Co-crystalline forms of 4-[4-[3-chloro-4-[1-(2-pyridinyl)-2-hydroxy-ethoxy] pyrazolo [1, 5-a] pyridin-6-yl]-5-methyl-triazol-1-yl] piperidine-1-carbonitrile derivatives with gallic acid and nicotinamide

Abstract

The invention relates to a co-crystal form (I) of 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy] pyrazolo [1, 5-a] pyridine-6-yl]-5-methyl-triazol-1-yl] piperidine-1-carbonitrile R-enantiomer ("isomer 2") and gallic acid, and relates to a co-crystal form (I) of 4-[4-[3-chloro-4-[1-(2-pyridyl)-2-hydroxy-ethoxy] pyrazolo [1, 5-a] pyridin-6-yl]-5-methyl-triazol-1-yl] piperidine-1-carbonitrile R-enantiomer ("isomer 2") and gallic acid. The present invention relates to a eutectic form (II) of [1, 5-a] pyridin-6-yl]-5-methyl-triazol-1-yl] piperidine-1-formonitrile R-enantiomer ("isomer A") with gallic acid and nicotinamide. The compounds are Fibroblast Growth Factor Receptor 3 (FGFR3) inhibitors for use in methods of treating, for example, cancer. Also provided herein are methods for preparing the eutectic forms. # imgabs0 #

Description

[0001] The present disclosure relates to the field of cancer treatment.

[0002] Background

[0003] Fibroblast growth factor (FGF) is an important mediator of many physiological processes such as morphogenesis, fibrosis, and angiogenesis during development. The fibroblast growth factor receptor (FGFR) family consists of five members, four of which (FGFR 1-4) are glycoproteins composed of extracellular immunoglobulin (Ig)-like domains, a hydrophobic transmembrane region, and a cytoplasmic portion containing a tyrosine kinase domain. FGF binding results in FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient to recruit and activate specific downstream signaling partners that are involved in the regulation of multiple processes such as cell growth, cell metabolism, and cell survival. Thus, the FGF / FGFR signaling pathway has pleiotropic effects on many biological processes that are crucial for tumor cell proliferation, migration, invasion, and angiogenesis.

[0004] It is useful to develop new forms of FGFR3 inhibitors for treating cancer. It is also useful to develop improved solid forms or forms with improved chemical stability. It is useful to develop forms of FGFR3 inhibitors with improved solubility compared to existing forms of FGFR3 inhibitors (such as FGFR3 inhibitors in the free base form). It is useful to develop forms of FGFR3 inhibitors with improved chemical stability compared to existing forms of FGFR3 inhibitors (such as the SDD form of FGFR3 inhibitors). It is useful to develop forms of FGFR3 inhibitors that can improve the absorption of FGFR3 inhibitors. It is useful to develop forms of FGFR3 inhibitors that enable oral administration of FGFR3 inhibitors. It is useful to develop forms that, compared to existing forms of FGFR3 inhibitors (such as the SDD form of FGFR3 inhibitors), result in fewer method steps, a simplified supply chain, and fewer unit operations. It is useful to develop forms that use less solvent or have a smaller environmental impact compared to existing forms of FGFR3 inhibitors (such as the SDD form of FGFR3 inhibitors).

[0005] Overview

[0006] WO / 2022 / 187443 (International Patent Application No. PCT / US2022 / 018644) and US2023 / 0095122A1 (US Patent Application 17 / 685,753) disclose compounds or their salts that can be used as FGFR3 inhibitors. Examples of the FGFR3 inhibitors disclosed therein are 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, which has the following structure:

[0007]

[0008] In Examples 45 and 46 of WO / 2022 / 187443 (International Patent Application No. PCT / US2022 / 018644) and US2023 / 0095122A1 (US Patent Application 17 / 685,753), the compound is disclosed in the form of individual isomers. As disclosed therein, the compound exists in the form of isomers. In addition, as described in Examples 45 and 46 of these documents, the isomers can be separated using preparative chiral HPLC. When using an HPLC column: ART Cellulose-SB, 2*25 cm, 5 μm and eluting with a solution of 20% 5:1 Hex:DCM (0.5% 2M NH3 in MeOH) in EtOH, Example 45 is the first eluting isomer and Example 46 is the second eluting isomer.

[0009] Example 45, 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 1 (hereinafter referred to as "isomer 1") is the R-enantiomer. Isomer 1 has the following structure:

[0010]

[0011] Example 46, 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 (hereinafter referred to as "isomer 2") is the S-enantiomer. Isomer 2 has the following structure:

[0012]

[0013] WO / 2022 / 187443 (International Patent Application No. PCT / US2022 / 018644) and US2023 / 0095122A1 (US Patent Application 17 / 685,753) disclose how to prepare Examples 45 and 46.

[0014] Another FGFR3 inhibitor disclosed in WO / 2022 / 187443 (International Patent Application No. PCT / US2022 / 018644) and US2023 / 0095122A1 (US Patent Application 17 / 685,753) is 4-[4-[3-chloro-4-[2-hydroxy-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 1 (hereinafter referred to as "isomer A"), which has the following structure:

[0015]

[0016] This compound is disclosed as Example 151 in both PCT / US / 2022 / 018644 and US Patent Application 17 / 685,753. WO / 2022 / 187443 (International Patent Application No. PCT / US2022 / 018644) and US2023 / 0095122A1 (US Patent Application 17 / 685,753) disclose how to prepare Example 151.

[0017] The biological assays disclosed herein demonstrate that isomers 1, 2, and A are FGFR3 inhibitors. The following assays demonstrate that the specific compounds provided herein selectively target FGFR3.

[0018] FGFR3 and FGFR1 enzyme assays: FGFR3 protein was purchased from Reaction Biology (Catalog No. 1068), and FGFR1 protein was purchased from ThermoFisher Scientific (Catalog No. PV4105). KinEASE TM -TK assay kit (CisBio, Catalog No. 62TKOPEC) was used to monitor enzyme activity according to the manufacturer's instructions. All assays were performed at the respective KmATP for various kinases in KinEASE TM kinase buffer. Reactions were carried out in white low-volume polystyrene 384-well plates (Greiner, Catalog No. 784075-25).

[0019] Incubate with FGFR3 protein or FGFR1 protein, 125.0 nM TK-biotin substrate (CisBio), 7.81 nM streptavidin-XL665 (CisBio), 0.25x anti-phospho-TK-biotin-cryptate (CisBio). The final enzyme concentration is 0.25 nM, in a 10 uL reaction. Titrate isomers 1, 2, and A in 100% dimethyl sulfoxide (DMSO) starting from 1 uM in a semi-logarithmic manner. Pre-incubate FGFR1 protein and isomers 1, 2, and A at room temperature for 15 minutes and FGFR3 protein and isomers 1, 2, and A on ice for 15 minutes before initiating the reaction with adenosine triphosphate (ATP). Conduct the reaction at 30 °C for 30 minutes. Quench the plate by adding the anti-TK cryptate antibody / streptavidin-XL665 mixture. After 1 hour, read the plate in the termination solution on an Envision plate reader ((Perkin Elmer) (excitation filter 320 nm and Em1 665 nm / Em2 615 nm)).

[0020] Convert the ratio to percent of control (POC) using the ratio emission factor. Determine 100 POC without using the test compound and 0 POC in the presence of an appropriate control inhibitor at 1 uM. Fit a 4-parameter logistic curve to the POC values as a function of the concentrations of isomers 1, 2, and A, and the IC 50 value is the point at which the best-fit curve intersects 50 POC.

[0021] In the above assay, isomers 1, 2, and A all showed IC 50 values of less than 350 nM for FGFR3. In the above assay, isomers 2 and A both showed IC 50 values of less than 100 nM for FGFR3, and the selectivity for FGFR3 was at least 3-fold that for FGFR1. In the above assay, isomers 2 and A both showed IC 50 values of less than 50 nM for FGFR3, and the selectivity for FGFR3 was at least 10-fold that for FGFR1.

[0022] New co-crystalline forms of the above-identified FGFR3 inhibitors are disclosed herein. Compared to existing forms of FGFR3 inhibitors (e.g., the SDD form of FGFR3 inhibitors), these forms exhibit improved solid-state and chemical stability. They can be incorporated into pharmaceutical formulations, which are expected to exhibit superior stability compared to previously known non-cocrystal forms. Thus, described herein are co-crystalline forms of the above FGFR3 inhibitors and their pharmaceutical compositions.

[0023] Isomer 2 form

[0024] The present disclosure relates to a eutectic form comprising an isomer 2 and a gallic acid coformer. Gallic acid, also known as 3,4,5-trihydroxybenzoic acid, has the following structure:

[0025]

[0026] In one embodiment, gallic acid may have a variable water content that varies between anhydrous and gallic acid monohydrate. In one embodiment, gallic acid is anhydrous gallic acid. In one embodiment, gallic acid is gallic acid monohydrate.

[0027] In one embodiment, THF may have a variable water content. In one embodiment, THF is anhydrous THF. In one embodiment, THF is wet THF. In one embodiment, THF may contain some water. In one embodiment, water is added to THF.

[0028] In one embodiment, the ratio of isomer 2 to gallic acid in the eutectic form is about 2:1.

[0029] In one embodiment, the eutectic form further comprises a solvent. In one embodiment, the solvent is water and the eutectic form is a hydrate. In one embodiment, the eutectic form has a hemihydrate (referred to herein as "the eutectic form of Formula I"). In one embodiment, the eutectic form of Formula I is

[0030]

[0031] In one embodiment, the eutectic form of Formula I has a variable water content. In one embodiment, by thermogravimetric analysis (TGA), the water content of the eutectic form of Formula I ranges from about 0% to about 3.2%.

[0032] In one embodiment, the eutectic form is the form after the eutectic form of Formula I loses water, i.e., "dehydrated hydrate". In one embodiment, the eutectic form of Formula I is dehydrated (referred to herein as "the eutectic form of Formula II"). In one embodiment, the eutectic form of Formula II is

[0033]

[0034] The present disclosure relates to a eutectic form comprising an isomer 2 and a monogallic acid coformer. In one embodiment, the ratio of isomer 2 to gallic acid in the eutectic form is about 1:1 (referred to herein as "the eutectic form of Formula III").

[0035] In one embodiment, the eutectic form of Formula III is

[0036]

[0037] In one embodiment, the eutectic form of Formula III has a solvent. In one embodiment, the solvent is acetonitrile. In one embodiment, the eutectic form of Formula III has a monoacetonitrile solvent (referred to herein as "the eutectic form of Formula IV"). In one embodiment, the eutectic form of Formula IV is

[0038]

[0039] Isomer A form

[0040] The present disclosure provides eutectic forms of the co-formations of isomer A and gallic acid. In one embodiment, the eutectic form comprises isomer A and a mono-gallic acid co-formation. In one embodiment, the ratio of isomer A to gallic acid in the eutectic form of Formula V is about 1:1 (referred to herein as "the eutectic form of Formula V"). In one embodiment, the eutectic form of Formula V is

[0041]

[0042] The present disclosure provides eutectic forms of the co-formations of isomer A and nicotinamide. Nicotinamide, also known as pyridine-3-carboxamide, has the structure shown below:

[0043]

[0044] In one embodiment, the eutectic form comprises isomer A and a mono-nicotinamide co-formation. In one embodiment, the ratio of isomer A to nicotinamide is about 1:1 (referred to herein as "the eutectic form of Formula VI"). In one embodiment, the eutectic form of Formula VI is

[0045]

[0046] Also provided are pharmaceutical compositions comprising the eutectic forms described above, methods of using the eutectic forms to treat conditions treatable by inhibiting FGFR3, and methods of synthesizing the eutectic forms.

[0047] Accordingly, the present text describes the co-crystalline forms of FGFR3 and their pharmaceutical compositions. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent or excipient. Also described are pharmaceutical compositions comprising a co-crystalline form and further comprising a pharmaceutically acceptable carrier, diluent or excipient. Also described are pharmaceutical compositions wherein the composition contains at least about 80% by weight of any of the said co-crystalline forms. Also described are pharmaceutical compositions wherein the composition contains at least about 90% by weight of any of the said co-crystalline forms. Also described are pharmaceutical compositions wherein the composition contains at least about 95% by weight of any of the said co-crystalline forms.

[0048] In one embodiment, the pharmaceutical composition is for treatment. In another embodiment, the present text discloses the use of the co-crystalline forms of Formula I, II, V or VI in a therapy for treating a disease selected from systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and cancer.

[0049] The present text discloses a method for treating cancer related to FGFR3, which comprises administering to a patient in need an effective amount of the co-crystalline form of Formula I, II, V or VI:

[0050]

[0051] or its pharmaceutical composition.

[0052] In one embodiment, the method for treating cancer related to FGFR3 comprises administering to a patient in need an effective amount of the co-crystalline form of Formula I, II, V or VI, or its pharmaceutical composition.

[0053] In one aspect, the present text discloses the co-crystalline forms of Formula I, II, V or VI:

[0054]

[0055] which are used for treating cancer related to FGFR3.

[0056] In one embodiment, the co-crystalline form of Formula I, II, V or VI is used for treating cancer related to FGFR3, wherein the cancer related to FGFR3 is non-muscle invasive bladder cancer.

[0057] In one embodiment, the co-crystalline form of Formula I, II, V or VI is used for treating cancer related to FGFR3, wherein the cancer related to FGFR3 is intermediate-risk non-muscle invasive bladder cancer.

[0058] In one embodiment, the eutectic forms of Formula I, II, V or VI are used for treating cancers associated with FGFR3, wherein the cancers associated with FGFR3 are non-muscle invasive bladder cancers that are unresponsive to Bacillus Calmette-Guerin (BCG) or non-muscle invasive bladder cancers that recur after treatment with Bacillus Calmette-Guerin (BCG).

[0059] In one embodiment, the eutectic forms of Formula I, II, V or VI are used for treating cancers associated with FGFR3, wherein the cancers associated with FGFR3 are high-risk non-muscle invasive bladder cancers.

[0060] In one aspect, the present disclosure provides the use of an effective amount of a eutectic form of Formula I, II, V or VI or a pharmaceutical composition thereof in the preparation of a medicament for treating cancers associated with FGFR3:

[0061]

[0062] In one embodiment, the present disclosure provides the use of an effective amount of a eutectic form of Formula I, II, V or VI or a pharmaceutical composition thereof in the preparation of a medicament for treating cancers associated with FGFR3, wherein the cancers associated with FGFR3 are non-muscle invasive bladder cancers.

[0063] In one embodiment, the present disclosure provides the use of an effective amount of a eutectic form of Formula I, II, V or VI or a pharmaceutical composition thereof in the preparation of a medicament for treating cancers associated with FGFR3, wherein the cancers associated with FGFR3 are intermediate-risk non-muscle invasive bladder cancers.

[0064] In one embodiment, the present disclosure provides the use of an effective amount of a eutectic form of Formula I, II, V or VI or a pharmaceutical composition thereof in the preparation of a medicament for treating cancers associated with FGFR3, wherein the cancers associated with FGFR3 are non-muscle invasive bladder cancers that are unresponsive to Bacillus Calmette-Guerin (BCG) or non-muscle invasive bladder cancers that recur after treatment with Bacillus Calmette-Guerin (BCG).

[0065] In one embodiment, the present disclosure provides the use of an effective amount of a eutectic form of Formula I, II, V or VI or a pharmaceutical composition thereof in the preparation of a medicament for treating cancers associated with FGFR3, wherein the cancers associated with FGFR3 are high-risk non-muscle invasive bladder cancers.

[0066] In another aspect, the present disclosure provides a method for preparing a eutectic form of Formula I, the method comprising adding 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile (isomer 2) and gallic acid to a solvent to obtain a slurry, and adding cyclopentyl methyl ether to the slurry to form a white precipitate. In one embodiment, the method for preparing the eutectic form of Formula I further comprises inoculating the slurry with the eutectic form of Formula I.

[0067] The present disclosure provides a method for preparing a eutectic form of Formula II, the method comprising the step of heating the eutectic form of Formula I.

[0068] The present disclosure provides a method for preparing a eutectic form of Formula IV, the method comprising the step of combining the eutectic form of Formula I with acetonitrile.

[0069] The present disclosure provides a method for preparing a eutectic form of Formula V, the method comprising adding gallic acid to isomer A dissolved in ethyl acetate.

[0070] The present disclosure provides a method for preparing a eutectic form of Formula VI, the method comprising dissolving isomer A in ethyl acetate saturated with nicotinamide. Detailed description of the invention

[0072] In one embodiment, the eutectic form of Formula I has a variable water content. In one embodiment, the water content of the eutectic form of Formula I ranges from about 0% to about 3.2%.

[0073] In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by having an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and one or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by having an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and four or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by having an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and five or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by having an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and six or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by having an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and seven or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees.In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and eight or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and nine or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by an X-ray powder diffraction (XRPD) pattern using CuKα irradiation, the X-ray powder diffraction pattern comprising a peak at 8.4° and ten or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0074] In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by an XRPD pattern using CuKα irradiation, the XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by an XRPD pattern using CuKα irradiation, the XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and two or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by an XRPD pattern using CuKα irradiation, the XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and three or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0075] In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are each characterized by an XRPD pattern using CuKα irradiation, the XRPD pattern having a diffraction peak at diffraction angle 2θ of 8.4° and one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°, and a combination with one or more peaks at 9.2°, 10.0°, 13.4°, 14.1°, 16.9°, 18.4°, 19.6°, or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the diffraction peak at diffraction angle 2θ of 8.4° is strong. In one embodiment, one or more of the peaks at diffraction angle 2θ selected from 15.6°, 21.3°, 6.7°, and 23.4° are strong. In one embodiment, one or more of the peaks at diffraction angle 2θ selected from 15.6° and 21.3° are strong.

[0076] In one embodiment, the eutectic form of Formula I and the eutectic form of Formula II are characterized by 13 a solid-state C NMR spectrum that includes peaks at the following positions relative to the carbonyl resonance of glycine (δ = 176.5 ppm): 8.1, 11.1, 26.6, 28.2, 32.3, 35.0, 80.7, 81.7, 99.6, 102.3, 110.9, 158.0, 160.0, 168.2, 175.0 ppm, with an allowable difference of ±0.2 ppm.

[0077] In one embodiment, the eutectic form of Formula IV is characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 14.6° and one or more peaks at 5.7°, 6.5°, 9.8°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, 19.7°, 23.8°, or 24.5°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the eutectic form of Formula IV is characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula IV is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and two or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula IV is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and three or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0078] In one embodiment, the eutectic form of Formula IV is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°, and a combination with one or more peaks at 5.7°, 6.5°, 9.8°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, 19.7°, 23.8°, or 24.5°, with an allowable difference in diffraction angle of ±0.2 degrees. In one embodiment, the diffraction peak at diffraction angle 2θ 14.6° is strong. In one embodiment, one or more of the peaks at diffraction angle 2θ selected from 9.8°, 23.8°, 6.5°, and 19.7° are strong. In one embodiment, one or more of the peaks at diffraction angle 2θ selected from 9.8° and 23.8° are strong.

[0079] In one embodiment, the eutectic form of Formula V is characterized by its XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 6.9° and one or more peaks at 9.1°, 10.5°, 12.7°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 18.4°, 21.0°, or 23.4°, with an allowable difference of ±0.2 ppm. In one embodiment, the eutectic form of Formula V is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula V is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 6.9° and two or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula V is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 6.9° and three or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0080] In one embodiment, the eutectic form of Formula V is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, and a combination of one or more peaks selected from 10.5°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 21.0°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0081] In one embodiment, the diffraction peak at diffraction angle 2θ 6.9° of the eutectic form of Formula V is strong. In one embodiment, one or more of the peaks at diffraction angle 2θ selected from 12.7°, 18.4°, 9.1°, and 23.4° are strong. In one embodiment, one or more of the peaks at diffraction angle 2θ selected from 12.7° and 18.4° of the eutectic form of Formula V are strong.

[0082] In one embodiment, the eutectic form of Formula VI is characterized by its XRPD pattern using CuKα irradiation, which contains a peak at 13.7° and one or more peaks at 6.8°, 8.2°, 9.6°, 12.3°, 15.8°, 17.5°, 17.9°, 18.7°, 19.0°, 22.2°, 22.9°, 24.7°, or 26.1°, with an allowable difference of ±0.2 ppm. In one embodiment, the eutectic form of Formula VI is characterized by an XRPD pattern using CuKα irradiation, which has a combination of a diffraction peak at diffraction angle 2θ of 13.7° and one or more peaks selected from 9.6°, 17.9°, and 24.7°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula VI is characterized by an XRPD pattern using CuKα irradiation, which has a combination of a diffraction peak at diffraction angle 2θ of 13.7° and two or more peaks selected from 9.6°, 17.9°, and 24.7°; the allowable difference in diffraction angle is ±0.2 degrees. In one embodiment, the eutectic form of Formula VI is characterized by an XRPD pattern using CuKα irradiation, which has a combination of a diffraction peak at diffraction angle 2θ of 13.7° and peaks selected from 9.6°, 17.9°, and 24.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0083] In one embodiment, the eutectic form of Formula VI is characterized by an XRPD pattern using CuKα irradiation, which has a combination of a diffraction peak at diffraction angle 2θ of 13.7° and one or more peaks selected from 9.6°, 17.9°, and 24.7°, and a combination of one or more peaks selected from 6.8°, 8.2°, 12.3°, 15.8°, 17.5°, 18.7°, 19.0°, 22.2°, 22.9°, or 26.1°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0084] In one embodiment, the diffraction peak at diffraction angle 2θ of 13.7° of the eutectic form of Formula VI is strong. In one embodiment, one or more peaks at diffraction angle 2θ selected from 9.6°, 17.9°, and 24.7° are strong. In one embodiment, one or more peaks at diffraction angle 2θ of the eutectic form of Formula VI selected from 9.6° and 17.9° are strong.

[0085] Some eutectic forms can provide improved solubility compared to other eutectic forms or existing formulations (e.g., free base or spray dried dispersion (SDD)). For example, the solubility of the eutectic form of Formula I can be about 2 to about 5 times, about 3 to about 5 times, or about 4 to about 5 times that of the free base form of isomer 2. For example, the solubility of the eutectic form of Formula I can be about 4 to about 5 times that of the free base form of isomer 2, e.g., in simulated intestinal fluid in the fasting state. For example, the solubility of the eutectic form of Formula I can be about 2 to about 3 times that of isomer 2 with HPMC SDD, e.g., in simulated intestinal fluid in the fasting state. Some eutectic forms enable oral administration of the FGFR3 inhibitor compared to other eutectic forms or existing formulations, such as spray dried dispersion (SDD).

[0086] Some eutectic forms can be more stable than other eutectic forms or existing formulations (e.g., spray dried dispersion (SDD)). For example, the crystalline form of Formula I is more stable at 40 °C and 75% relative humidity than a variety of existing SDD formulations containing isomer 2 (e.g., isomer 2 with HPMC SDD, isomer 2 with HPMC-AS-M SDD, and isomer 2 with PVP-VA SDD). The eutectic form can be more stable than SDD. The eutectic form can have improved properties, such as lower hygroscopicity. Certain embodiments of the present disclosure are directed to eutectic forms that utilize fewer required method of manufacture steps than existing formulations. The eutectic form can result in fewer method of manufacture steps, which includes the benefits of a simplified supply chain and a reduced number of unit operations. The eutectic form undergoes fewer material transfers from different locations, e.g., transferring once to incorporate the eutectic into a formulation, such as tablets, capsules, and suspensions. It is recognized that SDD formulations start at the first location where the active pharmaceutical ingredient (API) is produced, are transferred to a second location where the API is incorporated into the SDD, and then transferred to a third location where the SDD and API are incorporated into a formulation (e.g., tablets, capsules, and suspensions). Certain embodiments of the present disclosure use eutectic forms that require less solvent than existing formulations, resulting in less environmental impact.

[0087] In one embodiment, the pharmaceutical composition is used for treating cancers associated with FGFR3. Examples of cancers associated with FGFR3 include, but are not limited to, breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, metastatic urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle invasive urothelial carcinoma, non-muscle invasive bladder cancer, muscle invasive urothelial carcinoma, muscle invasive bladder cancer, upper tract cancer, upper tract urothelial carcinoma, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer. In one embodiment, the cancer associated with FGFR3 is urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle invasive bladder cancer, or muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is urothelial carcinoma. In one embodiment, the cancer associated with FGFR3 is bladder cancer. In one embodiment, the cancer associated with FGFR3 is urothelial bladder cancer. In one embodiment, the cancer associated with FGFR3 is advanced urothelial bladder cancer. In one embodiment, the cancer associated with FGFR3 is metastatic urothelial bladder cancer. In one embodiment, the cancer associated with FGFR3 is non-muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is intermediate-risk non-muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is non-muscle invasive bladder cancer that is non-responsive to Bacillus Calmette-Guerin (BCG). In one embodiment, the cancer associated with FGFR3 is non-muscle invasive bladder cancer that recurs after treatment with Bacillus Calmette-Guerin (BCG). In one embodiment, the cancer associated with FGFR3 is high-risk non-muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is muscle invasive bladder cancer.

[0088] Definitions

[0089] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the following terms have the meanings set forth below for them, unless otherwise indicated.

[0090] As used herein, "cancer" refers to cancers associated with FGFR3. Cancers associated with FGFR3 can exhibit at least one of point mutations / insertions / deletions and / or fusions. Examples of specific cancers that can be treated with the compounds disclosed herein include, but are not limited to, breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer. Alternatively, the cancer is urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, or muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is urothelial cancer. In one embodiment, the cancer associated with FGFR3 is bladder cancer. In one embodiment, the cancer associated with FGFR3 is urothelial bladder cancer. In one embodiment, the cancer associated with FGFR3 is advanced urothelial bladder cancer. In one embodiment, the cancer associated with FGFR3 is metastatic urothelial bladder cancer. In one embodiment, the cancer associated with FGFR3 is non-muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is intermediate-risk non-muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is non-muscle invasive bladder cancer that is non-responsive to Bacillus Calmette-Guérin (BCG). In one embodiment, the cancer associated with FGFR3 is non-muscle invasive bladder cancer that recurs after treatment with Bacillus Calmette-Guérin (BCG). In one embodiment, the cancer associated with FGFR3 is high-risk non-muscle invasive bladder cancer. In one embodiment, the cancer associated with FGFR3 is muscle invasive bladder cancer.

[0091] The term "NMIBC" or "non-muscle invasive bladder cancer" means bladder cancer that is staged T0, Ta, T1, or CIS according to the Tumor, Node, Metastasis (TNM) staging. The term "T0" means the first stage of disease with no evidence of primary tumor according to the Tumor, Node, Metastasis (TNM) staging. The terms "Ta", "T1", "T2", "T3", and "T4" mean the size or extent of the primary tumor according to the Tumor, Node, Metastasis (TNM) staging.

[0092] The terms "intermediate-risk non-muscle-invasive bladder cancer", "intermediate-risk NMIBC" or "IR NMIBC" mean multiple or recurrent low-grade Ta tumors. Factors to be considered are the number of tumors (e.g., more than 1), tumor size (e.g., greater than 3 cm), time (e.g., recurrence within 1 year), recurrence frequency (e.g., more than 1 recurrence per year), and prior treatment.

[0093] The terms "high-risk non-muscle-invasive bladder cancer", "high-risk NMIBC" or "HR NMIBC" mean recurrent, BCG-unresponsive, high-grade, T1 or CIS tumors, where recurrence can be after BCG treatment. Factors to be considered include tumor grade, tumor size (e.g., greater than 3 cm), time (e.g., recurrence within 1 year), recurrence frequency (e.g., more than 1 recurrence per year), and prior treatment.

[0094] Terms such as "treatment" are intended to include slowing, halting, or reversing the progression of a disorder. These terms also include alleviating, improving, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disease or condition is not actually eliminated, even if the progression of the disease or condition itself is not slowed, halted, or reversed.

[0095] "Effective amount" means an amount of the eutectic form (eutectic forms of Formulas I, II, V or VI) that will elicit a biological or medical response in a patient or the therapeutic effect desired by the treating clinician for the patient.

[0096] As used herein, "patient" refers to a mammal, and more preferably, to a human.

[0097] An effective amount can be readily determined by the attending diagnostician (as a person skilled in the art) by using known techniques and by observing results obtained in comparable circumstances. In determining the effective amount for a patient, the attending diagnostician takes into account a number of factors, including but not limited to: the species of the patient; its size, age, and general health; the specific disease or disorder involved; the degree or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the dosage form administered; the dosing regimen selected; the use of concomitant medications; and other relevant circumstances.

[0098] In some embodiments, an "eutectic" refers to a solid of a crystalline material that is typically composed of a compound of two or more different molecules in a stoichiometric ratio. A more general definition is that an eutectic contains two or more components that form a unique crystal structure with unique properties. An eutectic hydrate refers to a crystalline material composed of a compound of two or more different molecules (usually in a stoichiometric ratio) and water. The amount of water can be stoichiometric, but can also be non-stoichiometric. Removal of water from the crystal may or may not disrupt the lattice and is commonly referred to as a dehydrated hydrate. Hydrates are known in the art (see, for example, Chapter 6 of Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; Hygroscopicity and Hydrates in Pharmaceutical Solids (Rolf Hilfiker, Markus von Raumer, eds., John Wiley & Sons, 2018)).

[0099] The various eutectic forms (eutectic forms of Formula I, Formula II, Formula IV, Formula V or Formula VI) are preferably formulated as pharmaceutical compositions, which are administered by any route that renders the compound bioavailable, including oral, intravenous and transdermal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods for their preparation are known in the art (see, for example, Remington: The Science and Practice of Pharmacy (D.B. Troy, ed., 21 st th Edition, Lippincott, Williams & Wilkins, 2006).

[0100] The term "strong" is defined herein as a detected signal from a sample being greater than the background signal from the instrument.

[0101] For the sake of providing a more concise description, some quantitative representations herein are recited as a range from about amount X to about amount Y. It is understood that when a range is recited, the range is not limited to the recited upper and lower limits, but includes the full range from about amount X to about amount Y or any range therein.

[0102] "Room temperature" or "RT" refers to the ambient temperature of a typical laboratory, usually about 25 °C.

[0103] In some embodiments, the term "excipient" refers to any substance required to formulate a composition into the desired form. For example, suitable excipients include, but are not limited to, diluents or fillers, binders or granulating agents or adhesives, disintegrants, lubricants, anti-adhesion agents, glidants, dispersants or wetting agents, dissolution retardants or dissolution enhancers, adsorbents, buffers, chelating agents, preservatives, pigments, flavoring agents, and sweetening agents.

[0104] "Pharmaceutically acceptable carrier, diluent, or excipient" is a medium commonly accepted in the art for delivering a bioactive agent to a mammal (e.g., a human). The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., which are not biologically or otherwise undesirable. The use of such media and substances for a pharmaceutically active substance is well known in the art. Such media and substances are contemplated for use in therapeutic formulations unless any conventional medium or substance is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the formulations. In addition, various excipients can be included, such as those commonly used in the art. These and other such compounds are described in the literature, e.g., Merck Index, Merck & Company, Rahway, N.J. For example, in Gilman et al. (eds.) (2010); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12 th th Edition, The McGraw-Hill Companies describes considerations for including various components in pharmaceutical compositions.

[0105] In some embodiments, unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents.

[0106] In some embodiments, ranges and amounts may be expressed as "about" a particular value or range. About also includes the exact amount. Thus, "about 5 grams" means "about 5 grams" and "5 grams." It is also understood that the ranges expressed herein include the integers and their decimals within the range. For example, the range between 5 grams and 20 grams includes integer values such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 grams, as well as decimals within the range, including but not limited to 5.25, 6.5, 8.75, and 11.95 grams.

[0107] In some embodiments, "optional" or "optionally" means that the subsequently described event or circumstance occurs or does not occur, and the description includes examples where the event or circumstance occurs and examples where the event or circumstance does not occur. For example, a reaction mixture that "optionally contains a catalyst" means that the reaction mixture contains a catalyst or does not contain a catalyst.

[0108] In some embodiments, "relative intensity" means the percentage of any peak relative to the tallest peak in the relevant spectrum.

[0109] It will be understood that certain features of the present disclosure that are described in the context of separate embodiments for clarity can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure that are described in the context of a single embodiment for brevity can also be provided separately or in any suitable sub-combination.

[0110] The present disclosure specifically includes all combinations of embodiments related to the aspects described herein, to the extent that such combinations include all possible aspects, as if each and every combination were explicitly recited separately. Additionally, the present disclosure specifically includes all sub-combinations of embodiments included within the aspects described herein and all sub-combinations of embodiments included within all other aspects described herein, as if every sub-combination of all embodiments were explicitly recited herein. Examples

[0111] The following examples further illustrate the present disclosure.

[0112] The XRPD patterns of Examples 1 - 3 were obtained on a Bruker D8 Endeavor X-ray powder diffractometer equipped with a CuKα source and a Linxeye detector, operating at 40 kV and 40 mA. The sample scan range was 4 to 42 2θ°, the step size was 0.009 2θ°, the scan rate was 0.5 seconds / step, using a 0.3° primary slit opening and a 3.9° PSD opening. The dry powder was loaded onto a quartz or silicon sample holder, and a smooth surface was obtained using a cover slip. The crystalline diffraction patterns were collected at ambient temperature and relative humidity. In MDI-Jade, the crystal peak positions were determined after a full-spectrum shift based on an internal NIST 675 standard with peaks at 8.853 and 26.774 2θ°.

[0113] For any given crystalline form, it is well known in the field of crystallography that the relative intensities of diffraction peaks can vary due to preferred orientation caused by factors such as crystal morphology and habit. When the influence of preferred orientation is present, the peak intensities are altered, but the characteristic peak positions of the form remain unchanged. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843 - 1844, 1995. Additionally, it is well known in the field of crystallography that for any given crystalline form, the angular peak positions can vary slightly. For example, the peak positions may be offset due to changes in temperature during analysis of the sample, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variation of ±0.2 2θ° is presumed to account for these potential variations without preventing the unambiguous identification of the indicated crystalline form. The crystalline form can be confirmed based on any unique combination of distinguishing peaks.

[0114] Solid state NMR was obtained on an Agilent DD2 - 400 spectrometer (100.6 MHz). The sample was loaded into a 4 mm PENCIL - type silicon nitride rotor and spun at the magic angle at 12 kHz. Spectra were acquired under the following conditions: at ambient temperature, using phase - modulated (SPINAL - 64) high - power 1 1H decoupling, 5 - millisecond ramped amplitude cross - polarization contact time, 30 - millisecond acquisition time, 10 - second scan interval delay, 45 kHz spectral width, 2678 data points, 1600 accumulative scans. The free induction decay (FID) was processed using Agilent VNMRJ 3.2A software, with 65536 points and a 10 Hz exponential line broadening factor to improve the signal - to - noise ratio. The VNMR linear prediction algorithm was used to back - predict the first three data points of the FID to generate a flat baseline. The chemical shifts of the spectral peaks were referenced externally to the carbonyl carbon resonance of glycine at 176.5 ppm.

[0115] Dynamic vapor sorption (DVS) analysis was obtained at 25 °C using a TA Instruments Q5000SA VTI flow moisture balance, running TAThermal Advantage v5.2.6 and Universal Analysis 2000 v4.5a software. The equilibration criterion was <0.01% weight change within 5 minutes, for up to 60 minutes. Humidity verification calibration was performed with sodium bromide. Weight calibration was performed using standards provided by the manufacturer.

[0116] Differential scanning calorimetry (DSC) analysis was obtained using a TA Q2000 DSC run by TA Thermal Advantage software v5.2.6 and data analysis was performed by Universal Analysis 2000 v4.5a. The samples were equilibrated at 25 °C in crimped aluminum pans and heated at a rate of 10 °C / min to 300 °C with a purge of nitrogen at 50 mL / min. Temperature and heat flow were calibrated against the melting of indium.

[0117] Thermogravimetric analysis (TGA) was obtained using a TA Instruments Q5000 TGA run by TA Thermal Advantage software v5.2.6 and data analysis was performed by Universal Analysis 2000 v4.5a. Samples were heated from ambient temperature (ca. 25 °C) to 200 °C at a rate of 10 °C / min. Nitrogen was used as the carrier (10 mL / min) and purge (50 mL / min) gas. Temperature was calibrated by Curie temperature determination using nickel and aluminum standards. Weight calibration was performed using standards provided by the manufacturer.

[0118] Example 1

[0119] 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2, gallic acid cocrystal form, hemihydrate (“the cocrystal form of Formula I”)

[0120]

[0121] 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 (2.25 g) and gallic acid (0.69 g) were suspended in THF (10.4 mL). The slurry was heated to 50 °C while stirring at 200 rpm; all solids dissolved. The solution was cooled to 25 °C, the stirring rate was increased to 400 rpm, and cyclopentyl methyl ether (30 mL) was added at a rate of 0.04 mL / min (over ~12 h), during which a white precipitate formed. After stirring overnight at 25 °C, the solid product was separated by vacuum filtration onto a medium pore sintered filter. The wet filter cake was washed with cyclopentyl methyl ether (5 mL) and dried in vacuo at 50 °C. The title compound (2.25 g) was produced in 86% yield.

[0122] 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 (7.0 g) and gallic acid (2.64 g) were suspended in THF (33.2 mL). The slurry was heated to 50 °C; all solids dissolved. The solution was cooled to 25 °C and seeded with 415 mg of the gallic acid hemihydrate cocrystal. The thin slurry was aged at 25 °C for 25 minutes and then cyclopentyl methyl ether (77.5 mL) was added at a rate of 0.11 mL / min, during which a thick off-white slurry formed. After stirring overnight at 25 °C, the solid product was isolated by vacuum filtration onto a medium pore sintered filter. The wet filter cake was washed with cyclopentyl methyl ether (16.5 mL) and dried in vacuo at 50 °C. The title compound (7.38 g) was produced in 89% yield. The 13 C solid state NMR (101 MHz) of the cocrystal form of formula I includes peaks at δ 8.1, 11.1, 26.6, 28.2, 32.3, 35.0, 80.7, 81.7, 99.6, 102.3, 110.9, 158.0, 160.0, 168.2, 175.0. XRPD of 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2, gallic acid hemihydrate cocrystal form (“the cocrystal form of formula I”)

[0123] The prepared sample of the cocrystal form of formula I was characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having diffraction peaks (2-θ values) as set forth in Table 1 below, in particular having a peak at 8.4 in combination with one or more peaks selected from 15.6, 21.3, 6.7 and 23.4; the allowable difference in diffraction angle is ±0.2 degrees.

[0124] Table 1. XRPD peaks of Example 1

[0125]

[0126] When examined by polarized light microscopy, the cocrystal form of formula I exhibited a needle shape (needle morphology).

[0127] The prepared sample of the cocrystal form of formula I was characterized by dynamic vapor sorption and had a moisture content ranging from about 1% at 0% RH to about 3.2% at 90% RH.

[0128] Example 1 A 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2, semigallic acid cocrystal form, dehydrated hydrate (“cocrystal form of Formula II”)

[0129]

[0130] The prepared sample of the cocrystal form of Formula I was characterized by thermogravimetric analysis and had a step change due to a loss of water of approximately 1.7% prior to the melting of the cocrystal form of Formula II.

[0131] Example 2

[0132] 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2, monogallic acid cocrystal form, monoacetonitrile (“cocrystal form of Formula IV”)

[0133]

[0134] The cocrystal form of Formula I (285 mg) was combined with acetonitrile (4 mL) and stirred overnight at ambient temperature. A thick white slurry was formed, which was transferred to a centrifuge tube filter (5 mL Centrex MF-5.0, 0.45 μm, nylon) and centrifuged (330 rpm) for 5 minutes at ambient temperature. The resulting solid was dried to give the title compound.

[0135] XRPD of 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2, monogallic acid cocrystal form (“cocrystal form of Formula IV”)

[0136] The prepared sample of the cocrystal form of Formula IV was characterized by an XRPD pattern using CuKα irradiation, which had diffraction peaks (2-θ values) as described in Table 2 below, particularly having a peak at 14.6 in combination with one or more peaks selected from 9.8, 23.8, 6.5, and 19.7; the allowable difference in diffraction angle was ±0.2 degrees.

[0137] Table 2. XRPD Peaks of Example 2

[0138] Peak Angle (°2-Θ) + / - 0.2° Relative intensity (% of the strongest peak) 1 5.7 31.9 2 6.5 85.7 3 9.8 90.7 4 13.0 56.9 5 13.5 26.8 6 14.6 84.2 7 16.5 34.7 8 17.1 56.0 9 18.9 58.7 10 19.7 100 11 23.8 85.6 12 24.5 70.1

[0139] Example 3

[0140] 4-[4-[3-Chloro-4-[2-hydroxy-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 1, monogallic acid cocrystal form (“cocrystal form of Formula V”)

[0141]

[0142] Dissolve 4-[4-[3-chloro-4-[2-hydroxy-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 1 (9.76 g) in ethyl acetate. Add gallic acid (4.23 g) and filter the resulting slurry. Place the solid in ethyl acetate (60 mL) and stir at 45 °C for 30 min. Filter the resulting slurry. Place the solid in ethyl acetate (50 mL) and stir at room temperature for 2 days. Filter the resulting slurry. Dry the solid under a nitrogen stream for 15 min and then dry in a vacuum oven (75 °C, for 2 h). Place the solid in cyclopentyl methyl ether (40 mL) and stir at room temperature for 5 days. Filter the resulting slurry and dry at 75 °C overnight. Place the solid in cyclopentyl methyl ether (40 mL) and stir at room temperature for 1 day. Filter the resulting slurry and dry at 75 °C overnight to obtain the title compound (8.9 g).

[0143] XRPD of 4-[4-[3-chloro-4-[2-hydroxy-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 1, monogallic acid cocrystal form (“cocrystal form of Formula V”)

[0144] The prepared sample of the cocrystal form of Formula V is characterized by an XRPD pattern using CuKα irradiation, the XRPD pattern having diffraction peaks (2-θ values) as set forth in Table 3, in particular having a peak at 6.9 in combination with one or more peaks selected from 12.7, 18.4, 9.1, and 23.4; the allowable difference in diffraction angle is ±0.2 degrees.

[0145] Table 3. XRPD Peaks of Example 3

[0146] Peak Angle (°2-Θ) + / - 0.2° Relative intensity (% of the strongest peak) 1 6.9 100 2 9.1 27.7 3 10.5 17.1 4 12.7 59.5 5 15.7 18.2 6 16.3 26.6 7 16.8 21.5 8 17.1 13.6 9 17.9 21.0 10 18.4 84.8 11 21.0 17.4 12 23.4 31.9

[0147] Example 4

[0148] 4-[4-[3-chloro-4-[2-hydroxy-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 1, mononicotinamide cocrystal form (“cocrystal form of Formula VI”)

[0149]

[0150] 4-[4-[3-Chloro-4-[2-hydroxy-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 1 (0.253 g),

[0151]

[0152] was dissolved in ethyl acetate (8 mL, saturated with nicotinamide) and stirred at room temperature for 35 min. The resulting slurry was filtered. The solid was dried under vacuum and under a nitrogen stream for 15 min to give the title compound (0.236 g).

[0153] XRPD of 4-[4-[3-chloro-4-[2-hydroxy-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 1, mononicotinamide cocrystal form (“cocrystal form of formula VI”)

[0154] The prepared sample of the cocrystal form of formula VI is characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having diffraction peaks (2-θ values) as set forth in Table 4, in particular having a peak at 13.7 in combination with one or more peaks selected from 9.6, 17.9 and 24.7; the allowable difference in diffraction angle is ±0.2 degrees.

[0155] Table 4. XRPD peaks of Example 4

[0156] Peak Angle (°2-Θ) + / - 0.2° Relative intensity (% of the strongest peak) 1 6.8 13.4 2 8.2 42.5 3 9.6 66.1 4 12.3 20.8 5 13.7 67.2 6 15.8 18.4 7 17.5 37.2 8 17.9 83.4 9 18.7 63.0 10 19.0 23.2 11 22.2 61.8 12 22.9 14.7 13 24.7 100 14 26.1 62.6

[0157] Example 5A 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 2, 30% SDD (spray dried dispersion), containing HPMC (“isomer 2 HPMC SDD”)

[0158] 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 2 (300.66 mg) was dissolved in acetone (10 mL) and methanol (10 mL). HPMC (hydroxypropyl methylcellulose; 702.19 mg) was added and the material was vortexed for 20 - 30 minutes. The material was spray dried (water bath at 60 °C, oil bath at 200 °C, nitrogen at 60 psi, starting temperature 45 °C, final temperature 72 °C, 1 mL / min, 15 - 20 min) to give the title compound (615 mg, 61%).

[0159] Example 5B 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 2, 30% SDD (spray dried dispersion), containing HPMC-AS-M ("Isomer 2 HPMC-AS-M

[0160] SDD")[[]]END]]

[0161] 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 2 (300.06 mg) was dissolved in acetone (10 mL) and methanol (10 mL). HPMC-AS-M (hydroxypropyl methylcellulose acetate succinate; 701.13 mg) was added and the material was vortexed for 20 minutes. The material was spray dried (water bath at 60 °C, oil bath at 200 °C, nitrogen at 60 psi, starting temperature 45 °C, final temperature 72 °C, 4 mL / min, 5 - 10 min) to give the title compound (781 mg, 78%).

[0162] Example 5C 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,4-triazol-1-yl]piperidine-1-carbonitrile isomer 2, 30% SDD (spray dried dispersion), containing PVP-VA ("Isomer 2 PVP-VA SDD")[[]]END]]

[0163] 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 (301.48 mg) was dissolved in acetone (10 mL) and methanol (10 mL). PVP-VA (poly(1-vinylpyrrolidone-vinyl acetate) copolymer; 703.28 mg) was added and the material was vortexed for 1 minute. The material was spray dried (water bath at 60 °C, oil bath at 200 °C, nitrogen at 60 psi, starting temperature 45 °C, final temperature 72 °C, 2 mL / min, 10 min) to give the title compound (907 mg, 90%).

[0164] Samples of isomer 2 HPMC SDD, isomer 2 HPMC-AS-M SDD, isomer 2 PVP-VA SDD, and the co-crystalline forms of Formula I or Formula II in the media of Table 5 were prepared at approximately 2 mg / ml. Samples of 2 mg / ml of isomer 2 HPMC SDD, isomer 2 HPMC-AS-M SDD, isomer 2 PVP-VA SDD, and the co-crystalline forms of Formula I or Formula II were placed in a rotary mixer or rotary stirrer for approximately 2 hours or approximately 24 hours. Samples of isomer 2 HPMC SDD, isomer 2 HPMC-AS-M SDD, isomer 2 PVP-VA SDD, and the co-crystalline forms of Formula I or Formula II were centrifuged. The supernatants of samples of isomer 2 HPMC SDD, isomer 2 HPMC-AS-M SDD, isomer 2 PVP-VA SDD, and the co-crystalline forms of Formula I or Formula II were analyzed by HPLC using the following conditions: Agilent ZORBAX Bonus-RP, rapid separation, 4.6 * 75, 3.5 um; gradient elution using a can (0.1% TFA) solution of 95% to 5% to 95% H2O, flow rate: 1.5 mL / min.

[0165] Table 5. Solubilities of isomer 2 free base, isomer 2 HPMC SDD, and co-crystalline forms of Formula I or Formula II

[0166]

[0167] Example 6

[0168] Samples of isomer 2 HPMC SDD, isomer 2 HPMC-AS-M SDD, isomer 2 PVP-VA SDD, and the co-crystalline forms of Formula I or Formula II were placed in a chamber at 40 °C / 5% RH and the lid was closed. After 7 or 14 days, samples of isomer 2 HPMC SDD, isomer 2 HPMC-AS-M SDD, isomer 2 PVP-VA SDD, and the co-crystalline forms of Formula I or Formula II were removed from the chamber.

[0169] Partial deliquescence of isomer 2 HPMC SDD was observed at all time points at 40 °C / 75% RH. Complete deliquescence of isomer 2 PVP-VA SDD was observed at all time points at 40 °C / 75% RH. Isomer 2 HPMC-AS-M SDD was observed as a fine white powder at all time points at 40 °C / 75% RH. The eutectic form of Formula I or Formula II was observed as a free-flowing white powder at all time points at 40 °C / 75% RH.

[0170] The samples were analyzed by HPLC using the following conditions: Agilent ZORBAX Bonus-RP, rapid separation, 4.6 * 75, 3.5 μm; elution with a gradient of 95% to 5% to 95% ACN (0.1% TFA) solution in H2O, flow rate: 1.5 mL / min. Table 6. Solid state stability of isomer 2 HPMC SDD, isomer 2 HPMC-AS-M SDD, isomer 2 PVP-VA SDD, and the eutectic form of Formula I or Formula II

[0171]

[0172] Embodiment 1. A eutectic form of a co-formation of the following formula ("isomer 2") and gallic acid:

[0173]

[0174] Embodiment 2. The eutectic form of Embodiment 1, wherein the ratio of isomer 2 to gallic acid is about 2:1.

[0175] Embodiment 3. The eutectic form of Embodiment 1 or 2, wherein the water content ranges from about 0% to about 3.2%.

[0176] Embodiment 4. The eutectic form of any one of Embodiments 1 to 3, wherein the eutectic form is Formula I:

[0177]

[0178] Embodiment 5. The eutectic form of Embodiment 4, which is dehydrated or partially dehydrated.

[0179] Embodiment 6. The eutectic form of any one of Embodiments 1 to 3, wherein the eutectic form is Formula II:

[0180]

[0181] Embodiment 7. The eutectic form of any one of Embodiments 1 to 6, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 8.4° and one or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0182] Embodiment 8. The eutectic form of any one of Embodiments 1 to 7, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0183] Embodiment 9. The eutectic form of any one of Embodiments 1 to 8, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and two or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0184] Embodiment 10. The eutectic form of any one of Embodiments 1 to 9, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and three or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0185] Embodiment 11. The eutectic form of any one of Embodiments 1 to 8, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°, and a combination of one or more peaks selected from 9.2°, 10.0°, 13.4°, 14.1°, 16.9°, 18.4°, 19.6°, and 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0186] Embodiment 12. The eutectic form of any one of Embodiments 1 to 11, characterized by 1313C solid-state NMR spectrum, said NMR spectrum comprising peaks at positions selected from the following, referenced to the carbonyl resonance of glycine: 8.1, 11.1, 26.6, 28.2, 32.3, 35.0, 80.7, 81.7, 99.6, 102.3, 110.9, 158.0, 160.0, 168.2, and 175.0, with an allowable difference of ±0.2 ppm.

[0187] Embodiment 13. The eutectic form of Formula I,

[0188] which can be obtained by: adding 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 and gallic acid to a solvent to obtain a slurry, and

[0189] adding cyclopentyl methyl ether to the said slurry to form a white precipitate.

[0190] Embodiment 14. The eutectic form of Embodiment 13, wherein the solvent comprises THF.

[0191] Embodiment 15. The eutectic form of Embodiment 13 or 14, wherein the slurry is seeded with the eutectic form of Formula I.

[0192] Embodiment 16. The eutectic form of Formula II:

[0193] which can be obtained by: the eutectic form of Formula I: heating to form a dehydrated hydrate.

[0194] Embodiment 17. The eutectic form of Embodiment 16, wherein the heating step is from about 25 °C to 200 °C at a rate of 10 °C / min.

[0195] Embodiment 18. The eutectic form of Embodiment 16 or 17, wherein nitrogen is the carrier gas at about 10 mL / min.

[0196] Embodiment 19. The eutectic form of any one of Embodiments 16 to 18, wherein nitrogen is the purge gas at about 50 mL / min.

[0197] Embodiment 20. The eutectic form of Embodiment 1, wherein the ratio of isomer 2 to gallic acid is about 1:1.

[0198] Embodiment 21. The eutectic form of Embodiment 1 or 20, wherein the eutectic form is

[0199]

[0200] Embodiment 22. The eutectic form according to any one of Embodiments 1, 20 or 21, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 14.6° and one or more peaks at 5.7°, 6.5°, 9.8°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, 19.7°, 23.8° or 24.5°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0201] Embodiment 23. The eutectic form according to any one of Embodiments 1 or 20 - 22, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0202] Embodiment 24. The eutectic form according to any one of Embodiments 1 or 20 - 23, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and two or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0203] Embodiment 25. The eutectic form according to any one of Embodiments 1 or 20 - 24, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and three or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0204] Embodiment 26. The eutectic form according to any one of Embodiments 1, 20 - 25, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°, and a combination of one or more peaks selected from 5.7°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, and 24.5°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0205] Embodiment 27. The eutectic form,

[0206] which can be obtained by: combining with acetonitrile.

[0207] Embodiment 28. A eutectic form of the following formula and the gallic acid co - former:

[0208]

[0209] Embodiment 29. The eutectic form of Embodiment 28, wherein the ratio of isomer A to gallic acid is about 1:1.

[0210] Embodiment 30. The eutectic form of Embodiment 28 or 29, wherein the eutectic form is

[0211]

[0212] Embodiment 31. The eutectic form of any one of Embodiments 28 to 30, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 6.9° and one or more peaks at 9.1°, 10.5°, 12.7°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 18.4°, 21.0° or 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0213] Embodiment 32. The eutectic form of any one of Embodiments 28 to 31, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0214] Embodiment 33. The eutectic form of any one of Embodiments 28 to 32, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and two or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0215] Embodiment 34. The eutectic form of any one of Embodiments 28 to 33, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and three or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0216] Embodiment 35. The eutectic form according to any one of Embodiments 28 to 31, characterized by having an XRPD pattern using CuKα irradiation, the XRPD pattern comprising a peak at 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, and a combination with one or more peaks selected from 9.1°, 10.5°, 12.7°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 18.4°, 21.0°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0217] Embodiment 36. The eutectic form,

[0218] which can be obtained by: adding gallic acid to dissolved in ethyl acetate.

[0219] Embodiment 37. A pharmaceutical composition comprising the eutectic form according to any one of Embodiments 1 to 36, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0220] Embodiment 38. The pharmaceutical composition of Embodiment 37, wherein the composition contains at least about 80% by weight of any of the said eutectic forms.

[0221] Embodiment 39. The pharmaceutical composition of Embodiment 37 or 38, wherein the composition contains at least about 90% by weight of any of the said eutectic forms.

[0222] Embodiment 40. The pharmaceutical composition according to any one of Embodiments 37 to 39, wherein the composition contains at least about 95% by weight of any of the said eutectic forms.

[0223] Embodiment 41. A method for treating cancer, which comprises administering to a patient in need an effective amount of the eutectic form according to any one of Embodiments 1 to 36.

[0224] Embodiment 42. A method for treating cancer, which comprises administering to a patient in need an effective amount of the pharmaceutical composition according to any one of Embodiments 37 to 40.

[0225] Embodiment 43. The method of Embodiment 41 or 42, wherein the cancer is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0226] Embodiment 44. The method of any one of Embodiments 41 to 43, wherein the cancer is selected from: urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle invasive bladder cancer, and muscle invasive bladder cancer.

[0227] Embodiment 45. The method of any one of Embodiments 41 to 44, wherein the cancer is urothelial cancer.

[0228] Embodiment 46. The method of any one of Embodiments 41 to 44, wherein the cancer is bladder cancer.

[0229] Embodiment 47. The method of any one of Embodiments 41 to 44, wherein the cancer is urothelial bladder cancer.

[0230] Embodiment 48. The method of any one of Embodiments 41 to 44, wherein the cancer is advanced urothelial bladder cancer.

[0231] Embodiment 49. The method of any one of Embodiments 41 to 44, wherein the cancer is metastatic urothelial bladder cancer.

[0232] Embodiment 50. The method of any one of Embodiments 41 to 44, wherein the cancer is non-muscle invasive bladder cancer.

[0233] Embodiment 51. The method of any one of Embodiments 41 to 44, wherein the cancer is muscle invasive bladder cancer.

[0234] Embodiment 52. A method of inhibiting bladder cancer, comprising administering to a patient in need thereof an effective amount of the eutectic form of any one of Embodiments 1 to 36.

[0235] Embodiment 53. A method of inhibiting bladder cancer, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of any one of Embodiments 37 to 40.

[0236] Embodiment 54. The eutectic form of any one of Embodiments 1 to 36 for use in therapy.

[0237] Embodiment 55. The eutectic form of any one of Embodiments 1 to 36 for use in treating cancer.

[0238] Embodiment 56. The eutectic form used according to Embodiment 54 or 55, wherein the cancer is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0239] Embodiment 57. The eutectic form used according to Embodiment 54 or 55, wherein the cancer is selected from: urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle invasive bladder cancer, and muscle invasive bladder cancer.

[0240] Embodiment 58. The eutectic form used according to any one of Embodiments 55 to 57, wherein the cancer is urothelial cancer.

[0241] Embodiment 59. The eutectic form used according to any one of Embodiments 55 to 57, wherein the cancer is bladder cancer.

[0242] Embodiment 60. The eutectic form used according to any one of Embodiments 55 to 57, wherein the cancer is urothelial bladder cancer.

[0243] Embodiment 61. The eutectic form used according to any one of Embodiments 55 to 57, wherein the cancer is advanced urothelial bladder cancer.

[0244] Embodiment 62. The eutectic form used according to any one of Embodiments 55 to 57, wherein the cancer is metastatic urothelial bladder cancer.

[0245] Embodiment 63. The eutectic form used according to any one of Embodiments 55 to 57, wherein the cancer is non-muscle invasive bladder cancer.

[0246] Embodiment 64. The eutectic form used according to any one of Embodiments 55 to 57, wherein the cancer is muscle-invasive bladder cancer.

[0247] Embodiment 65. The pharmaceutical composition according to any one of Embodiments 37 to 40, which is used for treatment.

[0248] Embodiment 66. The pharmaceutical composition according to any one of Embodiments 37 to 40, which is used for treating cancer.

[0249] Embodiment 67. The pharmaceutical composition for the use according to Embodiment 66, wherein the cancer is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle-invasive urothelial carcinoma, non-muscle-invasive bladder cancer, muscle-invasive urothelial carcinoma, muscle-invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial carcinoma, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer and testicular cancer.

[0250] Embodiment 68. The pharmaceutical composition for the use according to Embodiment 66 or 67, wherein the cancer is selected from: urothelial carcinoma, bladder cancer, advanced urothelial carcinoma, metastatic urothelial carcinoma, non-muscle-invasive urothelial carcinoma, and muscle-invasive urothelial carcinoma.

[0251] Embodiment 69. The pharmaceutical composition for the use according to Embodiments 66 and 67, wherein the cancer is selected from: urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle-invasive bladder cancer and muscle-invasive bladder cancer.

[0252] Embodiment 70. The pharmaceutical composition for the use according to any one of Embodiments 66 to 67, wherein the cancer is urothelial carcinoma.

[0253] Embodiment 71. The pharmaceutical composition for the use according to any one of Embodiments 66 to 67, wherein the cancer is bladder cancer.

[0254] Embodiment 72. The pharmaceutical composition for the use according to any one of Embodiments 66 to 67, wherein the cancer is urothelial bladder cancer.

[0255] Embodiment 73. The pharmaceutical composition for the use according to any one of Embodiments 66 to 67, wherein the cancer is advanced urothelial bladder cancer.

[0256] Embodiment 74. A pharmaceutical composition for use according to any one of embodiments 66 to 67, wherein the cancer is metastatic urothelial bladder cancer.

[0257] Embodiment 75. A pharmaceutical composition for use according to any one of embodiments 66 to 67, wherein the cancer is non-muscle invasive bladder cancer.

[0258] Embodiment 76. A pharmaceutical composition for use according to any one of embodiments 66 to 67, wherein the cancer is muscle invasive bladder cancer.

[0259] Embodiment 77. Use of an eutectic form according to any one of embodiments 1 to 36 in the preparation of a medicament for the treatment of cancer.

[0260] Embodiment 78. Use of a pharmaceutical composition according to any one of embodiments 37 to 40 in the preparation of a medicament for the treatment of cancer.

[0261] Embodiment 79. Use according to embodiment 77 or 78, wherein the cancer is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle invasive urothelial carcinoma, non-muscle invasive bladder cancer, muscle invasive urothelial carcinoma, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial carcinoma, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0262] Embodiment 80. Use according to any one of embodiments 77 to 79, wherein the cancer is selected from: urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle invasive urothelial carcinoma, non-muscle invasive bladder cancer, muscle invasive urothelial carcinoma, and muscle invasive bladder cancer.

[0263] Embodiment 81. Use according to any one of embodiments 77 to 80, wherein the cancer is urothelial carcinoma.

[0264] Embodiment 82. Use according to any one of embodiments 77 to 80, wherein the cancer is bladder cancer.

[0265] Use according to any one of embodiments 77 to 80, wherein the cancer is urothelial bladder cancer.

[0266] Embodiment 84. Use according to any one of embodiments 77 to 80, wherein the cancer is advanced urothelial bladder cancer.

[0267] Embodiment 85. Use according to any one of embodiments 77 to 80, wherein the cancer is metastatic urothelial bladder cancer.

[0268] Embodiment 86. Use according to any one of embodiments 77 to 80, wherein the cancer is non-muscle invasive bladder cancer.

[0269] Embodiment 87. Use according to any one of embodiments 77 to 80, wherein the cancer is muscle invasive bladder cancer.

[0270] Embodiment 88. A method for preparing a eutectic form according to any one of embodiments 1 to 12, the method comprising the following steps:

[0271] Adding 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 and gallic acid to a solvent to obtain a slurry, and

[0272] Adding cyclopentyl methyl ether to the slurry to form a white precipitate.

[0273] Embodiment 89. The method of embodiment 88, wherein the solvent is THF.

[0274] Embodiment 90. The method of embodiment 88 or 89, wherein the slurry is inoculated with the eutectic form of formula I.

[0275] Embodiment 91. A method for preparing a eutectic form according to any one of embodiments 1 to 3 or 5 to 12, which comprises a step of heating to form a dehydrated hydrate.

[0276] Embodiment 92. A method for preparing a eutectic form according to any one of embodiments 1 to 3 or 21 to 26, which comprises a step of combining with acetonitrile.

[0277] Embodiment 93. A method for preparing a eutectic form according to any one of embodiments 28 to 35, which comprises adding gallic acid to dissolved in ethyl acetate.

[0278] Embodiment 94. A eutectic form of a co-formation of the following formula ("isomer 2") and gallic acid:

[0279]

[0280] Embodiment 95. The eutectic form of Embodiment 94, wherein the ratio of isomer 2 to gallic acid is about 2:1.

[0281] Embodiment 96. The eutectic form of Embodiment 94 or 95, wherein the water content ranges from about 0% to about 3.2%.

[0282] Embodiment 97. The eutectic form of any one of Embodiments 94 to 96, wherein the eutectic form is

[0283]

[0284] Embodiment 98. The eutectic form of Embodiment 97, which is dehydrated or partially dehydrated.

[0285] Embodiment 99. The eutectic form of any one of Embodiments 94 to 96 or 98, wherein the eutectic form is

[0286]

[0287] Embodiment 100. The eutectic form of any one of Embodiments 94 to 99, characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 8.4° and one or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0288] Embodiment 101. The eutectic form of any one of Embodiments 94 to 100, characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0289] Embodiment 102. The eutectic form of any one of Embodiments 94 to 101, characterized by an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and two or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0290] Embodiment 103. A eutectic form of any one of Embodiments 94 to 102, characterized by having an XRPD pattern using CuKα irradiation, the XRPD pattern having a diffraction peak at a diffraction angle 2θ of 8.4° in combination with three or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

[0291] Embodiment 104. A eutectic form of any one of Embodiments 94 to 103, characterized by having an XRPD pattern using CuKα irradiation, the XRPD pattern having a diffraction peak at a diffraction angle 2θ of 8.4° in combination with one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°, and in combination with one or more peaks selected from 9.2°, 10.0°, 13.4°, 14.1°, 16.9°, 18.4°, 19.6°, and 24.2°, the allowable difference in diffraction angle is ±0.2 degrees.

[0292] Embodiment 105. A eutectic form of any one of Embodiments 94 to 104, characterized by 13 a solid-state C NMR spectrum, the NMR spectrum containing peaks at positions selected from the following with reference to the carbonyl resonance of glycine: 8.1, 11.1, 26.6, 28.2, 32.3, 35.0, 80.7, 81.7, 99.6, 102.3, 110.9, 158.0, 160.0, 168.2, and 175.0, the allowable difference is ±0.2 ppm.

[0293] Embodiment 106. A eutectic form,

[0294] which can be obtained by: adding 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 and gallic acid to a solvent to obtain a slurry, and

[0295] adding cyclopentyl methyl ether to the slurry to form a white precipitate, wherein the crystal form has improved solubility relative to the free base form of isomer 2 of the following formula:

[0296]

[0297] Embodiment 107. The eutectic form of Embodiment 106, wherein the solvent comprises THF.

[0298] Embodiment 108. The eutectic form of Embodiment 106 or 107, wherein the slurry is inoculated with the eutectic form.

[0299] Embodiment 109. Eutectic form,

[0300] which can be obtained by: heating to form a dehydrated hydrate, wherein the crystal form has improved solubility relative to the free base form of isomer 2 of the following formula:

[0301]

[0302] Embodiment 110. The eutectic form of Embodiment 109, wherein the heating step is from about 25 °C to 200 °C at a rate of 10 °C / min.

[0303] Embodiment 111. The eutectic form of Embodiment 109 or 110, wherein nitrogen is the carrier gas at about 10 mL / min.

[0304] Embodiment 112. The eutectic form of any one of Embodiments 109 to 111, wherein nitrogen is the purge gas at about 50 mL / min.

[0305] Embodiment 113. The eutectic form of Embodiment 94, wherein the ratio of isomer 2 to gallic acid is about 1:1.

[0306] Embodiment 114. The eutectic form of Embodiment 94 or 113, wherein the eutectic form is

[0307]

[0308] Embodiment 115. The eutectic form of any one of Embodiments 94, 113 or 114, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 14.6° and one or more peaks at 5.7°, 6.5°, 9.8°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, 19.7°, 23.8° or 24.5°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0309] Embodiment 116. The eutectic form of Embodiment 94 or any one of Embodiments 113 - 115, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 14.6° and one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0310] Eutectic form of any one of Embodiment 117, Embodiment 94 or Embodiments 113 - 116, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ 14.6° in combination with two or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0311] Eutectic form of any one of Embodiment 118, Embodiment 94 or Embodiments 113 - 116, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ 14.6° and selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

[0312] Eutectic form of any one of Embodiment 119, Embodiment 94 or Embodiments 113 - 116, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ 14.6° in combination with one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°, and in combination with one or more peaks selected from 5.7°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, and 24.5°, the allowable difference in diffraction angle is ±0.2 degrees.

[0313] Embodiment 120. Eutectic form,

[0314] which can be obtained by: combining with acetonitrile, wherein said crystal form has improved solubility relative to the free base form of isomer 2 of the following formula:

[0315]

[0316] Embodiment 121. Eutectic form of a co - formation of isomer A of the following formula with gallic acid or a co - formation with nicotinamide:

[0317]

[0318] Embodiment 122. The eutectic form of Embodiment 121, wherein the ratio of isomer A to gallic acid is about 1:1.

[0319] Embodiment 123. The eutectic form of Embodiment 121 or 122, wherein the eutectic form is

[0320]

[0321] Embodiment 124. The eutectic form of any one of Embodiments 121 to 123, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 6.9° and one or more peaks at 9.1°, 10.5°, 12.7°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 18.4°, 21.0°, or 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0322] Embodiment 125. The eutectic form of any one of Embodiments 121 to 124, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0323] Embodiment 126. The eutectic form of any one of Embodiments 121 to 124, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and two or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0324] Embodiment 127. The eutectic form of any one of Embodiments 121 to 126, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and three or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0325] Embodiment 128. The eutectic form of any one of Embodiments 121 to 124, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, and a combination with one or more peaks selected from 9.1°, 10.5°, 12.7°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 18.4°, 21.0°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0326] Embodiment 129. Eutectic form

[0327] which can be obtained by: adding gallic acid to dissolved in ethyl acetate, wherein said crystal form has improved solubility relative to the free base form of isomer A of the following formula:

[0328]

[0329] Embodiment 130. The eutectic form of Embodiment 121, wherein the ratio of isomer A to nicotinamide is about 1:1.

[0330] Embodiment 131. The eutectic form of Embodiment 121 or 130, wherein the eutectic form is

[0331]

[0332] Embodiment 132. The eutectic form of any one of Embodiments 121, 130 to 131, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 13.7° and one or more peaks at 6.8°, 8.2°, 9.6°, 12.3°, 15.8°, 17.5°, 17.9°, 18.7°, 19.0°, 22.2°, 22.9°, 24.7° or 26.1°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0333] Embodiment 133. The eutectic form of any one of Embodiments 121, 130 to 132, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 13.7° and one or more peaks selected from 9.6°, 17.9°, and 24.7°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0334] Embodiment 134. The eutectic form of any one of Embodiments 121, 130 to 133, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 13.7° and two or more peaks selected from 9.6°, 17.9°, and 24.7°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0335] Embodiment 135. The eutectic form of any one of Embodiments 121, 130 to 133, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 13.7° and a peak selected from 9.6°, 17.9°, and 24.7°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0336] Embodiment 136. The eutectic form of any one of Embodiments 121, 130 to 133, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 13.7° and one or more peaks selected from 9.6°, 17.9°, and 24.7°, and a combination with one or more peaks selected from 6.8°, 8.2°, 12.3°, 15.8°, 17.5°, 18.7°, 19.0°, 22.2°, 22.9°, and 26.1°, with an allowable difference in diffraction angle of ±0.2 degrees.

[0337] Embodiment 137. The eutectic form,

[0338]

[0339] or a pharmaceutically acceptable salt thereof, obtainable by:

[0340] Dissolving

[0341] in ethyl acetate saturated with nicotinamide, wherein said crystalline form has improved solubility relative to the free base form of isomer A of the following formula:

[0342]

[0343] Embodiment 138. A pharmaceutical composition comprising the eutectic form of any one of Embodiments 94 to 137, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0344] Embodiment 139. The pharmaceutical composition of Embodiment 138, wherein the composition contains at least about 80% by weight of said eutectic form.

[0345] Embodiment 140. The pharmaceutical composition of Embodiment 138 or 139, wherein the composition contains at least about 90% by weight of any of said eutectic forms.

[0346] Embodiment 141. The pharmaceutical composition of any one of Embodiments 138 to 140, wherein the composition contains at least about 95% by weight of any of said eutectic forms.

[0347] Embodiment 142. A method of treating cancer associated with FGFR3, comprising administering to a patient in need thereof an effective amount of the eutectic form of any one of Embodiments 94 to 137.

[0348] Embodiment 143. A method of treating cancer associated with FGFR3, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition of any one of Embodiments 138 to 141.

[0349] Embodiment 144. The method of Embodiment 142 or 143, wherein the cancer associated with FGFR3 is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0350] Embodiment 145. The method of any one of Embodiments 142 to 144, wherein the cancer associated with FGFR3 is selected from: urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle invasive bladder cancer, and muscle invasive bladder cancer.

[0351] Embodiment 146. The method of any one of Embodiments 142 to 144, wherein the cancer associated with FGFR3 is urothelial cancer.

[0352] Embodiment 147. The method of any one of Embodiments 142 to 144, wherein the cancer associated with FGFR3 is intermediate-risk non-muscle invasive bladder cancer.

[0353] Embodiment 148. The method of any one of Embodiments 142 to 144, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer that is non-responsive to Bacillus Calmette-Guérin (BCG) or non-muscle invasive bladder cancer that recurs after treatment with Bacillus Calmette-Guérin (BCG).

[0354] Embodiment 149. The method of any one of Embodiments 142 to 144, wherein the cancer associated with FGFR3 is high-risk non-muscle invasive bladder cancer.

[0355] Embodiment 150. The eutectic form of any one of Embodiments 94 to 137 for use in therapy.

[0356] Embodiment 151. The eutectic form of any one of Embodiments 94 to 137 for use in the treatment of cancer associated with FGFR3.

[0357] Embodiment 152. The eutectic form used according to Embodiment 151, wherein the cancer associated with FGFR3 is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0358] Embodiment 153. The eutectic form used according to Embodiment 151 or 152, wherein the cancer associated with FGFR3 is selected from: urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle invasive bladder cancer, and muscle invasive bladder cancer.

[0359] Embodiment 154. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is urothelial cancer.

[0360] Embodiment 155. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is bladder cancer.

[0361] Embodiment 156. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is urothelial bladder cancer.

[0362] Embodiment 157. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is advanced urothelial bladder cancer.

[0363] Embodiment 158. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is metastatic urothelial bladder cancer.

[0364] Embodiment 159. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer.

[0365] Embodiment 159. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is intermediate-risk non-muscle-invasive bladder cancer.

[0366] Embodiment 160. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is non-muscle-invasive bladder cancer that is non-responsive to Bacillus Calmette-Guérin (BCG) or non-muscle-invasive bladder cancer that recurs after treatment with Bacillus Calmette-Guérin (BCG).

[0367] Embodiment 161. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is high-risk non-muscle-invasive bladder cancer.

[0368] Embodiment 162. The eutectic form used according to any one of Embodiments 151 to 153, wherein the cancer associated with FGFR3 is muscle-invasive bladder cancer.

[0369] Embodiment 163. Use of the eutectic form according to any one of Embodiments 94 to 137 in the preparation of a medicament for the treatment of cancer associated with FGFR3.

[0370] Embodiment 164. The use of Embodiment 163, wherein the cancer associated with FGFR3 is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle-invasive urothelial carcinoma, non-muscle-invasive bladder cancer, muscle-invasive urothelial carcinoma, muscle-invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial carcinoma, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0371] Embodiment 165. The use of Embodiment 163 or 164, wherein the cancer associated with FGFR3 is selected from: urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle-invasive urothelial carcinoma, non-muscle-invasive bladder cancer, muscle-invasive urothelial carcinoma, and muscle-invasive bladder cancer.

[0372] Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is urothelial carcinoma.

[0373] Embodiment 167. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is bladder cancer.

[0374] Embodiment 168. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is urothelial bladder cancer.

[0375] Embodiment 169. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is advanced urothelial bladder cancer.

[0376] Embodiment 170. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is metastatic urothelial bladder cancer.

[0377] Embodiment 171. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer.

[0378] Embodiment 172. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is intermediate-risk non-muscle invasive bladder cancer.

[0379] Embodiment 173. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer that is unresponsive to Bacillus Calmette-Guérin (BCG) or non-muscle invasive bladder cancer that recurs after treatment with Bacillus Calmette-Guérin (BCG).

[0380] Embodiment 174. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is high-risk non-muscle invasive bladder cancer.

[0381] Embodiment 175. Use according to any one of embodiments 163 to 165, wherein the cancer associated with FGFR3 is non-muscle invasive urothelial carcinoma.

[0382] Embodiment 176. A method for preparing a eutectic form according to any one of embodiments 94 to 104, the method comprising the following steps:

[0383] 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, isomer 2:

[0384]

[0385] Gallic acid and are added to a solvent to obtain a slurry, and

[0386] Cyclopentyl methyl ether is added to the slurry to form a white precipitate.

[0387] Embodiment 177. The method of embodiment 176, wherein the solvent is THF.

[0388] Embodiment 178. The method of embodiment 176 or 177, wherein the slurry is inoculated with a eutectic form of the following formula:

[0389]

[0390] Embodiment 179. A method for preparing a eutectic form according to any one of embodiments 94 to 96, 98 to 104, the method comprising the steps of:

[0391] Heat to form a dehydrated hydrate. Heat to form a dehydrated hydrate.

[0392] Embodiment 180. A method for preparing a eutectic form according to any one of embodiments 94, 114 to 120, the method comprising combining with acetonitrile.

[0393] Embodiment 181. A method for preparing a eutectic form according to any one of embodiments 121 to 128, the method comprising adding gallic acid to dissolved in ethyl acetate.

[0394] Embodiment 182. A method for preparing a eutectic form according to any one of embodiments 121, 130 to 136, the method comprising dissolving in ethyl acetate saturated with nicotinamide.

Claims

1. A eutectic form of the following formula (“Isomer 2”) and gallic acid co - formation:

2. The eutectic form of claim 1, wherein the ratio of isomer 2 to gallic acid is about 2:

1.

3. The eutectic form of claim 1 or 2, wherein the water content ranges from about 0% to about 3.2%.

4. The eutectic form of any one of claims 1 to 3, wherein the eutectic form is 5. The eutectic form of claim 4, which is dehydrated or partially dehydrated.

6. The eutectic form of any one of claims 1 to 3 or 5, wherein the eutectic form is 7. The eutectic form of any one of claims 1 to 6, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 8.4° and one or more peaks at 6.7°, 9.2°, 10.0°, 13.4°, 14.1°, 15.6°, 16.9°, 18.4°, 19.6°, 21.3°, 23.4° or 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees.

8. The eutectic form of any one of claims 1 to 7, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

9. The eutectic form of any one of claims 1 to 8, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and two or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

10. The eutectic form of any one of claims 1 to 9, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a combination of a diffraction peak at diffraction angle 2θ 8.4° and three or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°; the allowable difference in diffraction angle is ±0.2 degrees.

11. The eutectic form according to any one of claims 1 to 8, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ of 8.4° and one or more peaks selected from 15.6°, 21.3°, 6.7°, and 23.4°, and a combination with one or more peaks selected from 9.2°, 10.0°, 13.4°, 14.1°, 16.9°, 18.4°, 19.6°, and 24.2°, with an allowable difference in diffraction angle of ±0.2 degrees.

12. The eutectic form according to any one of claims 1 to 11, characterized by 13 a solid-state C NMR spectrum, said NMR spectrum comprising peaks at positions selected from the following, with reference to the carbonyl resonance of glycine: 8.1, 11.1, 26.6, 28.2, 32.3, 35.0, 80.7, 81.7, 99.6, 102.3, 110.9, 158.0, 160.0, 168.2 and 175.0, with an allowable difference of ±0.2 ppm.

13. The eutectic form, which can be obtained by: adding 4-[4-[3-chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2 and gallic acid to a solvent to obtain a slurry, and adding cyclopentyl methyl ether to the slurry to form a white precipitate, wherein the crystal form has improved solubility relative to the free base form of isomer 2 of the following formula:

14. The eutectic form according to claim 13, wherein the solvent comprises THF.

15. The eutectic form according to claim 13 or 14, wherein the slurry is seeded with the eutectic form.

16. The eutectic form, which can be obtained by: heating to form a dehydrated hydrate, wherein the crystal form has improved solubility relative to the free base form of isomer 2 of the following formula:

17. The eutectic form according to claim 16, wherein the heating step is from about 25°C to 200°C at a rate of 10°C / min.

18. The eutectic form according to claim 16 or 17, wherein nitrogen is the carrier gas at about 10 mL / min.

19. The eutectic form according to any one of claims 16 to 18, wherein nitrogen is the purge gas at about 50 mL / min.

20. The eutectic form according to claim 1, wherein the ratio of isomer 2 to gallic acid is about 1:

1.

21. The eutectic form according to claim 1 or 20, wherein the eutectic form is 22. The eutectic form of any one of claims 1, 20 or 21, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 14.6° and one or more peaks at 5.7°, 6.5°, 9.8°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, 19.7°, 23.8° or 24.5°, with an allowable difference in diffraction angle of ±0.2 degrees.

23. The eutectic form of any one of claims 1 or 20 - 22, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ 14.6° in combination with one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

24. The eutectic form of any one of claims 1 or 20 - 23, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ 14.6° in combination with two or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

25. The eutectic form of any one of claims 1 or 20 - 24, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ 14.6° in combination with three or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°; the allowable difference in diffraction angle is ±0.2 degrees.

26. The eutectic form of any one of claims 1 or 20 - 23, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern having a diffraction peak at diffraction angle 2θ 14.6° in combination with one or more peaks selected from 9.8°, 23.8°, 6.5°, and 19.7°, and in combination with one or more peaks selected from 5.7°, 13.0°, 13.5°, 16.5°, 17.1°, 18.9°, and 24.5°, the allowable difference in diffraction angle is ±0.2 degrees.

27. The eutectic form, which can be obtained by: combining with acetonitrile, wherein said crystal form has improved solubility relative to the free base form of isomer 2 of the following formula:

28. The eutectic form of a co - form of isomer A of the following formula with gallic acid or a co - form with nicotinamide:

29. The eutectic form of claim 28, wherein the ratio of isomer A to gallic acid is about 1:

1.

30. The eutectic form of claim 28 or 29, wherein the eutectic form is 31. The eutectic form of any one of claims 28 to 30, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 6.9° and one or more peaks at 9.1°, 10.5°, 12.7°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 18.4°, 21.0° or 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

32. The eutectic form of any one of claims 28 to 31, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

33. The eutectic form of any one of claims 28 to 32, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and two or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

34. The eutectic form of any one of claims 28 to 33, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 6.9° and three or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

35. The eutectic form of any one of claims 28 to 32, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 6.9° and one or more peaks selected from 12.7°, 18.4°, 9.1°, and 23.4°, and a combination with one or more peaks selected from 9.1°, 10.5°, 12.7°, 15.7°, 16.3°, 16.8°, 17.1°, 17.9°, 18.4°, 21.0°, and 23.4°, with an allowable difference in diffraction angle of ±0.2 degrees.

36. The eutectic form, which can be obtained by: adding gallic acid to dissolved in ethyl acetate, wherein said crystal form has improved solubility relative to the free base form of isomer A of the following formula:

37. The eutectic form of claim 28, wherein the ratio of isomer A to nicotinamide is about 1:

1.

38. The eutectic form of claim 28 or 37, wherein the eutectic form is 39. The eutectic form of any one of claims 28, 37 to 38, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a peak at 13.7° and one or more peaks at 6.8°, 8.2°, 9.6°, 12.3°, 15.8°, 17.5°, 17.9°, 18.7°, 19.0°, 22.2°, 22.9°, 24.7° or 26.1°, with an allowable difference in diffraction angle of ±0.2 degrees.

40. The eutectic form of any one of claims 28, 37 to 39, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 13.7° and one or more peaks selected from 9.6°, 17.9°, and 24.7°, with an allowable difference in diffraction angle of ±0.2 degrees.

41. The eutectic form of any one of claims 28, 37 to 40, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 13.7° and two or more peaks selected from 9.6°, 17.9°, and 24.7°, with an allowable difference in diffraction angle of ±0.2 degrees.

42. The eutectic form of any one of claims 28, 37 to 41, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 13.7° and peaks selected from 9.6°, 17.9°, and 24.7°, with an allowable difference in diffraction angle of ±0.2 degrees.

43. The eutectic form of any one of claims 28, 37 to 40, characterized by having an XRPD pattern using CuKα irradiation, said XRPD pattern comprising a combination of a peak at 13.7° and one or more peaks selected from 9.6°, 17.9°, and 24.7°, and a combination of one or more peaks selected from 6.8°, 8.2°, 12.3°, 15.8°, 17.5°, 18.7°, 19.0°, 22.2°, 22.9°, and 26.1°, with an allowable difference in diffraction angle of ±0.2 degrees.

44. The eutectic form, or a pharmaceutically acceptable salt thereof, obtainable by: By Dissolved in ethyl acetate saturated with nicotinamide, wherein the crystalline form has improved solubility relative to the free base form of isomer A of the following formula:

45. A pharmaceutical composition comprising a cocrystal form according to any one of claims 1 to 44, further comprising a pharmaceutically acceptable carrier, diluent or excipient.

46. The pharmaceutical composition of claim 45, wherein the composition contains at least about 80% by weight of the cocrystal form.

47. The pharmaceutical composition of claim 45 or 46, wherein the composition contains at least about 90% by weight of any of the cocrystal forms.

48. The pharmaceutical composition of any one of claims 45 to 47, wherein the composition contains at least about 95% by weight of any of the cocrystal forms.

49. A method of treating cancer associated with FGFR3, which comprises administering to a patient in need thereof an effective amount of a cocrystal form according to any one of claims 1 to 44.

50. A method of treating cancer associated with FGFR3, which comprises administering to a patient in need thereof an effective amount of a pharmaceutical composition according to any one of claims 45 to 48.

51. The method of claim 49 or 50, wherein the cancer associated with FGFR3 is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial cancer, advanced urothelial bladder cancer, metastatic urothelial cancer, metastatic urothelial bladder cancer, non-muscle invasive urothelial cancer, non-muscle invasive bladder cancer, muscle invasive urothelial cancer, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer and testicular cancer.

52. The method of any one of claims 49 to 51, wherein the cancer associated with FGFR3 is selected from: urothelial cancer, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle invasive bladder cancer and muscle invasive bladder cancer.

53. The method of any one of claims 49 to 52, wherein the cancer associated with FGFR3 is urothelial cancer.

54. The method of any one of claims 49 to 52, wherein the cancer associated with FGFR3 is intermediate-risk non-muscle invasive bladder cancer.

55. The method according to any one of claims 49 to 52, wherein the cancer associated with FGFR3 is non-muscle-invasive bladder cancer that is non-responsive to bacillus Calmette-Guérin (BCG) or non-muscle-invasive bladder cancer that recurs after treatment with bacillus Calmette-Guérin (BCG).

56. The method according to any one of claims 49 to 52, wherein the cancer associated with FGFR3 is high-risk non-muscle-invasive bladder cancer.

57. The eutectic form according to any one of claims 1 to 44 for use in therapy.

58. The eutectic form according to any one of claims 1 to 44 for use in the treatment of cancer associated with FGFR3.

59. The eutectic form for use according to claim 58, wherein the cancer associated with FGFR3 is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle-invasive urothelial carcinoma, non-muscle-invasive bladder cancer, muscle-invasive urothelial carcinoma, muscle-invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial carcinoma, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

60. The eutectic form for use according to claim 58 or 59, wherein the cancer associated with FGFR3 is selected from: urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, non-muscle-invasive bladder cancer, and muscle-invasive bladder cancer.

61. The eutectic form for use according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is urothelial carcinoma.

62. The eutectic form for use according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is bladder cancer.

63. The eutectic form for use according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is urothelial bladder cancer.

64. The eutectic form for use according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is advanced urothelial bladder cancer.

65. The eutectic form for use according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is metastatic urothelial bladder cancer.

66. The eutectic form used according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer.

67. The eutectic form used according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is intermediate-risk non-muscle invasive bladder cancer.

68. The eutectic form used according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer that is non-responsive to Bacillus Calmette-Guérin (BCG) or non-muscle invasive bladder cancer that recurs after treatment with Bacillus Calmette-Guérin (BCG).

69. The eutectic form used according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is high-risk non-muscle invasive bladder cancer.

70. The eutectic form used according to any one of claims 58 to 60, wherein the cancer associated with FGFR3 is muscle invasive bladder cancer.

71. Use of the eutectic form according to any one of claims 1 to 44 in the preparation of a medicament for the treatment of cancer associated with FGFR3.

72. The use of claim 71, wherein the cancer associated with FGFR3 is selected from: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle invasive urothelial carcinoma, non-muscle invasive bladder cancer, muscle invasive urothelial carcinoma, muscle invasive bladder cancer, upper urinary tract cancer, upper urinary tract urothelial carcinoma, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvic cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer and testicular cancer.

73. The use of claims 71 to 72, wherein the cancer associated with FGFR3 is selected from: urothelial carcinoma, bladder cancer, urothelial bladder cancer, advanced urothelial bladder cancer, metastatic urothelial bladder cancer, advanced urothelial carcinoma, advanced urothelial bladder cancer, metastatic urothelial carcinoma, metastatic urothelial bladder cancer, non-muscle invasive urothelial carcinoma, non-muscle invasive bladder cancer, muscle invasive urothelial carcinoma, and muscle invasive bladder cancer.

74. The use of any one of claims 72 to 73, wherein the cancer associated with FGFR3 is urothelial carcinoma.

75. The use of any one of claims 72 to 73, wherein the cancer associated with FGFR3 is bladder cancer. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is urothelial bladder cancer.

77. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is advanced urothelial bladder cancer.

78. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is metastatic urothelial bladder cancer.

79. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer.

80. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is intermediate-risk non-muscle invasive bladder cancer.

81. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is non-muscle invasive bladder cancer that is non-responsive to Bacillus Calmette-Guérin (BCG) or non-muscle invasive bladder cancer that recurs after treatment with Bacillus Calmette-Guérin (BCG).

82. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is high-risk non-muscle invasive bladder cancer.

83. Use according to any one of claims 72 to 73, wherein the cancer associated with FGFR3 is non-muscle invasive urothelial carcinoma.

84. A method for preparing the eutectic form according to any one of claims 1 to 12, the method comprising the following steps: 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile isomer 2: and gallic acid are added to a solvent to obtain a slurry, and cyclopentyl methyl ether is added to the slurry to form a white precipitate.

85. The method of claim 84, wherein the solvent is THF.

86. The method of claim 84 or 85, wherein the slurry is seeded with the eutectic form of the following formula:

87. A method for preparing the eutectic form according to any one of claims 1 to 3 or 5 to 12, the method comprising the following steps: Heat to form a dehydrated hydrate.

88. A method for preparing the eutectic form according to any one of claims 1 or 20 to 26, the method comprising the following steps: Combine with acetonitrile.

89. A method for preparing the eutectic form according to any one of claims 28 to 35, the method comprising the following steps: Add gallic acid to dissolved in ethyl acetate. A method for preparing the eutectic form according to any one of claims 28, 37 to 43, the method comprising the following steps: Dissolve in ethyl acetate saturated with nicotinamide.

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