorimetry thermogram comprising an endotherm with a peak between about 225° C. and about 245° C. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a differential scanning calorimetry thermogram comprising an endotherm with a peak at about 235° C. In some embodiments, the crystalline form of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide has a differential scanning calorimetry thermogram substantially as shown in FIG. 7, wherein by “substantially” is meant that the reported DSC features can vary by about ±6° C. and by about ±20 joules per gram.

Form B of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form B of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide salt can be prepared as described in Example 5. In some embodiments, Form B of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide can be prepared by heating (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide containing one or more crystalline forms other than Form B. In some embodiments, Form B of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide can be prepared by recrystallizing crystalline (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide containing one or more crystalline forms other than Form B.

EXAMPLES
General Experimental

XRPD: XRPD patterns were collected with a Rigaku SmartLab® diffractometer (Rigaku Corp., Tokyo, Japan), using an incident beam of Cu Kα (1.541904 Å) radiation generated using Cross Beam optics (40 kV×44 mA). Powder samples were packed using the top fill method onto zero-background holders and scans were acquired at a scan speed of 1° or 3.0°/min and step size of 0.02 or 0.04° 20 over 2-40 °2θ range in the bragg-brentano or parallel beam configuration (reflection geometry). Data was analyzed using commercial software (JADE®, version 9, Materials Data Inc., Livermore, Calif.).

XRPD data were also obtained using a Rigaku MiniFlexII (Rigaku Corp., Tokyo, Japan) diffractometer. The radiation used was CuKα (1.541837 Å) with voltage and current of 30 kV and 15 mA. Data was collected at ambient temperature from 2.0 to 40.0 °2θ using a step size of 0.020°. A low background sample holder was used and the stage was rotated at a revolution time of 1.0 seconds. The incident beam path was equipped with a 0.02 rad soller slit, 15 mm mask, 4° fixed anti-scatter slit and a programmable divergence slit. The diffracted beam was equipped with a 0.02 rad soller slit, programmable anti-scatter slit and a 0.02 mm nickel filter.

DSC general conditions: DSC analysis was conducted on a TA Instruments Q100 or Q2000 instrument. A sample size of approximately 1-5 mg was weighed out into a standard DSC pan; the pan was crimped. The sample was heated at 10° C./min from ambient temperature to 250-300° C. under dry nitrogen at 50 mL/min.

TGA general conditions: TGA was conducted on a TA Instruments Q500 instrument. A sample size of approximately 1-10 mg was used in a standard pan. The sample was heated at 10°/min from ambient temperature to 250-350° C. under dry nitrogen at 25 mL/min.

Example 1

Acetic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (104 mg) was suspended in ethyl acetate (15 mL). Acetic acid (1.32 mL of a 0.2 mol/L solution in ethyl acetate) was added. The suspension was stirred for 1 week and the solid isolated by centrifugation and then analyzed. The physical properties of the non-solvated acetic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 1 below.

TABLE 1

XRPD
FIG. 1: Peaks of ≥40% relative height at about 6.1,

14.0, 63.4, 18.3, 20.4, 20.9, 22.9, 24.3, 25.3, 25.5,

25.9, 26.5, and 28.8 °2θ.

DSC
FIG. 52: Endotherm with extrapolated onset temperature

about 115° C. Endotherm at about 167° C. Endotherm with

extrapolated onset temperature about 260° C.

TGA
FIG. 52: About 16.6% weight loss up to about 220° C.

Certain XRPD diffraction peaks for the non-solvated acetic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 2 below.

TABLE 2

SCAN: 3.0055/39.9125/0.013/1 (sec), Cu, I (p) = 2941, 02/17/16 10:23 a

PEAK: 27 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
6.100
14.4774
694
1165
60.5
16310
46.5
0.155

2
9.816
9.0030
851
173
9.0
6372
18.2
0.407

3
10.191
8.6725
867
187
9.7
6521
18.6
0.385

4
12.923
6.8447
992
519
27.0
9460
27.0
0.201

5
13.576
6.5172
1005
204
10.6
5852
16.7
0.317

6
13.992
6.3242
1016
1925
100.0
25674
73.2
0.147

7
15.358
5.7649
1121
173
9.0
1882
5.4
0.120

8
16.239
5.4538
1097
1220
63.4
14429
41.1
0.131

9
17.203
5.1505
1169
321
16.7
3570
10.2
0.123

10
17.903
4.9505
1127
485
25.2
14808
42.2
0.338

11
18.282
4.8488
1172
1063
55.2
17346
49.4
0.180

12
19.097
4.6436
1148
396
20.5
5437
15.5
0.152

13
19.659
4.5122
1148
422
21.9
4810
13.7
0.126

14
20.387
4.3526
1150
998
51.8
17658
50.3
0.195

15
20.633
4.3013
1137
570
29.6
14078
40.1
0.273

16
20.894
4.2480
1134
880
45.7
17205
49.0
0.216

17
22.049
4.0281
1131
418
21.7
9363
26.7
0.248

18
22.908
3.8791
1132
973
50.5
20919
59.6
0.238

19
23.234
3.8253
1130
453
23.5
12979
37.0
0.317

20
24.066
3.6948
1134
404
21.0
16578
47.2
0.453

21
24.274
3.6638
1136
797
41.4
23288
66.4
0.323

22
24.508
3.6293
1138
475
24.6
14708
41.9
0.343

23
25.275
3.5209
1223
1577
81.9
35093
100.0
0.246

24
25.482
3.4927
1260
842
43.7
33509
95.5
0.440

25
25.913
3.4356
1180
1010
52.5
21026
59.9
0.230

26
26.250
3.3923
1180
632
32.8
14662
41.8
0.256

27
26.508
3.3598
1258
1294
67.2
21508
61.3
0.184

28
27.340
3.2595
1129
344
17.9
4394
12.5
0.141

29
27.771
3.2098
1138
639
33.2
9239
26.3
0.160

30
28.096
3.1735
1144
758
39.4
13673
39.0
0.199

31
28.784
3.0991
1120
1265
65.7
23997
68.4
0.210

32
29.148
3.0613
1096
401
20.9
7285
20.8
0.201

33
29.860
2.9898
1074
149
7.8
1872
5.3
0.139

34
30.228
2.9543
1068
370
19.2
6364
18.1
0.190

35
30.891
2.8923
1066
288
14.9
6602
18.8
0.254

36
31.619
2.8274
1064
111
5.8
3061
8.7
0.303

37
31.918
2.8016
1058
349
18.1
14746
42.0
0.467

38
32.255
2.7731
1053
376
19.5
14746
42.0
0.433

39
33.180
2.6978
1034
220
11.4
3939
11.2
0.198

40
34.050
2.6309
1011
274
14.2
3721
10.6
0.150

41
34.711
2.5823
1009
262
13.6
4729
13.5
0.199

42
35.338
2.5379
1036
241
12.5
3668
10.5
0.168

43
35.892
2.5000
1053
187
9.7
2440
7.0
0.144

44
36.481
2.4610
1040
109
5.7
2427
6.9
0.245

45
37.118
2.4202
1034
699
36.3
16168
46.1
0.255

46
37.442
2.3999
1008
369
19.2
12498
35.6
0.374

47
38.225
2.3526
990
158
8.2
1605
4.6
0.112

48
39.315
2.2898
985
248
12.9
5004
14.3
0.223

Example 2 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide ethanedisulfonic acid hydrate

Method A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (101 mg) was suspended in ethyl acetate (15 mL). 1,2-Ethanedisulfonic acid (54.5 mg) was added and the suspension stirred for 1 day. The solid was isolated via centrifugation and then analyzed.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (˜15 g) was weighed into a 250 mL round-bottom flask, and then 230 mL of isopropanol was added. 1.0 equivalent of 1,2-ethanedisulfonic acid was slowly added into the sample. Then the suspension was kept stirring on a magnetic stirrer at room temperature for 24 hrs. After that, acetone was added in order to obtain more solid precipitation. The solid was isolated by vacuum filtering. The sample was purified with acetone and dried under reduced pressure at 40° C. overnight.

The physical properties of the hydrate of the ethanedisulfonic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 3 below.

TABLE 3

XRPD
FIG. 2: Peaks of ≥25% relative height at about 10.6, 11.7, 14.2,

17.6, 21.2, 21.8, 22.2, 22.5, 22.7, and 23.4 °2θ.

DSC
FIG. 53: Endotherm with extrapolated onset temperature about

87° C. and enthalpy of fusion about 77 J/g. Exotherm with

extrapolated onset temperature about 262° C.

TGA
FIG. 53: About 4.7% weight loss up to about 200° C.

Certain XRPD diffraction peaks for the non-solvated acetic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 4 below.

TABLE 4

SCAN: 3.0055/39.9125/0.013/1 (sec), Cu, I (p) = 4426, 02/17/16 10:25 a

PEAK: 21 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
5.852
15.0910
253
842
20.2
8732
18.4
0.115

2
8.984
9.8353
176
976
23.4
9148
19.2
0.104

3
10.595
8.3429
150
2638
63.3
25074
52.7
0.105

4
11.664
7.5805
148
1208
29.0
13250
27.9
0.121

5
12.650
6.9917
151
568
13.6
4978
10.5
0.097

6
13.471
6.5675
151
770
18.5
7647
16.1
0.110

7
14.185
6.2386
159
1114
26.7
11881
25.0
0.118

8
14.420
6.1374
164
256
6.1
3313
7.0
0.143

9
14.564
6.0771
153
247
5.9
3204
6.7
0.143

10
14.966
5.9150
167
777
18.6
15063
31.7
0.214

11
15.251
5.8048
168
373
9.0
5951
12.5
0.176

12
15.861
5.5829
159
952
22.9
8560
18.0
0.099

13
16.580
5.3424
164
66
1.6
491
1.0
0.083

14
17.021
5.2052
174
396
9.5
3968
8.3
0.111

15
17.591
5.0376
170
1354
32.5
15602
32.8
0.127

16
18.008
4.9219
174
404
9.7
5003
10.5
0.137

17
18.775
4.7225
205
557
13.4
6628
13.9
0.131

18
19.099
4.6432
204
379
9.1
3128
6.6
0.091

19
19.556
4.5358
224
587
14.1
6092
12.8
0.115

20
20.310
4.3689
259
225
5.4
2367
5.0
0.116

21
20.750
4.2772
223
320
7.7
4646
9.8
0.160

22
21.180
4.1915
259
4167
100.0
47577
100.0
0.126

23
21.466
4.1362
271
1028
24.7
22820
48.0
0.245

24
21.791
4.0753
271
3268
78.4
35338
74.3
0.119

25
22.207
3.9999
271
2079
49.9
28983
60.9
0.154

26
22.520
3.9450
271
1462
35.1
25680
54.0
0.194

27
22.740
3.9073
319
2256
54.1
33384
70.2
0.163

28
23.220
3.8275
271
394
9.4
7175
15.1
0.201

29
23.441
3.7919
260
1291
31.0
17720
37.2
0.152

30
23.818
3.7328
244
711
17.1
9284
19.5
0.144

31
24.025
3.7011
235
406
9.7
9318
19.6
0.253

32
24.482
3.6330
212
71
1.7
967
2.0
0.151

33
24.975
3.5624
197
361
8.7
4695
9.9
0.144

34
25.431
3.4996
195
126
3.0
1843
3.9
0.161

35
25.795
3.4510
194
156
3.8
5399
11.3
0.382

36
26.016
3.4223
194
561
13.5
11498
24.2
0.227

37
26.470
3.3645
204
233
5.6
2224
4.7
0.106

38
27.159
3.2807
184
792
19.0
21785
45.8
0.304

39
27.367
3.2562
179
973
23.4
19943
41.9
0.226

40
27.628
3.2260
172
234
5.6
3971
8.3
0.188

41
28.342
3.1464
181
556
13.4
8623
18.1
0.171

42
28.797
3.0977
162
232
5.6
5833
12.3
0.278

43
29.044
3.0719
163
117
2.8
1995
4.2
0.189

44
29.344
3.0413
195
166
4.0
1988
4.2
0.133

45
29.941
2.9819
163
696
16.7
10780
22.7
0.171

46
30.486
2.9299
161
215
5.2
7550
15.9
0.388

47
30.762
2.9042
155
122
2.9
6641
14.0
0.601

48
31.125
2.8711
158
50
1.2
1532
3.2
0.339

49
31.384
2.8480
149
77
1.8
1532
3.2
0.220

50
32.099
2.7862
146
177
4.2
8796
18.5
0.550

51
32.424
2.7590
149
289
6.9
9870
20.7
0.377

52
32.932
2.7176
159
47
1.1
802
1.7
0.187

53
33.286
2.6895
164
104
2.5
2741
5.8
0.290

54
33.543
2.6695
164
117
2.8
3361
7.1
0.318

55
33.971
2.6369
171
215
5.2
4667
9.8
0.240

56
34.255
2.6156
188
46
1.1
476
1.0
0.114

57
34.673
2.5850
175
304
7.3
4597
9.7
0.167

58
35.053
2.5579
163
180
4.3
4641
9.8
0.285

59
35.271
2.5425
157
94
2.3
3419
7.2
0.402

60
36.246
2.4764
144
116
2.8
2631
5.5
0.251

61
36.705
2.4464
147
65
1.6
2488
5.2
0.423

62
37.246
2.4121
146
212
5.1
7887
16.6
0.410

63
37.508
2.3959
146
112
2.7
4546
9.6
0.449

64
38.235
2.3520
145
105
2.5
4349
9.1
0.457

65
38.418
2.3412
144
247
5.9
7053
14.8
0.315

66
38.743
2.3223
142
242
5.8
6371
13.4
0.290

Example 3

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide fumaric acid salt hydrate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (102 mg) was suspended in ethyl acetate (15 mL). Fumaric acid (34.5 mg) was added and the suspension stirred for 1 day. The solid was isolated by centrifugation and dried at room temperature under vacuum. The solid was exposed to 100% RH at room temperature for 3 days and then analyzed.

The physical properties of the hydrate of the fumaric acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 5 below.

TABLE 5

XRPD
FIG. 3.

Example 4

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide Form A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (28.6 mg) was dissolved in propyl acetate (6 mL) in a 20 mL vial. The material was allowed to evaporate at ambient to give Form A. Form A is a non-solvated crystalline form of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide. The physical properties of Form A are summarized in Table 6 below.

TABLE 6

Aqueous
0.1N HCl: 49.9; FedSIF pH 5: 10.2; FasSIF pH 6.8: 2.4;

Solubility
H₂O: 0.12

(mg/mL)

XRPD
FIG. 4: Peaks of ≥10% relative height at about 9.7, 12.1,

16.1, 19.5, 19.9, 21.7, 23.4, 24.4, 27.0, 29.4, and 32.2 °2θ.

DSC
FIG. 5: Endotherm with extrapolated onset temperature about

268° C. and enthalpy of fusion about 95 J/g.

TGA
FIG. 5: No weight loss until melt/degradation.

Certain XRPD diffraction peaks for (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide Form A are shown in Table 7 below.

TABLE 7

SCAN: 4.0/40.0/0.04/1 (sec), Cu (40 kV, 44 mA), I (p) = 5467,

01/12/16 02:48 p

PEAK: 11 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
9.371
9.4294
216
297
5.6
2546
12.2
0.291

2
9.677
9.1324
214
935
17.8
5164
24.8
0.188

3
12.146
7.2807
199
5268
100.0
18551
89.0
0.120

4
12.660
6.9864
215
185
3.5
1159
5.6
0.213

5
14.873
5.9517
174
302
5.7
1295
6.2
0.146

6
16.061
5.5138
168
876
16.6
4268
20.5
0.166

7
18.828
4.7094
171
416
7.9
1536
7.4
0.125

8
19.452
4.5596
211
2846
54.0
13626
65.4
0.163

9
19.932
4.4510
223
5108
97.0
20846
100.0
0.139

10
21.681
4.0957
217
578
11.0
2871
13.8
0.169

11
21.927
4.0502
215
250
4.8
1499
7.2
0.204

12
22.807
3.8959
217
225
4.3
907
4.4
0.137

13
23.396
3.7992
216
2195
41.7
10647
51.1
0.165

14
24.435
3.6400
209
1372
26.0
5520
26.5
0.137

15
25.480
3.4929
194
186
3.5
606
2.9
0.111

16
26.341
3.3807
191
91
1.7
291
1.4
0.109

17
27.011
3.2983
182
673
12.8
3405
16.3
0.172

18
28.173
3.1649
187
112
2.1
514
2.5
0.157

19
29.008
3.0757
206
407
7.7
2359
11.3
0.197

20
29.364
3.0392
188
890
16.9
5866
28.1
0.224

21
29.752
3.0004
190
144
2.7
1708
8.2
0.402

22
30.891
2.8923
182
288
5.5
1054
5.1
0.124

23
32.211
2.7768
206
880
16.7
5107
24.5
0.197

24
32.724
2.7344
204
99
1.9
1591
7.6
0.547

25
35.973
2.4945
163
118
2.2
755
3.6
0.218

26
36.313
2.4719
165
119
2.3
865
4.1
0.246

27
36.981
2.4288
171
83
1.6
1024
4.9
0.421

28
37.363
2.4048
178
181
3.4
2093
10.0
0.393

29
37.719
2.3830
183
90
1.7
532
2.5
0.202

30
38.517
2.3354
206
101
1.9
993
4.8
0.334

31
39.196
2.2965
219
52
1.0
881
4.2
0.575

Example 5

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide Form B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (24.6 mg) was dissolved in ethyl formate (5 mL) in a 20 mL scintillation vial at room temperature. The solution was filtered and placed into a clean 20 mL scintillation vial. The vial top was left open and the solution evaporated under ambient conditions. The sample could be heated to 130° C. in a TGA under nitrogen (10° C./min to 140° C. and then cooled to ambient) to remove solvent. Form B is a non-solvated crystalline form of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide. The physical properties of Form B are summarized in Table 8 below.

TABLE 8

XRPD
FIG. 6: Peaks of ≥25% relative height at about 9.1, 13.6,

18.4, 18.8, 20.0, 20.9, 23.1, 24.3, 27.3, 28.8, and 31.8 °2θ.

DSC
FIG. 7: Endotherm at about 235° C.

Certain XRPD diffraction peaks for (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, Form B are shown in Table 9 below.

TABLE 9

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 317.0,

11/02/12 01:49 p

PEAK: 25 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
9.102
9.7081
21
61
25.4
599
10.1
0.166

2
10.460
8.4505
23
31
12.9
294
5.0
0.161

3
12.341
7.1662
22
39
16.4
609
10.3
0.263

4
13.561
6.5242
25
195
80.9
2610
44.1
0.228

5
15.338
5.7721
27
37
15.4
778
13.1
0.356

6
16.303
5.4326
33
35
14.3
829
14.0
0.408

7
18.439
4.8079
53
89
37.0
1999
33.8
0.381

8
18.838
4.7070
53
62
25.8
1141
19.3
0.312

9
19.081
4.6475
56
55
22.6
2027
34.2
0.631

10
20.000
4.4359
56
212
87.7
5919
100.0
0.476

11
20.678
4.2920
56
60
24.7
1860
31.4
0.531

12
20.923
4.2423
56
70
28.8
1226
20.7
0.300

13
22.339
3.9765
87
58
24.1
922
15.6
0.270

14
23.062
3.8534
85
115
47.6
1770
29.9
0.262

15
24.279
3.6629
76
241
100.0
5108
86.3
0.360

16
24.858
3.5790
83
55
23.0
1381
23.3
0.424

17
27.320
3.2617
72
74
30.7
875
14.8
0.201

18
28.839
3.0933
69
61
25.3
1466
24.8
0.409

19
31.783
2.8132
71
78
32.3
1977
33.4
0.431

20
33.143
2.7008
70
51
21.1
1016
17.2
0.340

21
38.416
2.3413
63
43
17.9
1171
19.8
0.460

22
38.857
2.3157
62
29
12.1
777
13.1
0.453

Example 6 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide cyclopropyl methyl ether solvate

Method A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (27.2 mg) was dissolved in cyclopentyl methyl ether (7.5 mL) in a 20 mL scintillation vial at room temperature. The solution was filtered and placed into a clean 20 mL scintillation vial. The vial top was left open and the solution evaporated under ambient conditions.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was dissolved at 200 mg/mL in pyridine 65° C. The solution was diluted to 10 mg/mL with cyclopentyl methyl ether and cooled from 65° C. to 10° C. over 14.5 h. The mixture was allowed to evaporate until dry to yield the cyclopentyl methyl ether solvate.

The physical properties of the cyclopropyl methyl ether solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 10 below.

TABLE 10

XRPD
FIG. 8: Peaks of ≥10% relative height at about 9.9, 10.6, 12.1,

15.2, 18.9, 19.8, 21.8, 22.7, 23.1, 26.0, 29.9, 31.8, and

37.1 °2θ.

DSC
FIG. 9: Endotherm with extrapolated onset temperature about

80° C. and enthalpy of fusion about 13 J/g. Endotherm with

extrapolated onset temperature about 262° C. and enthalpy of

fusion about 64 J/g.

TGA
FIG. 9: About 3.0% weight loss up to about 160° C.

Certain XRPD diffraction peaks for the cyclopropyl methyl ether solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 11 below.

TABLE 11

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 1048,

10/24/12 11:28 a

PEAK: 27 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
9.877
8.9479
61
280
30.0
3364
14.7
0.204

2
10.600
8.3391
105
671
71.9
18612
81.5
0.471

3
12.119
7.2971
85
94
10.1
927
4.1
0.168

4
15.160
5.8396
100
167
17.9
3160
13.8
0.321

5
18.860
4.7014
114
934
100.0
22831
100.0
0.416

6
19.802
4.4800
141
882
94.5
13810
60.5
0.266

7
21.803
4.0730
132
114
12.2
2233
9.8
0.333

8
22.236
3.9946
163
93
9.9
4418
19.4
0.809

9
22.681
3.9172
116
230
24.6
10284
45.0
0.760

10
23.057
3.8542
116
143
15.3
5002
21.9
0.594

11
23.863
3.7259
114
55
5.8
1557
6.8
0.486

12
24.302
3.6595
112
69
7.4
1557
6.8
0.385

13
26.001
3.4242
109
335
35.8
9055
39.7
0.460

14
27.944
3.1903
111
72
7.7
975
4.3
0.231

15
28.377
3.1426
110
37
4.0
1889
8.3
0.862

16
28.943
3.0824
120
52
5.5
619
2.7
0.204

17
29.919
2.9840
109
228
24.5
2837
12.4
0.211

18
31.783
2.8132
96
195
20.9
3113
13.6
0.272

19
36.603
2.4530
75
54
5.8
780
3.4
0.246

20
37.119
2.4201
69
121
13.0
3293
14.4
0.463

Example 7 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,2-dichloroethane solvate

Method A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (29.8 mg) was dissolved in 1,2-dichloroethane (4 mL) in a 20 mL scintillation vial at room temperature. The solution was filtered and placed into a clean 20 mL scintillation vial. The vial top was left open and the solution evaporated under ambient conditions.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was dissolve at 33.3 mg/mL in 2:1 (v/v) 1,2-dichloroethane:methanol at 65° C. The solution was cooled from 65° C. to 10° C. over 14.5 h, then evaporated to until dry to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,2-dichloroethane solvate.

The physical properties of the 1,2-dichloroethane solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 12 below.

TABLE 12

XRPD
FIG. 10: Peaks of ≥12% relative height at about 8.6, 9.9, 15.8,

17.3, 19.9, 21.3, 21.8, 23.6, 25.1, 26.0, 27.1, 31.5, and

31.9 °2θ.

DSC
FIG. 11: Endotherm with extrapolated onset temperature about

103° C. and enthalpy of fusion about 56 J/g. Endotherm with

extrapolated onset temperature about 254° C. and enthalpy of

fusion about 42 J/g.

TGA
FIG. 11: About 11.6% weight loss up to about 145° C.

Certain XRPD diffraction peaks for the 1,2-dichloroethane solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 13 below.

TABLE 13

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 1112,

10/24/12 11:47 a

PEAK: 17 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
8.635
10.2324
9
131
12.2
1439
12.8
0.186

2
9.882
8.9437
10
169
15.7
1620
14.4
0.163

3
12.612
7.0130
12
82
7.6
842
7.5
0.174

4
15.780
5.6115
17
160
14.8
1676
14.9
0.178

5
16.726
5.2960
21
85
7.9
871
7.8
0.174

6
17.258
5.1341
23
400
37.1
4107
36.6
0.175

7
18.262
4.8541
23
122
11.3
1038
9.3
0.145

8
19.042
4.6570
22
125
11.6
1327
11.8
0.180

9
19.484
4.5522
25
31
2.9
563
5.0
0.306

10
19.900
4.4579
35
676
62.7
4949
44.1
0.124

11
21.323
4.1636
30
210
19.5
2872
25.6
0.232

12
21.781
4.0772
31
135
12.6
1619
14.4
0.203

13
22.242
3.9935
43
108
10.1
954
8.5
0.150

14
23.581
3.7697
34
1078
100.0
11212
100.0
0.177

15
24.222
3.6715
40
49
4.6
387
3.5
0.134

16
25.081
3.5477
40
413
38.3
5700
50.8
0.235

17
25.999
3.4244
40
401
37.2
5083
45.3
0.215

18
27.140
3.2829
36
152
14.1
2916
26.0
0.326

19
27.378
3.2550
39
101
9.3
2062
18.4
0.348

20
27.780
3.2088
38
32
3.0
411
3.7
0.218

21
27.985
3.1858
34
62
5.8
927
8.3
0.254

22
29.258
3.0499
36
30
2.8
196
1.7
0.111

23
30.820
2.8989
52
142
13.2
1078
9.6
0.129

24
31.537
2.8346
42
270
25.1
5076
45.3
0.319

25
31.859
2.8066
35
135
12.6
3485
31.1
0.438

26
32.321
2.7676
35
85
7.8
984
8.8
0.198

27
33.336
2.6856
38
55
5.1
556
5.0
0.173

28
33.902
2.6420
42
79
7.4
750
6.7
0.161

29
34.555
2.5936
36
77
7.1
1633
14.6
0.363

30
34.937
2.5661
38
33
3.1
635
5.7
0.325

31
35.761
2.5088
35
50
4.6
1005
9.0
0.345

32
36.393
2.4667
34
34
3.2
930
8.3
0.465

33
37.981
2.3671
34
44
4.1
774
6.9
0.301

34
38.437
2.3401
40
50
4.7
1703
15.2
0.576

35
38.779
2.3203
40
45
4.2
899
8.0
0.337

36
39.277
2.2920
40
58
5.4
1190
10.6
0.347

37
39.539
2.2774
40
49
4.6
1190
10.6
0.410

Example 8

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-methyltetrahydrofuran solvate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (28.1 mg) was dissolved in 2-methyltetrahydrofuran (2 mL) in a 20 mL scintillation vial at room temperature. The solution was filtered and placed into a clean 20 mL scintillation vial. The vial top was left open and the solution evaporated under ambient conditions.

The physical properties of the 2-methyltetrahydrofuran solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 14 below.

TABLE 14

XRPD
FIG. 12: Peaks of ≥5% relative height at about 9.4, 10.5, 12.2,

18.9, 19.9, 22.9, 24.5, 26.2, 26.9, 32.0, and 37.2 °2θ.

DSC
FIG. 13: Endotherms at about 93° C. and about 266° C.

SCXRD
FIG. 14.

Certain XRPD diffraction peaks for the 2-methyltetrahydrofuran solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 15 below.

TABLE 15

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 934.0,

10/25/12 09:24 a

PEAK: 45 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
9.400
9.4009
37
258
29.0
3707
20.8
0.244

2
10.521
8.4016
109
345
38.8
17692
99.1
0.871

3
12.161
7.2723
45
889
100.0
16226
90.9
0.310

4
18.920
4.6866
71
396
44.6
17856
100.0
0.766

5
19.921
4.4535
71
410
46.1
9713
54.4
0.402

6
22.903
3.8798
119
86
9.7
2627
14.7
0.517

7
24.460
3.6363
103
449
50.5
10024
56.1
0.380

8
26.195
3.3993
125
51
5.7
2223
12.4
0.741

9
26.901
3.3116
118
92
10.3
3336
18.7
0.619

10
32.043
2.7909
72
101
11.4
1808
10.1
0.304

11
37.221
2.4137
64
100
11.3
3275
18.3
0.555

For single crystal X-ray diffraction, (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was dissolved at 500 mg/mL in 2,2,2-trifluoroethanol at 65° C. The solution was diluted to 25 mg/mL with 2-methyltetrahydrofuran and cooled from 65° C. to 10° C. over 14.5 h. Crystals for diffraction were pulled directly from resulting saturated solution. A colorless plate of C₁₆H₂₀BrN₅O having approximate dimensions of 0.20×0.20×0.12 mm was mounted on a fiber in a random orientation. Preliminary examination and data collection were performed Cu K_aradiation (1=1.54184 Å) on a Rigaku Rapid II equipped with confocal optics. The data were collected at a temperature of 150(1)K. Cell constants for data collection were obtained from least-squares refinement, using the setting angles of 35,637 reflections in the range 3<q<70°. The space group was determined by the program XPREP. There were no systematic absences; the space group was determined to be P−1(#2). A total of 35,637 reflections were collected, of which 7,284 were unique. Frames were integrated using program CrystalClear. Lorentz and polarization corrections were applied to the data. An empirical absorption correction using CrystalClear was applied. Transmission coefficients ranged from 0.425 to 0.716. Intensities of equivalent reflections were averaged. The structure was solved by direct methods using Charge Flipping in PLATON. The remaining atoms were located in succeeding difference Fourier syntheses. Hydrogen atoms were included in the refinement but restrained to ride on the atom to which they are bonded. The structure was refined in full-matrix least-squares where the function minimized was Sw(|Fo|²−|Fc|²)²and the weight w is defined as 1/[s²(Fo²)+(0.1012P)²+10.7676P] where P=(Fo²+2Fc²)/3. Scattering factors were taken from the “International Tables for Crystallography”. Residual electron density was adjusted using the SQUEEZE option in PLATON. Refinement was performed on a LINUX PC using SHELX-97. The crystal structure of the asymmetric unit of the 2-methyltetrahydrofuran solvate is shown in FIG. 14.

Example 9

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-pentanol solvate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (26.5 mg) was dissolved in 1-pentanol (1.5 mL) in a 20 mL scintillation vial at room temperature. The solution was filtered and placed into a clean 20 mL scintillation vial. The vial top was left open and the solution evaporated under ambient conditions. The physical properties of the 1-pentanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 16 below.

TABLE 16

XRPD
FIG. 15: Peaks of ≥25% relative height at about 8.6, 9.7, 15.3,

17.4, 19.5, 21.4, 22.2, 23.1, 24.1, 26.2, 27.0, and 31.4 °2θ.

DSC
FIG. 16: Endotherms at about 112° C. and about 263° C.

Certain XRPD diffraction peaks for the 1-pentanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 17 below.

TABLE 17

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 617.0,

10/25/12 09:43 a

PEAK: 21 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
8.640
10.2264
23
235
44.0
2785
42.8
0.202

2
9.462
9.3394
23
84
15.8
2453
37.7
0.494

3
9.661
9.1471
16
141
26.4
2572
39.6
0.310

4
12.041
7.3440
21
122
22.8
1531
23.5
0.214

5
15.340
5.7716
24
333
62.5
3734
57.4
0.191

6
15.764
5.6172
33
64
12.0
1008
15.5
0.267

7
16.237
5.4544
33
69
13.0
1001
15.4
0.246

8
17.381
5.0982
37
205
38.6
2300
35.4
0.190

9
18.342
4.8330
50
68
12.8
464
7.1
0.115

10
19.021
4.6620
47
82
15.4
3022
46.5
0.624

11
19.501
4.5484
51
259
48.6
5129
78.9
0.336

12
19.936
4.4500
51
66
12.4
1469
22.6
0.378

13
20.899
4.2471
51
40
7.5
455
7.0
0.193

14
21.356
4.1572
71
367
68.9
4393
67.6
0.203

15
22.160
4.0082
76
202
37.9
2975
45.8
0.250

16
23.121
3.8437
84
533
100.0
6502
100.0
0.207

17
24.101
3.6896
52
182
34.1
5195
79.9
0.485

18
26.221
3.3959
49
285
53.5
5358
82.4
0.319

19
27.036
3.2953
48
138
26.0
2228
34.3
0.274

20
29.081
3.0681
46
84
15.7
971
14.9
0.197

21
29.975
2.9786
47
27
5.1
303
4.7
0.188

22
31.437
2.8434
64
145
27.2
3730
57.4
0.438

23
32.198
2.7779
61
45
8.4
697
10.7
0.266

24
33.426
2.6786
46
32
6.1
345
5.3
0.182

25
34.101
2.6271
48
30
5.7
414
6.4
0.233

26
34.639
2.5875
47
70
13.0
1621
24.9
0.396

27
36.222
2.4780
52
59
11.1
901
13.9
0.258

28
39.557
2.2764
55
28
5.2
335
5.2
0.206

Example 10

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide pyridine solvate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (29.9 mg) was dissolved in pyridine (1 mL) in a 20 mL scintillation vial at room temperature. The solution was filtered and placed into a clean 20 mL scintillation vial. The vial top was left open and the solution evaporated under ambient conditions. The physical properties of the pyridine solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 18 below.

TABLE 18

XRPD
FIG. 17: Peaks of ≥25% relative height at about 10.8, 16.3,

18.8, 19.3, 19.6, 21.2, 21.7, 22.4, 23.0, 29.8, and 31.9 °2θ.

DSC
FIG. 18: Endotherms at about 102° C. and about 266° C.

Certain XRPD diffraction peaks for the pyridine solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 19 below.

TABLE 19

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 647.0,

10/25/12 11:01 a

PEAK: 23 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
8.203
10.7695
11
49
8.0
578
6.0
0.199

2
9.586
9.2188
13
46
7.5
597
6.2
0.219

3
10.839
8.1558
19
540
87.3
5609
57.9
0.176

4
12.503
7.0742
18
79
12.8
1064
11.0
0.228

5
14.276
6.1993
21
79
12.8
823
8.5
0.176

6
16.275
5.4418
25
163
26.4
2384
24.6
0.249

7
16.679
5.3109
28
43
6.9
417
4.3
0.165

8
18.800
4.7162
28
602
97.3
7107
73.4
0.201

9
19.320
4.5905
28
619
100.0
9214
95.1
0.253

10
19.621
4.5207
28
468
75.6
9688
100.0
0.352

11
20.102
4.4138
28
60
9.7
1044
10.8
0.297

12
21.220
4.1836
52
301
48.7
5459
56.3
0.308

13
21.682
4.0955
51
457
73.8
7775
80.3
0.289

14
22.379
3.9695
51
409
66.1
6782
70.0
0.282

15
22.999
3.8639
51
176
28.4
2551
26.3
0.247

16
23.479
3.7859
66
138
22.3
1277
13.2
0.157

17
24.041
3.6987
56
68
11.0
648
6.7
0.162

18
24.416
3.6427
54
74
11.9
1090
11.2
0.252

19
24.794
3.5880
53
30
4.8
358
3.7
0.203

20
25.262
3.5226
50
48
7.8
1454
15.0
0.514

21
25.465
3.4950
49
74
12.0
1454
15.0
0.332

22
26.559
3.3535
43
87
14.1
1883
19.4
0.367

23
27.006
3.2990
42
70
11.4
1285
13.3
0.311

24
28.059
3.1775
41
125
20.2
1668
17.2
0.226

25
28.401
3.1400
41
96
15.6
2265
23.4
0.400

26
28.858
3.0914
41
136
22.0
4122
42.5
0.514

27
29.821
2.9936
41
214
34.6
2611
26.9
0.207

28
30.442
2.9340
41
64
10.4
1514
15.6
0.400

29
30.799
2.9008
41
93
15.1
2034
21.0
0.371

30
31.301
2.8554
41
117
19.0
3950
40.8
0.572

31
31.937
2.7999
41
164
26.6
5554
57.3
0.575

32
32.740
2.7331
50
105
17.0
2400
24.8
0.388

33
34.958
2.5646
50
35
5.7
616
6.4
0.297

34
35.657
2.5159
63
62
10.0
565
5.8
0.155

35
37.263
2.4111
61
79
12.7
2159
22.3
0.466

36
37.521
2.3951
57
76
12.4
2407
24.8
0.535

37
38.661
2.3271
56
59
9.5
365
3.8
0.106

38
39.316
2.2898
66
78
12.7
2725
28.1
0.590

Example 11

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1,4-dioxane solvate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (26.1 mg) was dissolved in 1,4-dioxane (1.5 mL) in a 20 mL scintillation vial at room temperature. The solution was filtered and placed into a clean 20 mL scintillation vial. The top was covered tightly with aluminum foil and allowed to evaporate under ambient conditions. The physical properties of the 1,4-dioxane solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 20 below.

TABLE 20

XRPD
FIG. 19: Peaks of ≥25% relative height at about 11.0, 18.8,

19.4, 19.9, 20.6, 21.3, 21.7, 22.3, 26.5, 28.4, 29.4, and

31.7 °2θ.

DSC
FIG. 20: Endotherms at about 135° C. and about 265° C.

Certain XRPD diffraction peaks for the 1,4-dioxane solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 21 below.

TABLE 21

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 269.0,

10/29/12 12:11 p

PEAK: 27 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
10.960
8.0663
11
163
64.8
2125
32.9
0.221

2
12.944
6.8338
11
49
19.3
681
10.5
0.238

3
13.723
6.4478
18
46
18.2
273
4.2
0.101

4
16.860
5.2543
15
51
20.3
1010
15.6
0.335

5
18.780
4.7212
17
252
100.0
4273
66.2
0.288

6
19.359
4.5814
17
137
54.4
2719
42.1
0.337

7
19.940
4.4492
17
223
88.5
3959
61.3
0.301

8
20.600
4.3082
17
132
52.4
1977
30.6
0.254

9
21.261
4.1757
17
83
33.0
1243
19.3
0.254

10
21.743
4.0840
17
128
50.8
6259
96.9
0.829

11
22.340
3.9763
24
190
75.3
6457
100.0
0.578

12
23.557
3.7736
27
33
13.0
486
7.5
0.252

13
24.080
3.6927
26
62
24.4
991
15.3
0.274

14
25.145
3.5388
24
27
10.7
257
4.0
0.162

15
26.521
3.3581
22
71
28.1
1232
19.1
0.296

16
27.503
3.2405
22
38
15.2
696
10.8
0.309

17
28.417
3.1383
22
78
31.0
1843
28.5
0.400

18
29.420
3.0335
22
111
44.1
2614
40.5
0.399

19
31.744
2.8165
28
65
25.7
3183
49.3
0.834

20
32.419
2.7595
38
54
21.6
2453
38.0
0.766

21
34.278
2.6139
32
27
10.9
666
10.3
0.413

22
37.916
2.3710
37
40
16.0
391
6.1
0.165

23
39.314
2.2899
42
44
17.5
1121
17.4
0.431

Example 12

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 2-butanol solvate: 2-butanol (1.5 mL) and heptane (7.5 mL) were added to (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (25.9 mg). The mixture was placed in the refrigerator at approximately 5° C. for 5 days. Solvent was removed from the suspension while still cold and the material analyzed while still damp with solvent. The physical properties of the 2-butanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 22 below.

TABLE 22

XRPD
FIG. 21: Peaks of ≥20% relative height at about 8.3, 9.5,

14.5, 16.5, 18.0, 19.1, 21.5, 22.4, and 27.1 °2θ.

DSC
FIG. 22: Endotherms at about 70° C. and about 267° C.

Certain XRPD diffraction peaks for the 2-butanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 23 below.

TABLE 23

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 559.0,

11/19/12 10:19 a

PEAK: 27 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
8.279
10.6709
10
221
41.9
4905
42.6
0.377

2
8.940
9.8841
11
96
18.1
2073
18.0
0.369

3
9.502
9.3004
11
411
77.8
3632
31.6
0.150

4
11.193
7.8985
15
69
13.2
728
6.3
0.178

5
14.521
6.0948
13
393
74.6
5025
43.7
0.217

6
15.148
5.8440
13
51
9.7
861
7.5
0.285

7
16.520
5.3619
19
107
20.4
4078
35.4
0.645

8
18.018
4.9193
19
114
21.7
2948
25.6
0.438

9
19.078
4.6481
19
424
80.4
6836
59.4
0.274

10
19.721
4.4981
19
88
16.8
2054
17.8
0.395

11
21.500
4.1297
31
401
75.9
10031
87.2
0.426

12
22.379
3.9694
31
528
100.0
11508
100.0
0.371

13
24.518
3.6278
44
56
10.6
1242
10.8
0.378

14
27.078
3.2904
47
183
34.8
4405
38.3
0.408

15
28.279
3.1533
50
44
8.3
444
3.9
0.173

16
30.042
2.9721
67
81
15.4
1008
8.8
0.211

17
30.837
2.8973
69
87
16.5
1578
13.7
0.308

18
31.678
2.8222
38
92
17.4
1802
15.7
0.333

19
32.979
2.7138
38
43
8.2
1141
9.9
0.451

20
33.903
2.6419
38
53
10.0
1919
16.7
0.616

21
34.779
2.5774
38
42
8.0
1380
12.0
0.559

22
34.981
2.5629
38
51
9.7
1380
12.0
0.460

23
36.278
2.4743
54
77
14.5
2024
17.6
0.449

Example 13 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide anisole solvate

Method A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (27.6 mg) was dissolved in anisole (4 mL) at approximately 60° C. The solution was removed from the cooling block and allowed to cool to ambient. The vial was then placed into a freezer at about 18° C. and left there for 3 weeks. The solvent was removed while the sample was still cold and the solid analyzed while still damp with solvent.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was dissolved at 25 mg/mL in anisole 65° C., and cooled from 65° C. to 10° C. over 14.5 h. Solids were isolated via filtration to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide anisole solvate.

The physical properties of the anisole solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 24 below.

TABLE 24

XRPD
FIG. 23: Peaks of ≥15% relative height at about 15.6, 18.9,

19.5, 20.0, 20.7, 21.4, 22.9, 24.1, and 29.7 °2θ.

DSC
FIG. 24: Endotherm with extrapolated onset temperature about

108° C. and enthalpy of fusion about 76 J/g. Endotherm with

extrapolated onset temperature about 264° C. and enthalpy of

fusion about 68 J/g.

TGA
FIG. 24: About 13.0% weight loss up to about 140° C.

Certain XRPD diffraction peaks for the anisole solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 25 below.

TABLE 25

SCAN: 2.0/40.0/0.02/0.6 (sec), Cu (30 kV, 15 mA), I (p) = 587.0,

12/03/12 02:55 p

PEAK: 27 (pts)/Parabolic Filter, Threshold = 3.0, Cutoff = 0.1%,

BG = 3/1.0, Peak-Top = Summit

NOTE: Intensity = Counts, 2T (0) = 0.0 (deg), Wavelength to Compute

d-Spacing = 1.54059 Å (Cu/K-alpha1)

#
2-Theta
d (Å)
BG
Height
H %
Area
A %
FWHM

1
9.156
9.6509
11
62
11.0
1049
10.7
0.287

2
9.441
9.3600
15
81
14.4
1722
17.5
0.362

3
9.978
8.8576
15
35
6.2
428
4.4
0.209

4
10.678
8.2788
30
43
7.6
627
6.4
0.249

5
15.144
5.8456
31
50
8.9
1000
10.2
0.338

6
15.596
5.6771
35
105
18.7
1427
14.5
0.230

7
16.197
5.4678
37
38
6.8
314
3.2
0.139

8
16.658
5.3177
31
74
13.2
680
6.9
0.156

9
18.335
4.8349
25
23
4.1
287
2.9
0.212

10
18.919
4.6869
24
563
100.0
9835
100.0
0.297

11
19.520
4.5438
24
207
36.7
7786
79.2
0.640

12
20.002
4.4355
24
100
17.7
1811
18.4
0.309

13
20.662
4.2953
24
139
24.7
2126
21.6
0.261

14
21.400
4.1487
24
347
61.6
6203
63.1
0.304

15
22.243
3.9935
24
77
13.6
1200
12.2
0.266

16
22.901
3.8802
24
272
48.3
6568
66.8
0.411

17
24.118
3.6870
39
96
17.1
1747
17.8
0.309

18
24.503
3.6300
39
28
5.0
490
5.0
0.296

19
25.120
3.5422
38
49
8.7
505
5.1
0.175

20
27.720
3.2156
40
69
12.3
930
9.5
0.228

21
29.280
3.0477
77
80
14.1
1062
10.8
0.227

22
29.684
3.0071
69
95
16.8
1621
16.5
0.291

23
31.277
2.8575
62
61
10.8
663
6.7
0.185

24
31.550
2.8334
54
83
14.8
2800
28.5
0.572

25
32.001
2.7945
57
47
8.4
1348
13.7
0.486

26
34.279
2.6139
38
28
4.9
404
4.1
0.248

27
37.140
2.4188
51
50
8.8
566
5.8
0.194

Example 14

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide 1-propanol solvate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was suspended at 60° C. in heptane (1 mL). 1-Propanol (2 mL) was added. The solids dissolved. The solution allowed to cool to ambient. The vial was then placed into a freezer at about −18° C. and left there for 3 weeks. The solvent was removed while the sample was still cold and the solid analyzed while still damp with solvent. The physical properties of the 1-propanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 26 below.

TABLE 26

XRPD
FIG. 25: Peaks of ≥20% relative height at about 8.4, 9.4, 14.5,

17.7, 19.0, 21.5, 21.8, 22.3, 22.6, and 26.8 °2θ.

Certain XRPD diffraction peaks for the 1-propanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 27 below.

TABLE 27

SCAN: 2.0/40.0/0.02/0.6(sec), Cu(30 kV, 15 mA),

I(p) = 446.0, 12/18/12 09:44a

PEAK: 21(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
8.438
10.4709
11
172
41.3
3015
35.4
0.297

2
8.822
10.0153
14
92
22.1
1915
22.5
0.353

3
9.441
9.3603
12
233
55.7
2482
29.1
0.181

4
11.138
7.9373
12
63
15.2
697
8.2
0.187

5
14.539
6.0877
11
369
88.2
4456
52.3
0.206

6
15.179
5.8323
11
34
8.0
588
6.9
0.298

7
16.301
5.4333
19
56
13.3
792
9.3
0.242

8
16.998
5.2119
28
84
20.0
1792
21.0
0.364

9
17.740
4.9955
26
160
38.3
2012
23.6
0.214

10
18.580
4.7717
30
45
10.7
598
7.0
0.227

11
19.000
4.6672
34
268
64.1
3122
36.6
0.198

12
21.079
4.2112
24
42
10.1
498
5.8
0.201

13
21.462
4.1370
27
297
71.0
6018
70.6
0.345

14
21.842
4.0658
28
271
64.8
6637
77.9
0.417

15
22.261
3.9903
28
418
100.0
8520
100.0
0.347

16
22.641
3.9242
41
116
27.9
1302
15.3
0.190

17
24.561
3.6216
34
70
16.7
778
9.1
0.189

18
25.357
3.5096
33
25
6.0
588
6.9
0.402

19
26.841
3.3189
33
121
29.0
2977
34.9
0.417

20
27.592
3.2302
29
27
6.6
420
4.9
0.261

21
29.279
3.0478
31
37
8.9
803
9.4
0.368

22
29.902
2.9857
32
74
17.7
1288
15.1
0.295

23
30.519
2.9267
46
53
12.7
803
9.4
0.256

24
30.873
2.8940
43
45
10.7
439
5.2
0.167

25
31.678
2.8223
27
56
13.5
992
11.6
0.299

26
33.500
2.6728
34
33
8.0
674
7.9
0.343

27
34.864
2.5713
37
56
13.5
891
10.5
0.269

28
35.827
2.5044
37
25
5.9
153
1.8
0.106

29
36.161
2.4820
32
53
12.6
1338
15.7
0.433

30
39.442
2.2828
35
33
7.9
495
5.8
0.254

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 15 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-ethanol solvate

Method A: A saturated solution of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was generated at 65° C. without stirring and the sample was held at 65° C. for 24 hours. Solid consisting of plates were observed above the liquid level. The solution was cooled to room temperature.

Method B: A saturated solution of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was generated in ethanol at room temperature. The solution was subjected to vapor diffusion using water and isooctane. The vial within vials were placed in a refrigerator at about 5-10° C. to give some plates of the ethanol solvate.

A yellow plate 0.050×0.040×0.030 mm in size was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using and scans. Crystal-to-detector distance was 60 mm and exposure time was 5 seconds per frame using a scan width of 2.0°. Data collection was 98.4% complete to 67.000° in q. A total of 32,872 reflections were collected covering the indices, −11<=h<=11, −11<=k<=11, −15<=l<=15. 7,254 reflections were found to be symmetry independent, with an R_intof 0.0248. Indexing and unit cell refinement indicated a primitive, triclinic lattice. The space group was found to be P 1 (No. 1). The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by iterative methods (SHELXT-2014) produced a complete heavy-atom phasing model consistent with the proposed structure. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014. The crystal structure of the asymmetric unit for the bis-ethanol solvate is shown in FIG. 26.

The XRPD of the bis-ethanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, as calculated from the SCXRD data at 100 K, is shown in FIG. 28 and summarized in Table 28 below.

TABLE 28

XRPD
FIG. 27: Peaks of ≥30% relative height at about 9.5, 14.6,

18.0, 19.8, 20.2, 20.4, 21.7, 21.9, 22.1, 23.0, 23.7, 24.7,

and 29.7 °2θ.

Certain calculated XRPD diffraction peaks for the bis-ethanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 29 below.

TABLE 29

SCAN: 2.0/40.0/0.02/0.1(sec), Cu, I(p) = 10000, 02/05/16 11:12a

PEAK: 15(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
7.338
12.0378
8
1491
15.0
10309
13.2
0.118

2
9.537
9.2664
32
9968
100.0
78258
100.0
0.133

3
9.858
8.9651
31
2871
28.8
34398
44.0
0.204

4
11.280
7.8380
10
1190
11.9
8194
10.5
0.117

5
12.520
7.0642
10
498
5.0
3572
4.6
0.122

6
13.098
6.7536
11
584
5.9
5617
7.2
0.163

7
14.139
6.2588
35
2907
29.2
23604
30.2
0.138

8
14.557
6.0800
40
3315
33.3
29799
38.1
0.153

9
15.083
5.8691
39
2409
24.2
16922
21.6
0.119

10
16.383
5.4063
47
2000
20.1
14372
18.4
0.122

11
16.758
5.2860
53
1729
17.3
12328
15.8
0.121

12
18.000
4.9241
64
6375
64.0
42365
54.1
0.113

13
19.121
4.6378
71
2340
23.5
17156
21.9
0.125

14
19.783
4.4841
71
7857
78.8
62870
80.3
0.136

15
20.201
4.3923
71
5057
50.7
55380
70.8
0.186

16
20.399
4.3501
71
3309
33.2
38500
49.2
0.198

17
20.897
4.2475
71
1902
19.1
15605
19.9
0.139

18
21.683
4.0953
277
8971
90.0
75923
97.0
0.144

19
21.921
4.0514
277
8357
83.8
74257
94.9
0.151

20
22.141
4.0117
277
9328
93.6
77230
98.7
0.141

21
22.402
3.9655
277
2359
23.7
23831
30.5
0.172

22
22.820
3.8938
320
2037
20.4
29004
37.1
0.242

23
23.023
3.8598
251
4270
42.8
32690
41.8
0.130

24
23.663
3.7569
195
4577
45.9
40247
51.4
0.149

25
23.860
3.7263
195
757
7.6
15074
19.3
0.338

26
24.343
3.6535
109
1296
13.0
10236
13.1
0.134

27
24.679
3.6045
111
4026
40.4
34332
43.9
0.145

28
24.937
3.5677
88
2133
21.4
18544
23.7
0.148

29
25.197
3.5316
88
472
4.7
5059
6.5
0.182

30
25.539
3.4850
98
167
1.7
780
1.0
0.079

31
25.785
3.4524
101
198
2.0
864
1.1
0.074

32
26.257
3.3913
88
1728
17.3
11091
14.2
0.109

33
26.717
3.3340
88
839
8.4
5522
7.1
0.112

34
27.096
3.2882
125
851
8.5
8269
10.6
0.165

35
27.340
3.2594
85
1009
10.1
8744
11.2
0.147

36
27.598
3.2296
85
2054
20.6
21762
27.8
0.180

37
27.762
3.2108
85
2922
29.3
28601
36.5
0.166

38
28.520
3.1272
85
843
8.5
5226
6.7
0.105

39
28.862
3.0909
85
1652
16.6
13348
17.1
0.137

40
29.219
3.0540
85
600
6.0
8712
11.1
0.247

41
29.662
3.0093
85
3488
35.0
48456
61.9
0.236

42
29.858
2.9900
85
1934
19.4
37292
47.7
0.328

43
30.080
2.9684
85
830
8.3
15575
19.9
0.319

44
30.379
2.9399
85
490
4.9
5353
6.8
0.186

45
30.777
2.9028
85
2419
24.3
17572
22.5
0.124

46
31.001
2.8823
85
817
8.2
11227
14.3
0.234

47
31.260
2.8591
85
1231
12.4
13104
16.7
0.181

48
31.479
2.8396
85
1544
15.5
13371
17.1
0.147

49
31.937
2.7999
85
909
9.1
12362
15.8
0.231

50
32.439
2.7577
85
898
9.0
8322
10.6
0.158

51
32.840
2.7250
85
531
5.3
6016
7.7
0.193

52
33.222
2.6945
85
520
5.2
7051
9.0
0.230

53
33.420
2.6791
100
546
5.5
4272
5.5
0.133

54
33.880
2.6437
100
927
9.3
18600
23.8
0.341

55
34.083
2.6284
100
2063
20.7
17666
22.6
0.146

56
34.640
2.5874
102
379
3.8
4042
5.2
0.181

57
35.062
2.5572
87
2365
23.7
21954
28.1
0.158

58
35.642
2.5169
68
884
8.9
5669
7.2
0.109

59
36.101
2.4860
68
211
2.1
1117
1.4
0.090

60
36.342
2.4700
68
329
3.3
5650
7.2
0.292

61
36.879
2.4353
79
484
4.9
8151
10.4
0.286

62
37.140
2.4188
88
2015
20.2
30446
38.9
0.257

63
38.262
2.3504
88
793
8.0
9301
11.9
0.199

64
38.617
2.3296
88
573
5.7
6454
8.2
0.192

65
38.782
2.3201
108
407
4.1
15742
20.1
0.658

66
39.201
2.2963
108
1616
16.2
25916
33.1
0.273

67
39.640
2.2718
108
995
10.0
11361
14.5
0.194

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 16

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide bis-methanol solvate: X-ray quality crystals were grown from a saturated, heated methanol solution of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide followed by the slow cooling and evaporation of the solvent overnight and allowing the super saturated solution to stand for 2 months to give colorless plates.

A colorless plate 0.060×0.040×0.020 mm in size was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using phi and omega scans. Crystal-to-detector distance was 60 mm and exposure time was 10 seconds per frame using a scan width of 1.0°. Data collection was 100.0% complete to 25.000° in q. A total of 39,817 reflections were collected covering the indices, −11<=h<=11, −15<=k<=15, −21<=l<=21. 14799 reflections were found to be symmetry independent, with an R_intof 0.0383. Indexing and unit cell refinement indicated a primitive, triclinic lattice. The space group was found to be P 1 (No. 1). The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by iterative methods (SHELXT) produced a complete heavy-atom phasing model consistent with the proposed structure. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014. Absolute stereochemistry was unambiguously determined to be R at C15, C31, C47, and C63, respectively. The crystal structure of the asymmetric unit for the bis-methanol solvate along the crystallographic b axis is shown in FIG. 28.

The XRPD of the bis-methanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide, as calculated from the SCXRD data at 100 K, is shown in FIG. 30 and summarized in Table 30 below.

TABLE 30

XRPD
FIG. 29: Peaks of ≥30% relative height at about 10.1, 13.9,

14.7, 18.7, 20.1, 20.6, 21.6, 21.8, 22.2, 22.4, 23.4, and

30.8 °2θ.

Certain calculated XRPD diffraction peaks for the bis-methanol solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 31 below.

TABLE 31

SCAN: 2.0/40.0/0.02/0.1(sec), Cu, I(p) = 10000, 02/16/16 09:58a

PEAK: 15(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
7.683
11.4979
7
2372
23.8
17496
18.8
0.125

2
10.119
8.7342
31
9969
100.0
92690
99.5
0.158

3
11.259
7.8526
31
1036
10.4
6116
6.6
0.100

4
13.018
6.7953
39
372
3.7
2111
2.3
0.096

5
13.902
6.3648
65
3284
32.9
26858
28.8
0.139

6
14.682
6.0285
63
3837
38.5
40955
43.9
0.181

7
15.403
5.7478
26
636
6.4
5053
5.4
0.135

8
16.781
5.2788
26
2038
20.4
18785
20.2
0.157

9
17.041
5.1989
27
1438
14.4
15701
16.8
0.186

10
18.461
4.8023
44
1991
20.0
22827
24.5
0.195

11
18.697
4.7421
63
6269
62.9
45796
49.1
0.124

12
18.899
4.6918
72
1292
13.0
32234
34.6
0.424

13
19.460
4.5579
72
1012
10.1
9151
9.8
0.154

14
20.142
4.4050
197
6728
67.5
51107
54.8
0.129

15
20.321
4.3666
204
2615
26.2
31856
34.2
0.207

16
20.580
4.3123
214
3350
33.6
23467
25.2
0.119

17
21.281
4.1717
228
2702
27.1
46637
50.0
0.293

18
21.561
4.1183
228
7755
77.8
93202
100.0
0.204

19
21.819
4.0701
228
3497
35.1
73763
79.1
0.359

20
22.222
3.9972
228
6561
65.8
52318
56.1
0.136

21
22.460
3.9554
228
8692
87.2
77673
83.3
0.152

22
23.202
3.8306
143
2207
22.1
32991
35.4
0.254

23
23.359
3.8051
143
3085
30.9
30407
32.6
0.168

24
23.639
3.7606
143
2070
20.8
17990
19.3
0.148

25
24.159
3.6809
142
751
7.5
4274
4.6
0.097

26
24.663
3.6068
140
1438
14.4
10531
11.3
0.125

27
24.940
3.5674
139
665
6.7
4693
5.0
0.120

28
25.419
3.5012
138
823
8.3
4821
5.2
0.100

29
25.820
3.4477
138
2207
22.1
21569
23.1
0.166

30
26.182
3.4009
138
2546
25.5
25111
26.9
0.168

31
26.599
3.3485
138
902
9.0
9483
10.2
0.179

32
26.821
3.3213
138
2159
21.7
16220
17.4
0.128

33
27.222
3.2733
112
1058
10.6
8151
8.7
0.131

34
27.378
3.2550
112
584
5.9
7189
7.7
0.209

35
27.720
3.2156
112
1202
12.1
7229
7.8
0.102

36
28.421
3.1379
112
950
9.5
12173
13.1
0.218

37
28.581
3.1206
112
1805
18.1
26783
28.7
0.252

38
28.861
3.0910
112
450
4.5
10698
11.5
0.404

39
29.259
3.0498
112
1676
16.8
13308
14.3
0.135

40
29.741
3.0016
144
481
4.8
5532
5.9
0.196

41
30.419
2.9361
125
1779
17.8
34567
37.1
0.330

42
30.800
2.9007
125
3394
34.0
56300
60.4
0.282

43
31.201
2.8643
125
1522
15.3
18172
19.5
0.203

44
31.683
2.8218
125
2983
29.9
25452
27.3
0.145

45
32.178
2.7795
125
802
8.0
7982
8.6
0.169

46
32.622
2.7427
125
943
9.5
8138
8.7
0.147

47
33.097
2.7045
196
357
3.6
5065
5.4
0.241

48
33.301
2.6883
195
225
2.3
1819
2.0
0.137

49
33.643
2.6618
210
425
4.3
1684
1.8
0.067

50
33.920
2.6406.
102
384
3.9
4371
4.7
0.194

51
34.180
2.6212
102
1116
11.2
7906
8.5
0.120

52
34.483
2.5988
102
976
9.8
9291
10.0
0.162

53
35.161
2.5503
102
457
4.6
2580
2.8
0.096

54
35.700
2.5130
102
1175
11.8
17948
19.3
0.260

55
35.938
2.4969
102
1071
10.7
11373
12.2
0.180

56
36.321
2.4714
102
1077
10.8
10553
11.3
0.167

57
37.019
2.4264
88
1583
15.9
19451
20.9
0.209

58
37.401
2.4025
88
484
4.9
8511
9.1
0.299

59
38.200
2.3541
88
393
3.9
3658
3.9
0.158

60
38.381
2.3434
88
352
3.5
3050
3.3
0.147

61
38.783
2.3200
93
1910
19.2
22138
23.8
0.197

62
39.259
2.2930
93
1672
16.8
24368
26.1
0.248

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 17

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide methyl tert-butyl ether solvate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was dissolve at 200 mg/mL in pyridine at 65° C. The solution was diluted to 10 mg/mL with methyl tert-butyl ether and cooled from 65° C. to 10° C. over 14.5 h. The mixture was evaporated until dry to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide methyl tert-butyl ether solvate. The physical properties of the methyl tert-butyl ether solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 32 below.

TABLE 32

XRPD
FIG. 30: Peaks of ≥20% relative height at about

10.7, 16.0, 18.6, 19.2, 21.0, 21.5, 22.2, 23.2,

25.3, 28.1, 28.6, 29.6, and 31.8 °2θ.

DSC
FIG. 31: Endotherm with extrapolated onset temperature

about 100° C. and enthalpy of fusion about 46 J/g.

Endotherm with extrapolated onset temperature about

261° C. and enthalpy of fusion about 62 J/g.

TGA
FIG. 31: About 6.7% weight loss up to about 120° C.

Certain XRPD diffraction peaks for the methyl tert-butyl ether solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 33 below.

TABLE 33

SCAN: 2.0/40.0/0.02/0.6(sec), Cu(30 kV, 15 mA),

I(p) = 391.0, 09/21/11 10:42a

PEAK: 29(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
8.092
10.9179
14
24
6.4
149
1.2
0.105

2
9.257
9.5457
15
24
6.4
590
4.7
0.420

3
10.700
8.2614
17
374
100.0
5094
41.0
0.231

4
12.019
7.3578
18
74
19.7
1335
10.7
0.307

5
12.421
7.1204
18
73
19.4
897
7.2
0.210

6
14.077
6.2863
17
51
13.6
703
5.7
0.235

7
16.022
5.5272
19
108
28.7
2453
19.7
0.388

8
16.589
5.3395
19
28
7.4
163
1.3
0.101

9
18.620
4.7614
24
346
92.5
4890
39.3
0.240

10
19.219
4.6145
38
333
89.0
11412
91.8
0.583

11
21.023
4.2224
31
208
55.6
6035
48.6
0.493

12
21.520
4.1260
37
275
73.6
12429
100.0
0.767

13
22.179
4.0048
37
136
36.5
1548
12.5
0.193

14
22.702
3.9137
38
60
16.0
1596
12.8
0.452

15
23.218
3.8278
38
158
42.2
3401
27.4
0.366

16
24.238
3.6690
37
71
19.1
1053
8.5
0.251

17
25.338
3.5122
36
85
22.7
1394
11.2
0.279

18
26.938
3.3071
39
65
17.4
1558
12.5
0.407

19
27.840
3.2020
36
58
15.4
987
7.9
0.292

20
28.181
3.1640
36
83
22.1
1270
10.2
0.262

21
28.622
3.1163
38
106
28.4
3296
26.5
0.526

22
29.620
3.0135
44
124
33.2
1757
14.1
0.240

23
30.683
2.9115
45
39
10.4
470
3.8
0.205

24
31.320
2.8537
51
56
14.8
2833
22.8
0.868

25
31.758
2.8153
63
83
22.1
2226
17.9
0.459

26
32.621
2.7428
55
60
16.2
795
6.4
0.224

27
34.298
2.6124
31
25
6.6
347
2.8
0.240

28
35.304
2.5402
35
32
8.6
566
4.6
0.299

29
35.839
2.5035
37
31
8.4
897
7.2
0.485

30
37.345
2.4060
42
67
18.0
1778
14.3
0.449

31
39.459
2.2818
49
46
12.2
939
7.6
0.350

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 18 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide toluene solvate

Method A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (26.4 mg) was heated in toluene (5 mL) at 50° C. in a shaker block for 22 days. The sample was cooled to ambient and the solid removed and analyzed by XRPD while still damp with solvent.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (28.8 mg) was slurried in toluene (5 mL) at 25° C. in a shaker block for 24 days. The solid was removed and analyzed by XRPD while still damp with solvent.

Method C: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was dissolved at 10 mg/mL in toluene at 65° C. The solution was cooled from 65° C. to 10° C. over 14.5 h, then held at 5° C. until crystals formed. Solids were isolated via filtration to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide toluene solvate.

The physical properties of the toluene solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 34 below.

TABLE 34

XRPD
FIG. 32: Peaks of ≥20% relative height at about

12.1, 16.0, 19.4, 19.8, 21.6, 21.9, 23.3, 24.3, 29.3,

and 32.1 °2θ.

DSC
FIG. 33: Endotherm with extrapolated onset temperature

about 107° C. and enthalpy of fusion about 67 J/g.

Endotherm with extrapolated onset temperature about

266° C. and enthalpy of fusion about 91 J/g.

TGA
FIG. 33: About 11.2% weight loss up to about 140° C.

Certain XRPD diffraction peaks for the toluene solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 35 below.

TABLE 35

SCAN: 2.0/40.0/0.02/0.6(sec), Cu(30 kV,15 mA),

I(p) = 778.0, 11/12/12 02:43p

PEAK: 21 (pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
9.302
9.5000
13
99
13.0
1451
13.0
0.250

2
9.603
9.2023
13
144
18.9
1514
13.6
0.179

3
12.062
7.3312
12
239
31.4
2962
26.5
0.211

4
12.619
7.0090
13
88
11.6
1186
10.6
0.229

5
14.818
5.9737
18
114
15.0
1483
13.3
0.222

6
15.961
5.5483
19
225
29.6
3111
27.9
0.235

7
18.742
4.7306
19
137
18.1
2109
18.9
0.261

8
19.381
4.5763
19
759
100.0
11168
100.0
0.250

9
19.841
4.4711
19
460
60.6
7237
64.8
0.267

10
20.299
4.3713
19
38
5.1
908
8.1
0.402

11
21.619
4.1072
33
293
38.6
5096
45.6
0.296

12
21.860
4.0626
32
166
21.8
3411
30.5
0.350

13
22.719
3.9109
34
78
10.2
1338
12.0
0.293

14
23.318
3.8117
34
506
66.7
7880
70.6
0.265

15
24.320
3.6569
29
156
20.5
2135
19.1
0.233

16
25.399
3.5039
26
89
11.7
1051
9.4
0.202

17
26.259
3.3911
31
55
7.2
653
5.8
0.202

18
26.940
3.3069
33
122
16.0
2093
18.7
0.293

19
28.083
3.1748
30
69
9.1
1129
10.1
0.277

20
28.883
3.0887
35
124
16.4
2618
23.4
0.358

21
29.259
3.0499
52
196
25.8
3557
31.8
0.308

22
29.616
3.0139
33
74
9.7
3454
30.9
0.795

23
29.993
2.9769
33
40
5.2
535
4.8
0.228

24
30.819
2.8990
36
124
16.4
2055
18.4
0.281

25
32.139
2.7828
43
176
23.2
3535
31.6
0.341

26
32.797
2.7285
31
48
6.4
1072
9.6
0.376

27
33.021
2.7105
31
38
5.1
326
2.9
0.144

28
34.603
2.5901
29
25
3.2
434
3.9
0.300

29
35.838
2.5036
29
51
6.7
1247
11.2
0.417

30
36.176
2.4810
31
54
7.1
1247
11.2
0.391

31
37.222
2.4136
36
74
9.8
1282
11.5
0.294

32
38.458
2.3389
42
44
5.8
819
7.3
0.314

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 19

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was dissolved at 500 mg/mL in 2,2,2-trifluoroethanol at 65° C. The solution was diluted to 25 mg/mL with butyronitrile and cooled from 65° C. to 10° C. over 14.5 h. Solids were isolated via filtration to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide butyronitrile solvate. The physical properties of the butyronitrile solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 36 below.

TABLE 36

XRPD
FIG. 34: Peaks of ≥40% relative height at about

9.8, 15.7, 17.1, 19.4, 19.9, 21.3, 21.6, 22.2, 23.2,

23.4, 25.1, and 47.9 °2θ.

DSC
FIG. 35: Endotherm with extrapolated onset temperature

about 100° C. and enthalpy of fusion about 75 J/g.

Endotherm with extrapolated onset temperature about

267° C. and enthalpy of fusion about 92 J/g.

TGA
FIG. 35: About 8.5% weight loss up to about 120° C.

Certain XRPD diffraction peaks for the butyronitrile solvate of the free base of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 37 below.

TABLE 37

SCAN: 2.0/40.0/0.02/0.6(sec), Cu(30 kV, 15 mA),

I(p) = 336.0, 09/20/11 05:02p

PEAK: 21(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
8.496
10.3991
21
88
31.2
867
16.5
0.167

2
9.242
9.5611
23
29
10.2
949
18.1
0.559

3
9.840
8.9816
19
160
56.6
2402
45.7
0.256

4
12.001
7.3687
23
51
18.2
844
16.1
0.280

5
12.440
7.1095
23
71
25.3
838
16.0
0.200

6
14.677
6.0306
24
31
11.0
361
6.9
0.198

7
15.681
5.6466
32
260
92.0
2847
54.2
0.186

8
17.141
5.1688
37
137
48.5
1362
25.9
0.169

9
18.550
4.7793
37
55
19.4
671
12.8
0.208

10
18.901
4.6914
46
89
31.4
1540
29.3
0.295

11
19.358
4.5817
58
134
47.4
2791
53.1
0.355

12
19.879
4.4626
54
282
100.0
5253
100.0
0.316

13
21.257
4.1764
54
189
67.1
3225
61.4
0.290

14
21.558
4.1188
61
169
59.9
5075
96.6
0.510

15
21.840
4.0661
69
112
39.6
2629
50.1
0.400

16
22.176
4.0054
67
156
55.3
1253
23.8
0.136

17
23.218
3.8279
70
130
46.2
3182
60.6
0.415

18
23.420
3.7954
66
155
54.9
3630
69.1
0.398

19
24.877
3.5762
59
109
38.6
1542
29.4
0.241

20
25.101
3.5449
58
131
46.3
1584
30.1
0.206

21
25.916
3.4352
53
82
29.1
1257
23.9
0.260

22
26.878
3.3144
55
97
34.5
1739
33.1
0.304

23
27.299
3.2642
54
61
21.6
1367
26.0
0.380

24
28.360
3.1445
58
33
11.8
414
7.9
0.211

25
29.220
3.0538
61
29
10.2
579
11.0
0.343

26
29.796
2.9961
69
31
11.0
321
6.1
0.176

27
30.701
2.9098
67
46
16.3
380
7.2
0.140

28
31.364
2.8498
67
53
18.8
1415
26.9
0.452

29
31.705
2.8199
60
60
21.2
2242
42.7
0.638

30
32.118
2.7846
55
55
19.5
2379
45.3
0.735

31
33.740
2.6544
55
46
16.2
549
10.4
0.204

32
34.736
2.5805
55
65
23.2
532
10.1
0.138

33
36.083
2.4872
48
40
14.2
1559
29.7
0.661

34
37.424
2.4011
56
39
14.0
268
5.1
0.115

35
38.140
2.3577
57
135
47.9
1884
35.9
0.237

36
38.640
2.3283
60
39
14.0
617
11.7
0.266

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54050 Å (Cu/K-alpha1)

Example 20 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-methanesulfonic acid salt hydrate

Method A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (40 mg, 0.11 mmol) was suspended in about 1 mL of acetone. Methanesulfonic acid (0.22 mmol, 20.3 mg) was added and the resulting suspension stirred for one day. The solids were isolated by centrifugation.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (40 mg, 0.11 mmol) was dissolved in about 1 mL of tetrahydrofuran. Methanesulfonic acid (0.22 mmol, 20.3 mg) was added and the resulting suspension stirred for one day. The solids were isolated by centrifugation.

The physical properties of the hydrate of the di-mesylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 38 below.

TABLE 38

XRPD
FIG. 36: Peaks of ≥10% relative height at about 4.4,

6.2, 6.7, 8.5, 14.5, 20.6, 21.4, 22.9, 23.9, 25.3, and

27.9 °2θ.

DSC
FIG. 37: Endotherm with extrapolated onset temperature

about 86° C. and enthalpy of fusion about 111 J/g.

Endotherm with extrapolated onset temperature about

186° C. and enthalpy of fusion about 63 J/g.

TGA
FIG. 38: About 3.4% weight loss up to about130° C.

Certain XRPD diffraction peaks for the hydrate of the di-mesylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 39 below.

TABLE 39

SCAN: 4.0/40.0055/0.01975/21.6(sec), Cu(40 kV, 40 mA),

I(p) = 26838, 09/08/13 05:40p

PEAK: 19(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
4.435
19.9098
1024
25814
100.0
340263
100.0
0.221

2
6.232
14.1708
921
1630
6.3
14494
4.3
0.149

3
6.666
13.2489
883
3759
14.6
58061
17.1
0.259

4
8.541
10.3441
810
2387
9.2
20384
6.0
0.143

5
8.916
9.9106
829
236
0.9
2550
0.7
0.182

6
12.021
7.3563
1226
819
3.2
6353
1.9
0.130

7
12.492
7.0802
1358
239
0.9
1959
0.6
0.137

8
14.488
6.1089
1649
1564
6.1
27687
8.1
0.297

9
15.696
5.6414
1540
913
3.5
8066
2.4
0.148

10
17.349
5.1073
1205
705
2.7
7104
2.1
0.169

11
17.868
4.9602
1123
939
3.6
11325
3.3
0.202

12
18.317
4.8395
1037
1175
4.6
9978
2.9
0.143

13
18.897
4.6924
966
859
3.3
10263
3.0
0.200

14
19.225
4.6129
944
729
2.8
7890
2.3
0.182

15
19.958
4.4452
877
961
3.7
7303
2.1
0.128

16
20.628
4.3023
885
3999
15.5
39012
11.5
0.164

17
21.462
4.1370
857
2418
9.4
35879
10.5
0.249

18
22.409
3.9642
796
731
2.8
26557
7.8
0.610

19
22.899
3.8804
793
1862
7.2
38499
11.3
0.347

20
23.868
3.7251
793
2524
9.8
45137
13.3
0.300

21
24.266
3.6650
748
919
3.6
20859
6.1
0.381

22
24.637
3.6106
658
833
3.2
13491
4.0
0.272

23
25.270
3.5215
681
1805
7.0
15904
4.7
0.148

24
25.846
3.4443
611
1075
4.2
9921
2.9
0.155

25
26.220
3.3960
561
518
2.0
5560
1.6
0.180

26
27.088
3.2892
541
668
2.6
5678
1.7
0.143

27
27.621
3.2269
589
273
1.1
4261
1.3
0.262

28
27.939
3.1909
575
1720
6.7
23567
6.9
0.230

29
29.182
3.0578
603
438
1.7
7751
2.3
0.297

30
29.975
2.9786
564
122
0.5
1078
0.3
0.148

31
30.504
2.9282
532
361
1.4
6266
1.8
0.291

32
31.197
2.8646
514
197
0.8
1649
0.5
0.140

33
31.908
2.8024
490
321
1.2
7424
2.2
0.388

34
32.279
2.7710
480
368
1.4
4902
1.4
0.224

35
33.329
2.6861
457
603
2.3
9548
2.8
0.266

36
33.958
2.6378
457
193
0.7
2424
0.7
0.211

37
34.614
2.5893
457
209
0.8
5124
1.5
0.412

38
35.225
2.5458
486
368
1.4
10668
3.1
0.487

39
35.839
2.5036
511
188
0.7
3531
1.0
0.315

40
36.312
2.4720
469
276
1.1
8435
2.5
0.512

41
36.866
2.4362
497
159
0.6
2224
0.7
0.235

42
38.009
2.3655
458
257
1.0
2647
0.8
0.173

43
39.099
2.3020
453
181
0.7
1846
0.5
0.171

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 21 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate

Method A: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (40 mg, 0.11 mmol) was dissolved in about 1 mL of tetrahydrofuran. Ethanesulfonic acid (0.22 mmol, 24.5 mg) was added and the resulting suspension stirred for one day. The solids were isolated by centrifugation.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (40 mg, 0.11 mmol) was suspended in about 1 mL of acetone. Ethanesulfonic acid (0.22 mmol, 24.5 mg) was added and the resulting suspension stirred for one day. The solids were isolated by centrifugation.

The physical properties of the hydrate of the di-esylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 40 below.

TABLE 40

XRPD
FIG. 39: Peaks of ≥5% relative height at about 4.5,

6.2, 6.7, 8.6, 16.8, 17.8, 18.5, 21.6, 23.5, 24.0, and

27.7 °2θ.

DSC
FIG. 40: Endotherm with extrapolated onset temperature

about 56° C. and enthalpy of fusion about 83 J/g.

Endotherm with extrapolated onset temperature about

202° C. and enthalpy of fusion about 52 J/g.

TGA
FIG. 41: About 3.3% weight loss up to about 126° C.

Certain XRPD diffraction peaks for the of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 41 below.

TABLE 41

SCAN: 4.0/40.0055/0.01975/21.6(sec), Cu(40 kV, 40 mA),

I(p) = 11324, 09/08/13 05:40p

PEAK: 19(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
4.514
19.5616
914
10410
100.0
167672
100.0
0.270

2
6.211
14.2195
736
2294
22.0
22548
13.4
0.165

3
6.746
13.0930
698
1761
16.9
34370
20.5
0.328

4
8.622
10.2473
654
627
6.0
8284
4.9
0.222

5
9.010
9.8065
658
137
1.3
1695
1.0
0.207

6
11.684
7.5680
932
201
1.9
1722
1.0
0.144

7
12.335
7.1697
1077
282
2.7
4733
2.8
0.282

8
14.151
6.2534
1408
397
3.8
8856
5.3
0.374

9
14.492
6.1072
1469
312
3.0
5288
3.2
0.284

10
16.799
5.2732
1192
606
5.8
5943
3.5
0.165

11
17.785
4.9831
1076
711
6.8
6147
3.7
0.145

12
18.518
4.7874
1037
862
8.3
12719
7.6
0.248

13
18.772
4.7233
984
403
3.9
13963
8.3
0.581

14
19.205
4.6178
984
230
2.2
3208
1.9
0.234

15
19.528
4.5421
964
332
3.2
3466
2.1
0.176

16
21.185
4.1905
810
628
6.0
15192
9.1
0.406

17
21.638
4.1038
834
1141
11.0
17589
10.5
0.259

18
22.588
3.9333
839
490
4.7
7497
4.5
0.257

19
22.975
3.8679
860
360
3.5
7248
4.3
0.338

20
23.496
3.7832
867
642
6.2
5928
3.5
0.155

21
23.989
3.7066
847
583
5.6
6870
4.1
0.198

22
24.561
3.6215
723
461
4.4
5415
3.2
0.197

23
25.484
3.4924
617
176
1.7
1833
1.1
0.174

24
25.843
3.4447
585
211
2.0
3940
2.3
0.313

25
26.375
3.3765
575
409
3.9
4348
2.6
0.178

26
26.972
3.3030
569
141
1.4
1036
0.6
0.123

27
27.721
3.2154
595
575
5.5
7815
4.7
0.228

28
28.432
3.1366
622
130
1.3
2170
1.3
0.280

29
28.965
3.0802
600
478
4.6
9430
5.6
0.331

30
30.306
2.9468
539
184
1.8
1499
0.9
0.137

31
31.077
2.8755
511
251
2.4
4379
2.6
0.293

32
31.471
2.8404
513
192
1.8
3762
2.2
0.328

33
31.789
2.8126
524
113
1.1
1308
0.8
0.194

34
32.495
2.7532
542
210
2.0
2217
1.3
0.178

35
33.212
2.6953
526
197
1.9
4634
2.8
0.395

36
33.642
2.6619
489
97
0.9
2297
1.4
0.397

37
34.238
2.6168
474
99
1.0
2432
1.5
0.411

38
34.755
2.5791
478
160
1.5
3467
2.1
0.364

39
35.485
2.5277
473
169
1.6
4029
2.4
0.400

40
35.838
2.5036
456
113
1.1
4601
2.7
0.686

41
37.492
2.3969
447
84
0.8
1348
0.8
0.269

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 22

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-methanesulfonic acid salt: Approximately 5.0 g of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was weighed into a 500 mL of round-bottom flask, and then approximately 250 mL of acetone was added. 1.0 equivalents of methanesulfonic acid was slowly titrated into the reaction bulb. The suspension was kept stirring on a magnetic stirrer at room temperature. After 24 hrs, the remaining solid was separated by vacuum filtration. The wet cake was dried under reduced pressure at 35° C. overnight. The physical properties of the non-solvated mono-mesylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 42 below.

TABLE 42

XRPD
FIG. 42: Peaks of ≥15% relative height at about 8.7,

9.0, 12.1, 14.3, 15.8, 19.0, 20.6, 21.6, 22.7, 24.7,

26.7, and 27.6 °2θ.

DSC
FIG. 43: Exotherm with extrapolated onset temperature

about 236° C. and enthalpy of fusion about 217 J/g.

TGA
FIG. 43: About 2.4% weight loss up to about 120° C.

Certain XRPD diffraction peaks for the non-solvated mono-mesylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 43 below.

TABLE 43

SCAN: 4.0/40.0087/0.01972/18.6(sec), Cu(40 kV, 40 mA),

I(p) = 2002, 09/11/14 11:24p

PEAK: 27(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
8.654
10.2098
186
776
44.2
13180
48.7
0.285

2
8.988
9.8305
172
567
32.3
12995
48.0
0.384

3
12.124
7.2939
167
518
29.5
7254
26.8
0.235

4
14.313
6.1829
158
479
27.3
6889
25.5
0.241

5
15.773
5.6140
162
437
24.9
5981
22.1
0.229

6
17.037
5.2002
174
109
6.2
2119
7.8
0.325

7
17.960
4.9348
202
216
12.3
2694
10.0
0.209

8
19.046
4.6559
230
1034
58.9
27057
100.0
0.438

9
19.892
4.4597
238
153
8.7
2229
8.2
0.244

10
20.565
4.3154
246
894
50.9
16212
59.9
0.304

11
21.571
4.1163
246
1756
100.0
24154
89.3
0.231

12
22.260
3.9905
236
95
5.4
1174
4.3
0.207

13
22.656
3.9216
217
298
17.0
5881
21.7
0.330

14
23.166
3.8364
237
78
4.4
340
1.3
0.073

15
24.725
3.5978
175
571
32.5
15604
57.7
0.458

16
25.394
3.5046
197
154
8.7
2404
8.9
0.262

17
26.699
3.3361
167
268
15.3
8017
29.6
0.501

18
27.623
3.2267
165
266
15.1
4593
17.0
0.289

19
28.056
3.1778
165
78
4.4
1070
4.0
0.230

20
28.826
3.0947
159
75
4.3
949
3.5
0.212

21
29.559
3.0196
157
93
5.3
1439
5.3
0.260

22
29.949
2.9811
151
82
4.7
1178
4.4
0.241

23
30.958
2.8863
150
160
9.1
6850
25.3
0.719

24
31.648
2.8248
159
124
7.1
8032
29.7
1.084

25
32.102
2.7860
150
139
7.9
2200
8.1
0.266

26
32.929
2.7179
148
150
8.5
2834
10.5
0.317

27
34.136
2.6244
150
96
5.4
1110
4.1
0.195

28
35.336
2.5381
174
126
7.2
1549
5.7
0.205

29
36.027
2.4909
165
124
7.1
2513
9.3
0.339

30
37.174
2.4166
150
85
4.8
1424
5.3
0.280

31
38.040
2.3636
148
63
3.6
712
2.6
0.190

32
38.924
2.3119
142
46
2.6
2074
7.7
0.757

33
39.360
2.2873
137
89
5.1
2074
7.7
0.392

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 23

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt: Approximately 10 g of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was weighed into a 500 mL round-bottom flask, and then approximately 500 mL of acetone was added. 1.0 equivalents of ethanesulfonic acid was slowly titrated into the sample. The suspension was kept stirring on a magnetic stirrer at room temperature. After 24 hrs, the remaining solid was isolated by vacuum filtering. After that, the wet cake was suspended with 180 mL acetone for purification. The purified solid samples were isolated by vacuum filtering and dried under reduced pressure at room temperature. The physical properties of the non-solvated mono-esylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 44 below.

TABLE 44

XRPD
FIG. 44: Peaks of ≥15% relative height at about 8.7,

9.1, 12.1, 14.4, 15.7, 18.0, 19.0, 20.4, 21.3, 22.5,

29.5, and 26.4, °2θ.

DSC
FIG. 45: Exotherm with extrapolated onset temperature

about 246° C. and enthalpy of fusion about 220 J/g.

TGA
FIG. 45: About 0.2% weight loss up to about 120° C.

Certain XRPD diffraction peaks for the non-solvated mono-esylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 45 below.

TABLE 45

SCAN: 4.0/40.0102/0.01973/18.6(sec), Cu(40 kV, 40 mA),

I(p) = 3055, 11/28/13 12:26a

PEAK: 23(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
8.677
10.1827
206
835
30.6
16425
33.5
0.330

2
9.074
9.7383
201
771
28.2
11030
22.5
0.240

3
12.050
7.3389
186
679
24.9
8943
18.2
0.221

4
14.377
6.1559
195
936
34.3
11306
23.0
0.203

5
15.660
5.6542
199
749
27.4
9346
19.0
0.209

6
16.743
5.2908
198
158
5.8
2278
4.6
0.241

7
17.203
5.1503
205
174
6.4
2423
4.9
0.233

8
18.028
4.9164
212
463
17.0
4943
10.1
0.179

9
18.443
4.8069
249
293
10.7
9172
18.7
0.524

10
18.957
4.6775
249
2345
85.9
49093
100.0
0.351

11
19.883
4.4618
249
236
8.7
2266
4.6
0.161

12
20.398
4.3504
324
1066
39.0
17646
35.9
0.278

13
21.325
4.1633
323
2732
100.0
34862
71.0
0.214

14
22.546
3.9404
254
550
20.1
7406
15.1
0.226

15
23.281
3.8177
237
256
9.4
2976
6.1
0.195

16
24.046
3.6980
256
156
5.7
1716
3.5
0.184

17
24.837
3.5820
250
805
29.5
19930
40.6
0.415

18
25.310
3.5160
237
277
10.1
4634
9.4
0.281

19
26.416
3.3713
252
823
30.1
16123
32.8
0.328

20
27.226
3.2728
263
83
3.0
1505
3.1
0.304

21
27.678
3.2203
238
298
10.9
5718
11.6
0.322

22
28.724
3.1054
200
173
6.3
2684
5.5
0.261

23
29.453
3.0302
201
120
4.4
2522
5.1
0.352

24
30.520
2.9267
212
293
10.7
4356
8.9
0.249

25
30.893
2.8922
248
229
8.4
8266
16.8
0.606

26
31.388
2.8477
248
373
13.6
10107
20.6
0.455

27
31.882
2.8046
284
196
7.2
3215
6.5
0.275

28
32.438
2.7579
240
195
7.1
4840
9.9
0.416

29
34.050
2.6309
251
128
4.7
2007
4.1
0.262

30
34.723
2.5814
247
205
7.5
5423
11.0
0.443

31
35.096
2.5548
263
135
4.9
3384
6.9
0.421

32
35.726
2.5112
253
127
4.6
1145
2.3
0.152

33
36.242
2.4766
248
319
11.7
5357
10.9
0.282

34
36.680
2.4481
236
117
4.3
1846
3.8
0.264

35
37.996
2.3662
243
187
6.8
4435
9.0
0.397

36
39.048
2.3049
228
73
2.7
1814
3.7
0.416

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 24 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-benzenesulfonic acid salt

Method A: Approximately 40 mg of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was weighed into a 4 mL vial and suspended with suitable amount of THF, then 2 equivalents of benzenesulfonic acid was added. The mixture was stirred for 1 day.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (40 mg) was weighed into a 4 mL centrifuge tube and added into 2 mL of THF to form a suspension. An appropriate amount of benzenesulfonic acid (39 mg, content 90%) was added into the suspension to keep the molar ratio of API:acid equal to 1:2.1. The suspension was mixed completely on a rotary shaker for 1 day at room temperature. The precipitation was centrifuged at 10,000 rpm for 3 minutes, and dried under reduced pressure for 1 day at room temperature.

The physical properties of the non-solvated di-besylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 46 below.

TABLE 46

XRPD
FIG. 46: Peaks of ≥5% relative height at about 4.6,

6.8, 8.0, 9.6, 13.0, 14.9, 18.4, 19.3, 20.9, 21.3, 21.9,

25.6, and 27.2 °2θ.

Certain XRPD diffraction peaks for the non-solvated di-besylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 47 below.

TABLE 47

SCAN: 4.0/39.9975/0.01975/21.6(sec), Cu(40 kV,40 mA),

I(p) = 12887, 09/10/13 05:02p

PEAK: 21(pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
4.631
19.0640
992
11895
100.0
186126
100.0
0.263

2
6.843
12.9061
789
1639
13.8
24874
13.4
0.255

3
7.968
11.0866
747
4350
36.6
41038
22.0
0.158

4
9.193
9.6124
656
435
3.7
6144
3.3
0.237

5
9.587
9.2176
655
1232
10.4
13993
7.5
0.191

6
13.040
6.7836
968
900
7.6
8108
4.4
0.151

7
13.532
6.5381
1038
283
2.4
2873
1.5
0.170

8
14.346
6.1688
1066
550
4.6
10814
5.8
0.330

9
14.923
5.9319
1055
679
5.7
13008
7.0
0.322

10
16.370
5.4107
1031
126
1.1
1528
0.8
0.203

11
16.696
5.3055
987
461
3.9
6064
3.3
0.221

12
17.038
5.2000
955
324
2.7
4015
2.2
0.208

13
18.376
4.8243
907
1090
9.2
12376
6.6
0.191

14
19.285
4.5939
986
1352
11.4
21425
11.5
0.266

15
20.231
4.3858
991
500
4.2
2760
1.5
0.093

16
20.899
4.2472
1060
658
5.5
4575
2.5
0.117

17
21.316
4.1650
992
1219
10.3
16320
8.8
0.225

18
21.909
4.0535
1006
1081
9.1
26070
14.0
0.405

19
22.603
3.9307
1008
331
2.8
3437
1.8
0.174

20
23.392
3.7999
946
480
4.0
4252
2.3
0.149

21
23.984
3.7073
870
583
4.9
14238
7.6
0.410

22
24.441
3.6391
891
134
1.1
2320
1.2
0.291

23
24.929
3.5689
841
511
4.3
4336
2.3
0.142

24
25.563
3.4819
778
801
6.7
12001
6.4
0.252

25
26.214
3.3969
759
526
4.4
10023
5.4
0.320

26
27.163
3.2802
773
1108
9.3
17128
9.2
0.259

27
27.459
3.2456
726
391
3.3
12046
6.5
0.517

28
28.149
3.1675
728
409
3.4
4000
2.1
0.164

29
28.902
3.0867
694
304
2.6
5259
2.8
0.290

30
29.650
3.0105
649
358
3.0
8965
4.8
0.421

31
30.120
2.9646
662
252
2.1
4560
2.4
0.304

32
31.646
2.8250
584
209
1.8
4984
2.7
0.400

33
32.183
2.7792
556
137
1.2
3653
2.0
0.448

34
32.593
2.7451
581
145
1.2
1516
0.8
0.175

35
33.660
2.6605
536
185
1.6
4939
2.7
0.449

36
34.035
2.6320
519
304
2.6
9050
4.9
0.500

37
35.832
2.5041
486
117
1.0
2354
1.3
0.337

38
36.954
2.4305
473
129
1.1
3136
1.7
0.408

39
37.388
2.4033
476
162
1.4
3179
1.7
0.330

40
38.478
2.3377
479
197
1.7
4907
2.6
0.417

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 25 (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-toluenesulfonic acid salt

Method A: Approximately 40 mg of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide was weighed into a 4 mL vial and suspended with suitable amount of acetone or THF, then 2 equivalents of toluenesulfonic acid was added and the mixture was stirred for 1 day.

Method B: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (40 mg) was weighed into a 4 mL centrifuge tube and added into 2 mL of IPA (isopropanol) to form a suspension. An appropriate amount of toluenesulfonic acid monohydrate (43 mg, content 99%) was added into the suspension to keep the molar ratio of API:acid equal to 1:2.1. The suspension was mixed completely on a rotary shaker for 1 day at room temperature. The precipitation were centrifuged at 10,000 rpm for 3 minutes, and dried under reduced pressure for 1 day at room temperature.

The physical properties of the non-solvated di tosylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 48 below.

TABLE 48

XRPD
FIG. 47: Peaks of ≥5% relative height at about 4.5,

6.7, 7.1, 9.4, 12.6, 19.3, 20.4, 21.6, and 25.9 °2θ.

DSC
FIG. 48: Endotherm at about 222° C.

Certain XRPD diffraction peaks for the non-solvated di tosylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are shown in Table 49 below.

TABLE 49

SCAN: 4.0/39.9975/0.01975/21.6(sec), Cu(40 kV, 40 mA),

I(p) = 17690, 09/10/13 05:02p

PEAK: 21 (pts)/Parabolic Filter, Threshold = 3.0,

Cutoff = 0.1%, BG = 3/1.0, Peak-Top = Summit

#
2-Theta
d(Å)
BG
Height
H %
Area
A %
FWHM

1
4.533
19.4790
886
16804
100.0
279482
100.0
0.279

2
6.746
13.0921
756
2740
16.3
71478
25.6
0.438

3
7.139
12.3721
747
5314
31.6
64806
23.2
0.205

4
8.246
10.7132
714
226
1.3
1568
0.6
0.116

5
9.352
9.4492
699
1560
9.3
21039
7.5
0.226

6
9.645
9.1626
710
641
3.8
6977
2.5
0.183

7
12.609
7.0148
1042
1113
6.6
14355
5.1
0.216

8
13.616
6.4983
1217
602
3.6
8832
3.2
0.246

9
14.214
6.2258
1220
476
2.8
7468
2.7
0.263

10
14.882
5.9478
1223
685
4.1
9425
3.4
0.231

11
16.461
5.3808
1103
411
2.4
3980
1.4
0.163

12
16.792
5.2754
1069
579
3.4
5092
1.8
0.148

13
17.598
5.0356
1017
167
1.0
758
0.3
0.076

14
18.179
4.8761
1038
353
2.1
6059
2.2
0.288

15
18.631
4.7587
1108
832
4.9
13744
4.9
0.277

16
19.265
4.6034
1108
951
5.7
10741
3.8
0.190

17
19.638
4.5168
1021
507
3.0
4543
1.6
0.150

18
20.427
4.3441
989
1637
9.7
20628
7.4
0.212

19
21.121
4.2030
1016
606
3.6
12612
4.5
0.350

20
21.636
4.1042
889
1755
10.4
36261
13.0
0.347

21
22.224
3.9968
889
287
1.7
1714
0.6
0.100

22
23.214
3.8286
899
621
3.7
9548
3.4
0.258

23
23.568
3.7718
853
658
3.9
11310
4.0
0.289

24
23.962
3.7106
859
372
2.2
8546
3.1
0.386

25
24.537
3.6250
895
163
1.0
1222
0.4
0.126

26
25.246
3.5249
848
407
2.4
5619
2.0
0.232

27
25.857
3.4428
779
1484
8.8
22642
8.1
0.256

28
26.704
3.3355
785
180
1.1
1699
0.6
0.159

29
27.021
3.2972
737
345
2.1
11718
4.2
0.571

30
27.301
3.2639
698
521
3.1
18187
6.5
0.586

31
27.657
3.2228
698
314
1.9
4301
1.5
0.230

32
28.625
3.1159
648
325
1.9
6310
2.3
0.326

33
29.020
3.0744
654
188
1.1
7215
2.6
0.644

34
29.712
3.0044
658
361
2.2
4547
1.6
0.211

35
30.204
2.9565
622
111
0.7
3010
1.1
0.454

36
30.793
2.9013
630
220
1.3
2516
0.9
0.192

37
31.704
2.8200
585
211
1.3
3290
1.2
0.261

38
32.573
2.7468
571
126
0.7
4095
1.5
0.546

39
32.985
2.7133
549
155
0.9
4095
1.5
0.444

40
34.349
2.6087
543
101
0.6
6110
2.2
1.012

41
34.790
2.5766
566
111
0.7
2264
0.8
0.344

42
36.129
2.4841
497
80
0.5
2551
0.9
0.536

43
38.358
2.3447
492
195
1.2
4681
1.7
0.403

NOTE:

Intensity = Counts, 2T(0) = 0.0(deg), Wavelength to Compute d-Spacing = 1.54059 Å (Cu/K-alpha1)

Example 26

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethane sulfonic acid salt: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-ethanesulfonic acid salt hydrate was heated to 130° C. in a DSC apparatus and then cooled to room temperature. The anhydrate re-absorbs water at 80% RH and is converted to anhydrate. The physical properties of the non-solvated di-esylate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 50 below.

TABLE 50

XRPD
FIG. 49.

DSC
FIG. 50: Endotherm with extrapolated onset temperature

about 203° C. and enthalpy of fusion about 56 J/g.

TGA
FIG. 51: Less than 0.08% weight loss up to about 130° C.

Example 27

Maleic acid salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide: Prepared by methods similar to those disclosed herein. The physical properties of the non-solvated mono-maleate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 51 below.

TABLE 51

Aqueous
>10 at pH ≤ 7

Solubility

(mg/mL)

DSC/TGA
Melting point about 214° C. No weight loss until

melt/degradation.

DVS
Non-hygroscopic, 0.3% wt./wt. gain at 80% RH.

Example 28

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide HBr salt methanol solvate: Prepared by methods similar to those disclosed herein. The physical properties of the methanol solvate of the HBr salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 52 below.

TABLE 52

DSC/TGA
Onset of desolvation at approximately 112° C.

Example 29

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HCl salt: Prepared by methods similar to those disclosed herein. The physical properties of the non-solvated di-HCl salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 53 below.

TABLE 53

DSC/TGA
Single endotherm due to melting/decomposition at ~209°

C. ~7% weight loss by TGA, which occurs upon melting.

DVS
Non-hygroscopic below 80% RH. Converts to a

crystalline dihydrate form above 80% RH.

Example 30

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide di-HBr salt: Prepared by methods similar to those disclosed herein. The physical properties of the non-solvated di-HBr salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide are summarized in Table 54 below.

TABLE 54

DSC/TGA
Anhydrous solids with a concurrent melt/decomposition

exotherm at ~273° C. Analysis of the post-DVS solids

shows ~4% step-wise weight loss by TGA with an onset of

desolvation at 81.2° C. Further heating on the DSC shows

the same exothermic behavior as the starting material

however, the onset of the exotherm is at ~217° C.

DVS
Non-hygroscopic below 80% RH. Upon desorption the solids

were found to convert to a new mono-hydrate crystal form.

Example 31

Crystalline forms of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide salts with tartaric, succinic, and phosphoric acids, and solvates thereof, were also prepared by methods similar to those disclosed herein (data not shown).

Example 32

Excipient compatibility study of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt: (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide mono-ethanesulfonic acid salt and excipients were weighed according to formulation of Composite 2 and Composite 4 with equivalent incremental addition and ground thoroughly in a mortar, respectively (Table 55). Composite blanks (same formulation without API) were placed as controls with the same process. Each of about 100 mg of composite blends was pressed to a tablet formulation (diameter 8 mm, thickness 1 mm) with manual sheeter under the pressure (4 MPa) for half a minute. The tablet was transferred into a 40 mL glass vial for the storage conditions (Table 56). The stability samples in the vials were capped and sealed with parafilm. The samples were placed at 30° C. (closed), 40° C. (closed) and 50° C. (closed) for 0 day, 1 month, 3 months, 6 months, 12 months and backup in duplicate and monitored with physical appearance, impurities/degradants and recovery at each time point, respectively. The excipient blanks as controls were conducted in single.

TABLE 55

Actual weight (mg) for

Composition (%, w/w)
tablets

Composite-
Composite-
Composite-
Composite-

Excipients
2 blend
4 blend
2 blend
4 blend

Mono-esylate
5
5
202.60
199.54

MCC
44.5
68
1782.31
2731.29

Starch
44.5
20
1780.08
798.85

Crocarmellose
5
—
200.95
—

sodium

Crospovidone
—
5
—
200.66

Silicon dioxide
—
1
—
42.29

Mg stearate
1
1
40.14
40.26

TABLE 56

Recovery (%)
TRS (%)

Stress

1^st
3^rd
6^th
12^th

1^st
3^rd
6^th
12^th

Samples
condition
Initial
month
month
month
month
Initial
month
month
month
month

Mono-esylate
50° C.-
96.1
95.2
95.0
95.1

0.41
0.49
0.56
0.51

composite-2
closed

blend (MCC,
40° C.-

95.1
94.3
95.3

0.40
0.43
0.41

Starch, etc)
closed

30° C.-

95.7
95.3
94.6

0.42
0.40
0.33

closed

Mono-esylate
50° C.-
97.4
95.1
95.8
96.4

0.41
0.56
0.56
0.48

composite-4
closed

blend (MCC,
40° C.-

96.6
97.3
97.7

0.51
0.42
0.39

Starch,
closed

Crospovidone
30° C.-

96.8
96.3
97.0

0.44
0.43
0.39

etc)
closed

Example 33

Chemical characteristics of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base (Form A) and maleate salt crystal forms: The stability of the crystal forms described in Examples 4 and 27 was measured neat as well as in a Powder-in-Capsule (PiC) formulation. The stability as neat powder was measured over a period of 1-year for the free base and 3-months for the maleate salt, under ambient (25° C./60% RH) and accelerated (40° C./75% RH) conditions. The free base was found to show very good stability with no chiral or achiral degradation observed under any condition for a period of 1-year. The maleate salt under the same conditions, after 3-months on stability, was found to show very slight degradation under accelerated conditions. It should be noted that the maleate salt used in the neat powder stability study contained high levels (˜9% wt./wt.) of residual tetrahydrofuran (THF). The PiC stability using 15 mg of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide in Size 0 hard gelatin capsules was carried out over a period of 2-months at 5° C., ambient and accelerated conditions. Similar to the neat powder, the PiC formulation did not cause any significant physical or chemical degradation in the free base formulation and the maleate salt, containing no residual THF, was also found to be stable.

To further investigate the chemical properties of these crystal forms, an abbreviated excipient compatibility study was run at 50° C. with 20% H₂O added. The excipients used in the study consisted of common diluents and disintegrants and the study was conducted over a period of 4 weeks. The free base was found to show significant degradation with lactose and Ac-Di-Sol® (croscarmellose sodium) whereas the maleate salt was found to show significant degradation with all excipients investigated. Notably, the maleate salt also showed the same degradant formation as the free base in lactose suggesting that the salt does not fully attenuate the presumed Maillard reaction. Overall, the free base Form A appears to be more stable with excipients than the maleate salt of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide.

Example 34

Biological characteristics of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide free base (Form A) and maleate salt crystal forms: The oral absorption of the crystal forms described in Examples 4 and 27 as PiC formulations was investigated in a preclinical pharmacokinetic study conducted in canines using a reduced Latin square crossover design at 3 mg/kg to compare the solid formulations to a solution of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide. The results of this study showed that the area under the curve (AUC) variability is consistent between (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide formulations (PiC vs. solution) and that the maximal concentration (C_max) data suggest the maleate salt PiC is less variable, however high variability was observed throughout the study. Consistent terminal elimination phases as well as half-life (t_1/2) values were observed between formulations and the time to maximum concentration (T_max) values were consistent with the toxicokinetic values obtained in GLP toxicology studies. No trends observed by AUC or t_1/2could be discerned for each of the three formulations. In addition, the median C_maxvalues were similar across all formulations. (See FIG. 54). Overall, no significant differences in absorption were found between the freebase and maleate crystal forms of (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

	Number	Date	Country
Parent	15054611	Feb 2016	US
Child	15806650		US

CRYSTALLINE FORMS OF A PYRROLOPYRIDINE COMPOUND

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