Niraparib salt

Abstract

Novel salts of niraparib are provided. Also provided are pharmaceutical compositions comprising those salts, and methods and uses related thereto.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 740,872, filed on October 3, 2018, which is incorporated herein by reference in its entirety. Field of the Invention

[0003] The present disclosure relates to novel salts of niraparib, pharmaceutical compositions comprising these salts, and uses thereof. Summary of the invention

[0004] Niraparib is the international nonproprietary name for 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, and has the following chemical structure

[0005]

[0006] A method for synthesizing niraparib is given in Jones et al., J. Med. Chem., 52:7170-7185, 2009.

[0007] Niraparib is an orally available, selective inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and 2. Niraparib has been shown to have an IC 50 The inhibition of PARP-1 and PARP-2 was 3.8 nM and 2.1 nM, respectively, and in whole cell assays, it inhibited PARP activity (EC 50 =4 nM) and proliferation of cancer cells with mutant BRCA1 and BRCA2 (CC 50 In the range of 10 to 100 nM) (see Jones et al., J. Med. Chem., 52: 7170-7185, 2009). Niraparib can also be used to treat cancers characterized by defects in certain genes involved in the homologous recombination repair (HRR) pathway (including non-BRCA1 / 2 HRR genes). The activity of niraparib enables it to treat a wide range of conditions, including cancers (particularly cancers that are difficult to treat with platinum-based chemotherapy), as well as conditions such as stroke, autoimmune diabetes, neurological diseases, inflammatory diseases, metabolic diseases, and cardiovascular diseases.

[0008] In recent years, niraparib has been approved for maintenance or treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after a complete or partial response to platinum-based chemotherapy. TM ) are capsules containing 100 mg of niraparib in the form of a single hydrated p-toluenesulfonate salt (niraparib p-toluenesulfonate monohydrate).

[0009] As a drug substance, niraparib p-toluenesulfonate monohydrate (i.e., 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 4-methylbenzenesulfonate hydrate 1:1:1) is a white to off-white, non-hygroscopic crystalline solid with low water solubility. Methods for preparing niraparib p-toluenesulfonate monohydrate include methods described in PCT / US2018 / 029131.

[0010] Despite the commercial success of niraparib p-toluenesulfonate monohydrate, there remains a need to provide additional forms of niraparib having desirable pharmaceutical properties, particularly for formulation into solid (eg oral) pharmaceutical dosage forms.

[0011] Surprisingly, it has now been discovered that camphorate, mandelate and camphorsulfonate salts of niraparib possess these desirable properties, including improved water solubility, low hygroscopicity and / or good stability.

[0012] Therefore, in one aspect, the present invention provides a 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salt selected from 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate and 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate.

[0013] In an aspect or embodiment, the invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate.

[0014] In an aspect or embodiment, the invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate.

[0015] In an aspect or embodiment, the invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate.

[0016] In an aspect or embodiment, the present invention provides crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate.

[0017] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 6.5, 11.7, 13.4, 14.1, 14.5, 15.2, 16.2, 17.5, 18.0, 20.0, 20.4, 21.6, 22.3, 22.8, 24.0, 24.5, 26.9 and 27.6 degrees 2θ when detected using Cu K radiation.

[0018] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 11.7, 13.4, 15.2, 16.2, 17.5, 18.0, 20.0, 20.4, 21.6, 22.8 and 24.0 degrees 2θ when detected using Cu K radiation.

[0019] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 13.4, 15.2, 16.2, 17.5, 18.0, 20.0, 20.4, 21.6 and 24.0 degrees 2θ when detected using Cu K radiation.

[0020] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an X-ray powder diffraction (XRPD) pattern comprising one or more XRPD diffraction angles at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2° 2θ.

[0021] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising at least two diffraction angles at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2° 2θ.

[0022] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising at least three diffraction angles at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2° 2θ.

[0023] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising at least four diffraction angles at 16.2, 17.5, 20.013.4 and / or 15.2±0.2° 2θ.

[0024] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising diffraction angles at 16.2, 17.5, 20.0, 13.4 and 15.2±0.2° 2θ.

[0025] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising one or more XRPD diffraction angles at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0026] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising two or more diffraction angles at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0027] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising three or more diffraction angles at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0028] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising four or more diffraction angles at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0029] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising diffraction angles at 20.4, 21.6, 24.0, 11.7 and 18.0±0.2° 2θ.

[0030] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising diffraction angles at 16.2, 17.5, 20.0, 13.4, 15.2, 20.4, 21.6, 24.0, 11.7 and 18.0 ± 0.2° 2θ.

[0031] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising at least one diffraction angle at 14.8, 18.0, 22.8 and / or 27.6±0.2° 2θ.

[0032] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising at least two diffraction angles at 14.8, 18.0, 22.8 and / or 27.6±0.2° 2θ.

[0033] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising at least three diffraction angles at 14.8, 18.0, 22.8 and / or 27.6±0.2° 2θ.

[0034] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising diffraction angles at 14.8, 18.0, 22.8 and 27.6±0.2° 2θ.

[0035] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising one or more diffraction angles at 16.2, 17.5, 20.0, 13.4, 15.2, 20.4, 21.6, 24.0, 11.7, 18.0, 22.8, 18.9, 14.5, 14.1, 14.8, 27.6, 26.9, 6.5, 22.3 and / or 24.5 ± 0.2° 2θ.

[0036] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate has an XRPD pattern comprising diffraction angles having 2θ values ​​(±0.2° 2θ), and optionally relative intensities, according to the following table:

[0037]

[0038]

[0039] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate is characterized by an XRPD pattern substantially similar to Figure 3 Consistent.

[0040] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate salt is characterized by a melting point of about 260°C to about 270°C.

[0041] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate salt is characterized by a melting point of about 264°C.

[0042] In an embodiment, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate salt is characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 264°C and / or wherein the minimum of the peak is about 268°C.

[0043] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate salt is characterized by a DSC thermogram substantially as follows Figure 5 as shown in .

[0044] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate is characterized by comprising a -1 、About 1693cm -1 and about 1649cm -1 Peaks of infrared spectra.

[0045] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate is characterized by an infrared spectrum substantially as Figure 2 as shown in .

[0046] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate is characterized by absorbing no more than about 0.3% water by weight at a relative humidity of about 25°C up to about 90%.

[0047] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate salt is characterized by a GVS thermogram substantially as follows Figure 6 as shown in .

[0048] In an aspect or embodiment, the invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate.

[0049] In an aspect or embodiment, the invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate.

[0050] In an aspect or embodiment, the present invention provides crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate.

[0051] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 6.5, 11.6, 13.4, 14.0, 14.5, 15.1, 16.2, 17.4, 18.9, 19.9, 20.2, 20.3, 21.5, 21.9, 22.2, 22.3, 23.9, 24.4 and 26.9 degrees 2θ when detected using Cu K radiation.

[0052] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 11.6, 13.4, 15.1, 16.2, 17.4, 19.9, 20.2, 20.3, 22.2, 22.3, 24.4 and 26.9 degrees 2θ when detected using Cu K radiation.

[0053] In an embodiment, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 11.6, 15.1, 16.2, 17.4, 19.9, 20.2, 20.3, 22.3 and 24.4 degrees 2θ when detected using Cu K radiation.

[0054] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising one or more diffraction angles at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2° 2θ.

[0055] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising at least two diffraction angles at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2° 2θ.

[0056] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising at least three diffraction angles at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2° 2θ.

[0057] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising at least four diffraction angles at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2° 2θ.

[0058] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising diffraction angles at 20.3, 17.4, 16.2, 15.1 and 20.2±0.2° 2θ.

[0059] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising one or more diffraction angles at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0060] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising at least two diffraction angles at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0061] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising at least three diffraction angles at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0062] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising at least four diffraction angles at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0063] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising diffraction angles at 24.4, 19.9, 11.6, 22.3 and 22.2±0.2° 2θ.

[0064] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising diffraction angles at 20.3, 17.4, 16.2, 15.1, 20.2, 24.4, 19.9, 11.6, 22.3 and 22.2±0.2° 2θ.

[0065] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising a diffraction angle at 16.0±0.2° 2θ.

[0066] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising a diffraction angle at 21.9±0.2° 2θ.

[0067] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising diffraction angles at 16.0 and 21.9±0.2° 2θ.

[0068] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising at least one diffraction angle at 20.3, 17.4, 16.2, 15.1, 20.2, 24.4, 19.9, 11.6, 22.3, 22.2, 13.4, 16.0, 26.9, 6.5, 23.9, 18.9, 14.5, 14.0, 21.9 and / or 21.5 ± 0.2° 2θ.

[0069] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate has an XRPD pattern comprising diffraction angles with 2θ values ​​(±0.2° 2θ), and optionally relative intensities, according to the following table:

[0070]

[0071]

[0072] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by an XRPD pattern substantially as follows Fig. 9 as shown in .

[0073] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by a melting point of about 220°C to about 230°C.

[0074] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate salt is characterized by a melting point of about 226°C.

[0075] In an embodiment, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate salt is characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 226°C and / or wherein the minimum of the peak is about 230°C.

[0076] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by a DSC thermogram substantially as follows Fig.11 as shown in .

[0077] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by comprising a -1 、About 1693cm -1 and about 1648cm -1 The peak of the infrared spectrum.

[0078] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by an infrared spectrum substantially as Figure 8 as shown in .

[0079] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by absorbing no more than about 1% water by weight at a relative humidity of about 25°C up to about 90%.

[0080] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate is characterized by a GVS thermogram substantially as follows Fig.12 as shown in .

[0081] In an aspect or embodiment, the invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate salt.

[0082] In an aspect or embodiment, the invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt.

[0083] In an aspect or embodiment, the invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt.

[0084] In an aspect or embodiment, the present invention provides crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt.

[0085] In an embodiment, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 4.3, 8.4, 8.6, 8.7, 12.4, 13.7, 14.1, 16.1, 16.4, 17.4, 18.4, 18.5, 21.5, 25.1, 27.3, 27.6, 27.7, 28.0 and 28.7 degrees 2θ when detected using Cu K radiation.

[0086] In an embodiment, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 8.4, 8.6, 8.7, 13.7, 14.1, 16.4, 17.4, 18.4, 18.5, 21.5, 25.1, 27.3, 27.6, 27.7, 28.0 and 28.7 degrees 2θ when detected using Cu K radiation.

[0087] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 8.6, 8.7, 13.7, 16.4, 17.4, 18.4, 18.5, 21.5, 25.1, 27.3, 27.6, 28.0 and 28.7 degrees 2θ when detected using Cu K radiation.

[0088] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising one or more diffraction angles at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0089] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising at least two diffraction angles at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0090] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising at least three diffraction angles at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0091] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising at least four diffraction angles at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0092] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising diffraction angles at 18.5, 16.4, 17.4, 8.6 and 17.6 ± 0.2° 2θ.

[0093] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising one or more diffraction angles at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0094] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising two or more diffraction angles at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0095] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising three or more diffraction angles at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0096] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising four or more diffraction angles at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0097] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising diffraction angles at 8.7, 18.4, 25.1, 27.6 and 13.7 ± 0.2° 2θ.

[0098] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising diffraction angles at 18.5, 16.4, 17.4, 8.6, 17.6, 8.7, 18.4, 25.1, 27.6 and 13.7 ± 0.2° 2θ.

[0099] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising one or more diffraction angles at 18.5, 16.4, 17.4, 8.6, 17.6, 8.7, 18.4, 25.1, 27.6, 13.7, 8.4, 28.7, 28.0, 4.3, 21.5, 27.3, 14.1, 27.7, 12.4 and / or 16.1 ± 0.2° 2θ.

[0100] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt has an XRPD pattern comprising diffraction angles with 2θ values ​​(±0.2° 2θ), and optionally relative intensities, according to the following table:

[0101] Position [°2θ] Relative strength [%] 4.3 22.3 8.4 27.0 8.6 57.9 8.7 48.3 12.4 17.4 13.7 31.9 14.1 19.9 16.1 17.0 16.4 99.2 17.4 75.9 17.6 52.5 18.4 44.4 18.5 100 21.5 22.2 25.1 39.0 27.3 20.3 27.6 35.9 27.7 19.0 28.0 22.5 28.7 24.8

[0102] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by an XRPD pattern substantially as follows Fig.15 as shown in .

[0103] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by a melting point of about 190°C to about 200°C.

[0104] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by a melting point of about 197°C.

[0105] In embodiments, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 197°C and / or wherein the minimum of the peak is about 201°C.

[0106] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by a DSC thermogram substantially as follows Fig.18 as shown in .

[0107] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by comprising a -1 、About 3340cm -1 , about 1671cm -1 and about 1638cm -1 The peak of the infrared spectrum.

[0108] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by an infrared spectrum substantially as Fig.14 as shown in .

[0109] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt is characterized by a DVS thermogram substantially as follows Fig.19 as shown in .

[0110] In an aspect or embodiment, the invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate.

[0111] In an aspect or embodiment, the invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate.

[0112] In an aspect or embodiment, the invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate.

[0113] In an aspect or embodiment, the present invention provides crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt.

[0114] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 6.7, 9.5, 11.1, 13.5, 14.3, 16.0, 16.4, 16.7, 16.9, 17.6, 20.3, 22.8, 23.7, 24.3, 24.6, 25.0, 25.2, 25.8 and 26.8 degrees 2θ when detected using Cu K radiation.

[0115] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 11.1, 13.5, 16.0, 16.4, 16.7, 17.6, 20.3, 23.7, 24.3, 24.6, 25.0, 25.2 and 25.8 degrees 2θ when detected using Cu K radiation.

[0116] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles selected from about 11.1, 13.5, 16.0, 16.4, 16.7, 17.6, 20.3, 23.7, 24.3 and 24.6 degrees 2θ when detected using Cu K radiation.

[0117] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising one or more diffraction angles at 16.0, 13.5, 17.6, 24.3 and / or 24.6±0.2° 2θ.

[0118] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising at least two diffraction angles at 16.0, 13.5, 17.6, 24.3 and / or 24.6±0.2° 2θ.

[0119] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising at least three diffraction angles at 16.0, 13.5, 17.6, 24.3 and / or 24.6±0.2° 2θ.

[0120] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising at least four diffraction angles at 16.0, 13.5, 17.6, 24.3 and / or 24.6±0.2° 2θ.

[0121] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising diffraction angles at 16.0, 13.5, 17.6, 24.3 and 24.6 ± 0.2° 2θ.

[0122] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising one or more diffraction angles at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0123] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising two or more XRPD diffraction angles at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0124] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising three or more diffraction angles at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0125] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising four or more diffraction angles at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0126] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising diffraction angles at 11.1, 16.4, 23.7, 16.7 and 20.3±0.2° 2θ.

[0127] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising diffraction angles at 16.0, 13.5, 17.6, 24.3, 24.6, 11.1, 16.4, 23.7, 16.7 and 20.3±0.2° 2θ.

[0128] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising one or more XRPD diffraction angles at 6.7, 16.4, 23.7 and / or 25.2±0.2° 2θ.

[0129] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising at least two diffraction angles at 6.7, 16.4, 23.7 and / or 25.2±0.2° 2θ.

[0130] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising at least three diffraction angles at 6.7, 16.4, 23.7 and / or 25.2±0.2° 2θ.

[0131] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt has an XRPD pattern comprising diffraction angles at 6.7, 16.4, 23.7 and 25.2±0.2° 2θ.

[0132] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising at least one diffraction angle at 16.0, 13.5, 17.6, 24.3, 24.6, 11.1, 16.4, 23.7, 16.7, 20.3, 6.7, 25.2, 25.0, 25.8, 26.8, 22.8, 9.5, 16.9, 14.3 and / or 7.7 ± 0.2° 2θ.

[0133] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate has an XRPD pattern comprising diffraction angles having 2θ values ​​(±0.2° 2θ), and optionally relative intensities, according to the following table:

[0134] Position [°2θ] Relative strength [%] 6.7 13.8 7.7 8.9 9.5 10.4 11.1 22.2 13.5 58.6 14.3 9.1 16.0 100 16.4 20.4 16.7 19.1 16.9 9.8 17.6 55.4 20.3 14.5 22.8 11.6 23.7 19.6 24.3 47.4 24.6 45.9 25.0 12.9 25.2 13.4 25.8 12.0 26.8 11.6

[0135] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by an XRPD pattern substantially as follows Fig. 22 as shown in .

[0136] In embodiments, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by a melting point of about 235°C to about 245°C.

[0137] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by a melting point of about 239°C.

[0138] In an embodiment, the crystalline form of the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 235°C and / or wherein the minimum of the peak is about 246°C.

[0139] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by a DSC thermogram substantially as follows: Fig.24 as shown in .

[0140] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by comprising a crystalline phase at about 3467 cm -1 、About 3306cm -1 、About 1724cm -1 , about 1660cm -1 and about 1611cm -1 The peak of the infrared spectrum.

[0141] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by an infrared spectrum substantially as Fig.21 as shown in .

[0142] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by absorbing no more than about 2% water by weight at a relative humidity of about 25°C up to about 90%.

[0143] In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by absorbing about 1.3% by weight water at a relative humidity of up to about 90% at about 25°C.

[0144] In embodiments, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt is characterized by a GVS thermogram substantially as follows: Fig.25 as shown in .

[0145] In other aspects, the present invention provides a pharmaceutical composition comprising 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate as defined above, and at least one pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is suitable for oral administration.

[0146] In other aspects, the present invention provides a pharmaceutical composition comprising a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate as defined above, and at least one pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is suitable for oral administration.

[0147] In an embodiment, the pharmaceutical composition comprises a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate, and at least one pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is suitable for oral administration.

[0148] In an embodiment, the pharmaceutical composition comprises a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate, and at least one pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is suitable for oral administration.

[0149] In an embodiment, the pharmaceutical composition comprises a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt, and at least one pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is suitable for oral administration.

[0150] In an embodiment, the pharmaceutical composition comprises a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate, and at least one pharmaceutically acceptable excipient. In an embodiment, the pharmaceutical composition is suitable for oral administration.

[0151] In other aspects, the present invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate, or pharmaceutical compositions thereof and the pharmaceutical compositions defined above for use in therapy. In an embodiment, the present invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate, or a pharmaceutical composition thereof and the pharmaceutical compositions defined above for use in therapy.

[0152] In other aspects, the present invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate, or pharmaceutical compositions thereof and the use of the pharmaceutical compositions defined above in the preparation of drugs. In an embodiment, the present invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate, or a pharmaceutical composition thereof and the use of the pharmaceutical composition defined above in the preparation of a medicament.

[0153] In other aspects, the present invention provides a method for treating cancer, stroke, autoimmune diabetes, neurological disease, inflammatory disease, metabolic disease or cardiovascular disease in a human in need thereof, the method comprising administering to the human an effective amount of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate as defined above, or a pharmaceutical composition as defined above. In an embodiment, the method comprises administering to a human an effective amount of a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate, or a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate as defined above, or a pharmaceutical composition as defined above.

[0154] In embodiments, the method is a method of treating cancer.

[0155] In embodiments, the cancer is associated with a BRCA1 and / or BRCA2 mutation.

[0156] In embodiments, the cancer is associated with a mutation in ATM, ATR, BAP1, BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, or XRCC2, or any combination thereof.

[0157] In embodiments, the cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0158] In other aspects, the present invention provides a 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate, or a pharmaceutical composition as defined above, for use in a method as defined above. In an embodiment, it and the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate or the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate as defined above, or the pharmaceutical composition as defined above, are used in the method as defined above.

[0159] In other aspects, the present invention provides the use of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate as defined above, or a pharmaceutical composition as described above in the preparation of a medicament for use in a method as defined above. In an embodiment, the present invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate, or a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate as defined above, or the use of a pharmaceutical composition as described above in the preparation of a medicament for use in a method as defined above. BRIEF DESCRIPTION OF THE DRAWINGS

[0160] Figure 1 An exemplary XRPD pattern of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) p-toluenesulfonic acid monohydrate used in Example 10 is shown.

[0161] Figure 2 Shown is an exemplary FT-IR spectrum of crystalline Form 1 of the (1R,3S)-(+)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0162] Figure 3 Shown is an exemplary XRPD pattern of crystalline Form 1 of the (1R,3S)-(+)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0163] Figure 4 Shown is an exemplary XRPD pattern of crystalline Form 1 of the (1R,3S)-(+)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) after storage at 40°C and 75% relative humidity for 24 h.

[0164] Figure 5 Shown is an exemplary differential scanning calorimetry graph of crystalline Form 1 of the (1R,3S)-(+)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0165] Figure 6 Shown is an exemplary scanning gravimetric vapor sorption thermogram of crystalline Form 1 of the (1R,3S)-(+)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0166] Figure 7 Visible light microscopy images of crystalline Form 1 of the (1R,3S)-(+)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) are shown (top: non-polarized; bottom: polarized).

[0167] Figure 8 Shown is an exemplary FT-IR spectrum of crystalline Form 1 of the (1S,3R)-(-)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0168] Fig. 9Shown is an exemplary XRPD pattern of crystalline Form 1 of the (1S,3R)-(-)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0169] Fig.10 Shown is an exemplary XRPD pattern of crystalline Form 1 of the (1S,3R)-(-)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) after storage at 40°C and 75% relative humidity for 24 h.

[0170] Fig.11 Shown is an exemplary differential scanning calorimetry graph of crystalline Form 1 of the (1S,3R)-(-)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0171] Fig.12 Shown is an exemplary scanning gravimetric vapor sorption thermogram of crystalline Form 1 of the (1S,3R)-(-)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0172] Fig.13 Visible light microscopy images of crystalline Form 1 of the (1S,3R)-(-)-camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) are shown (top: non-polarized; bottom: polarized).

[0173] Fig.14 Shown is an exemplary FT-IR spectrum of the (R)-(-)-mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0174] Fig.15 Shown is an exemplary XRPD pattern of crystalline Form 1 of the (R)-(-)-mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0175] Fig.16 Shown is an exemplary XRPD pattern of crystalline Form 1 of the (R)-(-)-mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) after storage at 40°C and 75% relative humidity for 24 h.

[0176] Fig.17Shown is the structure of the (R)-(-)-mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib), determined by single crystal X-ray crystallography.

[0177] Fig.18 Shown is an exemplary differential scanning calorimetry graph of crystalline Form 1 of the (R)-(-)-mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0178] Fig.19 Shown is an exemplary dynamic vapor sorption thermogram of crystalline Form 1 of the (R)-(-)-mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0179] Fig. 20 Visible light microscopy images of crystalline Form 1 of the (R)-(-)-mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) are shown (top: non-polarized light; bottom: polarized light).

[0180] Fig.21 Shown is an exemplary FT-IR spectrum of crystalline Form 1 of the (1S)-(+)-camsylate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0181] Fig. 22 Shown is an exemplary XRPD pattern of crystalline Form 1 of the (1S)-(+)-camsylate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0182] Fig.23 Shown is an exemplary XRPD pattern of crystalline Form 1 of the (1S)-(+)-camsylate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) after storage at 40°C and 75% relative humidity for 24 h.

[0183] Fig.24 Shown is an exemplary differential scanning calorimetry graph of crystalline Form 1 of the (1S)-(+)-camsylate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0184] Fig.25Shown is an exemplary scanning gravimetric vapor sorption thermogram of crystalline Form 1 of the (1S)-(+)-camsylate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib).

[0185] Fig.26 Visible light microscopy images of crystalline Form 1 of the (1S)-(+)-camsylate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) are shown (top: non-polarized light; bottom: polarized light).

[0186] Detailed description

[0187] Although specific embodiments of the present disclosure will be described with reference to illustrations and examples, it should be understood that these embodiments are exemplary only and set forth only a few of the many possible specific embodiments that may represent applications of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art, given the benefit of this disclosure, and are considered to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0188] definition

[0189] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art belonging to the disclosure. Although any method and material similar or equivalent to those described herein can be used to implement or test the present invention, exemplary methods, equipment and materials are currently described. All technical and patent disclosures cited herein are incorporated herein by reference in their entirety. Any content herein is not to be construed as admitting that the present invention is not prior to the disclosed disclosure due to such disclosure of prior invention.

[0190] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art (see, e.g., Michael R. Green and Joseph Sambrook, Molecular Cloning; 4th ed., Cold Spring Harbor Laboratory Press 2012).

[0191] Numerical designations, such as pH values, temperatures, times, concentrations, molecular weights, etc. (including ranges) are approximate values ​​varying (+) or (-) in increments of 0.1 or 1.0, as appropriate. It should be understood that, although not always explicitly stated, all numerical designations are preceded by the term "about". It should also be understood that, although not always explicitly stated, the agents described herein are exemplary only and their equivalents are known in the art.

[0192] Unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" as used in this specification and claims include plural references. For example, the term "a cell" includes a plurality of cells, including mixtures thereof. Unless explicitly stated or obvious from the context, the term "or" as used herein should be understood to be inclusive. The term "including" as used herein means and is used interchangeably with the phrase "including but not limited to".

[0193] As used herein, and unless otherwise specified, the terms "about" and "approximately" when used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form, mean a dose, amount, or weight percentage considered by those skilled in the art to provide a pharmacological effect equivalent to that obtained by a specified dose, amount, or weight percentage. Specifically, when the terms "about" and "approximately" are used in this context, they encompass doses, amounts, or weight percentages within 15%, more specifically within 10%, and more specifically within 5% of a specified dose, amount, or weight percentage. As used herein, and unless otherwise specified, when the terms "about" and "approximately" are used in connection with a value or range of values ​​provided to characterize a particular solid form (e.g., a specific temperature or temperature range, such as describing a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as a mass change as a function of temperature and humidity; a solvent or water content, such as expressed in mass or percentage; or a peak position or diffraction angle, such as in an analysis by IR or Raman spectroscopy or XRPD), it indicates that the value or range of values ​​may vary to an extent that is considered reasonable by one skilled in the art but still describes the particular solid form. Specifically, in particular embodiments, when the terms "about" and "approximately" are used in this context, it indicates that the value or range of values ​​may vary by 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For XRPD, if a value is not expressed as a specific value, it is given as ±0.2 degrees 2θ.

[0194] As used herein, the terms "comprising" or "including" are intended to mean that compositions and methods include the listed elements, but do not exclude other elements. When "consisting essentially of..." is used to define compositions and methods, it should be meant that other elements that have any significance for the combination for the stated purpose are not included. Thus, a composition consisting essentially of the elements as defined herein will not exclude impurities from separation and purification methods and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, etc. "Consisting of..." should mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of the present disclosure or process steps for producing the compositions or achieving the desired results. Embodiments defined by each of these transition terms are within the scope of the present invention. The use of the term "comprising" herein is intended to encompass and disclose corresponding statements in which the term "comprising" is replaced by "consisting essentially of..." or "consisting of..."

[0195] The term "subject" is used to refer to an animal, preferably a mammal, including a human or non-human. The terms "patient" and "subject" can be used interchangeably.

[0196] "Administration" as defined herein is a method of providing a drug or a composition containing the drug to a subject in a manner that results in the drug being in the subject's body. Such administration can be by any route, including, but not limited to, oral, transdermal (e.g., through the vaginal, rectal or oral mucosa), by injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal or into the central nervous system) or by inhalation (e.g., oral or nasal). Of course, pharmaceutical preparations are administered in a form suitable for each route of administration.

[0197] "Therapeutically effective amount" or "effective amount" is the amount of a pharmaceutical agent that achieves a pharmacological effect. The term "therapeutically effective amount" includes, for example, a prophylactic effective amount. An "effective amount" of niraparib is the amount required to achieve the desired pharmacological effect or therapeutic improvement without undue adverse side effects. The effective amount of niraparib will be selected by those skilled in the art depending on the specific patient and disease. It should be understood that the "effective amount" or "therapeutically effective amount" may vary with each subject due to variations in the metabolism of niraparib, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. As used herein, improving or alleviating the symptoms of a particular disease, disorder, or condition by administering a particular compound or pharmaceutical composition refers to any reduction in severity, delayed onset, slowed progression, or shortened duration, whether permanent or temporary, continuous or transient, attributed to or associated with the administration of the compound or composition.

[0198] As used herein, the terms "treat", "treating" or "treatment" include alleviating, alleviating or ameliorating a disease or condition (e.g., cancer), symptoms; preventing other symptoms; ameliorating or preventing metabolic causes of symptoms; inhibiting a disease or condition, such as arresting the development of a disease or condition; relieving a disease or condition; causing regression of a disease or condition; alleviating symptoms caused by a disease or condition; or prophylactically and / or therapeutically suppressing the symptoms of a disease or condition.

[0199] The term "suffering from" in connection with the term "treating" refers to a patient or individual who has been diagnosed with or is susceptible to a disease. A patient may also be referred to as being "at risk of having a disease" because of a history of the disease in their family tree or because of the presence of a genetic mutation associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.

[0200] As used herein, "weight percent," "wt %," "percent by weight," "% by weight," and variations thereof refer to the concentration of a substance as the weight of the substance divided by the total weight of the composition and multiplied by 100.

[0201] As used herein, the terms "amorphous", "amorphous form" and related terms mean that the substance, component or product in question is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, a sample comprising an amorphous substance may be substantially free of other amorphous forms and / or crystalline forms.

[0202] As used herein, the term "crystalline" and related terms when used to describe a substance, component, product or form means that the substance, component or product is substantially crystalline as determined by X-ray diffraction (see, e.g., Remington's Pharmaceutical Sciences, 22nd edition, Pharmaceutical Press, 2012; The United States Pharmacopoeia, 30th edition, 2011).

[0203] The terms "crystalline form", "crystal form" and related terms herein refer to a crystalline solid form comprising a compound, and may refer to a specific single component or multiple component crystalline forms, including, but not limited to, polymorphs, solvates, hydrates or other molecular complexes, salts, hydrates of salts or other molecular complexes of salts, or polymorphs thereof.

[0204] The terms "polymorph", "polymorphic form" and related terms herein refer to two or more crystalline forms containing the same molecule, molecules or ions. Due to the different arrangements or configurations of the molecules or ions in the crystal lattice, different polymorphs can have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate and / or vibration spectrum. The differences in the physical properties exhibited by polymorphs affect the following pharmaceutical parameters: such as storage stability, compressibility and density (important in formulation and product manufacturing) and dissolution rate (an important factor in bioavailability). Differences in stability can be caused by changes in chemical reactivity (e.g., differential oxidation, which causes a dosage form containing one polymorph to change color more quickly than a dosage form containing another polymorph) or mechanical changes (e.g., tablets are broken during storage due to the conversion of a kinetically favorable polymorph into a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to rupture under high humidity). Due to solubility / dissolution differences, some polymorphic transformations can result in a lack of efficacy in extreme cases, or in other extreme cases, toxicity, which can result in a higher or lower incidence of unwanted side effects, or in a change in the severity of unwanted side effects. In addition, the physical properties of the crystals can be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0205] If the counterion (especially the anion in the salt) mentioned herein has one or more stereoisomers, and the specific stereochemistry of the counterion is not mentioned, it is meant that the reference covers all stereoisomers of the counterion and mixtures thereof. Stereoisomers include enantiomeric and diastereomeric forms and mixtures thereof. For example, "mandelate" mentioned herein without a stereochemical name means (R)-α-hydroxyphenylacetic acid, (S)-α-hydroxyphenylacetic acid and mixtures thereof, including racemic mixtures thereof.

[0206] Techniques used to characterize the crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), melting point, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy (e.g., polarizing microscopy), hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, dynamic vapor sorption (DVS) and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. The exemplary experimental values ​​described herein may vary according to standard measurements in the art (such as the exemplary variations described herein).

[0207] Where a crystalline form is characterized by one or more XRPD diffraction angles, and unless otherwise indicated, it is understood that the XRPD pattern is obtained under standard conditions (e.g., as described herein) and that the 2θ values ​​may vary according to standard measurements in the art. For example, the 2θ values ​​recited herein may vary by ±0.2°. In addition, where a crystalline form is characterized by one or more specified XRPD diffraction angles, those diffraction angles will generally represent diffraction angles having a relative intensity of at least 1%, such as at least 2%, 5%, or 10%, within the diffraction pattern.

[0208]

[0066] Recitation of an embodiment of a variation or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0209] A composition or method provided herein can be combined with one or more of any other compositions and methods provided herein.

[0210] This article uses the following abbreviations:

[0211] ℃ = degrees Celsius

[0212] DMSO = dimethyl sulfoxide

[0213] DSC = Differential Scanning Calorimetry

[0214] ESI = Electrospray Ionization

[0215] FT-IR = Fourier transform-infrared (spectroscopy)

[0216] GVS = Gravimetric Vapor Sorption

[0217] h = hours

[0218] HPLC = High Pressure Liquid Chromatography

[0219] Hz = Hertz

[0220] 2-MeTHF = 2-methyltetrahydrofuran

[0221] MHz = megahertz;

[0222] min = minutes

[0223] MS = Mass Spectrometry

[0224] NMR = Nuclear Magnetic Resonance

[0225] rt / RT = room temperature

[0226] SXRD = Single Crystal X-ray Diffraction

[0227] TBME = tert-butyl methyl ether

[0228] THF = Tetrahydrofuran

[0229] Salt

[0230] The present invention relates to novel salt forms of the drug 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) which have desirable properties for use in pharmaceutical formulations, such as improved water solubility, low hygroscopicity and / or good stability.

[0231] Thus, the present invention provides a camphorate, mandelate or camphorsulfonate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib). In particular, the present invention provides a camphorate, mandelate or camphorsulfonate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) in crystalline form, as described in detail later herein.

[0232] Exemplary crystalline forms of salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) are also described herein. Exemplary X-ray powder diffraction (XRPD) patterns are also described herein. In embodiments, the XRPD pattern is detected using Cu K radiation. In embodiments, the XRPD pattern is characterized by certain diffraction angles (peaks) as described herein.

[0233] Niraparib camphorate

[0234] In one aspect, the present invention provides a camphorate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) ("niraparib camphorate"). In a preferred aspect, the present invention provides crystalline niraparib camphorate.

[0235] The camphorate may be selected from a crystalline form of a (1R, 3S)-(+)-camphorate, a crystalline form of a (1S, 3R)-(+)-camphorate, a crystalline form of a (+ / -)-camphorate, and a mixture thereof.

[0236] In one embodiment, the camphorate is (1R, 3S)-(+)-camphorate (hereinafter referred to as "(+)-camphorate"). The (+)-camphorate includes an ionized form of (1R, 3S)-(+)-camphoric acid having the following structure:

[0237]

[0238] From this aspect, it can be seen that the present invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (+)-camphorate, for example, crystalline forms of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (+)-camphorate. In an embodiment, the crystalline forms of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (+)-camphorate include, for example, Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (+)-camphorate as described herein.

[0239] In embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, and / or 15.2°. In other embodiments, the crystalline form of niraparib (+)-camphorate is characterized by at least two XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, and / or 15.2°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by at least three XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, and / or 15.2°. In other embodiments, the crystalline form of niraparib (+)-camphorate salt (crystalline Form 1) is characterized by at least four XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4° and / or 15.2°.

[0240] In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at a 2θ value of 16.2°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at a 2θ value of 17.5°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at 2θ values ​​of 16.2° and 17.5°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at 2θ values ​​of 16.2°, 17.5°, and 20.0°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at 2θ values ​​of 16.2°, 17.5°, 20.0°, and 13.4°. In embodiments, the crystalline form of niraparib (+)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, and 15.2°.

[0241] In embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction angles at 2θ values ​​of 20.4°, 21.6°, 24.0°, 11.7°, and / or 18.0°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by at least two XRPD diffraction angles at 2θ values ​​of 20.4°, 21.6°, 24.0°, 11.7°, and / or 18.0°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by at least three XRPD diffraction angles at 2θ values ​​of 20.4°, 21.6°, 24.0°, 11.7°, and / or 18.0°. In other embodiments, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by at least four XRPD diffraction angles at 2θ values ​​of 20.4°, 21.6°, 24.0°, 11.7° and / or 18.0°. In embodiments, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.4°, 21.6°, 24.0°, 11.7° and 18.0°.

[0242] In embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by one or more (e.g., six, seven, eight, nine, or ten) XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, and / or 18.0°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by at least six XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, and / or 18.0°. In other embodiments, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by at least seven XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7° and / or 18.0°. In other embodiments, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by at least eight XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7° and / or 18.0°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by at least nine XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7° and / or 18.0°.

[0243] In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, and 20.4°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, and 21.6°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, and 24.0°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, and 11.7°. In an embodiment, the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, and 18.0°.

[0244] In embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by one or more (e.g., ten, eleven, twelve, thirteen, fourteen, or fifteen) XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, 18.0°, 22.8°, 18.9°, 14.5°, 14.1°, and 14.8°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by at least ten; at least eleven; at least twelve; at least thirteen; or at least fourteen XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, 18.0°, 22.8°, 18.9°, 14.5°, 14.1° and / or 14.8°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, 18.0°, 22.8°, 18.9°, 14.5°, 14.1°, and 14.8°.

[0245] In embodiments, the crystalline form of niraparib (+)-camphorate salt (crystalline Form 1) is characterized by one or more (e.g., fifteen, sixteen, seventeen, eighteen, nineteen or twenty) XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, 18.0°, 22.8°, 18.9°, 14.5°, 14.1°, 14.8°, 27.6°, 26.9°, 6.5°, 22.3° and / or 24.5°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by at least fifteen; at least sixteen; at least seventeen; at least eighteen; or at least nineteen XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, 18.0°, 22.8°, 18.9°, 14.5°, 14.1°, 14.8°, 27.6°, 26.9°, 6.5°, 22.3°, and / or 24.5°. In other embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.2°, 17.5°, 20.0°, 13.4°, 15.2°, 20.4°, 21.6°, 24.0°, 11.7°, 18.0°, 22.8°, 18.9°, 14.5°, 14.1°, 14.8°, 27.6°, 26.9°, 6.5°, 22.3°, and 24.5°.

[0246] In any of the above-mentioned embodiments, the XRPD pattern of the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) may comprise one or more diffraction angles at 2θ values ​​of 14.8°, 18.0°, 22.8°, and 27.6°. In embodiments, the XRPD pattern of the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) comprises at least two diffraction angles at 2θ values ​​of 14.8°, 18.0°, 22.8°, and / or 27.6°. In other embodiments, the XRPD pattern of the crystalline form of the niraparib (+)-camphorate salt (crystalline Form 1) comprises at least three diffraction angles at 2θ values ​​of 14.8°, 18.0°, 22.8°, and / or 27.6°.

[0247] In embodiments, the XRPD pattern of the crystalline form of niraparib (+)-camphorate (crystalline Form 1) comprises diffraction angles at 2θ values ​​of 18.0° and / or 22.8°. In other embodiments, the XRPD pattern of the crystalline form of niraparib (+)-camphorate (crystalline Form 1) comprises diffraction angles at 2θ values ​​of 14.8°, 18.0°, and 22.8°. In other embodiments, the XRPD pattern of the crystalline form of niraparib (+)-camphorate (crystalline Form 1) comprises diffraction angles at 2θ values ​​of 18.0°, 22.8°, and 27.6°. In other embodiments, the XRPD pattern of the crystalline form of niraparib (+)-camphorate (crystalline Form 1) comprises diffraction angles at 2θ values ​​of 14.8°, 18.0°, 22.8°, and 27.6°.

[0248] In embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles having substantially the 2θ values ​​(and, optionally, relative intensity values) as listed in Table 1 of Example 4. In embodiments, the position of the XRPD diffraction angles is within the range of ±0.2000° 2θ of the values ​​specified in Table 1 and / or the d-spacing is within the values ​​specified in Table 1. Or the value specified in Table 1 In an embodiment, the height and / or area of ​​the diffraction angle is within the range of ±10% of the value specified in Table 1 or ±5% of the value specified in Table 1. In an embodiment, the relative intensity is within the range of ±10% of the value specified in Table 1 or ±5% of the value specified in Table 1.

[0249] In an embodiment, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized as (or substantially as) Figure 3 XRPD pattern shown in .

[0250] In embodiments, the crystalline form of niraparib (+)-camphorate (Crystal Form 1) is characterized by a melting point of about 260° C. to about 270° C. In embodiments, the crystalline form of niraparib (+)-camphorate (Crystal Form 1) is characterized by a melting point of about 264° C.

[0251] For example, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) may be characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 264° C. and / or wherein the minimum of the peak is about 268° C. In embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) may be characterized by having (or substantially having) Figure 5 DSC thermogram shown in .

[0252] In an embodiment, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by having an infrared spectrum including a peak at about 3359 cm -1 The peak is at about 1693cm -1 The peak is at about 1649cm -1 In an embodiment, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by having (or substantially having) Figure 2 FT-IR spectrum shown in .

[0253] In an embodiment, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by being not hygroscopic. Hygroscopicity can be determined, for example, by GVS (e.g., as described in the Examples below). Thus, in an embodiment, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) can be characterized by absorbing less than 1% by weight of water at up to 90% relative humidity (e.g., at 25° C.). In an embodiment, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) is characterized by absorbing about 0.3% by weight of water at up to 90% relative humidity (e.g., at 25° C.). In an embodiment, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) can be characterized as (or substantially as) Figure 6 GVS thermogram shown in .

[0254] In embodiments, the crystalline form of niraparib (+)-camphorate (crystalline Form 1) may be characterized as being stable under conditions of elevated temperature and / or humidity.

[0255] In embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or 100%) of the crystalline form of niraparib (+)-camphorate (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at room temperature (e.g., about 25°C). In other embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or about 100%) of the crystalline form of niraparib (+)-camphorate (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at an elevated temperature (e.g., about 30°C, 40°C, 50°C, 60°C, or 75°C).

[0256] The crystalline form of niraparib (+)-camphorate (crystalline Form 1) may be further characterized by any combination of characteristic stability, melting point, FT-IR spectrum, differential scanning calorimetry thermogram, gravimetric vapor sorption thermogram, or XRPD diffraction angle values ​​as described herein.

[0257] In embodiments, the molar ratio of niraparib to camphoric acid in the salt is about 1:1.

[0258] In another embodiment, the camphorate is (1S, 3R)-(-)-camphorate (hereinafter referred to as "(-)-camphorate"). (-)-camphorate includes an ionized form of (1S, 3R)-(-)-camphoric acid, which has the following structure:

[0259]

[0260] From this aspect, the present invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (-)-camphorate, for example, niraparib (-)-camphorate. In an embodiment, the crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (-)-camphorate includes crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (-)-camphorate, for example as described herein.

[0261] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, and 20.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least two XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, and / or 20.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least three XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, and / or 20.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least four XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1° and / or 20.2°.

[0262] In an embodiment, the crystalline form of the niraparib (-)-camphorate salt (crystalline Form 1) is characterized by an XRPD diffraction at a 2θ value of 20.3°. In an embodiment, the crystalline form of the niraparib (-)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3° and 17.4°. In an embodiment, the crystalline form of the niraparib (-)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, and 16.2°. In an embodiment, the crystalline form of the niraparib (-)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, and 15.1°. In an embodiment, the crystalline form of the niraparib (-)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, and 15.1°. In an embodiment, the crystalline form of the niraparib (-)-camphorate salt is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, and 20.2°.

[0263] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction at 2θ values ​​of 24.4°, 19.9°, 11.6°, 22.3°, and 22.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least two XRPD diffraction angles at 2θ values ​​of 24.4°, 19.9°, 11.6°, 22.3°, and / or 22.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least three XRPD diffraction angles at 2θ values ​​of 24.4°, 19.9°, 11.6°, 22.3°, and / or 22.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate salt (crystalline Form 1) is characterized by at least four XRPD diffraction at 2θ values ​​of 24.4°, 19.9°, 11.6°, 22.3° and / or 22.2°. In embodiments, the crystalline form of niraparib (-)-camphorate salt is characterized by XRPD diffraction angles at 2θ values ​​of 24.4°, 19.9°, 11.6°, 22.3° and 22.2°.

[0264] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by one or more (e.g., six, seven, eight, nine, or ten) XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, and / or 22.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate is characterized by at least six XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, and / or 22.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least seven XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3° and / or 22.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate is characterized by at least eight XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3° and / or 22.2°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least nine XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3° and / or 22.2°.

[0265] In an embodiment, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, and 24.4°. In an embodiment, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, and 19.9°. In an embodiment, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, and 11.6°. In an embodiment, the crystalline form of the niraparib (-)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, and 22.3°. In an embodiment, the crystalline form of the niraparib (-)-camphorate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, and 22.2°.

[0266] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by one or more (e.g., ten, eleven, twelve, thirteen, fourteen, or fifteen) XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, 22.2°, 13.4°, 16.0°, 26.9°, 6.5°, and 23.9°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by at least ten; at least eleven; at least twelve; at least thirteen; or at least fourteen XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, 22.2°, 13.4°, 16.0°, 26.9°, 6.5° and / or 23.9°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, 22.2°, 13.4°, 16.0°, 26.9°, 6.5°, and 23.9°.

[0267] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by one or more (e.g., fifteen, sixteen, seventeen, eighteen, nineteen or twenty) XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, 22.2°, 13.4°, 16.0°, 26.9°, 6.5°, 23.9°, 18.9°, 14.5°, 14.0°, 21.9° and 21.5°. In other embodiments, the crystalline form of niraparib (-)-camphorate is characterized by at least fifteen; at least sixteen; at least seventeen; at least eighteen; or at least nineteen XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, 22.2°, 13.4°, 16.0°, 26.9°, 6.5°, 23.9°, 18.9°, 14.5°, 14.0°, 21.9° and / or 21.5°. In other embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 20.3°, 17.4°, 16.2°, 15.1°, 20.2°, 24.4°, 19.9°, 11.6°, 22.3°, 22.2°, 13.4°, 16.0°, 26.9°, 6.5°, 23.9°, 18.9°, 14.5°, 14.0°, 21.9°, and 21.5°.

[0268] In any of the above-mentioned embodiments, the XRPD pattern of the crystalline form of niraparib (-)-camphorate (crystalline Form 1) may comprise diffraction angles at 2θ values ​​of 16.0° and / or 21.9°. In an embodiment, the XRPD pattern of the crystalline form of niraparib (-)-camphorate (crystalline Form 1) comprises a diffraction angle at a 2θ value of 16.0°. In other embodiments, the XRPD pattern of the crystalline form of niraparib (-)-camphorate (crystalline Form 1) comprises a diffraction angle at a 2θ value of 21.9°. In other embodiments, the XRPD pattern of the crystalline form of niraparib (-)-camphorate (crystalline Form 1) comprises diffraction angles at 2θ values ​​of 16.0° and 21.9°.

[0269] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by XRPD diffraction angles having substantially the 2θ values ​​(and, optionally, relative intensity values) as listed in Table 2 of Example 4. In embodiments, the position of the XRPD diffraction angles is within the range of ±0.2000° 2θ of the values ​​specified in Table 2 and / or the interplanar spacings are the values ​​specified in Table 2. or the values ​​specified in Table 2 In an embodiment, the height and / or area of ​​the diffraction angle is within the range of ±10% of the value specified in Table 2 or ±5% of the value specified in Table 2. In an embodiment, the relative intensity is within the range of ±10% of the value specified in Table 2 or ±5% of the value specified in Table 2.

[0270] In an embodiment, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized in that (or substantially as) Fig. 9 XRPD pattern shown in .

[0271] In embodiments, the crystalline form of niraparib (-)-camphorate (Crystal Form 1) is characterized by a melting point of about 220° C. to about 230° C. In embodiments, the crystalline form of niraparib (-)-camphorate (Crystal Form 1) is characterized by a melting point of about 226° C.

[0272] For example, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) may be characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 226° C. and / or wherein the minimum of the peak is about 230° C. In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) may be characterized by having (or substantially having) Fig.11 DSC thermogram shown in .

[0273] In an embodiment, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by having an infrared spectrum including a peak at about 3367 cm -1 The peak at about 1693cm -1 The peaks at about 1648 cm -1 In an embodiment, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized by having (or substantially having) Figure 8 FT-IR spectrum shown in .

[0274] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) is characterized as not being hygroscopic. Hygroscopicity can be determined, for example, by GVS (e.g., as described in the Examples below). Thus, in embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) can be characterized as absorbing less than 1% by weight of water at up to 90% relative humidity (e.g., at 25° C.). In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) can be characterized as absorbing about 0.2% by weight of water at up to 90% relative humidity (e.g., at 25° C.). In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) can be characterized as (or substantially as) Fig.12 GVS thermogram shown in .

[0275] In embodiments, the crystalline form of niraparib (-)-camphorate (crystalline Form 1) may be characterized as being stable under conditions of elevated temperature and / or humidity.

[0276] In embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or 100%) of the crystalline form of niraparib (-)-camphorate (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at room temperature (e.g., about 25°C). In other embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or 100%) of the crystalline form of niraparib (-)-camphorate (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at elevated temperature (e.g., about 30°C, 40°C, 50°C, 60°C, or 75°C).

[0277] The crystalline form of niraparib (-)-camphorate (crystalline Form 1) may be further characterized by any combination of the characteristic stability, melting point, FT-IR spectrum, differential scanning calorimetry thermogram, gravimetric vapor sorption thermogram, or XRPD diffraction angle values ​​as described herein.

[0278] In embodiments, the molar ratio of niraparib to camphoric acid in the salt is about 1:1.

[0279] Niraparib mandelate

[0280] In another aspect, the present invention provides a mandelate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) ("niraparib mandelate"). Mandelate salts include mandelic acid (α-hydroxyphenylacetic acid) in an ionized form. In a preferred aspect, the present invention provides a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate salt.

[0281] The mandelate salt may be selected from the group consisting of (R)-(-)-mandelate salt, (S)-(+)-mandelate salt, (rac)-mandelate salt, and mixtures thereof.

[0282] In one embodiment, the mandelate salt is (R)-(-)-mandelate salt. The (R)-(-)-mandelate salt comprises an ionized form of (R)-(-)-mandelic acid having the following structure:

[0283]

[0284] From this aspect, the present invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate, for example, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate. In an embodiment, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate includes 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate Form 1, for example as described herein.

[0285] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, and / or 17.6°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least two XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, and / or 17.6°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt is characterized by at least three XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, and / or 17.6°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least four XRPD diffraction angles with 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6° and / or 17.6°.

[0286] In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt is characterized by an XRPD diffraction angle at a 2θ value of 18.5°. In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at a 2θ value of 16.4°. In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at a 2θ value of 18.5° and 16.4°. In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by an XRPD diffraction angle at a 2θ value of 18.5°, 16.4°, and 17.4°. In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, and 8.6°. In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, and 17.6°.

[0287] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction angles at 2θ values ​​of 8.7°, 18.4°, 25.1°, 27.6°, and / or 13.7°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least two XRPD diffraction angles at 2θ values ​​of 8.7°, 18.4°, 25.1°, 27.6°, and / or 13.7°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least three XRPD diffraction angles at 2θ values ​​of 8.7°, 18.4°, 25.1°, 27.6°, and / or 13.7°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least four XRPD diffraction angles at 2θ values ​​of 8.7°, 18.4°, 25.1°, 27.6° and / or 13.7°. In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt is characterized by XRPD diffraction angles at 2θ values ​​of 8.7°, 18.4°, 25.1°, 27.6° and 13.7°.

[0288] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by one or more (e.g., six, seven, eight, nine, or ten) XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, and / or 13.7°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least six XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, and / or 13.7°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least seven XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6° and / or 13.7°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least eight XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6° and / or 13.7°. In other embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by at least nine XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6° and / or 13.7°.

[0289] In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, and 8.7°. In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, and 18.4°. In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, and 25.1°. In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, and 27.6°. In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, and 13.7°.

[0290] In embodiments, the crystalline form of (R)-(-)-mandelate salt of niraparib (crystalline Form 1) is characterized by one or more (e.g., ten, eleven, twelve, thirteen, fourteen or fifteen) XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, 13.7°, 8.4°, 28.7°, 28.0°, 4.3° and / or 21.5°. In other embodiments, the crystalline form of (R)-(-)-mandelate salt of niraparib (crystalline Form 1) is characterized by at least ten; at least eleven; at least twelve; at least thirteen; or at least fourteen XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, 13.7°, 8.4°, 28.7°, 28.0°, 4.3° and / or 21.5°. In other embodiments, the crystalline form of (R)-(-)-mandelate salt of niraparib (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, 13.7°, 8.4°, 28.7°, 28.0°, 4.3°, and 21.5°.

[0291] In embodiments, the crystalline form of (R)-(-)-mandelate salt of niraparib (crystalline Form 1) is characterized by one or more (e.g., fifteen, sixteen, seventeen, eighteen, nineteen or twenty) XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, 13.7°, 8.4°, 28.7°, 28.0°, 4.3°, 21.5°, 27.3°, 14.1°, 27.7°, 12.4° and / or 16.1°. In other embodiments, the crystalline form of (R)-(-)-mandelate salt of niraparib (crystalline Form 1) is characterized by at least fifteen; at least sixteen; at least seventeen; at least eighteen; or at least nineteen XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, 13.7°, 8.4°, 28.7°, 28.0°, 4.3°, 21.5°, 27.3°, 14.1°, 27.7°, 12.4° and / or 16.1°. In other embodiments, the crystalline form of (R)-(-)-mandelate salt of niraparib (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6°, 13.7°, 8.4°, 28.7°, 28.0°, 4.3°, 21.5°, 27.3°, 14.1°, 27.7°, 12.4°, and 16.1°.

[0292] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by XRPD diffraction angles having substantially the 2θ values ​​(and, optionally, relative intensity values) listed in Table 3 of Example 4. In embodiments, the position of the XRPD diffraction angles is within the range of ±0.2000° 2θ of the values ​​specified in Table 3 and / or the interplanar spacings are within the values ​​specified in Table 3. or the value specified in Table 3 In an embodiment, the height and / or area of ​​the diffraction angle is within the range of ±10% of the value specified in Table 3 or within the range of ±5% of the value specified in Table 3. In an embodiment, the relative intensity is within the range of ±10% of the value specified in Table 3 or within the range of ±5% of the value specified in Table 3.

[0293] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by an XRPD pattern as (or substantially as) shown in Table 15.

[0294] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (Crystal Form 1) is characterized by a melting point of about 190° C. to about 200° C. In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (Crystal Form 1) is characterized by a melting point of about 197° C.

[0295] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 197° C. and / or wherein the minimum of the peak is about 201° C. In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by having (or substantially having) Fig.18 DSC thermogram shown in .

[0296] In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by having an infrared spectrum including a wavelength of about 3443 cm -1 The peak at about 3340cm -1 The peak at about 1671cm -1 The peaks at about 1638 cm -1 In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by having (or substantially having) Fig.14 FT-IR spectrum shown in .

[0297] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by being not hygroscopic. Hygroscopicity can be determined, for example, by GVS (e.g., as described in the Examples below). Thus, in embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) can be characterized by absorbing less than 1% by weight of water at up to 90% relative humidity (e.g., at 25°C). In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized by absorbing about 0.5% by weight of water at up to 90% relative humidity (e.g., at 25°C). In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) is characterized as (or substantially as) Fig.19 DVS thermogram shown in .

[0298] In embodiments, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) may be characterized as being stable under conditions of elevated temperature and / or humidity.

[0299] In embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or 100%) of the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at room temperature (e.g., about 25°C). In other embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or 100%) of the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at elevated temperature (e.g., about 30°C, 40°C, 50°C, 60°C, or 75°C).

[0300] In an embodiment, the crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) may be characterized as (or substantially as) Fig.18 The structure shown in .

[0301] The crystalline form of niraparib (R)-(-)-mandelate salt (crystalline Form 1) may be further characterized by any combination of the characteristic stability, melting point, FT-IR spectrum, differential scanning calorimetry thermogram, dynamic scanning vapor sorption thermogram, structure determined by single crystal X-ray crystallography, or XRPD diffraction angle values ​​as described herein.

[0302] Niraparib camphorsulfonate

[0303] In another aspect, the present invention provides a camphorsulfonate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) ("niraparib camphorsulfonate"). Camphorsulfonates include 7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid in ionized form. In a preferred aspect, the present invention provides a crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate salt.

[0304] The camphorsulfonate may be selected from (1S)-(+)-camphorsulfonate, (1R)-(-)-camphorsulfonate, (rac)-camphorsulfonate, and mixtures thereof.

[0305] In one embodiment, the camphorsulfonate is (1S)-(+)-camphorsulfonate. The (1S)-(+)-camphorsulfonate includes an ionized form of (1S)-(+)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid having the following structure:

[0306]

[0307] From this aspect, the present invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate, for example, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate. In an embodiment, a crystalline form of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate includes, for example, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate Form 1 as described herein.

[0308] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, and / or 24.6°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate is characterized by at least two XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, and / or 24.6°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by at least three XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, and / or 24.6°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by at least four XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3° and / or 24.6°.

[0309] In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by an XRPD diffraction angle at a 2θ value of 16.0°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by an XRPD diffraction angle at 2θ values ​​of 16.0° and 13.5°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by an XRPD diffraction angle at 2θ values ​​of 16.0° and 17.6°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by an XRPD diffraction angle at 2θ values ​​of 16.0°, 13.5°, and 17.6°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, and 24.3°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, and 24.6°.

[0310] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by one or more (e.g., one, two, three, four, or five) XRPD diffraction angles at 2θ values ​​of 11.1°, 16.4°, 23.7°, 16.7°, and / or 20.3°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by at least two XRPD diffraction angles at 2θ values ​​of 11.1°, 16.4°, 23.7°, 16.7°, and / or 20.3°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by at least three XRPD diffraction angles at 2θ values ​​of 11.1°, 16.4°, 23.7°, 16.7°, and / or 20.3°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate salt (crystalline Form 1) is characterized by at least four XRPD diffraction angles at 2θ values ​​of 11.1°, 16.4°, 23.7°, 16.7° and / or 20.3°. In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 11.1°, 16.4°, 23.7°, 16.7° and 20.3°.

[0311] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by one or more (e.g., six, seven, eight, nine, or ten) XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, and / or 20.3°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate is characterized by at least six XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, and / or 20.3°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate salt (crystalline Form 1) is characterized by at least seven XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7° and / or 20.3°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate salt (crystalline Form 1) is characterized by at least eight XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7° and / or 20.3°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by at least nine XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7° and / or 20.3°.

[0312] In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, and 11.1°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, and 16.4°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, and 23.7°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate salt is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, and 16.7°. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate salt (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, and 20.3°.

[0313] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by one or more (e.g., ten, eleven, twelve, thirteen, fourteen or fifteen) XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, 20.3°, 6.7°, 25.2°, 25.0°, 25.8° and / or 26.8°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate is characterized by at least ten; at least eleven; at least twelve; at least thirteen; or at least fourteen XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, 20.3°, 6.7°, 25.2°, 25.0°, 25.8° and / or 26.8°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, 20.3°, 6.7°, 25.2°, 25.0°, 25.8°, and 26.8°.

[0314] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by one or more (e.g., fifteen, sixteen, seventeen, eighteen, nineteen or twenty) XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, 20.3°, 6.7°, 25.2°, 25.0°, 25.8°, 26.8°, 22.8°, 9.5°, 16.9°, 14.3° and / or 7.7°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by at least fifteen; at least sixteen; at least seventeen; at least eighteen; or at least nineteen XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, 20.3°, 6.7°, 25.2°, 25.0°, 25.8°, 26.8°, 22.8°, 9.5°, 16.9°, 14.3° and / or 7.7°. In other embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by XRPD diffraction angles at 2θ values ​​of 16.0°, 13.5°, 17.6°, 24.3°, 24.6°, 11.1°, 16.4°, 23.7°, 16.7°, 20.3°, 6.7°, 25.2°, 25.0°, 25.8°, 26.8°, 22.8°, 9.5°, 16.9°, 14.3°, and 7.7°.

[0315] In any of the above-mentioned embodiments, the XRPD pattern of the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) may comprise one or more diffraction angles at 2θ values ​​of 6.7°, 16.4°, 23.7° and / or 25.2°. In embodiments, the XRPD pattern of the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) comprises at least two diffraction angles at 2θ values ​​of 6.7°, 16.4°, 23.7° and / or 25.2°. In other embodiments, the XRPD pattern of the crystalline form of niraparib (1S)-(+)-camsylate comprises at least three diffraction angles at 2θ values ​​of 6.7°, 16.4°, 23.7° and / or 25.2°.

[0316] In an embodiment, the XRPD pattern of the crystalline form of niraparib (1S)-(+)-camsylate (crystal Form 1) comprises a diffraction angle at a 2θ value of 16.4°. In an embodiment, the XRPD pattern of the crystalline form of niraparib (1S)-(+)-camsylate (crystal Form 1) comprises a diffraction angle at a 2θ value of 16.4° and 23.7°. In an embodiment, the XRPD pattern of the crystalline form of niraparib (1S)-(+)-camsylate (crystal Form 1) comprises a diffraction angle at a 2θ value of 6.7°, 16.4°, and 23.7°. In an embodiment, the XRPD pattern of the crystalline form of niraparib (1S)-(+)-camsylate (crystal Form 1) comprises a diffraction angle at a 2θ value of 6.7°, 16.4°, 23.7°, and 25.2°.

[0317] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by XRPD diffraction angles having substantially the 2θ values ​​(and, optionally, relative intensity values) as substantially listed in Table 4 of Example 4. In embodiments, the position of the XRPD diffraction angles is within the range of ±0.2000° 2θ of the values ​​specified in Table 4 and / or the interplanar spacing is within the range of ±0.2000° 2θ of the values ​​specified in Table 4. within the range or the values ​​specified in Table 4 In an embodiment, the height and / or area of ​​the diffraction angle is within the range of ±10% of the value specified in Table 4 or within the range of ±5% of the value specified in Table 4. In an embodiment, the relative intensity is within the range of ±10% of the value specified in Table 4 or within the range of ±5% of the value specified in Table 4.

[0318] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by an XRPD pattern as (or substantially as) shown in Table 22.

[0319] In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (Crystalline Form 1) is characterized by a melting point of about 235° C. to about 245° C. In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (Crystalline Form 1) is characterized by a melting point of about 239° C.

[0320] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 235° C. and / or wherein the minimum of the peak is about 246° C. In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate is characterized by having (or substantially having) Fig.24 DSC thermogram shown in .

[0321] In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by having an infrared spectrum including a wavelength of about 3467 cm -1 The peak at about 3306cm -1 The peak at about 1724cm -1 The peak at about 1660cm -1 The peaks are at about 1611cm -1 In an embodiment, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by having (or substantially having) Fig.21 FT-IR spectrum shown in .

[0322] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized as being slightly hygroscopic. Hygroscopicity can be determined, for example, by GVS (e.g., as described in the Examples below). Thus, in embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) can be characterized by absorbing less than 2% by weight of water at up to 90% relative humidity (e.g., at 25°C). In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized by absorbing about 1.3% by weight of water at up to 90% relative humidity (e.g., at 25°C). In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) is characterized as (or substantially as) Fig.25 GVS thermogram shown in .

[0323] In embodiments, the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) may be characterized as being stable under conditions of elevated temperature and / or humidity.

[0324] In embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or 100%) of the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at room temperature (e.g., about 25°C). In other embodiments, substantially all (e.g., at least 90%, at least 95%, at least 99%, or 100%) of the crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) remains in the same form (e.g., when assessed by XRPD) when it is exposed to 90% relative humidity at elevated temperature (e.g., about 30°C, 40°C, 50°C, 60°C, or 75°C).

[0325] The crystalline form of niraparib (1S)-(+)-camsylate (crystalline Form 1) may be further characterized by any combination of the characteristic stability, melting point, FT-IR spectrum, differential scanning calorimetry thermogram, gravimetric vapor sorption thermogram, or XRPD diffraction angle values ​​as described herein.

[0326] Solubility

[0327] The niraparib salts of the present invention have desirable properties for use in pharmaceutical formulations, including, in particular, desirable solubility. Viewed in this regard, the present invention provides 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate or 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate (e.g., as described herein) having a solubility of at least 1 mg / mL in an aqueous medium.

[0328] "Aqueous medium" means a liquid medium comprising water, and optionally one or more ionic species acting as a buffer and / or pH modifier. In the presence of another solvent, such as an organic solvent, in the medium, this preferably means a solution of less than 50% by volume (e.g., less than 20% by volume, less than 15% by volume, less than 10% by volume, less than 5% by volume, or less than 1% by volume). Exemplary aqueous media include water and the buffer solutions described in Example 10.

[0329] In an embodiment, the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salt has a solubility of at least 1 mg / mL in an aqueous medium, wherein the aqueous medium has a pH between 1 and 7. In an embodiment, the niraparib salt has a solubility of at least 1 mg / mL in an aqueous medium, wherein the aqueous medium has a pH between 1 and 5, such as between 1 and 3, between 1 and 2, or about 1. In other embodiments, the niraparib salt has a solubility of at least 1 mg / mL in an aqueous medium, wherein the aqueous medium has a pH of about 4.5 or about 6.8. In an embodiment, the aqueous medium has a pH below 7. In an embodiment, the aqueous medium is not composed solely of water.

[0330] In embodiments, the solubility of the niraparib salt is at least 1.2 mg / mL. In embodiments, the solubility of the niraparib salt is at least 1.5 mg / mL, for example, at least 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0 mg / mL. In embodiments, the solubility of the niraparib salt is at least 7 mg / mL, for example, at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / mL. In embodiments, the solubility of the niraparib salt is at least 25 mg / mL, for example, at least 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 mg / mL. In embodiments, the solubility of the niraparib salt is at least 125 mg / mL, for example, at least 150, 175 or 200 mg / mL.

[0331] In an embodiment, the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate (e.g., as defined herein, such as crystalline Form 1 of niraparib (1R, 3S)-(+)-camphorate) has a solubility of at least 1 mg / mL (e.g., about 1.2 mg / mL) in an aqueous medium having a pH of about 6.8. In an embodiment, the niraparib camphorate has a solubility of at least 10 mg / mL (e.g., at least 15 mg / mL, at least 20 mg / mL, or about 21 mg / mL) in an aqueous medium having a pH of about 1.

[0332] In an embodiment, the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate (e.g., a crystalline form as defined herein, such as a crystalline form of niraparib (R)-(-)-mandelate) has a solubility of at least 5 mg / mL (e.g., about 7.8 mg / mL) in an aqueous medium having a pH of about 6.8. In an embodiment, the niraparib mandelate has a solubility of at least 10 mg / mL in water (e.g., at least 20 mg / mL, at least 30 mg / mL, at least 40 mg / mL, or about 45 mg / mL). In an embodiment, the niraparib mandelate has a solubility of at least 20 mg / mL (e.g., at least 30 mg / mL, at least 40 mg / mL, at least 50 mg / mL, or about 54 mg / mL) in an aqueous medium having a pH of about 4.5. In embodiments, the niraparib mandelate has a solubility of at least 50 mg / mL (e.g., at least 75 mg / mL, at least 100 mg / mL, at least 125 mg / mL, at least 150 mg / mL, or about 163 mg / mL) in an aqueous medium having a pH of about 1.

[0333] In an embodiment, the 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camsylate (e.g., as defined herein, such as crystalline Form 1 of niraparib (1S)-(+)-camsylate) has a solubility of at least 1 mg / mL (e.g., at least 1.5 mg / mL or about 1.7 mg / mL) in an aqueous medium having a pH of about 6.8. In an embodiment, the niraparib camsylate has a solubility of at least 2.5 mg / mL (e.g., at least 3.0 mg / mL, at least 4.0 mg / mL, at least 5.0 mg / mL or about 5.9 mg / mL) in water. In embodiments, the niraparib camsylate has a solubility of at least 3.0 mg / mL (e.g., at least 4.0 mg / mL, at least 5.0 mg / mL, at least 6.0 mg / mL, or about 7.1 mg / mL) in an aqueous medium having a pH of about 4.5. In embodiments, the niraparib camsylate has a solubility of at least 5.0 mg / mL (e.g., at least 7.5 mg / mL, at least 10.0 mg / mL, or about 11.5 mg / mL) in an aqueous medium having a pH of about 1.

[0334] Methods for determining the solubility of a salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) as defined herein will be clear to those skilled in the art. In an embodiment, the method for determining the solubility of a salt as defined herein is the method as described in Example 10.

[0335] Pharmaceutical composition

[0336] In another aspect, the present invention provides a pharmaceutical composition comprising a camphorate, mandelate or camphorsulfonate salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (e.g., a salt as described herein), and at least one pharmaceutically acceptable excipient.

[0337] In an embodiment, the pharmaceutical composition comprises crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate (e.g., crystalline Form 1 of crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (+)-camphorate or crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (-)-camphorate as described herein). In an embodiment, the pharmaceutical composition comprises crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate (e.g., crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate as described herein). In an embodiment, the pharmaceutical composition comprises crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate (e.g., crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camphorsulfonate as described herein).

[0338] In an embodiment, the pharmaceutical composition comprises about 20-80 wt% of a niraparib salt, e.g., about 45-70 wt%, about 40-50 wt%, about 45-55 wt%, about 50-60 wt%, about 55-65 wt%, about 60-70 wt%, about 65-75 wt%, about 70-80 wt% or about 40-60 wt% of a niraparib salt (wherein the wt% is based on the weight of the niraparib free base, which is present in the salt as a percentage of the weight of the pharmaceutical composition).

[0339] The pharmaceutical composition comprises at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be any such excipient known in the art, including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro ed. 1985). The pharmaceutical composition of the compounds disclosed in the present invention may be prepared by conventional means known in the art, including, for example, mixing at least one compound disclosed in the present invention with a pharmaceutically acceptable excipient.

[0340] Exemplary pharmaceutically acceptable excipients for the purposes of the pharmaceutical compositions disclosed herein include, but are not limited to, binders, disintegrants, super disintegrants, lubricants, diluents, fillers, flavoring agents, glidants, absorbents, solubilizers, chelating agents, emulsifiers, thickeners, dispersants, stabilizers, suspending agents, adsorbents, granulating agents, preservatives, buffers, colorants and sweeteners or combinations thereof. In an embodiment, the pharmaceutically acceptable excipient includes hydroxypropyl methylcellulose, such as low-substituted hydroxypropyl cellulose. In an embodiment, the pharmaceutically acceptable excipient includes lactose, such as lactose monohydrate. In an embodiment, the pharmaceutically acceptable excipient includes magnesium stearate. In some embodiments, the pharmaceutically acceptable excipient is lactose monohydrate and magnesium stearate.

[0341] Various fillers or diluents may be used including, but not limited to, calcium carbonate (Barcroft TM 、MagGran TM Millicarb TM Pharma-Carb TM 、Precarb TM , Sturcal TM , Vivapres Ca TM ), Emcompress Anhydrous TM 、Fujicalin TM ), calcium hydrogen phosphate dihydrate (Calstar TM 、Di-Cafos TM 、Emcompress TM ), calcium phosphate (Tri-Cafos TM ,TRI-TAB TM ), calcium sulfate (Destab TM 、Drierite TM 、SnowWhite TM , Cal-Tab TM 、Compactrol TM ), powdered cellulose (Arbocel TM Elcema TM 、Sanacet TM ), silicified microcrystalline cellulose, cellulose acetate, compressible sugar (Di-Pac TM ), powdered sugar, dextran binder (Candex TM 、Emdex TM ), dextrin (Avedex TM 、Caloreen TM 、Primogran WTM ), dextrose (Caridex TM 、Dextrofin TM 、Tab fine D-IOO TM ), fructose TM 、Krystar TM ), Kaolin (Lion TM 、Sim 90 TM ), lactitol (Finlac DC TM 、Finlac MCX TM ), lactose (Anhydrox TM 、Capsulac TM 、Fast-Flo TM 、FlowLac TM 、Granulac TM 、InhaLac TM 、Lactochem TM 、Lactohaie TM 、Lactopress TM 、Microfme TM 、Microtose TM Pharmatose TM 、Prisma Lac TM 、Respitose TM 、SacheLac TM 、SorboLac TM 、Super-Tab TM 、Tablettose TM , Wyndale TM , Zeparox TM ), lactose monohydrate, magnesium carbonate, magnesium oxide (MagGran MO TM ), maltodextrin (C*Dry MD TM , Lycatab DSH TM 、Maldex TM Maitagran TM 、Maltrin TM 、Maltrin QD TM 、PaselliMD 10PH TM 、Star-Dri TM ), maltose (Advantose 100 TM ), Mannogem TM , Pearlitol TM), microcrystalline cellulose (Avicel PH TM 、Celex TM , Celphere TM , Ceolus KG TM 、Emcocel TM Pharmacel TM 、Tabulose TM , Vivapur TM ), Polydextrose (Litesse TM ), Simethicone (Dow Corning Q7-2243 LVA TM 、CowCorning Q7-2587 TM 、Sentry Simethicone TM ), Sodium Alginate TM 、Protanal TM ), sodium chloride (Alberger TM ), Sorbitol (Liponec 70-NC TM 、Liponic 76-NCv、Meritol TM 、Neosorb TM 、Sorbitol Instant TM , Sorbogem TM ), starch (Flufiex W TM 、Instant Pure-Cote TM Melojei TM , Meritena Paygel 55 TM 、Perfectamyl D6PH TM 、Pure-Cote TM 、Pure-Dent TM 、Pure-Gel TM 、Pure-Set TM 、Purity 21 TM 、Purity 826 TM 、Tablet White TM ), pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. In an embodiment, the filler comprises lactose monohydrate.

[0342] In embodiments, the composition comprises about 5-90% filler by weight, for example, the filler is present in an amount of about 10-80%, about 15-70%, about 20-60% or about 25-50% by weight. For example, the composition may comprise about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% filler by weight. In embodiments, the composition comprises about 25mg to about 1000mg filler, for example, the filler is present in an amount of about 50mg to about 750mg, about 100mg to about 600mg, about 150mg to about 500mg or about 200mg to about 450mg. For example, the composition may comprise about 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or 500mg filler.

[0343] A variety of lubricants can be used including, but not limited to, calcium stearate (HyQual TM ), propylene glycol monostearate (Imwitor TM 191 and 900, Kessco GMS5 TM , 450 and 600, Myvaplex 600P TM 、Myvatex TM 、Rita GMS TM 、Stepan GMS TM , Tegin TM , Tegin TM 503 and 515, Tegin 4100 TM , Tegin M TM 、Unimate GMS TM ), Glyceryl Behenate (Compritol 888ATO TM ), palmityl stearin (Precirol ATO 5 TM ), hydrogenated castor oil (Castorwax MP 80 TM Croduret TM 、Cutina HR TM 、Fancol TM ,Simulsol 1293 TM ), Type I hydrogenated vegetable oil 0 (Sterotex TM 、Dynasan P60 TM 、Hydrocote TM , Lipovol HS-K TM 、Sterotex HM TM), magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides (Captex 300 TM 、Labrafac CC TM 、Miglyol 810 TM 、Neobee M5 TM , Nesatol TM 、Waglinol 3 / 9280 TM ), Pluronic TM 、Synperonic TM ), polyethylene glycol (Carbowax Sentry TM 、Lipo TM , Lipoxol TM 、Lutrol E TM Pluriol E TM ), Sodium Benzoate (Antimol TM ), sodium chloride, sodium lauryl sulfate (Elfan 240 TM 、Texapon Kl 2P TM )、Sodium stearyl fumarate (Pruv TM ), stearic acid TM 、industrene TM , Kortacid 1895 TM Pristerene TM ), Talc TM , Luzenac TM 、Luzenac Pharma TM 、Magsil Osmanthus TM 、0Magsil Star TM 、Superiore TM ), sucrose stearate (Surfhope SE Pharma D-1803F TM ) and zinc stearate (Hyqual TM ), or mixtures thereof. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, glyceryl behenate, polyethylene glycol, polyethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silicon dioxide. In an embodiment, the lubricant comprises magnesium stearate.

[0344] In embodiments, the composition comprises about 0.1-5% by weight of a lubricant, such as the lubricant is present in an amount of about 0.2-2%, about 0.3-1%, about 0.4-0.75%, or about 0.5-0.7% by weight. For example, the composition may comprise about 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, or 0.8% by weight of a lubricant. In an embodiment, the composition comprises from about 0.01 mg to about 10 mg of lubricant, for example, the lubricant is present in an amount of about 0.01 mg to 0.05 mg, 0.05 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.25 mg, 0.25 mg to 0.5 mg, 0.5 mg to 0.75 mg, 0.7 mg to 0.95 mg, 0.9 mg to 1.15 mg, 1.1 mg to 1.35 mg, 1.3 mg to 1.5 mg, 1.5 mg to 1.75 mg, 1.75 to 1.95 mg, 1.9 mg to 2.15 mg, 2.1 mg to 2.35 mg, 2.3 mg to 2.55 mg, 2. The invention relates to an amount of at least one of the following: wherein the at least one of the following: said at least one of the following: said at least one of the following: said at least one of the following: said at least one of the following: said at least one of the following: said at least one of the following: said at least one of the following: said at least one of the following: said at least one of the following: For example, the composition can include about 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1.1 mg, 1.3 mg, 1.5 mg, 1.7 mg, 1.9 mg, 2. mg, 2.3 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.1 mg, 3.3 mg, 3.5 mg, 3.7 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, or 10.0 mg by weight of lubricant.

[0345] A variety of disintegrants can be used including, but not limited to, alginic acid (Protacid TM 、Satialgine H8 TM ), calcium phosphate (TRI-TAB TM ), carboxymethylcellulose calcium (ECG 505 TM), sodium carboxymethyl cellulose (Akucell TM 、Finnfix TM 、NymcelTylose CB TM ), colloidal silicon dioxide (Aerosil TM 、Cab-O-Sil TM 、Wacker HDK TM ), cross-linked carboxymethylcellulose sodium (Ac-Di-Sol TM Pharmacel XL TM 、Primellose TM , Solutab TM 、Vivasol TM ), cross-linked polyvinylpyrrolidone (Collison CL TM , Collison CL-M TM 、Polyplasdone XL TM ), docusate sodium, guar gum (Meyprodor TM 、Meyprofm TM 、Meyproguar TM ), low-substituted hydroxypropyl cellulose, magnesium aluminum silicate (Magnabite TM Neusilin TM 、Pharmsorb TM 、Veegum TM ), methylcellulose TM 、Metolose TM ), microcrystalline cellulose (Avicel PH TM , Ceoius KG TM , Emcoel TM Ethispheres TM Fibrocel TM Pharmacel TM , Vivapur TM ), Povidone (Collison TM 、Plasdone TM ), sodium alginate (Kelcosol TM , Ketone TM 、Protanal TM ), sodium starch glycolate, polyclinic potassium (Amberlite IRP88 TM ), silicified microcrystalline cellulose (Prosotv TM ), starch (Aytex P TM、Fluftex W TM Melojel TM 、Meritena TM 、Paygel 55 TM 、Perfectamyl D6PH TM 、Pure-Bind TM 、Pure-Cote TM 、Pure-Dent TM 、Purity 21 TM 、Purity 826 TM 、Tablet White TM ) or pregelatinized starch (Lycatab PGS TM Merigel TM 、National 78-1551 TM , Pharma-Gel TM 、Prejel TM 、Sepistab ST 200 TM 、Spress B820 TM 、Starch 1500G TM , Tablitz TM 、UnipureLD TM ), or mixtures thereof. In an embodiment, the composition comprises from about 0 to about 10% by weight of a disintegrant.

[0346] A variety of available glidants include, but are not limited to, calcium phosphate (TRI-TAB TM ), calcium silicate, powdered cellulose (Sanacel TM , Solka-Floe TM ), colloidal silicon dioxide (Aerosil TM 、Cab-O-Sil M-5P TM 、Wacker HDK TM ), magnesium silicate, magnesium trisilicate, starch (Melojel TM 、Meritena TM 、Paygel 55 TM 、Perfectamyl D6PH TM 、Pure-Bind TM 、Pure-Cote TM 、Pure-Dent TM 、Pure-Gel TM 、Pure-Set TM 、Purity 21 TM、Purity 826 TM 、Tablet White TM ) and talc (Luzenac Pharma TM 、Magsil Osmanthus TM 、Magsil Star TM 、Superiore TM ), or mixtures thereof. In an embodiment, the composition comprises from about 0 to about 15% by weight of a glidant.

[0347] Pharmaceutically acceptable surfactants include, but are limited to, nonionic and ionic surfactants used in pharmaceutical dosage forms. The ionic surfactants may include one or more of anionic, cationic or zwitterionic surfactants. A variety of available surfactants include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate, lecithin, stearyl alcohol, cetearyl alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamers or any other commercially available co-processed surfactants, such as 80 or 4000, and mixtures thereof. In an embodiment, the composition comprises from about 0 to about 5% by weight of a surfactant.

[0348] In an embodiment, a solid pharmaceutical composition of the present disclosure comprises a camphorate, mandelate or camphorsulfonate salt of niraparib (e.g., a salt as described herein), a diluent and a lubricant. In an embodiment, the solid pharmaceutical composition comprises a camphorate, mandelate or camphorsulfonate salt of niraparib (e.g., a crystalline salt as described herein), lactose monohydrate and magnesium stearate.

[0349] In an embodiment, a solid pharmaceutical composition of the present disclosure comprises (by weight of the composition) about 20-60% of a 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salt, about 20-80% of a diluent, and about 0.1-5% of a lubricant. In an embodiment, the pharmaceutical composition comprises (by weight of the composition) about 40-60% of the niraparib salt, about 40-70% of a diluent (e.g., lactose monohydrate), and about 0.2-2% of a lubricant (e.g., magnesium stearate).

[0350] The pharmaceutical composition can be formulated using, for example, hydroxypropylmethylcellulose in varying proportions (to provide the desired release characteristics), other polymer matrices, liposomes and / or microspheres to provide slow, delayed or controlled release of the active ingredient therein. The pharmaceutical composition may also optionally contain an opacifier and may be a composition that releases the active ingredient, optionally in a delayed manner, for example, only or preferentially in a certain portion of the gastrointestinal tract by using an enteric coating. Examples of embedding compositions include polymer matrices and waxes. If appropriate, the active ingredient may also be in microencapsulated form with one or more pharmaceutically acceptable carriers, excipients or diluents known in the art (see, for example, Remington's). The compounds disclosed herein may be formulated for sustained delivery according to methods known to those skilled in the art. Examples of these formulations can be found in U.S. Pat. Nos. 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.

[0351] synthesis

[0352] The 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salts of the present disclosure can be prepared, for example, from niraparib free base, for example, by slurrying niraparib free base in the presence of an appropriate acid.

[0353] The niraparib salts of the present disclosure in crystalline form can be prepared. A variety of techniques can be used to obtain salts in crystalline form. These techniques include self-solvent systems, such as by solvent evaporation, cooling and / or adding one or more anti-solvents (e.g., TBME) for preparation. These techniques may also include heating the salt, for example, close to or exceeding its melting point, and then cooling. Crystallization in solution can be implemented with or without seed crystals. Exemplary solvents for preparing crystalline salts of niraparib disclosed herein include acetone, acetonitrile, ethanol, ethyl acetate, methanol, THF, and mixtures thereof. In some cases, the crystalline salts of the present disclosure can be obtained by recrystallization from an organic solvent (e.g., methanol).

[0354] Methods for preparing the niraparib salts (including crystalline salts) of the present disclosure are demonstrated in the following examples.

[0355] Alternative methods for preparing the niraparib salts of the present disclosure and their crystalline forms are clear to those skilled in the art based on their common knowledge and the teachings of this application. For example, those skilled in the art will appreciate that the niraparib salts of the present disclosure in amorphous form can be obtained by, for example, spray drying a solution of the appropriate salt.

[0356] Medical indications

[0357] The 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salts and pharmaceutical compositions described herein can be used for treatment, in particular for therapeutic treatment of PARP-1 and PARP-2 mediated disorders in a subject. Methods for treating PARP-1 and PARP-2 mediated disorders are described in WO2018 / 005818.

[0358] In certain embodiments, the niraparib salts described herein can provide improved therapeutic benefits compared to the administration of different forms of niraparib (e.g., crystalline niraparib tosylate monohydrate). In embodiments, the improved therapeutic benefits can be changes (e.g., reductions) in the incidence and / or severity of unwanted side effects observed under different forms of niraparib. In embodiments, unwanted side effects are thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain / bloating, mucositis / stomatitis, diarrhea, dyspepsia, dry mouth, fatigue / fatigue, decreased appetite, urinary tract infection, AST / ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, taste disorders, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, or hypertension. In embodiments, unwanted side effects are hematological side effects (e.g., thrombocytopenia, anemia, neutropenia, or leukopenia). In embodiments, unwanted side effects are non-hematological side effects. In embodiments, the unwanted side effects are cardiovascular effects (e.g., palpitations). In embodiments, the unwanted side effects are gastrointestinal disorders (e.g., nausea, constipation, vomiting, abdominal pain / bloating, mucositis / stomatitis, diarrhea, dyspepsia, or dry mouth). In embodiments, the unwanted side effects are fatigue or weakness. In embodiments, the unwanted side effects are metabolic or nutritional disorders (e.g., decreased appetite). In embodiments, the unwanted side effects are infections or infections (e.g., urinary tract infections). In embodiments, the unwanted side effects are elevated AST / ALT. In embodiments, the unwanted side effects are musculoskeletal or connective tissue disorders (e.g., myalgia, back pain, arthralgia). In embodiments, the unwanted side effects are nervous system disorders (headache, dizziness, or taste disorders). In embodiments, the unwanted side effects are mental disorders (e.g., insomnia or anxiety). In embodiments, the unwanted side effects are respiratory, chest, or mediastinal disorders (e.g., nasopharyngitis, dyspnea, or cough). In embodiments, the unwanted side effects are skin or subcutaneous tissue disorders (e.g., rashes). In embodiments, the unwanted side effects are vascular disorders (e.g., hypertension).

[0359] In embodiments, the unwanted side effect is myelodysplastic syndrome / acute myeloid leukemia. In embodiments, the unwanted side effect is myelosuppression.

[0360] Patients treated according to the methods described herein include vertebrates, such as mammals. In preferred embodiments, the mammal is a human patient.

[0361] In one aspect, the present disclosure provides a camphorate, mandelate or camphorsulfonate salt of niraparib as described herein (e.g., a salt as described herein) for use in therapy. Also provided is the use of a camphorate, mandelate or camphorsulfonate salt of niraparib (e.g., a salt as described herein) in the manufacture of a medicament.

[0362] On the other hand, the present disclosure provides a method for treating cancer, stroke, autoimmune diabetes, neurological disease, inflammatory disease, metabolic disease or cardiovascular disease in a subject, the method comprising administering to the subject an effective amount of camphorate, mandelate or camphorsulfonate (e.g., a salt as described herein) of niraparib. Also provided is camphorate, mandelate or camphorsulfonate (e.g., a salt as described herein) of niraparib, which is used in a method for treating cancer, stroke, autoimmune diabetes, neurological disease, inflammatory disease, metabolic disease or cardiovascular disease. In addition, provided is the use of camphorate, mandelate or camphorsulfonate (e.g., a salt as described herein) of niraparib in the manufacture of a medicament for a method for treating cancer, stroke, autoimmune diabetes, neurological disease, inflammatory disease, metabolic disease or cardiovascular disease.

[0363] In another aspect, the present disclosure provides a method for treating a PARP-1 and / or PARP-2 mediated disorder in a subject, the method administering an effective amount of a camphorate, mandelate or camphorsulfonate salt of niraparib (e.g., a salt as described herein) to the subject. Also provided is a camphorate, mandelate or camphorsulfonate salt of niraparib (e.g., a salt as described herein) for use in a method for treating a PARP-1 and / or PARP-2 mediated disorder. Also provided is the use of a camphorate, mandelate or camphorsulfonate salt of niraparib (e.g., a salt as described herein) in the manufacture of a medicament for a method for treating a PARP-1 and / or PARP-2 mediated disorder.

[0364] Tumor diseases (cancer)

[0365] PARP inhibitors have demonstrated activity as monotherapy against tumors with existing DNA repair defects, such as BRCA1 and BRCA2, and as combination therapy when administered with anticancer agents that induce DNA damage. Despite several advances in the treatment of ovarian cancer, most patients eventually relapse and subsequent responses to additional treatment are often of limited duration. Women with germline BRCA1 or BRCA2 mutations are at increased risk for high-grade serous ovarian cancer (HGSOC), and their tumors appear to be particularly sensitive to treatment with PARP inhibitors. In addition, published scientific literature suggests that patients with platinum-sensitive HGSOC who do not have germline BRCA1 or BRCA2 mutations may also obtain clinical benefit from treatment with PARP inhibitors. Because PARP inhibitors block DNA repair, PARP inhibition causes synthetic lethality in cases where the cancer cells have BRCA mutations. For this reason, patients with germline mutations in the BRCA genes demonstrate significant clinical benefit following treatment with PARP inhibitors.

[0366] In one embodiment, the condition to be treated is cancer, particularly associated with DNA repair defects, such as associated with BRCA1 and / or BRCA2 mutations.

[0367] In embodiments, the cancer is a recurrent cancer.

[0368] In embodiments, the cancer is breast cancer, ovarian cancer, cervical cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, stomach cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, NSCLC, and SCLC), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancer, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, or In some embodiments, the present invention relates to a variety of malignant tumors, including hepatomas, leukemias, melanomas, sarcomas (e.g., liposarcoma), bladder cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., AML, CML, myelodysplastic syndrome, and promyelocytic leukemia), and lymphoid disorders (e.g., leukemias, multiple myeloma, mantle cell lymphoma, ALL, CLL, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma), which can be treated with the compounds and methods described herein.

[0369] The cancer can be selected from the group consisting of head and neck cancer, breast cancer (e.g., metastatic breast cancer), prostate cancer (e.g., metastatic prostate cancer), testicular cancer, ovarian cancer, endometrial cancer, colon cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), bladder cancer, pancreatic cancer (e.g., metastatic pancreatic cancer), brain and central nervous system cancers (e.g., primary malignant brain tumors), neuroendocrine cancers, rhabdoid cancer, gynecological cancers, peritoneal cancer, skin cancer, thyroid cancer, esophageal cancer, cervical cancer, gastric cancer, liver cancer, stomach cancer, renal cell carcinoma, biliary tract cancer, blood cancer, bone cancer, and hematological cancer.

[0370] In embodiments, the cancer is selected from colorectal cancer, colorectal cancer, head and neck cancer, seminoma, sarcoma, lung cancer, lung adenocarcinoma, bladder cancer, Barrett's adenocarcinoma, renal cancer, epidermoid carcinoma, and liver cancer. In embodiments, the cancer is selected from glioblastoma, astrocytoma, melanoma (e.g., metastatic melanoma), mesothelioma, myeloma, keratoacanthoma, neuroblastoma, histiocytic lymphoma, and lymphocytic leukemia. In embodiments, the cancer is a solid tumor (e.g., a malignant solid tumor), which may be an advanced solid tumor.

[0371] In embodiments, the cancer is a gynecological cancer, for example, selected from ovarian cancer, cancer of the fallopian tube, peritoneal cancer and breast cancer. In some embodiments, the gynecological cancer is associated with HRD and / or BRCA1 / 2 mutations. In some embodiments, the gynecological cancer is platinum-sensitive. In other embodiments, the gynecological cancer is not platinum-sensitive. In embodiments, the gynecological cancer previously had a (e.g., partial or complete) response to platinum-based therapy, but later developed resistance to platinum-based therapy.

[0372] In embodiments, the cancer is ovarian cancer (eg, epithelial ovarian cancer), cancer of the fallopian tube, or peritoneal cancer (eg, primary peritoneal cancer). In other embodiments, the cancer is breast cancer.

[0373] In some embodiments, the methods of the present invention treat subjects with ovarian cancer. In some embodiments, the methods of the present invention treat subjects with epithelial ovarian cancer. In some embodiments, the methods of the present invention treat subjects with fallopian tube cancer. In some embodiments, the methods of the present invention treat subjects with primary peritoneal cancer. In some embodiments, the methods of the present invention treat subjects with recurrent ovarian cancer. In some embodiments, the methods of the present invention treat subjects with recurrent epithelial ovarian cancer. In some embodiments, the methods of the present invention treat subjects with recurrent fallopian tube cancer. In some embodiments, the methods of the present invention treat subjects with recurrent primary peritoneal cancer.

[0374] In some embodiments, the methods of the present invention treat subjects with recurrent ovarian cancer after a complete or partial response to chemotherapy, such as platinum-based chemotherapy. In some embodiments, the methods of the present invention treat subjects with recurrent epithelial ovarian cancer after a complete or partial response to chemotherapy, such as platinum-based chemotherapy. In some embodiments, the methods of the present invention treat subjects with recurrent fallopian tube cancer after a complete or partial response to chemotherapy, such as platinum-based chemotherapy. In some embodiments, the methods of the present invention treat subjects with recurrent primary peritoneal cancer after a complete or partial response to chemotherapy, such as platinum-based chemotherapy.

[0375] In some embodiments, the methods of the present invention treat subjects with recurrent ovarian cancer, recurrent epithelial ovarian cancer, recurrent fallopian tube cancer, and / or recurrent primary peritoneal cancer after a complete or partial response to chemotherapy such as platinum-based chemotherapy, wherein the subject begins treatment no later than 8 weeks after their most recent platinum-containing regimen. For example, the subject may begin treatment with niraparib at about 7 weeks after their most recent platinum-containing course. For example, the subject may begin treatment with niraparib at about 6 weeks after their most recent platinum-containing course. For example, the subject may begin treatment with niraparib at about 6 weeks after their most recent platinum-containing course. For example, the subject may begin treatment with niraparib at about 5 weeks after their most recent platinum-containing course. For example, the subject may begin treatment with niraparib at about 4 weeks after their most recent platinum-containing course. For example, the subject may begin treatment with niraparib at about 3 weeks after their most recent platinum-containing course. For example, the subject may begin treatment with niraparib at about 2 weeks after their most recent platinum-containing course. For example, the subject can begin treatment with niraparib about 1 week after their most recent platinum-containing course of therapy.

[0376] In embodiments, the method treats cancer in a subject exhibiting a positive HRD state. In some embodiments, the subject is further characterized by the absence of mutations in BRCA1 and / or BRCA2. A positive HRD state can be determined by quantifying the number of regions indicating chromosomal aberrations in a patient sample. In some embodiments, a tumor sample from a subject has a positive HRD state.

[0377] In other embodiments, the method treats cancer in a subject exhibiting the absence of HRD (e.g., a subject with platinum-sensitive recurrent ovarian cancer). The absence of HRD can be characterized by the absence of chromosomal aberrations (changes in detectable chromosomal DNA that can fall into at least one of the following three overlapping categories: loss of heterozygosity, allelic imbalance (e.g., telomeric allelic imbalance), or large-scale transitions).

[0378] In embodiments, the methods described herein treat cancers associated with defects in at least one gene involved in a DNA repair pathway. There are multiple pathways for DNA repair, including base excision repair (BER), direct repair (DR), double-strand break (DSB) repair, homologous recombination repair (HRR), mismatch repair (MMR), nucleotide excision repair (NER), and non-homologous end joining (NHEJ) repair; interruptions in these pathways can lead to the development and / or growth of cancer (see, e.g., Kelley et al., Future Oncol. 10(7): 1215-1237), 2014.

[0379] Exemplary genes involved in DNA repair pathways are described in Table A.

[0380] Table A. DNA repair genes

[0381]

[0382]

[0383]

[0384]

[0385] In embodiments, the method treats cancer in a subject that exhibits the absence of germline mutations in BRCA1 and BRCA2. In some embodiments, the method treats cancer in a subject with a platinum-sensitive tumor that exhibits the absence of germline mutations in BRCA1 and BRCA2.

[0386] In one aspect, the invention features a method of treating cancer comprising: identifying a cancer patient having a defect in at least one gene listed in Table A.

[0387] In embodiments, the methods described herein treat cancer associated with a defect in at least one gene involved in the homologous recombination repair (HRR) pathway. In embodiments, the defect is a non-BRCA defect. In embodiments, the deficiency is in two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty-one or more, twenty-two or more, twenty-three or more, twenty-four or more, twenty-five or more, twenty-six or more, twenty-seven or more, twenty-eight or more, twenty-nine or more, or thirty or more genes selected from the group consisting of RFC2, XRCC6, POLD2, PCNA, RPA1, RPA2, ERCC3, UNG, ERCC5, MLH1, LIG1, MSH6, POLD4, RFC5, DDB2 / / / LHX3, POLD1, FANCG, POLB, XRCC1, MPG, ERCC1, TDG, FA NCA, RFC4, RFC3, APEX2, RAD1, EXO1, FEN1, MLH3, MGMT, RAD51, XRCC4, RECQL, ERCC8, FANCC, OGG1, MRE11A, RAD52, WR N, XPA, BLM, MSH3, POLE2, RAD51C, LIG4, ERCC6, LIG3, RAD17, , P276, POLE, XRCC3, NBN, SMUG1, FANCF, NEIL1, FANCE, ATM, ATR, BAP1, BARD1, BRIP1, PALB2, RAD51B, RAD51D and RAD54L.

[0388] In embodiments, cancer patients having a HRR defect due to at least one of the sixteen genes listed in Table B may benefit from the methods described herein.

[0389] Table B. Non-BRCA1 / 2 HRR pathway genes

[0390]

[0391] In embodiments, defects in genes involved in the HRR pathway are identified using a pre-specified gene set. In embodiments, the pre-specified gene set comprises the genes listed in Table A or Table B, or any combination thereof. In embodiments, the pre-specified gene set comprises: at least one of ATM, ATR, BAP1, BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, and XRCC2, and any combination thereof; and at least one of BRCA1 and BRCA2. In embodiments, the pre-specified gene set comprises: each of ATM, ATR, BAP1, BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, and XRCC2; and at least one of BRCA1 and BRCA2. In an embodiment, the pre-specified gene set comprises ATM, ATR, BAP1, BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, XRCC2, BRCA1, and BRCA2.

[0392] In embodiments, the method is a monotherapy treatment. In other embodiments, the method is a combination therapy treatment.

[0393] In embodiments, the method is a combination therapy treatment, wherein the camphorate, mandelate or camphorsulfonate (for example, salt as described herein) of niraparib is combined with a second therapy that induces DNA damage. In embodiments, the second therapy comprises radiosensitization (administering ionizing radiation) and / or chemotherapy sensitization (administering one or more DNA damaging agents). The DNA damaging agent can be, for example, selected from DNA methylating agents (such as dacarbazine or temozolomide), topoisomerase I inhibitors (such as camptothecin, topotecan or irinotecan) and cytotoxic agents (such as platinum-based drugs, such as cisplatin or carboplatin). The niraparib salt can be administered before, during and / or after the second therapy treatment. The scheme of these combination therapies can be easily determined by clinicians.

[0394] Non-neoplastic conditions

[0395] In an embodiment, the method of the present invention is used to treat a condition in a subject selected from a neurological or neurodegenerative disease, an inflammatory disease, a metabolic disease, and a cardiovascular disease or condition. Examples of these diseases are described by Curtin et al. (Mol Aspects Med. (2013) 34 (6): 1217-1256).

[0396] In one embodiment, the method treats a subject having or at risk of having a stroke. In another embodiment, the method treats a subject having a traumatic brain injury. In another embodiment, the method treats a subject having or at risk of having autoimmune diabetes.

[0397] In embodiments, the neurodegenerative disease is Parkinson's disease. In embodiments, the inflammatory disease is asthma or multiple sclerosis. In embodiments, the cardiovascular disease or disorder is myocardial infarction, circulatory shock, multiple injury, or acute respiratory distress syndrome.

[0398] Administration and Dosage

[0399] 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salts as described herein can be formulated as pharmaceutical compositions for oral, buccal, parenteral (e.g., intravenous, intraperitoneal, intramuscular or subcutaneous), topical, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation. These modes of administration and methods of preparing appropriate pharmaceutical compositions are described, for example, in Gibaldi's Drug Delivery Systems in Pharmaceutical Care (1st edition, American Society of 15 Health-System Pharmacists 2007).

[0400] In an embodiment, an exemplary administration regimen for niraparib is to take one or more 100 mg doses orally once daily (e.g., two doses equivalent to a total daily dose of 200 mg or three doses equivalent to a total daily dose of 300 mg). Patients may be encouraged to take their doses at approximately the same time each day. Bedtime administration may be a potential method for controlling nausea.

[0401] In some embodiments, the methods of the invention are administered once daily, twice daily, or three times daily at 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg to 275 mg, 300 mg, 325 mg, 350 mg or a pharmaceutically acceptable salt thereof to treat a subject having cancer. In some embodiments, the methods of the invention treat a subject having cancer with a dose of 150 mg to 175 mg, 170 mg to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 to 295 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, or 370 mg to 400 mg of niraparib or a pharmaceutically acceptable salt thereof once daily, twice daily, or three times daily. In some embodiments, the methods of the invention treat a subject having cancer with a dose of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of niraparib or a pharmaceutically acceptable salt thereof once daily, twice daily, or three times daily.

[0402] In some embodiments, the methods of the invention use about 1 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 25 mg, 35 mg to 50 mg, 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 2 30mg to 255mg, 250mg to 275mg, 270mg to 300mg, 290mg to 315mg, 310mg to 335mg, 330mg to 355mg, 350mg to 375mg, 370mg to 400mg, 400mg to 450mg, 450mg to 500mg, 500mg to 550mg, 550mg to 600mg, 600mg to 650mg, 650mg to 700mg, 700mg to 750mg, 750mg to 800mg g to 800 mg, 800 mg to 850 mg, 850 mg to 900 mg, 900 mg to 950 mg, 950 mg to 1000 mg, 1000 mg to 1050 mg, 1050 mg to 1100 mg, 1100 mg to 1150 mg, 1150 mg to 1200 mg, 1200 mg to about 1250 mg, 1250 mg to 1300 mg, 1300 mg to 1350 mg, 1350 mg to 1400 mg, 1400 mg to 1450 mg , 1450 mg to 1500 mg, 1500 mg to 1550 mg, 1550 mg to 1600 mg, 1600 mg to 1650 mg, 1650 mg to 1700 mg, 1700 mg to 1750 mg, 1750 mg to 1800 mg, 1800 mg to 1850 mg, 1850 mg to 1900 mg, 1900 mg to 1950 mg, or 1950 mg to 2000 mg of niraparib, or a pharmaceutically acceptable salt thereof, to treat a subject having cancer.In some embodiments, the methods of the invention use about 5 mg to 7.5 mg, 7 mg to 9.5 mg, 9 mg to 11.5 mg, 11 mg to 13.5 mg, 13 mg to 15.5 mg, 15 mg to 17.5 mg, 17 to 19.5 mg, 19 mg to 21.5 mg, 21 mg to 23.5 mg, 23 mg to 25.5 mg, 25 mg to 27.5 mg, 27 mg to 30 mg once daily, twice daily, or three times daily. , 30 mg to 35 mg, 35 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 to 65 mg, 65 mg to 70 mg, 70 mg to 75 mg, 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or 95 mg to 100 mg of niraparib or a pharmaceutically acceptable salt thereof to treat a subject having cancer.

[0403] In a preferred embodiment, the niraparib salt is formulated for oral administration, for example in solid form.

[0404] In a preferred embodiment, the pharmaceutical composition is an oral composition, more preferably a solid oral dosage form, such as a tablet, capsule, powder, granule or sachet. The oral composition can be provided in the form of a unit dosage form, wherein one or more of the unit doses are combined together to provide an effective amount for administration to a subject.

[0405] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable excipients as described herein. In the case of capsules, tablets and pills, the pharmaceutical composition may also include a buffer. Similar types of solid compositions may also be prepared in soft and hard filled gelatin capsules using fillers and excipients (such as lactose or milk sugar), and high molecular weight polyethylene glycols, etc. As an example, wherein the pharmaceutical composition is provided in capsule form, the composition may include one or more components, which are combined to produce a powder mixture for filling the capsule. The powder mixture may, for example, be filled into a gelatin capsule, such as a size 0 gelatin capsule. In this case, the term "pharmaceutical composition" is generally understood to refer to the contents of the capsule, i.e., the powder mixture.

[0406] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant and / or a dispersant. Molded tablets can be made by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. The tablets and other solid dosage forms (e.g., dragees, capsules, pills, and granules) can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the art.

[0407] In an embodiment, a solid dosage form for administering a therapeutically effective amount of niraparib to a subject comprises a niraparib salt in an amount of about 1 mg to about 1000 mg (based on the weight of the niraparib free base equivalent in the salt). In an embodiment, the solid dosage form comprises about 25 mg to about 750 mg of a niraparib salt, for example, about 50 mg to about 500 mg, about 60 mg to about 400 mg, or about 75 mg to about 300 mg (based on the weight of the niraparib free base equivalent in the salt). In other embodiments, the solid dosage form comprises about 50 mg to about 300 mg of a niraparib salt (based on the weight of the niraparib free base equivalent in the salt). In an embodiment, the solid dosage form comprises about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, or 350 mg of a niraparib salt (based on the weight of the niraparib free base equivalent in the salt). In an embodiment, a solid dosage form for administering a therapeutically effective amount of niraparib to a subject comprises an amount of niraparib salt greater than about 100 mg (based on the weight of the niraparib free base equivalent in the salt). In an embodiment, the solid dosage form comprises greater than about 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, or 280 mg of a niraparib salt (based on the weight of the niraparib free base equivalent in the salt).

[0408] In an embodiment, the solid dosage form is presented as one, two or three unit doses. In an embodiment, the solid oral dosage form is administered once, twice or three times a day so that a therapeutically effective amount of niraparib is used in a method as described herein. In a preferred embodiment, the solid dosage form presents a single unit dose, which is administered once a day, i.e., it provides a therapeutically effective daily dose of niraparib (such as, the amount of a salt equivalent to about 300 mg of niraparib free base). In another preferred embodiment, the solid dosage form is presented as two unit doses, which are administered together or separately, i.e., they work together to provide a therapeutically effective daily dose of niraparib (such as about 150 mg per unit dose). In another preferred embodiment, the solid dosage form is presented as three unit doses, which are administered together or separately, i.e., they work together to provide a therapeutically effective daily dose of niraparib (such as about 100 mg per unit dose).

[0409] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0410] In some embodiments, the pharmaceutical composition is administered by non-oral means, such as by topical application, transdermal application, injection, etc. In related embodiments, the pharmaceutical composition is administered parenterally by injection, infusion or implantation (e.g., intravenous, intramuscular, intraarterial, subcutaneous, etc.). In each case, the pharmaceutical composition is preferably stored and / or used in solid form in order to take advantage of the properties of the niraparib salt.

[0411] The pharmaceutical composition may be suitable for preparing an injectable formulation for parenteral administration (including using conventional catheter insertion techniques or infusion). The formulation for injection may be presented in a unit dosage form, such as in an ampoule or a multi-dose container, with an added preservative. The composition may take the form of a suspension or emulsion in an oily or aqueous medium, and may contain a preparatant, such as a suspending agent, a stabilizer and / or a dispersant as known to those skilled in the art. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

[0412] The pharmaceutical composition can be suitable for preparing sterile injectable preparations. These preparations can be sterilized by, for example, filtering through a bacteria-retaining filter, or by incorporating a sterilizing agent into a sterile solid composition, which can be dissolved in sterile water or some other sterile injectable medium just before use. To prepare these compositions, the active ingredient is dissolved or suspended in a parenterally acceptable liquid medium. Exemplary vehicles and solvents include, but are not limited to, water, water adjusted to a suitable pH value by adding an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. The pharmaceutical composition can also contain one or more preservatives, such as methylparaben, ethylparaben or n-propylparaben. To improve solubility, a dissolution enhancer or solubilizer can be added or the solvent can contain 10-60% w / w of propylene glycol, etc.

[0413] The pharmaceutical composition may contain one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders (which may be reconstituted into sterile injectable solutions or dispersions just before use). These pharmaceutical compositions may contain antioxidants; buffers; bacteriostats; solutes that make the preparation isotonic with the blood of the intended recipient; suspending agents; thickeners; preservatives, etc.

[0414] Examples of suitable aqueous and non-aqueous carriers (which can be used in the pharmaceutical compositions of the present invention) include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by using coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. In some embodiments, in order to prolong the effect of the active ingredient, it is necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline material with poor water solubility. The absorption rate of the active ingredient depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of the active ingredient administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. In addition, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0415] Controlled release parenteral compositions may be in the form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient may be incorporated into a biocompatible carrier, liposomes, nanoparticles, implants, or infusion devices. Materials for preparing microspheres and / or microcapsules include, but are not limited to, biodegradable / bioerodible polymers such as polysaccharides, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine), and poly(lactic acid). Biocompatible carriers that may be used when configuring controlled release parenteral formulations include carbohydrates (such as polydextrose), proteins (such as albumin, lipoproteins, or antibodies). Materials for implants may be non-biodegradable, such as polydimethylsiloxane, or biodegradable, such as poly(caprolactone), poly(lactic acid), poly(glycolic acid), or poly(orthoesters).

[0416] For topical administration, niraparib salts may be formulated as ointments or creams. The niraparib salts may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0417] For intranasal administration or administration by inhalation, niraparib salts can be conveniently delivered in the form of solutions or suspensions from a pump spray container that is squeezed or pumped by the patient, or in the form of an aerosol spray from a pressurized container or nebulizer, using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. The pressurized container or nebulizer can contain a solution or suspension. Capsules and cartridges (e.g., made of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of a niraparib salt and a suitable powder base (e.g., lactose or starch).

[0418] In a further aspect, the invention provides a dosage form or pharmaceutical composition as described herein for use in therapy, eg, for use in a method as defined herein.

[0419] In other aspects, the present invention provides an article (e.g., a kit) comprising a plurality of unit doses of a pharmaceutical composition as described herein in a sealed container having written instructions for use. In an embodiment, the article further comprises an induction seal, a desiccant, or a combination thereof.

[0420] Combination therapy

[0421] The crystalline forms of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salts described herein can be used as monotherapy or in combination therapy with administration of one or more additional therapeutic agents or series of therapies.

[0422] For example, the crystalline forms of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salts described herein can be administered in combination with surgery, radiation therapy, chemotherapy, immunotherapy, anti-angiogenic agents, or anti-inflammatory agents.

[0423] In the case where a crystalline form of a 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salt is administered in combination with one or more different therapeutic agents (e.g., as described herein), administration of the crystalline form of the niraparib salt can be sequential with administration of the one or more different therapeutic agents. For example, administration of the crystalline form of the niraparib salt is performed before administration of the one or more different therapeutic agents. In embodiments, administration of the crystalline form of the niraparib salt is performed after administration of the one or more different therapeutic agents. In other embodiments, administration of the crystalline form of the niraparib salt is performed simultaneously with administration of the one or more different therapeutic agents.

[0424] In embodiments, the crystalline form of the niraparib salt described herein is administered in combination with one or more immune checkpoint inhibitors. In embodiments, the checkpoint inhibitor is an agent capable of inhibiting any of the following: PD-1 (e.g., inhibited by anti-PD-1, anti-PD-L1 or anti-PD-L2 therapy), CTLA-4, TIM-3, TIGIT, LAG (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFRβ), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO or CSF-1R. In embodiments, the check point inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, or a toxin. In embodiments, the check point inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.

[0425] In the embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. In the embodiment, the PD-1 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof), a carbohydrate, a lipid, a metal, or a toxin. In the embodiment, the PD-1 inhibitor is a PD-1 binding agent (e.g., an antibody, an antibody conjugate, or an antigen-binding fragment thereof). In the embodiment, the PD-1 binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. In the embodiment, the PD-1 binding agent is TSR-042, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA01 2. BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010. In an embodiment, the PD-1 inhibitor is a PD-L1 or PD-L2 binding agent, such as durvalumab, atezolizumab, averumab, BGB-A333, SHR-1316, FAZ-053, CK-301 or PD-L1 millamolecule, or a derivative thereof. In an embodiment, the anti-PD-1 agent is pembrolizumab. In an embodiment, the anti-PD-1 agent is nivolumab. In some embodiments, the PD-1 antibody agent is disclosed in International Patent Application Publication No. WO2014 / 179664, No. WO2018 / 085468 or No. WO2018 / 129559. In other embodiments, the PD-1 antibody agent is administered according to the method disclosed in International Patent Application Publication No. WO2014 / 179664, No. WO2018 / 085468 or No. WO2018 / 129559. In an embodiment, the anti-PD-1 agent is TSR-042.

[0426] In the embodiment, the immune checkpoint inhibitor is a TIM-3 inhibitor. In the embodiment, the TIM-3 inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody, an antibody conjugate, or an antigen binding fragment thereof), a carbohydrate, a lipid, a metal, or a toxin. In the embodiment, the TIM-3 inhibitor is a TIM-3 binding agent (e.g., an antibody, an antibody conjugate, or an antigen binding fragment thereof). In the embodiment, the TIM-3 binding agent is an antibody, an antibody conjugate, or an antigen binding fragment thereof. In some embodiments, the TIM-3 antibody agent is MBG453, LY3321367, Sym023, TSR-022, or a derivative thereof. In some embodiments, the TIM-3 antibody agent is disclosed in International Patent Application Publication No. WO2016 / 161270, No. WO2018 / 085469, or No. WO2018 / 129553. In some embodiments, the TIM-3 antibody agent is administered as disclosed in International Patent Application Publication Nos. WO2016 / 161270, WO2018 / 085469, or WO2018 / 129553. In some embodiments, the TIM-3 antibody agent is TSR-022.

[0427] In embodiments, immune checkpoint inhibitors are LAG-3 inhibitors. In embodiments, anti-LAG-3 agents are antibodies, antibody conjugates, or antigen binding fragments thereof. In embodiments, anti-LAG-3 agents are small molecules, nucleic acids, polypeptides (e.g., antibodies), carbohydrates, lipids, metals, or toxins. In embodiments, anti-LAG-3 agents are small molecules. In embodiments, anti-LAG-3 agents are LAG-3 binding agents. In embodiments, anti-LAG-3 agents are antibodies, antibody conjugates, or antigen binding fragments thereof. In an embodiment, the anti-LAG-3 agent is IMP321, relatlimab (BMS-986016), BI 754111, GSK2831781 (IMP-731), Novartis LAG525 (IMP701), REGN3767, MK-4280, MGD-013, GSK-2831781, FS-118, XmAb22841, INCAGN-2385, FS-18, ENUM-006, AVA-017, AM-0003, Avacta PD-L1 / LAG-3 bispecific affimer, iOnctura anti-LAG-3 antibody, Arcus anti-LAG-3 antibody, or Sym022 or TSR-033. In some embodiments, the LAG-3 antibody agent is disclosed in International Patent Application Publication WO2016 / 126858 or International Patent Application No. PCT / US18 / 30027. In some embodiments, the LAG-3 antibody agent is administered as disclosed in International Patent Application Publication WO2016 / 126858 or International Patent Application No. PCT / US18 / 30027. In embodiments, the LAG-3 antibody agent is TSR-033.

[0428] In the embodiment, the niraparib tablet composition is applied in combination with a PD-1 inhibitor (eg, TSR-042, pailizumab or nivolumab). In the embodiment, the niraparib tablet composition is applied in combination with a TIM-3 inhibitor (eg, TSR-022). In the embodiment, the niraparib tablet composition is applied in combination with a LAG-3 inhibitor (eg, TSR-033). In the embodiment, the niraparib tablet composition is applied in combination with a PD-1 inhibitor (eg, TSR-042, pailizumab or nivolumab) and a TIM-3 inhibitor (eg, TSR-022). In the embodiment, the niraparib tablet composition is applied in combination with a PD-1 inhibitor (eg, TSR-042, pailizumab or nivolumab) and a LAG-3 inhibitor (eg, TSR-033). In the embodiment, the niraparib tablet composition is applied in combination with a TIM-3 inhibitor (eg, TSR-022) and a LAG-3 inhibitor (eg, TSR-033). In an embodiment, the niraparib tablet composition is administered in combination with a PD-1 inhibitor (e.g., TSR-042, pembrolizumab, or nivolumab), a TIM-3 inhibitor (e.g., TSR-022), and a LAG-3 inhibitor (e.g., TSR-033).

[0429] In an embodiment, the niraparib tablet composition is administered in combination with one or more chemotherapeutic agents.

[0430] In an embodiment, the niraparib tablet composition is administered in combination with a platinum-based chemotherapy agent (e.g., one or more of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatinium tetranitrate, phenanthriplatin, picoplatin, and satraplatin).

[0431] In an embodiment, the niraparib tablet composition is administered in combination with a chemotherapeutic agent, which chemotherapeutic agent is aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, buserelin, busulfan, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, gram cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin epirubicin, estradiol, estramnustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, inotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol,melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine ne), raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, or vinorelbine.

[0432] In an embodiment, the niraparib tablet composition is administered in combination with a second agent, which is a regulatory T cell (Treg) inhibitor, a macrophage inhibitor, an antigen-specific immune response enhancer, an antigen-specific immune response enhancer, an anti-angiogenic agent, a chemotherapeutic agent, or a combination thereof. In an embodiment, the second agent is any second agent described in International Application No. PCT / US18 / 33437, which is incorporated herein by reference in its entirety.

[0433] In an embodiment, the macrophage inhibitor is selected from the group consisting of: macrophage aggregation inhibitors (e.g., anti-CCL2 / CCR2 agents, anti-IL6 agents, anti-M-CSFR agents, and combinations thereof), M2 macrophage anti-survival agents, M1 macrophage enhancers, M2 to M1 polarization agents, macrophage activity inhibitors, and combinations thereof. In an embodiment, the macrophage aggregation inhibitor is selected from the group consisting of trabectedin, RS102895, PF-04136309, CNTO888, MLN1202, siltuximab, JNJ-28312141, GW2580, IMC-CS4 (LY3022855), emactuzumab, AMG820, pexidartinib, linifanib, OSI-930, CEP-32496, PLX7846, BLZ945, ARRY-382, JNJ-40346527, MCS110, PLX3397, PLX6134, PD-0360324, FPA008, and combinations thereof. In an embodiment, the M2 macrophage anti-survival agent is selected from the group consisting of: MMP inhibitors, clodronate, zoledronic acid, dichloromethylene bisphosphonates, trabectedin, dasatinib, retinoic acid, attenuated bacteria (e.g., Shigella flexneri, Salmonella typhimurium, Listeria monocytogens, Chlamydia psittaci, Legionella pneumophila), and combinations thereof. In an embodiment, the M1 macrophage enhancer or M2 to M1 polarizing agent is selected from the group consisting of anti-CD40 agents, anti-IL-10R agents, CD47 antagonists (e.g., Hu5F9-G4, CC-90002, and CD47-Fc fusion protein TTI-621), PolyI:C, LPS, monophosphoryl A, imiquimod, R-848, CpG-ODN, IFN-α, IFN-β, IFN-γ, GM-CSF, IL-12, IL-2, IL-15, Tα1, ibrutinib, EF-022, and combinations thereof.In an embodiment, the macrophage activity inhibitor is selected from the group consisting of a STAT3 inhibitor, a STAT6 inhibitor, or an anti-tumor agent (e.g., the macrophage activity inhibitor is WP1066, sunitinib, sorafenib, STA-21, IS3 295, S3I-M2001, AS1517499, leflunomide, TMC-264, histidine-rich glycoprotein (HRG), copper chelate (CuNG), 5,6-dimethyldibenzopyranone-4-acetic acid (MDXAA), vadimezan (ASA404), cisplatin, silibinin, proton pump inhibitor pantoprazole (PPZ) or CNI-1493, or a combination thereof). In an embodiment, the macrophage inhibitor is an anti-IL-1α agent (e.g., xilonix).

[0434] In embodiments, regulatory T cell (Treg) inhibitor is selected from the group consisting of: Treg ablator, Treg migration inhibitor, Treg function inhibitor, and their combination. In embodiments, Treg ablator is selected from the group consisting of: cyclophosphamide, paclitaxel, imatinib, sunitinib, sorafenib, dasatinib, temozolomide, daclizumab, denileukin diftitox, and their combination. In embodiments, Treg migration inhibitor is selected from the group consisting of: AMD3100, mogamulizumab, casuarinin, fucoidan, and their combination. In an embodiment, the inhibitor of Treg function is selected from the group consisting of anti-CTLA4 agents (e.g., ipilimumab, tremelimumab), anti-OX40 agents, anti-GITR agents, adenosine receptor antagonists (e.g., caffeine, theophylline, theobromine, and 8-phenylxanthine), P60, and combinations thereof.

[0435] In an embodiment, the antigen-specific immune response enhancer is selected from the group consisting of: anti-PD-1 agents, anti-PD-L1 agents, GITR (glucocorticoid-induced TNFR-related protein) stimulators, anti-CTLA4 agents, anti-TIM-3 agents, anti-LAG-3 agents, anti-IDO agents, agents that enhance tumor antigen presentation (e.g., personalized cancer vaccines, autoantigen-presenting cells, autologous dendritic cells, artificial antigen-presenting cells), chemokine signaling agents, anti-VEGF agents, cytokine signaling stimulators, and combinations thereof.

[0436] In the embodiment, the GITR stimulator is selected from the group consisting of: DTA-1, mGITRL, pGITRL, and combinations thereof. In the embodiment, the anti-CTLA4 agent is selected from the group consisting of: ipilimumab, tremelimumab, and combinations thereof. In the embodiment, the chemokine signaling agent is selected from the group consisting of: CXCL16, CXCR6 chemokine receptor (CD186) agonists, and combinations thereof. In the embodiment, the anti-VEGF agent is selected from the group consisting of: bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, ponatinib, regorafenib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept, and combinations thereof. In embodiments, the cytokine signaling stimulator is an interleukin or an interferon. In embodiments, the interleukin is selected from the group consisting of IL-2, IL-1, IL-7, IL-15, IL-12, IL-18, and combinations thereof. In embodiments, the interferon is IFNα.

[0437] In an embodiment, the antigen-specific immune response enhancer is selected from the group consisting of: flavonoids (e.g., flavonoid glycosides), lidocaine, lamotrigine, sulfamethoxazole, phenytoin, carbamazepine, sulfamethoxazole, phenytoin, allopurinol, paracetamol, mepivacaine, p-phenylenediamine, ciprofloxacin, and moxifloxacin.

[0438] In embodiments, the anti-angiogenic agent is TNP-470, platelet factor 4, thrombin-1, tissue inhibitors of metalloproteinases (TIMP1 and TIMP2), prolactin, angiostatin, endostatin, bFGF soluble receptor, transforming growth factor β, interferon α, soluble KDR and FLT-1 receptor, placental proliferation protein-related protein, and combinations thereof. In embodiments, the anti-angiogenic agent reduces the production of pro-angiogenic factors, inhibits the interaction between pro-angiogenic factors and pro-angiogenic receptors, inhibits the function of pro-angiogenic factors, inhibits the function of pro-angiogenic factor receptors, reduces blood flow by destroying blood vessels, inhibits vessel sprouting, or any combination thereof. In an embodiment, the anti-angiogenic agent is a small organic or inorganic molecule; saccharin; an oligosaccharide; a polysaccharide; a carbohydrate; a peptide; a protein; a peptide analog; a peptide derivative; a lipid; an antibody; an antibody fragment, a peptidomimetic; a nucleic acid; a nucleic acid analog; a nucleic acid derivative; an extract made from a biological material; a naturally occurring or synthetic composition; a metal; a toxin; or any combination thereof.In an embodiment, the anti-angiogenic agent is selected from the group consisting of: bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, fumacillin, CM101, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, angiostatic steroids, heparin, cartilage-derived angiogenesis inhibitor, matrix metalloproteinase inhibitors, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thrombospondin, thalidomide, prolactin, αVβ3 inhibitors, lenalidomide, linomide, inomide), ramucirumab, tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib, everolimus, tissue inhibitors of metalloproteinases (TIMP1 and TIMP2), bFGF soluble receptor, transforming growth factor β, interferon α, soluble KDR and FLT-1 receptors, placental proliferation protein-related protein, pazopanib, sunitinib, sorafenib, axitinib, ponatinib, cabozantinib, regorafenib, vandetanib, lenvatinib, semaxanib, SU6668, vatalanib, tivozanib, cediranib, protamine, heparin, steroids, ascorbyl ether, sulfated polysaccharide DS 4152, nicotinic acid, AGM 12470, neovastat, RO4929097, MRK-003, MK-0752, PF03084014, MEDI0639, curcumin, 3,3′-diindolylmethane (DIM), resveratrol, 3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD) and epigallocatechin-3-gallate (EGCG), honokiol, OMP-21M18, navicixizumab (OMP-305B83), Flt. 2-11 , CBO-P11, Je-11, V1, and any combination thereof.

[0439] In some embodiments, the anti-angiogenic agent inhibits the DLL4 / Notch signaling pathway.

[0440] In some embodiments, the angiogenesis inhibitor that inhibits the DLL4 / Notch signaling pathway is a gamma-secretase inhibitor (GSI), siRNA, or a monoclonal antibody against a Notch receptor or ligand. In some embodiments, the anti-angiogenesis agent is selected from the group consisting of RO4929097, MRK-003, MK-0752, PF03084014, MEDI0639, curcumin, 3,3′-diindolylmethane (DIM), resveratrol, 3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD) and epigallocatechin-3-gallate (EGCG), honokiol, and any combination thereof.

[0441] In some embodiments, the anti-angiogenic agent inhibits the vascular endothelial growth factor (VEGF) / vascular endothelial growth factor receptor (VEGFR) pathway. In some embodiments, the anti-angiogenic agent is selected from the group consisting of Akt inhibitors, calcineurin autoimmune inhibitory peptides, ET-18-OCH3, Go 6983, NG-nitro-L-arginine methyl ester, p21-activated kinase inhibitors, cPLA2α inhibitors, PI-103, PP2, SB 203580, U0126, VEGFR tyrosine kinase inhibitor V, VEGFR2 kinase inhibitor VI, VEGFR2 kinase inhibitor III, ZM 336372, and any combination thereof.

[0442] In some embodiments, the anti-angiogenic agent inhibits VEGF family proteins and / or VEGFR family proteins. In some embodiments, VEGF family proteins include VEGF-A, VEGF-B, VEGF-C, VEGF-D, PlGF (placental growth factor), VEGF-E (Orf-VEGF), Trimeresurus flavoviridis) svVEGF, or any combination thereof. In some embodiments, the anti-angiogenic agent is bevacizumab, ranibizumab, OPT-302, aflibercept, or any combination thereof. In some embodiments, the anti-angiogenic agent is Flt2-11, CBO-P11, Je-11, V1, or any combination thereof. In some embodiments, the anti-angiogenic agent is pazopanib, sunitinib, sorafenib, axitinib, ponatinib, cabozantinib, regorafenib, vandetanib, lenvatinib, semaxanib, SU6668, fantalanib, tivozanib, cediranib, or any combination thereof.

[0443] Having generally described herein, the following non-limiting examples are provided to further illustrate the invention.

[0444] Exemplary aspects and embodiments of the invention

[0445] Exemplary aspects and embodiments of the invention are described herein and are included in Items 1-125.

[0446] Item 1. 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) salt selected from niraparib camphorate, niraparib mandelate and niraparib camphorsulfonate.

[0447] Item 2. 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorate.

[0448] Entry 3. 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate.

[0449] Entry 4. Crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate.

[0450] Entry 5. Crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1R,3S)-(+)-camphorate.

[0451] Item 6. The crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to Item 5, which has an X-ray powder diffraction (XRPD) pattern comprising one or more XRPD peaks at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2°2θ.

[0452] Item 7. The crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to Item 5 or Item 6, which has an XRPD pattern comprising at least two peaks at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2° 2θ.

[0453] Item 8. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 7, which has an XRPD pattern comprising at least three peaks at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2° 2θ.

[0454] Item 9. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 8, which has an XRPD pattern comprising at least four peaks at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2° 2θ.

[0455] Item 10. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 9, having an XRPD pattern comprising peaks at 16.2, 17.5, 20.0, 13.4 and / or 15.2±0.2° 2θ.

[0456] Item 11. The crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 10, having an XRPD pattern comprising one or more XRPD peaks at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0457] Item 12. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 11, which has an XRPD pattern comprising two or more peaks at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0458] Item 13. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 12, having an XRPD pattern comprising three or more peaks at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0459] Item 14. The crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 13, which has an XRPD pattern comprising four or more peaks at 20.4, 21.6, 24.0, 11.7 and / or 18.0±0.2° 2θ.

[0460] Item 15. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 14, having an XRPD pattern comprising peaks at 20.4, 21.6, 24.0, 11.7 and 18.0±0.2° 2θ.

[0461] Item 16. The crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 15, having an XRPD pattern comprising peaks at 16.2, 17.5, 20.0, 13.4, 15.2, 20.4, 21.6, 24.0, 11.7 and 18.0±0.2°2θ.

[0462] Item 17. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 16, which has an XRPD pattern comprising at least one peak at 14.8, 18.0, 22.8 and / or 27.6±0.2° 2θ.

[0463] Item 18. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 17, which has an XRPD pattern comprising at least two peaks at 14.8, 18.0, 22.8 and / or 27.6±0.2° 2θ.

[0464] Item 19. The crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 18, which has an XRPD pattern comprising at least three peaks at 14.8, 18.0, 22.8 and / or 27.6±0.2° 2θ.

[0465] Item 20. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 19, having an XRPD pattern comprising peaks at 14.8, 18.0, 22.8 and 27.6±0.2° 2θ.

[0466] Item 21. The crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 20, having an XRPD pattern comprising one or more peaks at 16.2, 17.5, 20.0, 13.4, 15.2, 20.4, 21.6, 24.0, 11.7, 18.0, 22.8, 18.9, 14.5, 14.1, 14.8, 27.6, 26.9, 6.5, 22.3 and / or 24.5 ± 0.2° 2θ.

[0467] Item 22. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 21, having an XRPD pattern comprising peaks having 2θ values ​​(±0.2° 2θ) according to the following table, and optionally relative intensities.

[0468] Position [°2θ] Relative strength [%] 6.5 15.9 11.7 28.9 13.4 51.5 14.1 21.1 14.5 23.1 14.8 20.6 15.2 48.6 16.2 100 17.5 91.3 18.0 26.6 18.9 25.4 20.0 59.9 20.4 41.2 21.6 35.0 22.3 15.8 22.8 26.0 24.0 30.3 24.5 13.6 26.9 17.4 27.6 17.9

[0469] Item 23. The crystalline form 1 of niraparib (1R, 3S)-(+)-camphorate according to any one of items 5 to 22, characterized in that the XRPD pattern is substantially as follows Figure 3 as shown in .

[0470] Item 24. Crystalline Form 1 of the niraparib (1R,3S)-(+)-camphorate salt according to any one of Items 5 to 23, characterized by a melting point of about 260°C to about 270°C.

[0471] Item 25. Crystalline Form 1 of the niraparib (1R,3S)-(+)-camphorate salt according to any one of Items 5 to 24, characterized by a melting point of about 264°C.

[0472] Item 26. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 25, characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 264°C and / or wherein the minimum of the peak is about 268°C.

[0473] Item 27. The crystalline form 1 of niraparib (1R, 3S)-(+)-camphorate according to any one of items 5 to 26, characterized in that the DSC thermogram is substantially as follows Figure 5 as shown in .

[0474] Item 28. The crystalline form 1 of niraparib (1R, 3S)-(+)-camphorate according to any one of items 5 to 27, characterized in that it comprises a -1 、About 1693cm -1 and about 1649cm -1 The peak of the infrared spectrum.

[0475] Item 29. The crystalline form 1 of niraparib (1R, 3S)-(+)-camphorate according to any one of items 5 to 28, characterized in that the infrared spectrum is substantially as follows Figure 2 as shown in .

[0476] Item 30. Crystalline Form 1 of niraparib (1R,3S)-(+)-camphorate according to any one of Items 5 to 29, characterized in that it absorbs no more than about 0.3% by weight of water at a relative humidity of up to about 90% at 25°C.

[0477] Item 31. The crystalline form 1 of niraparib (1R, 3S)-(+)-camphorate according to any one of items 5 to 30, characterized in that the GVS thermogram is substantially as follows Figure 6 as shown in .

[0478] Entry 32. 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate.

[0479] Entry 33. Crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate.

[0480] Entry 34. Crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S,3R)-(-)-camphorate salt.

[0481] Item 35. The crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to Item 34, which has an XRPD pattern comprising one or more peaks at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2° 2θ.

[0482] Item 36. The crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to Item 34 or Item 3, which has an XRPD pattern comprising at least two peaks at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2°2θ.

[0483] Item 37. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 36, having an XRPD pattern comprising at least three peaks at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2° 2θ.

[0484] Item 38. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 37, having an XRPD pattern comprising at least four peaks at 20.3, 17.4, 16.2, 15.1 and / or 20.2±0.2° 2θ.

[0485] Item 39. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 38, having an XRPD pattern comprising peaks at 20.3, 17.4, 16.2, 15.1 and 20.2±0.2° 2θ.

[0486] Item 40. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 39, having an XRPD pattern comprising one or more peaks at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0487] Item 41. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 40, having an XRPD pattern comprising at least two peaks at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0488] Item 42. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 41, having an XRPD pattern comprising at least three peaks at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0489] Item 43. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 42, having an XRPD pattern comprising at least four peaks at 24.4, 19.9, 11.6, 22.3 and / or 22.2±0.2° 2θ.

[0490] Item 44. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 43, having an XRPD pattern comprising peaks at 24.4, 19.9, 11.6, 22.3 and 22.2±0.2° 2θ.

[0491] Item 45. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 44, having an XRPD pattern comprising peaks at 20.3, 17.4, 16.2, 15.1, 20.2, 24.4, 19.9, 11.6, 22.3 and 22.2±0.2° 2θ.

[0492] Item 46. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 45, having an XRPD pattern comprising a peak at 16.0±0.2° 2θ.

[0493] Item 47. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 46, having an XRPD pattern comprising a peak at 21.9±0.2° 2θ.

[0494] Item 48. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 47, having an XRPD pattern comprising peaks at 16.0 and 21.9±0.2° 2θ.

[0495] Item 49. The crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34-48, having an XRPD pattern comprising at least one peak at 20.3, 17.4, 16.2, 15.1, 20.2, 24.4, 19.9, 11.6, 22.3, 22.2, 13.4, 16.0, 26.9, 6.5, 23.9, 18.9, 14.5, 14.0, 21.9 and / or 21.5±0.2°2θ.

[0496] Item 50. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 49, having an XRPD pattern comprising peaks having 2θ values ​​(±0.2° 2θ) according to the following table, and optionally relative intensities.

[0497] Position [°2θ] Relative strength [%] 6.5 16.7 11.6 22.6 13.4 19.2 14.0 11.2 14.5 12.8 15.1 48.2 16.0 17.4 16.2 48.7 17.4 61.0 18.9 15.3 19.9 29.8 20.2 34.9 20.3 100 21.5 10.9 21.9 11.0 22.2 19.8 22.3 20.3 23.9 15.9 24.4 31.3 26.9 17.0

[0498] Item 51. The crystalline form 1 of niraparib (1S, 3R)-(-)-camphorate according to any one of Items 34-50, characterized in that the XRPD pattern is substantially as follows Fig. 9 shown.

[0499] Item 52. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 51, characterized by a melting point of about 220°C to about 230°C.

[0500] Item 53. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 52, characterized by a melting point of about 226°C.

[0501] Item 54. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34-53, characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 226°C and / or wherein the minimum of the peak is about 230°C.

[0502] Item 55. The crystalline form 1 of niraparib (1S, 3R)-(-)-camphorate according to any one of Items 34 to 54, characterized in that the DSC thermogram is substantially as follows Fig.11 shown.

[0503] Item 56. The crystalline form 1 of niraparib (1S, 3R)-(-)-camphorate according to any one of Items 34 to 55, characterized in that it comprises a -1 、About 1693cm -1 and about 1648cm -1 The peak of the infrared spectrum.

[0504] Item 57. The crystalline form 1 of niraparib (1S, 3R)-(-)-camphorate according to any one of Items 34 to 56, characterized in that the infrared spectrum is substantially as follows Figure 8 shown.

[0505] Item 58. Crystalline Form 1 of niraparib (1S,3R)-(-)-camphorate according to any one of Items 34 to 57, characterized in that it absorbs no more than about 1% by weight of water at a relative humidity of up to about 90% at 25°C.

[0506] Item 59. The crystalline form 1 of niraparib (1S, 3R)-(-)-camphorate according to any one of items 34-58, characterized in that the GVS thermogram is substantially as follows Fig.12 shown.

[0507] Entry 60. 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) mandelate.

[0508] Entry 61. 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt.

[0509] Entry 62. Crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt.

[0510] Entry 63. Crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt.

[0511] Item 64. The crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to Item 63, which has an XRPD pattern comprising one or more peaks at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0512] Item 65. The crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to Item 63 or 64, which has an XRPD pattern comprising at least two peaks at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0513] Item 66. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 65, having an XRPD pattern comprising at least three peaks at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0514] Item 67. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 66, having an XRPD pattern comprising at least four peaks at 18.5, 16.4, 17.4, 8.6 and / or 17.6±0.2° 2θ.

[0515] Item 68. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 67, having an XRPD pattern comprising peaks at 18.5, 16.4, 17.4, 8.6 and 17.6±0.2° 2θ.

[0516] Item 69. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 68, having an XRPD pattern comprising one or more peaks at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0517] Item 70. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 69, having an XRPD pattern comprising two or more peaks at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0518] Item 71. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 70, having an XRPD pattern comprising three or more peaks at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0519] Item 72. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 71, having an XRPD pattern comprising four or more peaks at 8.7, 18.4, 25.1, 27.6 and / or 13.7±0.2° 2θ.

[0520] Item 73. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 72, having an XRPD pattern comprising peaks at 8.7, 18.4, 25.1, 27.6 and 13.7±0.2° 2θ.

[0521] Item 74. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 73, having an XRPD pattern comprising peaks at 18.5, 16.4, 17.4, 8.6, 17.6, 8.7, 18.4, 25.1, 27.6 and 13.7±0.2° 2θ.

[0522] Item 75. The crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 74, having an XRPD pattern comprising one or more peaks at 18.5, 16.4, 17.4, 8.6, 17.6, 8.7, 18.4, 25.1, 27.6, 13.7, 8.4, 28.7, 28.0, 4.3, 21.5, 27.3, 14.1, 27.7, 12.4 and / or 16.1 ± 0.2° 2θ.

[0523] Item 76. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of Items 63 to 75, having an XRPD pattern comprising peaks having 2θ values ​​(±0.2° 2θ), and optionally relative intensities, according to the following table.

[0524]

[0525]

[0526] Item 77. The crystalline form 1 of niraparib (R)-(-)-mandelate salt according to any one of Items 63 to 76, characterized in that the XRPD pattern is substantially as follows Fig.15 shown.

[0527] Item 78. Crystalline Form 1 of niraparib (R)-(-)-mandelate salt according to any one of Items 63 to 77, characterized by a melting point of about 190°C to about 200°C.

[0528] Item 79. Crystalline Form 1 of niraparib (R)-(-)-mandelate salt according to any one of Items 63 to 78, characterized by a melting point of about 197°C.

[0529] Item 80. Crystalline Form 1 of (R)-(-)-mandelate salt of niraparib according to any one of items 63-79, characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 197°C and / or wherein the minimum of the peak is about 201°C.

[0530] Item 81. The crystalline form 1 of niraparib (R)-(-)-mandelate salt according to any one of Items 63 to 80, characterized in that the DSC thermogram is substantially as follows Fig.18 shown.

[0531] Item 82. The crystalline form 1 of niraparib (R)-(-)-mandelate salt according to any one of items 63 to 81, characterized in that it comprises a -1 、About 3340cm -1 , about 1671cm -1 and about 1638cm -1 The peak of the infrared spectrum.

[0532] Item 83. The crystalline form 1 of niraparib (R)-(-)-mandelate according to any one of Items 63-82, characterized in that the infrared spectrum is substantially as follows Fig.14 shown.

[0533] Item 84. The crystalline form 1 of niraparib (R)-(-)-mandelate according to any one of items 63 to 83, characterized in that the DVS thermogram is substantially as follows Fig.19 shown.

[0534] Item 85. 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) camphorsulfonate.

[0535] Entry 86. 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camphorsulfonate.

[0536] Entry 87. Crystalline 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camphorsulfonate.

[0537] Entry 88. Crystalline Form 1 of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (1S)-(+)-camsylate salt.

[0538] Item 89. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to Item 88, which has an XRPD pattern comprising one or more peaks at 16.0, 13.5, 17.6, 24.3 and / or 24.6±0.2° 2θ.

[0539] Item 90. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to Item 88 or Item 3, which has an XRPD pattern comprising at least two peaks at 16.0, 13.5, 17.6, 24.3 and / or 24.6±0.2°2θ.

[0540] Item 91. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 90, having an XRPD pattern comprising at least three peaks at 16.0, 13.5, 17.6, 24.3 and / or 24.6 ± 0.2° 2θ.

[0541] Item 92. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 91, having an XRPD pattern comprising at least four peaks at 16.0, 13.5, 17.6, 24.3 and / or 24.6±0.2° 2θ.

[0542] Item 93. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 92, having an XRPD pattern comprising peaks at 16.0, 13.5, 17.6, 24.3 and 24.6±0.2° 2θ.

[0543] Item 94. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 93, having an XRPD pattern comprising one or more peaks at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0544] Item 95. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 94, having an XRPD pattern comprising two or more XRPD peaks at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0545] Item 96. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 95, having an XRPD pattern comprising three or more peaks at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0546] Item 97. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 96, having an XRPD pattern comprising four or more peaks at 11.1, 16.4, 23.7, 16.7 and / or 20.3±0.2° 2θ.

[0547] Item 98. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 97, having an XRPD pattern comprising peaks at 11.1, 16.4, 23.7, 16.7 and 20.3±0.2° 2θ.

[0548] Item 99. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88-98, having an XRPD pattern comprising peaks at 16.0, 13.5, 17.6, 24.3, 24.6, 11.1, 16.4, 23.7, 16.7 and 20.3±0.2°2θ.

[0549] Item 100. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88-99, having an XRPD pattern comprising one or more XRPD peaks at 6.7, 16.4, 23.7 and / or 25.2±0.2° 2θ.

[0550] Item 101. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 100, having an XRPD pattern comprising at least two peaks at 6.7, 16.4, 23.7 and / or 25.2±0.2° 2θ.

[0551] Item 102. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 101, having an XRPD pattern comprising at least three peaks at 6.7, 16.4, 23.7 and / or 25.2±0.2° 2θ.

[0552] Item 103. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 102, having an XRPD pattern comprising peaks at 6.7, 16.4, 23.7 and 25.2±0.2° 2θ.

[0553] Item 104. The crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 103, having an XRPD pattern comprising at least one peak at 16.0, 13.5, 17.6, 24.3, 24.6, 11.1, 16.4, 23.7, 16.7, 20.3, 6.7, 25.2, 25.0, 25.8, 26.8, 22.8, 9.5, 16.9, 14.3 and / or 7.7 ± 0.2° 2θ.

[0554] Item 105. The crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 104, having an XRPD pattern comprising peaks having 2θ values ​​(±0.2° 2θ), and optionally relative intensities, according to the following table:

[0555] Position [°2θ] Relative strength [%] 6.7 13.8 7.7 8.9 9.5 10.4 11.1 22.2 13.5 58.6 14.3 9.1 16.0 100 16.4 20.4 16.7 19.1 16.9 9.8 17.6 55.4 20.3 14.5 22.8 11.6 23.7 19.6 24.3 47.4 24.6 45.9 25.0 12.9 25.2 13.4 25.8 12.0 26.8 11.6

[0556] Item 106. The crystalline form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88 to 105, characterized in that the XRPD pattern is substantially as follows Fig. 22 shown.

[0557] Item 107. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88 to 106, characterized by a melting point of about 235°C to about 245°C.

[0558] Item 108. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88 to 107, characterized by a melting point of about 239°C.

[0559] Item 109. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88-108, characterized by a DSC thermogram wherein the melting onset (endothermic peak) is about 235°C and / or wherein the minimum of the peak is about 246°C.

[0560] Item 110. The crystalline form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88 to 109, characterized in that the DSC thermogram is substantially as follows Fig.24 shown.

[0561] Item 111. The crystalline form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88 to 110, characterized in that it comprises a -1 、About 3306cm -1 、About 1724cm -1 , about 1660cm-1 and about 1611cm -1 The peak of the infrared spectrum.

[0562] Item 112. The crystalline form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88 to 112, characterized in that the infrared spectrum is substantially as follows Fig.21 shown.

[0563] Item 113. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 112, characterized in that it absorbs no more than about 2% by weight of water at a relative humidity of up to about 90% at 25°C.

[0564] Item 114. Crystalline Form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of Items 88 to 113, characterized by absorbing about 1.3% by weight of water at a relative humidity of up to about 90% at about 25°C.

[0565] Item 115. The crystalline form 1 of niraparib (1S)-(+)-camphorsulfonic acid according to any one of items 88 to 114, characterized in that the GVS thermogram is substantially as follows Fig.25 shown.

[0566] Item 116. A pharmaceutical composition comprising the niraparib camphorate, niraparib mandelate or niraparib camphorsulfonate according to any one of items 1 to 115, and at least one pharmaceutically acceptable excipient.

[0567] Item 117. The niraparib camphorate, niraparib mandelate or niraparib camphorsulfonate of any one of Items 1 to 115, or the pharmaceutical composition of Item 116, for use in therapy.

[0568] Item 118. Use of the niraparib camphorate, niraparib mandelate or niraparib camphorsulfonate according to any one of Items 1 to 115, or the pharmaceutical composition according to Item 116 in the manufacture of a medicament.

[0569] Item 119. A method for treating cancer, stroke, autoimmune diabetes, neurological disease, inflammatory disease, metabolic disease or cardiovascular disease in a subject, comprising administering to the subject an effective amount of niraparib camphorate, niraparib mandelate or niraparib camphorsulfonate according to any one of items 1 to 115, or the pharmaceutical composition of item 116.

[0570] Item 120. The method according to Item 119, wherein the method is a method for treating cancer.

[0571] Item 121. The method according to Item 120, wherein the cancer is associated with a BRCA1 and / or BRCA2 mutation.

[0572] Item 122. The method according to item 120 or 121, wherein the cancer is associated with a mutation in ATM, ATR, BAP1, BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L or XRCC2, or any combination thereof.

[0573] Item 123. The method according to any one of items 120 to 122, wherein the cancer is epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

[0574] Item 124. The niraparib camphorate, niraparib mandelate or niraparib camphorsulfonate of any one of items 1 to 115, or the pharmaceutical composition of item 116, for use in a method as defined in any one of items 119 to 123.

[0575] Item 125. Use of the niraparib camphorate, niraparib mandelate or niraparib camphorsulfonate of any one of items 1 to 115, or the pharmaceutical composition of item 116, for the preparation of a medicament for use in a method as defined in any one of items 119 to 123. Example

[0576] Analytical procedures

[0577] X-ray powder diffraction (XRPD)

[0578] XRPD analysis was typically performed on a PANalytical X'pert pro, scanning the sample between 3 and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous disk with a Kapton or Mylar polymer film supporting the sample. The porous disk was then placed in the diffractometer and the diffractometer was set up with a 40 kV / 40 mA generator, using Cu K radiation (α1 1 2θ) operating in transmission mode (step size 0.0130° 2θ). α1:α2 ratio = 0.5) for analysis.

[0579] Unless otherwise stated, XRPD analyses are conducted at room temperature and pressure and at a relative humidity between about 30-50% (eg, about 40% relative humidity).

[0580] NMR analysis

[0581] NMR methods were typically performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryogenic probe. Experiments were performed in deuterated DMSO and each sample was prepared to a concentration of approximately 10 mM. NMR spectra were obtained at room temperature (e.g., approximately 300 K) unless otherwise stated.

[0582] High performance liquid chromatography-ultraviolet detection (HPLC-UV)

[0583] HPLC is usually performed using the following parameters:

[0584]

[0585] The commonly used gradient programs are:

[0586] Time (minutes) Solvent B[%] 0 5 13.739 30 21.982 95 23.081 95 23.136 5 27.477 5

[0587] Polarized Light Microscopy (PLM)

[0588] The presence of crystallinity (birefringence) was routinely determined using an Olympus BX50 polarizing microscope equipped with a Motic camera and image grabbing software (Motic Images Plus 2.0). All images were recorded using a 20x objective unless otherwise stated.

[0589] Infrared spectroscopy (FT-IR)

[0590] Infrared spectroscopy is usually performed on a Bruker ALPHA P spectrometer. A sufficient amount of material is placed in the center of the spectrometer's disk and the spectrum is acquired using the following parameters:

[0591]

[0592] Thermogravimetric analysis (TGA)

[0593] Typically, approximately 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and maintained at room temperature. The sample was then heated from 20°C to 350°C at a rate of 10°C / min, during which time the sample weight change and any differential thermal events (DTA) were recorded. A flow rate of 300 cm 3 / min nitrogen was used as the purge gas.

[0594] Differential Scanning Calorimetry (DSC)

[0595] Typically, approximately 5 mg of material was weighed into an aluminum DSC pan and non-hermetically sealed with a perforated aluminum lid. The sample pan was then loaded into a Seiko DSC6200 (equipped with a cooler), cooled and maintained at 20°C. Once a stable heat flow response was obtained, the sample and reference were heated to melting (if possible) at a scan rate of 10°C / min and the heat flow response obtained was monitored. A flow rate of 50 cm was used. 3 / min nitrogen was used as the purge gas.

[0596] Gravimetric Vapor Sorption (GVS)

[0597] Typically, approximately 10-20 mg of sample is placed in a mesh vapor sorption balance pan and loaded into the IGASorp moisture sorption analyzer balance of Hiden Analytical. The sample is subjected to a ramping profile from 40% to 90% relative humidity (RH) in 10% increments, maintaining the sample at 25°C at each step until a stable weight has been achieved (98% step completion, minimum step length 30 minutes, maximum step length 60 minutes). After the sorption cycle is complete, the sample is dried to 0% RH using the same procedure and finally returned to the starting point of 40% RH. Two cycles are performed. The weight change during the sorption / desorption cycle is plotted to determine the hygroscopic properties of the sample.

[0598] Dynamic Vapor Sorption (DVS)

[0599] Typically, approximately 10 mg of sample is placed in a mesh vapor sorption balance pan and loaded in a DVS-1 / DVS Intrinsic / DVS Advantage dynamic vapor sorption balance from Surface Measurement Systems. The sample is subjected to a ramp profile from 40% to 90% relative humidity (RH) in 10% increments, and the sample is maintained at 25°C at each step until a stable weight has been achieved (dm / dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes). After the adsorption cycle is complete, the sample is dried to 0% RH using the same procedure, and finally returned to the starting point of 40% RH. Two cycles are performed. The weight change during the adsorption / desorption cycle is plotted to determine the hygroscopic properties of the sample.

[0600] Synthesis of Niraparib p-Toluenesulfonate and Niraparib Free Base

[0601] Niraparib p-toluenesulfonate monohydrate

[0602] Niraparib p-toluenesulfonate monohydrate is obtained from niraparib, for example as described in WO2014 / 088983 or PCT / US2018 / 029131. An exemplary XRPD pattern of niraparib p-toluenesulfonate monohydrate is shown in Figure 1 as shown in .

[0603] Niraparib free base

[0604]

[0605] At room temperature, 1% NaOH aqueous solution (500 mL) was added to a mixture of 50.0 g (97.9 mmol) of niraparib p-toluenesulfonic acid monohydrate in 2-MeTHF (1 L). After the mixture was stirred for 30 min, the aqueous layer was separated and extracted twice with 2-MeTHF (500 mL). The combined organics were then washed with water (1 L). Below 30 ° C, the solution was slowly concentrated under partial vacuum to obtain a suspension of about 20 mL. The mixture was stirred at room temperature for 30 min and filtered to obtain an off-white solid (23.8 g, 75.9% yield). MS (ESI) C 19 H 20 N4O theoretical value: 320, actual value: 321 [M+H] + .

[0606] 1 H NMR(500.12MHz,DMSO-d6)δ9.27(s,1H),8.59(dd,1H,J=1.8,4.7Hz),8.07(dd,1H,J=1.1,7 .0Hz),8.04(d,2H,J=8.7Hz),8.02(dd,1H,J=1.1,8.1Hz),7.90(br.s,1H),7.46(d,2H,J=8 .5Hz),7.27(dd,1H,J=7.2,8.3Hz),3.00(br.d,1H,J=12.1Hz),2.94(br.d,1H,J=12.1Hz), 2.70(m,1H),2.51(m,2H),1.91,(d,1H,J=13.0Hz),1.68(m,1H),1.61(m,1H),1.49(m,1H).

[0607] 13C NMR(125.77MHz,DMSO-d6)δ166.1,146.5,146.4,138.0,130.1,128.7,125.8,123.9,1 23.8,122.3,121.9,121.1,54.0,46.4,43.6,40.6,40.4,40.3,40.1,39.9,32.3,27.0.

[0608] Example 1: Crystalline Niraparib Camphorate

[0609] 1.1 Niraparib (1R,3S)-(+)-camphorate (Form 1) – “(+)-camphorate” salt

[0610]

[0611] Niraparib free base (5 g, 15.6 mmol) was weighed into a vial, and methanol (17.5 mL) was subsequently weighed. After adding a solution of (1R, 3S)-(+)-camphoric acid (16.4 mmol, 1.05 equiv) in THF (16.4 mL), the obtained slurry was thermally cycled for 72 hours (4 hours under ambient conditions, followed by 40 ° C for 4 hours) under stirring. After the thermal cycle was removed, the solid material present was separated by centrifuge filtration to obtain crude niraparib (1R, 3S)-(+)-camphorate (5.69 g). At 40 ° C, crude niraparib (1R, 3S)-(+)-camphorate (5.24 g) and (1R, 3S)-(+)-camphoric acid (4.0 g; 12.5 mmol; 0.8 equiv) were slurried in methanol (200 mL). After stirring for about 0.5 hours, the batch was cooled to room temperature and stirred for another 24 hours. The obtained slurry was stored in a refrigerator for an additional 24 hours, after which the solid was isolated by filtration and dried in a vacuum oven for 3 hours at 40°C. This obtained niraparib (1R, 3S)-(+)-camphorate (6.48 g, 75.0% overall yield) as a crystalline solid (melting point 264°C).

[0612] 1H NMR(500MHz,DMSO-d6)δ9.28(s,1H),8.57(br.s,1H),8.07(dt,2H,J=1.9,8.7Hz),8.06(dd,1H,J=1.0,6.9 Hz),8.02(dd,1H,J=1.0,8.3Hz),7.89(br.s,1H),7.49(d,2H,J=8.8Hz),7.27(dd,1H,J=7.1,8.1Hz),3.11( br.d,1H,J=12.0Hz),3.06(br.d,1H,J=12.3Hz),2.80(tt,1H,J=3.5,11.3Hz),2.75–2.56(m,3H),2.39–2.2 7(m,1H),2.05–1.88(m,2H),1.79–1.54(m,4H),1.41–1.32(m,1H),1.18,(s,3H),1.11(s,3H),0.80(s,3H).

[0613] FT-IR(cm -1 ):3359.44,3182.612,3120.66,2980.97,2964.28,2886.27,2860.66,2701.37,2513.23,1692.94,1648.76,1557.44,1523.02,1434.04,1396.55,1377.75,1331.85,1304.91,1264 .73,1229.82,1203.47,1156.66,1127.69,1091.44,1060.29,1001.87,946.70,871.18,827.13,794.09,755.21,717.77,678.26,615.99,551.87,535.68,494.00,463.87,411.96. The IR spectrum of niraparib (1R,3S)-(+)-camphorate is shown in Figure 2 shown.

[0614] 1.2 Niraparib (1S,3R)-(-)-camphorate (Form 1) – (-)-camphorate

[0615]

[0616] To a suspension of niraparib free base (250 mg; 0.78 mmol) in ethanol (2.5 mL) was slowly added a solution of (1S, 3R)-(-)-camphoric acid in THF (1.58 mL, 1.0 M, 2.1 equiv) at 40°C over 1 hour. The obtained solution was stirred at 40°C for one hour. The obtained suspension was cooled to room temperature over 1 hour. The mixture was filtered and the wet cake was dried under vacuum at 40°C for 3 hours to give niraparib (1S, 3R)-(-)-camphorate (331 mg) as a crystalline solid (melting point 226°C).

[0617] 1 H NMR(500MHz,DMSO-d6)δ9.28(s,1H),8.58(br.s,1H),8.08(dt,2H,J=2.0,8.6Hz),8.07(dd,1H,J=1.1,7 .0Hz),8.02(dd,1H,J=1.1,8.3Hz),7.89(br.s,1H),7.49(d,2H,J=8.6Hz),7.27(dd,1H,J=6.9,8.2Hz), 3.11(br.d,1H,J=11.9Hz),3.05(br.d,1H,J=12.5Hz),2.88–2.75(m,1H),2.75–2.56(m,3H),2.40–2.26 (m,1H),2.05–1.85(m,2H),1.80–1.52(m,4H),1.42–1.31(m,1H),1.18(s,3H),1.11(s,3H),0.79(s,3H).

[0618] FT-IR(cm -1):3366.88,3177.98,3120.30,3036.66,2978.54,2879.58,2790.08,2719.08,2507.15,2529.46,2371.80,2228.38,2030.21,1693.10,1648.46,1560.66,1523.93,1458.02,1429.67,1377.32,1331.43 ,1303.71,1269.54,1200.70,1156.87,1127.25,1085.34,1058.93,1000.35,932.27,914.62,869.18,839.71,794.24,780.48,753.71,721.16,673.17,604.09,543.75,522.65,487.43,453.97,409.48. The IR spectrum of niraparib (1R,3S)-(-)-camphorate is shown in Figure 8 shown.

[0619] Example 2: Crystalline Niraparib Mandelate

[0620]

[0621] To a suspension of 5.0 g (15.6 mmol) of niraparib free base in acetonitrile (100 mL) was added a solution of (R)-(-)-mandelic acid in THF (15.8 mL, 1.0 M, 1.05 equiv) as a bulk solution at room temperature. The obtained mixture was placed in a thermal cycle for 72 hours (maintained at room temperature for 4 hours, then maintained at 40° C. for 4 hours) under stirring. The mixture was filtered at room temperature to obtain the title compound (5.9 g). An approximate amount of solid (5.5 g) was dissolved in MeOH (80 mL) at 40° C. After cooling to room temperature, 10-20 mL of solvent was evaporated. After 24 hours, significant precipitation was observed. The solid was separated by filtration, and the suspension was stored in a refrigerator for another 24 hours before the filtered solid was dried in a vacuum oven at 40° C. for 3 hours. This obtained the title salt (3.8 g, 50.6% total yield) as a crystalline salt (melting point 197° C.).

[0622] 1H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.58(br.s,1H),8.10(dt,2H,J=1.9,8.7Hz ),8.08(dd,1H,J=1.1,6.9Hz),8.02(dd,1H,J=1.1,8.4Hz),7.90(br.s,1H),7.48 (d,2H,J=8.6Hz),7.41(m,2H),7.27(m,3H),7.17(tt,1H,J=1.9,8.0Hz),4.65(s, 1H),3.30–3.19(m,2H),3.00–2.90(m,2H),2.87–2.76(m,1H),1.90–1.64(m,4H).

[0623] FT-IR(cm -1 ):3443.90,3340.48,3150.83,3030.33,2982.99,2939.97,2621.21,2513.33,2442.51,1671.47,1637.65,1584.33,1524.97,1433.06,1465.81,1369.51,1320.36,1263.54 ,1204.03,1186.23,1142.43,1098.65,1062.22,961.17,905.79,870.89,828.56,764.89,730.97,693.15,674.78,622.88,591.13,555.73,536.97,508.16,455.43,406.54. The IR spectrum of niraparib (R)-(-)-mandelate is shown in Figure 1. Fig.14 shown.

[0624] Example 3: Crystalline Niraparib Camphorsulfonate

[0625]

[0626] To a suspension of niraparib free base (2.5 g; 7.8 mmol) in acetonitrile (100 mL) at room temperature was added a solution of (1S)-(+)-camphor-10-sulfonic acid in THF (7.9 mL, 1.0 M, 1.05 equiv) as bulk solution. The obtained mixture was placed in a thermal cycle (4 h cycle between room temperature and 40°C) under stirring. The solid was collected by filtration and completely dissolved in methanol (50 mL). Approximately 10 to 20 mL of the solvent in the obtained solution was evaporated very slowly over 24 h at room temperature. Precipitation was observed. The sample was placed in a refrigerator for another 24 h. The mixture was filtered and the wet cake was dried under vacuum to obtain niraparib camphorsulfonate (1.6 g; 37% yield) as a crystalline solid (m.p. 239°C).

[0627] 1 H NMR (500MHz, DMSO-d6) δ9.32 (s, 1H), 8.56 (br.s, 1H), 8.14 (dt, 2H, J = 1.9, 8.7Hz), 8.07 (dd, 1H, J = 1. 1,7.0Hz),8.03(dd,1H,J=1.1,8.4Hz),7.90(br.s,1H),7.56(d,2H,J=8.6Hz),7.29(dd,1H,J=7.1,8 .4Hz),3.47–3.21(m,2H),3.19–3.02(m,2H),2.99–2.87(m,2H),2.74–2.63(m,1H),2.41(d,1H,J=14 .7Hz), 2.24 (dt, 1H, J = 4.0, 18.0Hz), 2.02–1.71 (m, 7H), 1.36–1.22 (m, 2H), 1.06 (s, 3H), 0.75 (s, 3H).

[0628] FT-IR(cm -1):3466.56,3305.79,3134.98,2983.48,2966.85,2924.72,2855.25,2629.88,2529.59,2443.22,1724.23,1660.68,1611.04,1594.54,1525.74,1458.86,1378.40,1351.19,1305.30,12 77.01,1254.07,1196.23,1110.37,1032.65,941.09,906.51,867.55,826.34,784.10,756.64,717.04,668.42,689.10,618.76,599.80,583.63,558.36,514.62,497.92,456.56,432.40. The IR spectrum of niraparib camphorsulfonate is shown in Fig.21 shown.

[0629] Example 4: X-ray powder diffraction (XRPD)

[0630] The XRPD patterns of the crystalline solids produced in Examples 1 to 3 are Figure 3 , 9 , 15 and 22. Prior to XRPD analysis, niraparib (R)-(-)-mandelate was ground until a more homogeneous particle size was produced. The crystal form observed in each case was designated as "Form 1".

[0631] Tables 1 to 4 below list the Figure 3 , 8 , 13 and 19 XRPD diffraction angles.

[0632] Table 1: XRPD diffraction angles of Niraparib (+)-camphorate (Form 1)

[0633]

[0634] Table 2: XRPD diffraction angles of Niraparib (+)-camphorate (Form 1)

[0635]

[0636] Table 3: XRPD diffraction angles of Niraparib mandelate (Form 1)

[0637]

[0638]

[0639] Table 4: XRPD diffraction angles of Niraparib camphorsulfonate (Form 1)

[0640]

[0641] Example 5: Melting Characteristics

[0642] DSC was performed on the crystalline solids produced in Examples 1 to 3. The DSC thermograms can be found at Figure 5 , 11 , 18 and 24. Table 5 below lists the parameters from these thermograms.

[0643] Table 5:

[0644]

[0645] Example 6: Hygroscopicity

[0646] GVS was performed on the crystalline solids produced in Examples 1 and 3. DVS was performed on the crystalline solid produced in Example 2. The results are shown in Figure 6 , 12 , 19 and 25. Table 6 below summarizes the % mass gain observed for the samples at 90% RH. Camphorate and mandelate salts are not hygroscopic (≤ 0.5% mass gain); camphorsulfonate salt is slightly hygroscopic.

[0647] Table 6:

[0648] Niraparib salt Mass increase % (+)-Camphorate ～0.3 (-)-Camphorate ～0.2 Mandelate ～0.07 Camphorsulfonate ～1.3

[0649] Example 7: Storage stability

[0650] A sample of each of the crystalline solids produced in Examples 1 to 3 above was stored at 40°C and 75% RH for 24 hours and then analyzed by XRPD. All materials were unchanged after storage at 40°C / 75% RH for 24 h.

[0651] Example 8: Single Crystal Structure of Niraparib (R)-(-)-Mandelate Salt (Form 1)

[0652] Agilent Technologies (Dual Source) SuperNova diffractometer was used with monochromated CuKα SXRD analysis was performed with 100 nm radiation. The diffractometer was equipped with an Oxford Cryosystems cryogenic device to enable data collection to be performed at 120(1)K and the crystals were coated in a protective layer of Paratone oil. The collected data were corrected for absorption effects in a multifaceted crystal model based on Gaussian integration, which was implemented as part of the CrysAlisPro software package (Agilent Technologies, 2014).

[0653] The structure was solved by direct methods (SHELXS97)1 and improved by least squares corrections to F2 (SHELXL97)1 of the interfaced OLEX2 software package. Images were generated by OLEX2.2, data were collected, solved and improved using the ADDSYMM3 program of PLATON4 with orthorhombic space group P212121 and searches for higher order symmetries, but failed to reveal any higher order symmetries.

[0654] All non-hydrogen atoms are located in the Fourier map and their positions are refined before describing the anisotropic thermal shifts of all their non-hydrogen atoms. In this structure, a complete crystallographically independent niraparib-like unit is found in the asymmetric unit and the related mandelic acid-like unit is fully stoichiometric. In this structure, the parent niraparib molecule and the related mandelic acid are found to be disordered between two positions, 50% each. No further disorder is noted in the final structure. Within the disordered unit, the following distances are limited to And the esd is 0.01; C22A-C21 and C22B-C21.

[0655] A riding model was used with a fixed Uiso at 1.2x for all CH, CH2 and NH2 groups and 1.5x for all OH groups, so that all hydrogen atoms were located at the calculated positions. The highest residual Fourier peak was found from N2 approximately And the deepest Fourier hole is found in the N2 About

[0656] Niraparib (R)-(-)-mandelate salt refinement parameters

[0657]

[0658]

[0659] Example 9: Optical microscopy

[0660] The crystalline solids produced in Examples 1 to 3 were evaluated by optical microscopy using visible and PLM. Microscopic images are shown in Figure 7 , 13 , 20 and 26, and these results are summarized in Table 7 below.

[0661] Table 7:

[0662]

[0663] Example 10: Solubility Study

[0664] The solubility of the crystalline solids produced in Examples 1.1, 2 and 3 above was compared with that of crystalline niraparib tosylate monohydrate (eg Figure 1 The solubility of the 200 μM MgCl2O3 (characterized by the XRPD pattern of 200 μM MgCl2O3) was compared using the following scheme:

[0665] In an initial procedure (performed in triplicate), a small aliquot of the salt was added to deionized water or buffer solution (10 mL) until saturation was reached (approximately 20 mg was initially added), and the resulting slurry was shaken at 37° C. for 24 hours. The following buffers were used (50 mM in each case):

[0666] pH 1 25 mL KCl solution (1.49 g, dissolved in 100 mL water) and 42.5 mL HCl solution (1.66 mL concentrated HCl (about 37%), made up to 100 mL with water) were added together and made up to 100 mL with water;

[0667] pH 4.5: Dissolve anhydrous sodium acetate (1.07 g) in water (about 150 mL), then add 5.9 mL of acetic acid solution (make up 11.6 mL of glacial acetic acid to 100 mL with water). Make up the obtained solution to 500 mL with water; and

[0668] pH 6.8 25 mL of KH2PO4 solution (2.72 g, dissolved in about 80 mL of water and made up to 100 mL with water) and 11.2 mL of NaOH solution (800 mg of sodium hydroxide was dissolved in water and diluted to 100 mL) were added together and made up to 100 mL with water.

[0669] After the first hour, approximately 20 to 30 mg of the appropriate salt was added to the following samples: (i) (1R,3S)-(+)-camphorate in pH 1 buffer; (ii) (R)-(-)-mandelate 1 in water, pH 1 buffer, and pH 4.5 buffer; and (iii) (1S)-(+)-camphorsulfonate in all solvents.

[0670] Each sample was then filtered and the concentration of niraparib in the mother liquor was assessed by HPLC. Any solids isolated by filtration were assessed by XRPD to determine if the form of the material had changed.

[0671] For those samples with solubility greater than 30 mg / ml, the solution was observed after the first addition of 30 mg of the solid. The solubility assessment of these samples was repeated using the following procedure (samples prepared in triplicate):

[0672] The appropriate salt (30 mg) was weighed into a vial and water or buffer solution (1 mL) was added. The sample was shaken at 37°C for 24 hours. After 1 hour and after about 17 hours, salt was additionally added to the mandelate sample (except for those in pH 1 buffer solution) to obtain approximately 50-60 mg of solid. For the mandelate pH 1 sample, when a two-phase system was observed, the material was reloaded until saturation was achieved. The sample was analyzed as described above.

[0673] The solubility of niraparib salts is shown below in Table 8. In each case, the solubility value reported is the average of triplicate measurements, based on the concentration of niraparib free base in solution.

[0674] Table 8:

[0675]

[0676]

[0677] The data in Table 8 indicate that the camphorate, mandelate and camphorsulfonate salts have greater solubility than the p-toluenesulfonate salt, particularly in low pH media. The mandelate salt in particular exhibits high solubility over a wide range of pH values, which is an advantageous property (and surprising, given its lack of hygroscopicity).

[0678] The teachings of all patents, published applications, and references cited herein are incorporated by reference in their entirety.

[0679] While the invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the spirit and scope of the invention as contemplated by the appended claims.

Claims

1. A crystalline form of a salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, which is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate, characterized in that Having XRPD diffraction angles of ±0.2° 2θ at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4° and 25.1°.

2. A crystalline form of a salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, which is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate, characterized in that Having XRPD diffraction angles of ± 0.2° 2θ at 2θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1° and 27.6°.

3. A crystalline form of a salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, which is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate, characterized in that Having XRPD diffraction angles of ±0.2° 2Θ at 2Θ values ​​of 18.5°, 16.4°, 17.4°, 8.6°, 17.6°, 8.7°, 18.4°, 25.1°, 27.6° and 13.7°.

4. A crystalline form of a salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, which is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate salt having an XRPD pattern comprising peaks having 2θ values ​​±0.2° 2θ, and optionally relative intensities according to the following table:

5. A crystalline form of a salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide, which is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (niraparib) (R)-(-)-mandelate, characterized in that The XRPD pattern is basically shown in Figure 15.

6. The crystalline form according to any one of claims 1 to 5, characterized in that Melting point 190°C to 200°C.

7. The crystalline form according to claim 6, characterized in that Melting point of about 197°C.

8. The crystalline form according to claim 7, characterized in that A DSC thermogram wherein an endothermic peak has a melting onset temperature of about 197°C and / or wherein the minimum of said peak is about 201°C.

9. The crystalline form according to claim 7, characterized in that The DSC thermal analysis diagram is basically shown in Figure 18.

10. The crystalline form according to claim 8 or 9, characterized in that An infrared spectrum including peaks at about 3443 cm-1, about 3340 cm-1, about 1671 cm-1, and about 1638 cm-1.

11. The crystalline form according to claim 8 or 9, characterized in that The infrared spectrum is basically shown in Figure 14.

12. The crystalline form according to claim 10, characterized in that The DVS thermal analysis diagram is basically shown in Figure 19.

13. The crystalline form according to claim 11, characterized in that The DVS thermal analysis diagram is basically shown in Figure 19.

14. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 13, and at least one pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition is suitable for oral administration.

16. Use of the crystalline form according to any one of claims 1 to 13 or the pharmaceutical composition according to any one of claims 14 or 15 in the preparation of a medicament for treating cancer.

17. The use according to claim 16, wherein the cancer is associated with BRCA1 and / or BRCA2 mutations.

18. The use according to claim 16, wherein the cancer is associated with a mutation in ATM, ATR, BAP1, BARD1, BLM, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L or XRCC2, or any combination thereof.

19. Use according to any one of claims 16 to 18, wherein the cancer is epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

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