TW201720832A - Crystalline forms of quinolone analogs and their salts - Google Patents

Abstract

The present invention includes crystalline forms of 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide and crystalline forms of salts and/or solvates of 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide. Furthermore, the present invention provides compositions comprising the crystalline forms and therapeutic use of the crystalline forms and the compositions thereof.

Description

Crystalline form of quinolone analogues and their salts

The present invention relates to a crystalline form of a salt and/or a solvate of a tetracyclic quinolone compound or a tetracyclic quinolone compound, a pharmaceutical composition comprising the crystalline form, and a method of using the crystalline form.

Various tetracyclic quinolone compounds have been proposed to produce functions by interacting with a tetrameric domain of nucleic acids and modulating ribosomal RNA transcription. See, for example, U.S. Patent Nos. 7,928,100 and 8,853,234. Specifically, the tetracyclic quinolone compound can stabilize the G-quadruplex (G4s) of DNA in tumor cells, thereby inducing synthesis and lethality in cancer cells. Since treatment of cells with G4 stabilizers can lead to the formation of DNA double strand breaks (DSBs), the treatment of DSB formation by G4 stabilizing ligands/agents (such as tetracyclic quinolones) is more pronounced for the following cells: A repair pathway for both homologous end joining (NHEJ) and homologous recombination repair (HRR), with genetic defects or chemical suppression. Furthermore, the tetracyclic quinolone compound selectively inhibits rRNA synthesis of the polymerase I in the nucleolus, but does not inhibit mRNA synthesis of RNA polymerase II (Pol II), and does not inhibit DNA replication or protein synthesis. It has been proposed that targeting RNA polymerase I (Pol I) by nucleolar stress pathway to activate p53 can result in selective activation of p53 in tumor cells. By making cancer cells self-destructive, the p53 protein is passed Often function to inhibit tumors. Activation of p53 protein to kill cancer cells is a well-validated anti-cancer strategy, and many methods have been adopted to develop this pathway. In the treatment, control, and alleviation of tumor cells without affecting normal healthy cells, selective activation of p53 in tumor cells is an attractive approach. The aforementioned tetracyclic quinolone is disclosed in U.S. Patent Nos. 7,928,100 and 8,853,234, the disclosures of each of each of each of each of

Those skilled in the art will appreciate that crystallization of the active pharmaceutical ingredient is optimal for providing control of important biochemical properties such as stability, solubility, bioavailability, particle size, bulk density, fluidity, polymorph content, and other characteristics. method. Therefore, a crystalline form of the tetracyclic quinolone and a method of making the same are required. These crystalline forms should be suitable for medical use.

In a specific embodiment, the invention provides a crystalline form of a tetracyclic quinolone compound or a pharmaceutically acceptable salt, ester and/or solvate thereof. In a specific embodiment, the crystalline form of the tetracyclic quinolone compound is Compound I: Or a pharmaceutically acceptable salt, ester and/or solvate thereof. In a particular embodiment, the crystalline form of Compound I is the free base of Compound I. In another embodiment, the crystalline form of Compound I is a salt and/or solvate of Compound I. In a particular embodiment, the crystalline form of Compound I is the acid salt of Compound I.

In some embodiments, the crystalline form of Compound I exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ of about 7.730 ± 0.3, 22.050 ± 0.3, and 24.550 ± 0.3 degrees. In yet another embodiment, the crystalline form of Compound I further exhibits an XRPD peak at about 9.410 ± 0.3 and 27.700 ± 0.3 degrees at 2θ. In another embodiment, the crystalline form of Compound I further exhibits a peak XRPD of about 17.950 ± 0.3 and 25.400 ± 0.3 degrees at 2θ. In a particular embodiment, the crystalline form of Compound I further exhibits at least one XRPD peak at 2θ of about 11.230 ± 0.3, 11.630 ± 0.3, 16.900 ± 0.3, 18.580 ± 0.3, 23.300 ± 0.3, and 26.700 ± 0.3 degrees. In a specific embodiment, the crystalline form of Compound I exhibits an XRPD pattern comprising three or more peaks selected from the group consisting of: peaks at 2θ about 7.730 ± 0.3, 9.410 ± 0.3, 11.230 ± 0.3, 11.630±0.3, 16.900±0.3, 17.950±0.3, 18.580±0.3, 22.050±0.3, 23.300±0.3, 24.550±0.3, 25.400±0.3, 26.700±0.3, and 27.700±0.3 degrees. In another embodiment, the crystalline form of Compound I exhibits an XRPD pattern substantially similar to that of Figure 1. In a specific embodiment, the crystalline form of Compound I exhibits a differential scanning calorimetry (DSC) pattern having peak characteristic values at about 215.41 ± 2.0 °C.

In a specific embodiment, the crystalline form of Compound I is polymorph A. In some embodiments, the crystalline form of Compound I and/or the crystalline form of Polymorph A of Compound I has a purity of about 95%, about 97%, about 99%, about 99.5% or greater.

In another embodiment, the crystalline form of Compound I exhibits an XRPD pattern comprising a peak at about 2.720 ± 0.3 degrees from 2θ. In another embodiment, the crystalline form of Compound I exhibits an XRPD pattern substantially similar to that of Figure 7. In a specific embodiment, the crystalline form of Compound I exhibits a DSC pattern having peak characteristic values at about 246.47 ± 2.0 °C.

In a particular embodiment, the crystalline form of Compound I is polymorph C. In some embodiments, the crystalline form of Compound I and/or the crystalline form of Polymorph C of Compound I has a purity of about 95%, about 97%, about 99%, about 99.5% or greater.

In some embodiments, the crystalline form of Compound I exhibits an XRPD pattern comprising a peak at about 2.680 ± 0.2 degrees from 2θ. In a specific embodiment, the crystalline form of Compound I further exhibits an XRPD peak at about 22.200 ± 0.2, 12.600 ± 0.3, 25.360 ± 0.3, and 27.560 ± 0.3 degrees. In a specific embodiment, the crystalline form of Compound I exhibits an XRPD pattern comprising two or more peaks selected from the group consisting of: peaks at 2θ about 5.680 ± 0.2, 12.200 ± 0.2, 12.600 ± 0.3, 25.360 ± 0.3 and 27.560 ± 0.3. In another embodiment, the crystalline form of Compound I exhibits an XRPD pattern substantially similar to that of Figure 11. In one embodiment, the crystalline form of Compound I exhibits a DSC pattern having peak characteristic values at about 231.99 ± 2.0 °C.

In a particular embodiment, the crystalline form of Compound I is polymorph E. In some embodiments, the crystalline form of Compound I and/or the crystalline form of Polymorph E of Compound I has a purity of about 95%, about 97%, about 99%, about 99.5% or greater.

In a specific embodiment, the crystalline form of Compound I exhibits an XRPD pattern comprising peaks at about 0.0000 ± 0.3 and 6.060 ± 0.4 degrees at 2θ. In another specific embodiment, the crystalline form of Compound I exhibits an XRPD pattern substantially similar to that of Figure 16. In another embodiment, the crystalline form of Compound I exhibits a DSC pattern having peak characteristic values at about 222.11 ± 2.0 °C.

In a specific embodiment, the crystalline form of Compound I is polymorph G. In some embodiments, the crystalline form of Compound I and/or the crystalline form of Polymorph G of Compound I has a purity of about 95%, about 97%, about 99%, about 99.5% or greater.

In a particular embodiment, the crystalline form of Compound I exhibits a Compound I purity greater than about 90%, 95%, 97%, 98%, 99%, or 95%.

In a particular embodiment, the crystalline form of Compound I is an acid salt of Compound I selected from the group consisting of: hydrochloride, maleate, fumarate, citrate, malic acid Salt, acetate, sulfate, phosphate, L-(+)-tartrate, D-glucuronate, benzoate, succinate, ethanesulfonate, methanesulfonate, p-toluene Sulfonate, propionate, besylate and 1-hydroxy-2-naphthoate. In another embodiment, the crystalline form of the salt of Compound I is selected from the group consisting of: hydrochloride, maleate, fumarate, citrate, and L-malate .

In a particular embodiment, the crystalline form of Compound I is a solvate of Compound I. In some embodiments, the crystalline form of Compound I is a NMP (N-methylpyrrolidone) solvate of Compound I.

In a particular embodiment, the crystalline form of Compound I is the crystalline form of the hydrochloride salt of Compound 1. In some embodiments, the crystalline form of the hydrochloride salt of Compound I exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ of about 4.660 ± 0.3 and 24.540 ± 0.3 degrees. In a particular embodiment, the crystalline form of the hydrochloride salt of Compound I further exhibits one or more XRPD peaks at about 19.60 ± 0.4, 20.160 ± 0.4, 24.920 ± 0.3, and 26.360 ± 0.5 degrees at 2θ. In another embodiment, the crystalline form of the hydrochloride salt of Compound I further exhibits one or more XRPD peaks at about 13.30 ± 0.4, 14.540 ± 0.3, 25.380 ± 0.3, and 28.940 ± 0.3 degrees. In another embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits an XRPD pattern substantially similar to that of Figure 21. In another embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits a DSC pattern having peak characteristic values at about 266.27 ± 2.0 °C.

In a particular embodiment, the crystalline form of Compound I is the crystalline form of the maleate salt of Compound 1. In some embodiments, the crystalline form of the maleate salt of Compound I exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ of about 7.400 ± 0.3, 18.440 ± 0.5, and 26.500 ± 0.4 degrees.

In another embodiment, the crystalline form of the maleate salt of Compound I further exhibits one or more XRPD peaks at 2θ of about 22.320 ± 0.4, 23.920 ± 0.3, 24.300 ± 0.4, and 25.240 ± 0.7 degrees. In another embodiment, the crystalline form of the maleate salt of Compound I further exhibits one or more XRPD peaks at about 5.040 ± 0.3, 15.080 ± 0.3, 15.880 ± 0.4, 20.860 ± 0.4, and 28.540 ± 0.3 degrees at 2θ. . In another embodiment, the crystalline form of the maleate salt of Compound I exhibits an XRPD pattern substantially similar to that of Figure 26. In another embodiment, the crystalline form of the maleate salt of Compound I exhibits a DSC pattern having peak characteristic values at about 217.32 ± 2.0 °C.

In a particular embodiment, the crystalline form of Compound I is the crystalline form of the fumarate salt of Compound 1. In some embodiments, the crystalline form of the fumarate salt of Compound I exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ of about 6.360 ± 0.3 and 24.800 ± 0.3 degrees. In another embodiment, the crystalline form of the fumarate salt of Compound I further exhibits one or more XRPD peaks at about 19.60 ± 0.3, 20.420 ± 0.3, and 26.860 ± 0.3 degrees at 2θ. In another embodiment, the crystalline form of the fumarate salt of Compound I further exhibits one or more XRPD peaks at 2θ of about 12.680±0.3, 17.020±0.2, 25.180±0.2, and 28.280±0.3 degrees. In another embodiment, the crystalline form of the fumarate salt of Compound I exhibits an XRPD pattern substantially similar to that of Figure 31. In another embodiment, the crystalline form of the fumarate salt of Compound I exhibits a peak characteristic value at about 222.40 ± 2.0 °C.

In a particular embodiment, the crystalline form of Compound I is the crystalline form of the citrate salt of Compound 1. In some embodiments, the crystalline form of the citrate salt of Compound I exhibits X-rays The powder diffraction (XRPD) pattern contains peaks at about 2.900 ± 0.3, 25.380 ± 0.3, and 27.500 ± 0.4 degrees at 2θ. In another embodiment, the crystalline form of the citrate salt of Compound I further exhibits one or more XRPD peaks at about 22.360 ± 0.3, 18.100 ± 0.3, 19.300 ± 0.3, and 26.140 ± 0.4 degrees. In another embodiment, the crystalline form of the citrate salt of Compound I further exhibits one or more XRPD peaks at 2θ of about 17.400 ± 0.3, 18.680 ± 0.4, 24.040 ± 0.4, and 26.740 ± 0.3 degrees. In another embodiment, the crystalline form of the citrate salt of Compound I exhibits an XRPD pattern substantially similar to that of Figure 36. In another embodiment, the crystalline form of the citrate salt of Compound I exhibits a peak characteristic value at about 196.86 ± 2.0 °C.

In a particular embodiment, the crystalline form of Compound I is the crystalline form of the L-malate salt of Compound I. In some embodiments, the crystalline form of the L-malate salt of Compound I exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ of about 6.580 ± 0.2, 6.780 ± 0.3, and 25.560 ± 0.4 degrees. In another embodiment, the crystalline form of the L-malate salt of Compound I further exhibits one or more XRPD peaks at about 19.560 ± 0.4, 23.660 ± 0.4, 26.060 ± 0.7, and 26.960 ± 0.7 degrees at 2θ. In another embodiment, the crystalline form of the L-malate salt of Compound I further exhibits one or more XRPD peaks at 2θ of about 8.800 ± 0.3, 11.800 ± 0.3, 18.600 ± 0.3, 24.460 ± 0.5, and 25.080 ± 0.3. degree. In another embodiment, the crystalline form of the L-malate salt of Compound I exhibits an XRPD pattern substantially similar to that of Figure 41. In another embodiment, the crystalline form of the L-malate salt of Compound I exhibits a DSC pattern having peak characteristic values at about 209.67 ± 2.0 °C.

In a particular embodiment, a composition is provided comprising a crystalline form of Compound I as described herein or a pharmaceutically acceptable salt, ester and/or solvate thereof. In another embodiment, a composition comprising the crystalline form of the free base of Compound I is provided. In a specific embodiment, a composition comprising a crystalline form of a salt or solvate of Compound I is provided. In a specific embodiment There is provided a composition comprising a crystalline form of the acid salt of Compound 1. In a specific embodiment, a composition is provided comprising one or more crystalline forms of any of Compounds I as described herein. In some embodiments, any of the compositions described herein comprise at least one pharmaceutically acceptable carrier.

In a specific embodiment, a method of stabilizing a G-quadruplex (G4s) in an individual, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of Compound I as described herein, or Pharmaceutically acceptable salts, esters and/or solvates.

In a specific embodiment, a method of modulating p53 activity in an individual, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of Compound I as described herein, or a pharmaceutically acceptable salt thereof , esters and / or solvates.

In a specific embodiment, a method of treating or ameliorating a cell proliferative disorder in an individual, the method comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of Compound I as described herein, or in medicinal Acceptable salts, esters and/or solvates. In a specific embodiment, the method is provided to treat or alleviate cancer.

In a specific embodiment, a method for treating or ameliorating cancer is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of Compound I as described herein, or pharmaceutically acceptable thereof a salt, an ester and/or a solvate, wherein the cancer is selected from the group consisting of blood cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, pancreas Cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, skin cancer, kidney cancer and heart tumor. In a specific embodiment, the cancer treated or ameliorated by the method is selected from the group consisting of blood cancers of the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma. In a specific embodiment, the cancer treated or ameliorated by the method is a homologous recombination (HR) DNA double strand break (DSB) repair defective cancer, or a non-homologous end joining (NHEJ) DNA double strand break repair Defective cancer. in In another specific embodiment, the cancer treated or ameliorated by the method comprises the following defective cancer cells: breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2), and/or homologous Other members of the sexual recombination pathway. In another specific embodiment, the cancer cell is defective in BRCA1 and/or BRCA2. In another specific embodiment, the cancer cell refers to a genotype having a BRCA1 and/or BRCA2 mutation that is a homozygote. In another specific embodiment, the cancer cell refers to a genotype having a BRCA1 and/or BRCA2 mutation that is a heterozygote.

In a specific embodiment, the methods provided herein further comprise administering one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are anticancer agents or immunotherapeutic agents. In a specific embodiment, the one or more therapeutically active agents are immunotherapeutic agents. In some embodiments, the one or more immunotherapeutic agents include, but are not limited to, monoclonal antibodies, immune effector cells, adoptive cell transfers, immunotoxins, vaccines, or cytokines.

In a specific embodiment, a method for reducing or inhibiting cell proliferation is provided, the method comprising contacting a cell with a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt, ester and/or solvate thereof. In a specific embodiment, the cell is a cancer cell strain or a tumor cell in a body. In a specific embodiment, the cancer cell line in the above method is selected from the group consisting of blood cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, pancreas Cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, skin cancer, kidney cancer and heart tumor. In a specific embodiment, the blood cancer cell line described in the above method is selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma. In a specific embodiment, the cancer cell line described in the above method is the following defective cancer cell: homologous recombination (HR) DNA double strand break (DSB) repair or non-homologous end joining (NHEJ) DNA double strand break repair. In a specific embodiment, the cancer cell line is the following defective cancer cell: breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2) and/or other members of the homologous recombination pathway. In another specific embodiment, the cancer cell is defective in BRCA1 and/or BRCA2. In another specific embodiment, the cancer cell refers to a genotype having a BRCA1 and/or BRCA2 mutation that is a homozygote. In another specific embodiment, the cancer cell refers to a genotype having a BRCA1 and/or BRCA2 mutation that is a heterozygote.

Figure 1 is an X-ray powder diffraction (XRPD) pattern of polymorph A of Compound I (free base); Figure 2 is a differential scanning thermal analysis (DSC) pattern of polymorph A of Compound I (free base) Figure 3 is a thermogravimetric analysis (TGA) pattern of the polymorph A of Compound I (free base); Figure 4 is a DSC pattern of the polymorph A of Compound I (free base) and an overlay of the TGA pattern; Figure 5 is a hydrogen nuclear magnetic resonance ( ¹ H NMR) spectrum of polymorph A of Compound I (free base); Figure 6A is a photomicrograph of cross-polarized light of polymorph A of Compound I (free base) and Figure 6B is a micrograph of the polymorph A of Compound I (free base) using unpolarized light; Figure 7 is an XRPD pattern of polymorph C of Compound I (free base); Figure 8 is Compound I (free DSC spectrum of the polymorph C of the base; Figure 9 is the ¹ H NMR spectrum of the polymorph C of the compound I (free base); Figure 10A is the cross-form of the polymorph C of the compound I (free base) a photomicrograph of polarized light and FIG. 10B is a micrograph of the polymorph C of Compound I (free base) using unpolarized light; FIG. 11 is an XRPD pattern of polymorph E of Compound I (free base); Figure 12 is Compound I DSC spectrum of polymorph E of (free base); Figure 13 is the ¹ H NMR spectrum of polymorph E of compound I (free base); Figure 14A is polymorph E of compound I (free base) A photomicrograph of crossed polarized light is used, and FIG. 14B is a polymorphic form E of Compound I (free base) using a photomicrograph of unpolarized light; FIG. 15 is a heat of polymorph E of Compound I (free base) Gravimetric analysis (TGA) map.

Figure 16 is an XRPD pattern of polymorph G of Compound I (free base); Figure 17 is a DSC pattern of polymorph G of Compound I (free base); Figure 18 is a polycrystal of Compound I (free base) ¹ H NMR spectrum of Form G; Figure 19A is a photomicrograph of cross-polarized light of polymorph G of Compound I (free base) and Figure 31B is used for polymorph G of Compound I (free base) Micrograph of polarized light; Figure 20 depicts the solubility of several polymorphs of Compound I (free base) in methanol and THF; Figure 21 is the XRPD pattern of the hydrochloride salt of Compound I; Figure 22 is the hydrochloric acid of Compound I. a DSC spectrum of the salt; Figure 23 is a ¹ H NMR spectrum of the hydrochloride salt of Compound I; Figure 24 is a photomicrograph of the hydrochloride salt of Compound I using polarized light; Figure 25 is a TGA spectrum of the hydrochloride salt of Compound I; Figure 26 is an XRPD pattern of the maleate salt of Compound I; Figure 27 is a DSC spectrum of the maleate salt of Compound I; Figure 28 is a ¹ H NMR spectrum of the maleate salt of Compound I. Figure 29 is a horse of Compound I. A photomicrograph of polarized light is used for the acid salt; Figure 30 is a TGA map of the maleate salt of Compound I; and Figure 31 is an XRPD pattern of the fumarate of Compound I; Is the DSC spectrum of the fumarate of Compound I; Figure 33 is the ¹ H NMR spectrum of the fumarate of Compound I; Figure 34 is the photomicrograph of the fumarate of Compound I using polarized light; Figure 35 is the compound TGA spectrum of the fumarate of I; Figure 36 is the XRPD pattern of the citrate of Compound I; Figure 37 is the DSC spectrum of the citrate of Compound I; Figure 38 is the ¹ H NMR spectrum of the citrate of Compound I Figure 39 is a photomicrograph of the citrate salt of Compound I using polarized light; Figure 40 is a TGA map of the fumarate of Compound I; Figure 41 is an XRPD pattern of the L-malate salt of Compound I; Figure 42 is DSC spectrum of L-malate salt of Compound I; Figure 43 is a ¹ H NMR spectrum of L-malate salt of Compound I; Figure 44 is a photomicrograph of polarized light of L-malate salt of Compound I; 45 is a TGA map of the L-malate salt of Compound I.

The present invention relates to a crystalline form of a tetracyclic quinolone compound which stabilizes G-quadruplex (G4s) and/or inhibits polymerase I (Pol I), and also relates to salts and/or solvates of tetracyclic quinolone compounds. Crystalline form. These crystalline materials can be formulated into pharmaceutical compositions as well as for the treatment of diseases having cell proliferation characteristics.

Definitions It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. While any method and materials similar or equivalent to those described herein can be practiced or tested, representative methods and materials are described herein.

In accordance with the long-standing patent law practice, the terms "a", "an" and "the" are used in this application (including in the claim) to mean "one or more." Thus, for example, reference to "a carrier" includes either a plurality of carriers, two or more carriers, or the like.

Unless otherwise stated, it is used to indicate composition and reaction in the scope of the specification and patent application. All numbers such as the number of conditions are considered to be "about" in all cases. Accordingly, the numerical parameters set forth in the specification and claims are intended to be in the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Generally, the term "about" as used herein, when referring to a measured value, such as weight, time, and dosage, is intended to encompass: ±15% in one instance, relative to the specified amount. Or ±10% variation, in another example, ±5% variation, in another instance, ±1% variation, and in yet another example, ±0.1% variation, as long as Variations are appropriate for implementing the methods disclosed.

The term "compound of the invention" or "present compound" means 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia 1,11b diaza-benzo[c]indole-6-carboxylic acid (5-methyl-pyridin-2-ylmethyl)-amine (Compound I) or an isomer, salt, ester, N thereof - a crystalline form of an oxide or solvate. Alternatively, the above terms may refer to the salt of Compound I or Solvate or the two forms. The crystalline form of Compound I described herein includes any single isomer of Compound I and a crystalline form of a mixture of any number of isomers of Compound I.

The term "co-administered" means (a) a crystalline form of Compound I, or a crystalline form of a pharmaceutically acceptable salt, ester, solvate and/or prodrug of Compound I; and (b) one or more additional The therapeutic agents and/or radiation therapies are administered in combination, i.e., administered together in a coordinated manner.

The term "isomer" refers to a compound having the same chemical formula, but may have a different stereochemical formula, structural formula, or a particular atomic arrangement. Examples of isomers include stereoisomers, diastereoisomers, enantiomers, conformational isomers, rotamers, geometric isomers, and atropisomers.

"N-oxide", also known as amine oxide or amine-N-oxide, means a compound derived from a compound of the invention via oxidation of an amine group of a compound of the invention. The N-oxide typically contains a functional group R ₃ N ⁺ -O ^- (sometimes referred to as R ₃ N=O or R ₃ N→O).

Homomorphic polymorphism can have the following characteristics: the ability of a compound to crystallize into different crystalline forms while maintaining the same chemical formula. A crystalline polymorph of a particular drug substance is chemically identical to any other crystalline polymorph of the drug substance that is bonded to the same atom to each other in the same manner, as it has a different crystalline form and may affect one or more Physical properties such as stability, solubility, melting point, bulk density, fluidity, and bioavailability.

The term "composition" means a physical form of one or more substances, such as a solid, a liquid, a gas, or a mixture thereof. One example of a composition is a pharmaceutical composition, that is, a composition for medical treatment, medical preparation, or for medical use.

The term "carboxylic acid" refers to an organic acid having one or more carboxyl groups such as acetic acid and oxalic acid. "Sulphonic acid" means an organic acid having the formula R-(S(O) ₂ -OH) _n wherein R is an organic hydrocarbyl moiety and n is an integer greater than zero, such as 1, 2 and 3. The term "polyhydroxy acid" refers to a carboxylic acid containing two or more hydroxyl groups. Examples of polyhydroxy acids include, but are not limited to, lactobionic acid, gluconic acid, and galactose.

As used herein, "pharmaceutically acceptable" means without excessive toxicity, irritation, allergic reaction, and the like, and is suitable for use in contact with human and animal tissues, having a reasonable benefit/risk ratio, and The intended use within the scope of sound medical judgment is valid.

"Salt" includes derivatives of active agents which are modified by making acid or base addition salts thereof. Preferably, the salt is a pharmaceutically acceptable salt. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, and ammonium and alkylated ammonium salts. Acid addition salts include inorganic acids as well as salts of organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, and propylene Acid, mandelic acid, oxalic acid, bitter acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene salicylic acid, ethanedisulfonic acid, glucose Acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, ethylenediaminetetraacetic acid (EDTA), glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfate , nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthalenes, glycerophosphoric acid, salt ketoglutarate, and the like. Basic addition salt pack Including but not limited to ethylenediamine, N-methyl-glucosamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, Diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylhydroxyl Methylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and spermine Acid dicyclohexylamine and the like. Examples of the metal salt include salts of lithium, sodium, potassium, magnesium, and the like. Examples of ammonium and alkylated ammonium salts include salts of ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium. And similar. Examples of the organic base include lysine, arginine, guanidine, diethanolamine, choline, and the like. Standard methods for the preparation of pharmaceutically acceptable salts and their formulations are well known in the art and are disclosed in various references including, for example, "Remington: The Science and Practice of Pharmacy", A. Gennaro, ed., 20th Edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

As used herein, "solvate" means a complex of solvation (a combination of a solubilizing molecule with a molecule or ion of an active agent of the present invention) or an ion or molecule derived from a solvent (activity of the present invention) a complex comprising one or more solubilizing molecules. In the present invention, a preferred solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and the like. It will be understood by those of ordinary skill in the art that pharmaceutically acceptable salts of the present compounds may also exist in the form of solvates. The solvate is typically formed by hydration, either as part of the preparation of the compound or as a natural moisture absorption via the anhydrous compound of the invention. Solvates, including hydrates, may be stoichiometrically composed, for example, having two, three, or four salt molecules per solvate or per hydrate molecule. Another possibility, for example, the stoichiometry of two salt molecules involves three, five, seven solvent or hydrate molecules. a solvate for crystallization, Such as alcohols, especially methanol and ethanol; aldehydes; ketones, especially acetone; esters, such as ethyl acetate; can be embedded in the crystal lattice. Preferred are pharmaceutically acceptable solvates.

As used herein, the term "substantially similar" means to analyze a spectrum, such as an XRPD pattern, a Raman spectrum, etc., to a large extent similar to a reference spectrum at both the peak position and its intensity.

The terms "excipient", "carrier" and "vehicle" are used interchangeably herein and refer to a substance that is administered with a compound of the invention.

By "therapeutically effective amount" is meant an amount of crystalline form which, when administered to a patient to treat a disease or other undesirable physical condition, is sufficient to produce a beneficial effect on the disease or condition. The therapeutically effective amount will vary depending on the crystalline form, the disease or condition and its severity, and the age, weight, etc., of the subject being treated. The determination of the therapeutically effective amount of a particular crystalline form is within the ordinary skill of the art without routine experimentation.

The term "disease with cell proliferation characteristics" or "condition with cell proliferation characteristics" as used herein includes, but is not limited to, cancer, benign and malignant tumors. Examples of cancers and tumors include, but are not limited to, hyperplasia in the large intestine, breast, lung, liver, pancreas, lymph nodes, colon, prostate, brain, head and neck, skin, kidney, blood, and heart (such as leukemia, lymphoma, and malignant tumors). Cancer or tumor.

The term "treating" corresponds to a particular disease or condition, including preventing and/or alleviating, ameliorating, ameliorating or eliminating the symptoms and/or pathology of the disease or condition. Generally, the term is used herein to mean ameliorating, alleviating, ameliorating, and removing the symptoms of a disease or condition. A candidate molecule or compound described herein can be present in a formulation or drug in a therapeutically effective amount, which amount can result in a biological effect, such as apoptosis of a particular cell (eg, a cancer cell), reducing proliferation of a particular cell, or, for example, can cause disease. Or improvement, relief, alleviation or removal of symptoms of the condition. The term can also refer to reduction Or stop the cell proliferation rate (eg, slow or stop tumor growth) or reduce the number of proliferating cancer cells (eg, remove some or all of the tumor). These terms also apply to the reduction of microbial titers in microbial-infected systems (ie cells, tissues or individuals), the reduction in the rate of microbial reproduction, the number of symptoms or the effects of symptoms associated with microbial infections and/or in the system. The amount of microorganisms removed was detected. Examples of microorganisms include, but are not limited to, viruses, bacteria, and fungi.

As used herein, the terms "inhibiting," "decreasing," or "decreasing" cell proliferation means that when measured by methods known to those of ordinary skill in the art, slowing, reducing, or, for example, stopping the amount of cell proliferation, For example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% relative to proliferating cells that do not receive the methods and compositions of the present application.

As used herein, "apoptosis" refers to a cell's inherent self-destruction or suicide program. In response to a triggering stimulus, cells undergo cascade events, including cell shrinkage, cell membrane blebbing, and chromatin condensation and fragmentation. The final stage of this process is the formation of multiple particles with a complete membrane structure (apoptotic bodies), which are subsequently engulfed by macrophages.

Crystalline Material: In a particular embodiment, the invention provides a crystalline form of Compound I (free base). In another embodiment, the invention provides a crystalline form of a salt and/or solvate of Compound I. In a particular embodiment, the salt is a hydrochloric acid addition salt. In a particular embodiment, the salt is a sulfuric acid addition salt. In a particular embodiment, the salt is a sulfonic acid addition salt. In a particular embodiment, the salt is a carboxylic acid addition salt. In a particular embodiment, the salt is a polyhydroxy acid addition salt.

Examples of crystalline salts include, but are not limited to, hydrochloride, maleate, fumarate, citrate, malate, sulfate, acetate, phosphate, L-(+)-tartrate, D- Glucuronide, benzoate, succinate, ethanesulfonate, methanesulfonate, p-toluenesulfonate, malonate, benzene Sulfonate and 1-hydroxy-2-naphthoate. In a particular embodiment, the ratio of the compound I to the acid in the crystalline salt is from about 1:0.5 to about 1:3.

Examples of crystalline solvates include, but are not limited to, NMP (N-methyl-2-pyrrolidone) solvate of Compound I.

In a specific embodiment, the crystalline form is characterized by the spacing between the lattice faces determined by the X-ray powder diffraction pattern (XRDP). The XRDP spectrum is typically represented by a plot of peak intensity versus peak position (i.e., the angle of diffraction angle 2θ). Intensity is usually shown in parentheses in the following abbreviations: very strong = vst, strong = st; medium = m; weak = w; and very weak = vw. A particular XRDP characteristic peak can be selected based on the position of the peak and its relative intensity to distinguish such crystal structures from other crystal structures. The peak relative to the strongest peak intensity percentage can be expressed as I/Io.

Those skilled in the art will recognize that the measurement of the peak position and/or intensity of the XRDP for a given crystalline form of the same compound will vary within the margin of error. The value of angle 2θ allows for an appropriate margin of error. Typically, the error range is expressed as "±". For example, a 2 theta angle of about "8.716 ± 0.3" represents a range from about 8.716 + 0.3 (i.e., about 9.016) to about 8.716-0.3 (i.e., about 8.416). Depending on the sample preparation technique, the instrument calibration technique, human manipulation variations, etc., the skilled person may be aware that an appropriate XRDP error range may be about ±0.7; ±0.6; ±0.5; ±0.4; ±0.3; ±0.2; ±0.1 ; ± 0.05; or lower.

Further details of the methods and equipment used for XRDP analysis are described in the "Examples" section.

In a specific embodiment, the crystalline form is characterized by differential scanning thermal analysis (DSC). The DSC spectrum is typically a graphical representation of the measured sample temperature in watts per gram of normalized heat flow in watts per gram ("W/g"). The DSC map is usually used to evaluate the extrapolation start And the outset temperature, peak temperature and heat of fusion. The peak eigenvalues of the DSC spectrum are typically used to distinguish characteristic peaks of such crystal structures from other crystal structures.

Those skilled in the art will recognize that the measurement of the DSC pattern for a given crystalline form of the same compound will vary within the margin of error. The value of a single peak eigenvalue (expressed in degrees Celsius) allows for an appropriate margin of error. Typically, the error range is expressed as "±". For example, a single peak characteristic value of about "53.09 ± 2.0" means a range from about 53.09 + 2 (i.e., about 55.09) to about 53.09-2 (i.e., about 51.09). Depending on the sample preparation technique, applied to instrument calibration techniques, human manipulation variations, etc., the skilled person may be aware of an appropriate single peak eigenvalue error range of about ±2.5; ±2.0; ±1.5; ±1.0; ±0.5; smaller.

Further details of the methods and equipment used for DSC profiling are described in the "Examples" section.

In a specific embodiment, the crystalline form is characterized by Raman spectroscopy. The Raman spectrum is typically represented by a graph of the Raman intensity of the peak versus the Raman shift of the peak. The "peak" in the Raman spectrum is also called the "absorption band." Intensity is usually shown in parentheses in the following abbreviations: strong = st; medium = m; weak = w. The characteristic peaks of a given Raman spectrum can be selected based on the position of the peaks and their relative intensities to distinguish such crystal structures from other crystal structures.

Those skilled in the art will recognize that the measurement of the Raman peak shift and/or intensity for a given crystalline form of the same compound will vary within the margin of error. The value of the peak displacement, expressed as the inverse wave number (cm ^-1 ), allows for an appropriate error range. Typically, the error range is expressed as "±". For example, a representation of the "1310 ± 10" Raman shift ranges from about 1310 + 10 (ie, about 1320) to about 1310-10 (ie, about 1300). Depending on the sample preparation technique, applied to instrument calibration techniques, human manipulation variations, etc., the skilled person may recognize an appropriate single peak eigenvalue error range of ±12; ±10; ±8; ±5; ±3; ±1 Or smaller.

Details of other methods and apparatus for Raman spectroscopy are described in the "Examples" section.

In a particular embodiment, the crystalline form of Compound I (free base). In some embodiments, the crystalline form of Compound I (free base) exhibits different polymorphs. Examples of crystalline forms of Compound I (free base) include, but are not limited to, polymorphs A, C, E, and G, as defined in the following sections.

In some embodiments, one form of the polymorph is more stable than the other forms. In a particular embodiment, the polymorph A of the crystalline form of Compound I (free base) exhibits high stability. In some embodiments, different polymorphs of Compound I (free base) are converted to another polymorphic form under certain conditions. In some embodiments, the polymorphs C, E, and/or G are converted to polymorph A under suitable conditions. In a specific embodiment, each of polymorphs C, E, and G is independently converted to polymorph A in a solution at room temperature or elevated temperature. Polymorph A is the most thermodynamically stable form; however, other forms can be formed under certain conditions or are advantageous for kinetics.

In a particular embodiment of the invention, the crystalline form of Compound I may comprise a mixture of one or more forms of the polymorph of Compound I. In some embodiments, the crystalline form of Compound I can comprise a single polymorph type in substantially pure form. In a particular embodiment, the crystalline form of Compound I can comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%. Or about 99.0% of a single polymorph of Compound I. In another embodiment, the crystalline form of Compound I can include more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Compound I. A single polymorph. In a particular embodiment, the crystalline form of Compound I can include more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the compound. A single polymorph of I.

In a particular embodiment of the invention, the crystalline form of Compound I can comprise at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, About 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90% or about 85% of compound I Polymorph A of (free base).

In a particular embodiment of the invention, the crystalline form of Compound I can be a polymorph A of Compound I (free base) comprising about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6% , 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5 %, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% polymorph C, E or G or a mixture thereof.

In a particular embodiment of the invention, the crystalline form of Compound I can be a polymorph C of Compound I (free base) comprising about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6% , 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5 %, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% polymorph A.

In a particular embodiment of the invention, the crystalline form of Compound I can be a polymorph E of Compound I (free base) comprising about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6% , 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5 %, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% polymorph A.

In a particular embodiment of the invention, the crystalline form of Compound I can be a polymorph Form G of Compound I (free base) comprising about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6% , 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% , 19% or 20% polymorph A.

In a specific embodiment, the crystalline form of Compound I provided by the present invention is of high purity. In a particular embodiment of the invention, the crystalline form of Compound I may have a purity of at least 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%. About 9.91%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91% or about 90% of Compound I purity.

Other methods for characterizing the crystalline form of the invention are described in the "Examples" section.

Polymorph A

In a specific embodiment, the polymorph A of Compound I (free base) exhibits an XRDP comprising peaks at about 7.73, 22.050, and 24.550 degrees at 2θ, with an error range of about ±0.5; about ±0.4; about ±0.3; ±0.2; about ±0.1; about ±0.05; or less. In another embodiment, the XRDP of crystalline polymorph A of Compound I (free base) further comprises peaks at about 9.41 and 27.700 degrees at 2θ, with an error range of about ±0.5; about ±0.4; about ±0.3; 0.2; about ± 0.1; about ± 0.05; or less. In yet another embodiment, the crystalline form of the polymorph A of Compound I (free base) further comprises a peak at 2θ of about 17.950 and 25.400 degrees, with an error range of about ±0.5; about ±0.4; about ±0.3; 0.2; about ± 0.1; about ± 0.05; or less. In another embodiment, the crystalline form of the polymorph A of Compound I (free base) further comprises at least one peak at about 22.23, 11.630, 16.900, 18.580, 23.300, and 26.700 degrees with an error range of about ±0.5; About ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In yet another embodiment, the crystalline form of polymorph A of Compound I (free base) exhibits a XRDP comprising the peaks shown in Table 1 below: Table 1. Polymorphs of Compound I (free base) XRDP table of object A

In a particular embodiment, the crystalline form of polymorph A of Compound I (free base) exhibits an XRDP substantially similar to that of Figure 1.

In a specific embodiment, the crystalline form of the polymorph A of Compound I (free base) exhibits a DSC pattern comprising a sharp endothermic peak at about 215.41 ° C with an error range of about ±2.5; about ±2.0; 1.5; about ± 1.0; about ± 0.5; or less. In another embodiment, the crystalline form of polymorph A of Compound I (free base) further exhibits a DSC profile comprising one or more of the following peaks: An exothermic peak at about 216.92 ± 2.0 ° C, an endothermic peak at about 230.56 ± 2.0 ° C, an exothermic peak at about 232.84 ± 2.0 ° C, and an endothermic peak at about 241.56 ± 2.0 ° C. In a particular embodiment, the crystalline form of polymorph A of Compound I (free base) exhibits a DSC pattern substantially similar to that of Figure 2.

In a specific embodiment, the crystalline form of polymorph A of Compound I (free base) exhibits a ¹ H NMR spectrum substantially similar to that of Figure 5. In another embodiment, the crystalline form of polymorph A of Compound I (free base) may have a fine needle-like crystalline phase forming a loosely bound mass on a macroscopic scale, which is substantially Similar to Figures 6A and 6B.

Polymorph C

In a specific embodiment, the polymorph C of Compound I (free base) exhibits an XRDP comprising a peak at about 2.72 degrees from 2θ, an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2; ±0.1; about ±0.05; or less. In another embodiment, the crystalline form of crystalline polymorph C of Compound I (free base) exhibits an XRDP comprising the peaks shown in Table 2 below:

In a specific embodiment, the crystalline form of polymorph C of Compound I (free base) exhibits an XRDP substantially similar to that of Figure 7.

In a specific embodiment, the crystalline form of the polymorph C of Compound I (free base) exhibits a DSC spectrum comprising a peak characteristic value of about 246.47 ° C, an error range of about ±2.5; about ±2.0; about ±1.5; About ±1.0; about ±0.5; or less. In a specific embodiment, the crystalline form of polymorph C of Compound I (free base) exhibits a DSC pattern substantially similar to that of Figure 8.

In a specific embodiment, the crystalline form of the polymorph C of Compound I (free base) exhibits a ¹ H NMR spectrum substantially similar to that of Figure 9. In another embodiment, the crystalline form of polymorph C of Compound I (free base) can be composed of acicular agglomerates on a macroscopic scale, which is substantially similar to Figures 10A and 10B.

Polymorph E

In a specific embodiment, the polymorph E of Compound I (free base) exhibits an XRDP comprising a peak at about 2.78 degrees 2θ, an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2; ±0.1; about ±0.05; or less. In another embodiment, the XRDP of the crystalline polymorph E of Compound I (free base) further comprises at least one peak at 2θ 12.200, 12.600, 25.360, and 27.560 degrees with an error range of about ±0.5; about ±0.4; About ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In yet another embodiment, the crystalline form of the polymorph E of Compound I (free base) exhibits an XRDP comprising the peaks shown in Table 3 below:

In a particular embodiment, the crystalline form of polymorph E of Compound I (free base) exhibits an XRDP substantially similar to that of Figure 11.

In a specific embodiment, the crystalline form of the polymorph E of Compound I (free base) exhibits a DSC spectrum comprising a peak characteristic value of about 231.99 ° C with an error range of about ±2.5; about ±2.0; ±1.5; about ±1.0; about ±0.5; or less. In a specific embodiment, the crystalline form of Polymorph E of Compound I (free base) exhibits a DSC pattern substantially similar to that of Figure 12.

In a particular embodiment, the crystalline form of polymorph E of Compound I (free base) exhibits a ¹ H NMR spectrum substantially similar to that of Figure 13. In another embodiment, the crystalline form of polymorph E of Compound I (free base) is substantially similar to that of Figures 14A and 14B.

Polymorph G

In a specific embodiment, the polymorph Form G of Compound I (free base) exhibits an XRDP comprising peaks at about 2.000 and 6.060 degrees at 2 theta, with an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2 ; about ± 0.1; about ± 0.05; or less. In another embodiment, the crystalline form of the polymorph Form G of Compound I (free base) exhibits an XRDP comprising the peaks shown in Table 4 below:

In a particular embodiment, the crystalline form of polymorph G of Compound I (free base) exhibits an XRDP substantially similar to that of Figure 16.

In a specific embodiment, the crystalline form of the polymorph Form G of Compound I (free base) exhibits a DSC spectrum comprising a peak characteristic value of about 222.11 ° C, an error range of about ±2.5; about ±2.0; about ±1.5; About ±1.0; about ±0.5; or less. In a specific embodiment, the crystalline form of polymorph G of Compound I (free base) exhibits a DSC pattern substantially similar to that of Figure 17.

In a specific embodiment, the crystalline form of the polymorph G of Compound I (free base) exhibits a ¹ H NMR spectrum substantially similar to that of Figure 18. In another embodiment, the crystalline form of polymorph G of Compound I (free base) is substantially similar to that of Figures 19A and 19B.

Hydrochloride salt of compound I

In one embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits a peak in XRDP comprising about 4.60 and 24.540 degrees at 2θ, with an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2; 0.1; about ±0.05; or less. In another embodiment, the XRDP of the crystalline form of the hydrochloride salt of Compound I further comprises one, two, three or four peaks at a temperature selected from the group consisting of 2θ: 19.260, 20.160, 24.920 and 26.360 degrees, with an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In another embodiment, the crystalline form of the hydrochloride salt of Compound I further comprises one, two or three peaks at a temperature selected from the group consisting of 2?: 13.980, 14.540, 25.380 and 28.940 degrees, with an error range of about ±0.5; ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In yet another embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits a XRDP comprising the peaks shown in Table 6 below:

In a specific embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits an XRDP substantially similar to that of Figure 21.

In a specific embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits a DSC spectrum comprising a peak characteristic value of about 266.27 ° C, an error range of about ±2.5; about ±2.0; about ±1.5; about ±1.0; 0.5; or less. In a specific embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits a DSC pattern substantially similar to that of Figure 22. In a particular embodiment, the crystalline form of the hydrochloride salt of Compound I does not have a distinct melting point.

In a specific embodiment, the crystalline form of the hydrochloride salt of Compound I exhibits a ¹ H NMR spectrum substantially similar to that of Figure 23. In another embodiment, the crystalline form of the hydrochloride salt of Compound I consists of a small needle-like form of agglomerate on a macroscopic scale, which is substantially similar to Figure 24. In one embodiment, the ratio of hydrochloric acid and Compound I in the hydrochloride salt of Compound I is about 1:1.

Compound I maleate

In one embodiment, the crystalline form of the maleate salt of Compound I exhibits a peak in XRDP of about 7.40, 18.440, and 26.500 degrees at 2θ, with an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2 ; about ± 0.1; about ± 0.05; or less. In another embodiment, the XRDP of the crystalline maleate salt of Compound I further comprises one, two, three or four peaks at a temperature selected from the group consisting of 2θ: 22.320, 23.920, 24.300 and 25.240 degrees, with an error range of about ± 0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In another embodiment, the crystalline maleate salt of Compound I further comprises one, two, three, or four peaks selected from the group consisting of 2θ: about 5.040, 15.080, 15.880, 20.860, and 28.540 degrees, The error range is about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In yet another embodiment, the crystalline form of the maleate salt of Compound I exhibits a XRDP comprising the peaks shown in Table 7 below:

In a specific embodiment, the crystalline form of the maleate salt of Compound I exhibits an XRDP substantially similar to that of Figure 26.

In a specific embodiment, the crystalline form of the maleate salt of Compound I exhibits a DSC spectrum comprising a peak characteristic value of about 217.32 ° C, an error range of about ±2.5; about ±2.0; about ±1.5; about ±1.0; ±0.5; or less. In a specific embodiment, the crystalline form of the maleate salt of Compound I exhibits a DSC pattern substantially similar to that of Figure 27.

In a specific embodiment, the crystalline form of the maleate salt of Compound I exhibits a ¹ H NMR spectrum substantially similar to that of Figure 28. In another embodiment, the crystalline form of the maleate salt of Compound I consists of a small needle-like formed muscopolymer on a macroscopic scale, which is substantially similar to Figure 29. In a particular embodiment, the ratio of maleic acid and Compound I in the maleate salt of Compound I is about 1:1.

Compound I fumarate

In one embodiment, the crystalline form of the fumarate salt of Compound I exhibits a peak in XRDP of about 6.360 and 24.800 degrees with an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2; ±0.1; about ±0.05; or less. In another embodiment, the XRDP of the crystalline fumarate salt of Compound I further comprises at least one, two or three peaks selected from the group consisting of about 19.660, 20.420, and 26.860 degrees, with an error range of about ±0.5; about ±0.4; ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In another embodiment, the XRDP of the crystalline fumarate salt of Compound I further comprises one, two, three or four peaks at about 22.680, 17.020, 25.180 and 28.280 degrees at 2θ, with an error range of about ±0.5; about ±0.4 ; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In yet another embodiment, the crystalline form of the fumarate salt of Compound I exhibits an XRDP comprising the peaks shown in Table 8 below:

In a specific embodiment, the crystalline form of the fumarate salt of Compound I exhibits an XRDP substantially similar to that of Figure 31.

In a specific embodiment, the crystalline form of the fumarate salt of Compound I exhibits a DSC spectrum comprising a peak characteristic value of about 222.40 ° C, an error range of about ±2.5; about ±2.0; about ±1.5; about ±1.0; ±0.5; or less. In a specific embodiment, the crystalline form of the fumarate salt of Compound I exhibits a DSC pattern substantially similar to that of Figure 32.

In a specific embodiment, the crystalline form of the fumarate salt of Compound I exhibits a ¹ H NMR spectrum substantially similar to that of Figure 33. In another embodiment, the crystalline form of the fumarate salt of Compound I consists of a small needle-like form of agglomerate on a macroscopic scale, which is substantially similar to Figure 34. In a specific embodiment, the ratio of fumaric acid and Compound I in the fumarate salt of Compound I is about 1:1.

Citrate of Compound I

In a specific embodiment, the crystalline form of the citrate salt of Compound I exhibits a peak in XRDP comprising about 4.90, 25.380, and 27.500 degrees at 2θ, with an error range of about ±0.5; about ±0.4; about ±0.3; about ±0.2; About ±0.1; about ±0.05; or less. In another embodiment, the XRDP of the crystalline citrate of Compound I further comprises at least one, two, three or four peaks at about 22.360, 18.100, 19.300 and 26.140 degrees at 2θ, with an error range of about ±0.5; about ±0.4 ; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In another embodiment, the crystalline citrate of Compound I further comprises at least one, two, three or four peaks at about 17.400, 18.680, 24.040 and 26.740 degrees at 2θ, with an error range of about ±0.5; about ±0.4; ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In yet another embodiment, the crystalline form of the citrate salt of Compound I exhibits a XRDP comprising the peaks shown in Table 9 below:

In a specific embodiment, the crystalline form of the citrate salt of Compound I exhibits an XRDP substantially similar to that of Figure 36.

In a specific embodiment, the crystalline form of the citrate salt of Compound I exhibits a DSC spectrum comprising a peak characteristic value of about 196.86 ° C, an error range of about ±2.5; about ±2.0; about ±1.5; about ±1.0; 0.5; or less. In a specific embodiment, the crystalline form of the citrate salt of Compound I exhibits a DSC pattern substantially similar to that of Figure 37.

In a specific embodiment, the crystalline form of the citrate salt of Compound I exhibits a ¹ H NMR spectrum substantially similar to that of Figure 38. In another embodiment, the crystalline form of the citrate salt of Compound I consists of a small needle-like shaped cohesive mass on a macroscopic scale, which is substantially similar to Figure 39. In a particular embodiment, the ratio of citric acid and Compound I in the citrate salt of Compound I is about 1:1.

L-malate salt of Compound I

In one embodiment, the crystalline form of the L-malate salt of Compound I exhibits a peak in XRDP comprising peaks at about 6.580, 6.780, and 25.560 degrees, with an error range of about ±0.5; about ±0.4; about ±0.3; 0.2; about ± 0.1; about ± 0.05; or less. In another embodiment, the XRDP of the crystalline L-malate salt of Compound I further comprises one, two, three, or four peaks at a temperature selected from the group consisting of 2θ: about 19.560, 23.660, 26.060, and 26.960 degrees, with an error. The range is about ±0.7; about ±0.6; about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less. In another embodiment, the crystalline L-malate salt of Compound I further comprises one, two, three, four or five peaks selected from the group consisting of 2θ: about 8.800, 11.800, 18.600, 24.460 and 25.080 degrees, The error range is about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less.

In yet another embodiment, the crystalline form of the L-malate salt of Compound I exhibits a XRDP comprising the peaks shown in Table 10 below:

In a specific embodiment, the crystalline form of the L-malate salt of Compound I exhibits an XRDP substantially similar to that of Figure 41.

In a specific embodiment, the crystalline form of the L-malate salt of Compound I exhibits a DSC spectrum comprising a peak characteristic value of about 209.67 ° C, an error range of about ±2.5; about ±2.0; about ±1.5; about ±1.0; About ±0.5; or less. In a specific embodiment, the crystalline form of the L-malate salt of Compound I exhibits a DSC pattern substantially similar to that of Figure 42.

In a specific embodiment, the crystalline form of the L-malate salt of Compound I exhibits a ¹ H NMR spectrum substantially similar to that of Figure 43. In another embodiment, the crystalline form of the L-malate salt of Compound I consists of a small needle-like form of agglomerate on a macroscopic scale, which is substantially similar to Figure 44. In a specific embodiment, the ratio of L-malic acid and Compound I in the L-malate salt of Compound I is about 1:1.

Medical preparation

In another embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound I, or a pharmaceutically acceptable salt, ester and/or solvate thereof, as described herein, as an active ingredient In combination with a pharmaceutically acceptable excipient or carrier. The excipients are added to the formulation for a variety of uses.

The formulation of the invention may be added to a diluent. The diluent can increase the volume of the solid pharmaceutical composition and can make it easier for the patient and caregiver to handle the pharmaceutical dosage form containing the composition. Diluents for solid compositions include, for example, microcrystalline cellulose (such as AVICEL), microcellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, glucose binder, dextrin, glucose. , dicalcium phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (for example, EUDRAGIT®), potassium chloride, powdered cellulose, chlorination Sodium, sorbitol and talc.

Solid pharmaceutical compositions, such as troches, which are compressed into a dosage form, may contain excipients whose function comprises, after compression, aiding in the binding of the active ingredient to other excipients. Knot used in solid pharmaceutical compositions Binders include gum arabic, alginic acid, carbomer (eg, carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, tragacanth, hydrogenated vegetable oil, Hydroxyethyl cellulose, hydroxypropyl cellulose (eg, KLUCEL), hydroxypropyl methylcellulose (eg, METHOCEL), liquid glucose, magnesium aluminum citrate, maltodextrin, methyl cellulose, polymethyl Acrylate, povidone (eg, KOLLIDON, PLADONE), pregelatinized starch, sodium alginate, and starch.

The rate of dissolution of the compressed solid pharmaceutical composition in the stomach of a patient can be increased by the addition of a disintegrant to the composition. Disintegrators include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (eg, AC-DI-SOL and PRIMELLOSE), colloidal cerium oxide, croscarmellin sodium, crospovidone (eg , KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, potassium blakelin, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (eg , EXPLOTAB), potato starch and starch.

Glidants can be added to improve the flow of the non-compressed solid composition and to improve the accuracy of administration. Excipients having a glidant function include colloidal cerium oxide, magnesium tricaprate, powdered cellulose, starch, talc, and tricalcium phosphate.

When a dosage form such as a tablet is made by pressing a powdered composition, the composition is subjected to pressure from the punch and the die. Some excipients and active ingredients have a tendency to adhere to the surface of the punch and die, which may result in irregularities in the finished product and other surface irregularities. Lubricants can be added to the composition to reduce adhesion and allow the finished product to be more easily detached from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate. , sodium stearyl fumarate, stearic acid, talc and zinc stearate.

Flavoring and flavor enhancers then make the dosage form better for the patient to enter. The composition of the present invention may comprise a flavoring agent and a flavor enhancer commonly used in pharmaceutical products, including maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid. .

The solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or to facilitate patient identification of the product and unit dosage.

Liquid pharmaceutical compositions can be prepared using the crystalline forms of the invention, as well as any other solid excipient, wherein the ingredients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerol.

The liquid pharmaceutical composition may contain an emulsifier to uniformly disperse the active ingredient or other excipient which is insoluble in the liquid carrier throughout the composition. Emulsifiers useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, tragacanth, carrageen, pectin, methylcellulose, carbomer, cetyl stearin Alcohol and cetyl alcohol.

The liquid pharmaceutical composition may also contain a viscosity enhancer to improve the mouthfeel of the product and/or to form a film in the gastrointestinal tract. Viscosity enhancers include gum arabic, alginic acid bentonite, carbomer, calcium or sodium carboxymethylcellulose, cetearyl alcohol, methyl cellulose, ethyl cellulose, gelatin guar, hydroxyethyl cellulose , hydroxypropyl cellulose, hydroxypropyl methylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch Astragalus gum and xanthan gum.

Sweeteners such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.

To improve storage stability, a safe intake of preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butyl hydroxyanisole and ethylenediamine tetraacid can be added.

The liquid composition may also contain a buffer such as glycolic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. Pharmaceutical scientists can easily determine the choice and amount of excipients based on experience and standard procedures and reference work in this area.

The solid compositions of the present invention include powders, granules, aggregates, and compressed compositions. Dosage forms include those suitable for oral, buccal, intestinal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ocular administration. While the most appropriate mode of administration in any given situation will depend on the nature and severity of the condition being treated, the preferred route of the invention is oral. The dosage form can be conveniently presented in the form of a single dosage form and can be prepared by any of the methods known in the art.

Dosage forms include solid dosage forms such as lozenges, powders, capsules, suppositories, sachets, throat lozenges and lozenges, as well as liquid syrups, suspensions, aerosols and elixirs.

The dosage form of the present invention may be a capsule containing the composition in a hard or soft outer shell, preferably a powdered or granulated solid composition of the present invention. The outer shell can be made of gelatin and optionally contains a plasticizer such as glycerin and sorbitol with an opacifier or colorant.

Compositions for tableting or capsule filling can be prepared by wet granulation. In the wet granulation process, some or all of the active ingredients and excipients are mixed in powder form and then further mixed in a liquid (usually water) which causes the powder to agglomerate into granules. The granules are sieved and/or ground, dried, then sieved and/or ground to the desired particle size. The granules may be compressed, or other excipients may be added prior to the tableting, such as a glidant and/or a lubricant.

The tablet composition can be prepared conventionally by dry mixing. For example, a mixed composition of an active material and an excipient may be compressed into a cake or flake form and then mashed into pressed granules. The pressed granules can then be compressed into a tablet.

As an alternative to the dry granulation process, the mixed compositions can be directly compressed into a compact formulation using direct compression techniques. Direct compression produces a more uniform tablet without particles. Excipients that are particularly suitable for direct compression compacts include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal cerium oxide. Those skilled in the art having a specific formulation challenge for direct compression compacts are known to suitably use these and other excipients in direct compression compacts.

The capsule filling of the present invention may contain any of the foregoing mixing and granulation (described with reference to the ingot); however, they are not subjected to the final tableting step.

The active ingredients and excipients can be formulated into compositions and dosage forms according to methods known in the art.

In a specific embodiment, the pharmaceutical dosage form can be provided as a kit comprising the crystalline form of Compound I in separate components, as well as pharmaceutically acceptable excipients and carriers thereof. In some embodiments, the dosage form kit allows the physician and the patient to formulate the oral or injectable solution by dissolving, suspending or mixing the crystalline form of Compound I with its pharmaceutically acceptable excipients and carriers prior to use. In a specific embodiment, a pharmaceutical dosage form kit of the crystalline form of Compound I is provided having improved Compound I stability as compared to the pre-formulated liquid formulation of Compound 1.

The formulations of the invention do not necessarily contain only one crystalline form of Compound I. The crystalline form of the present invention is used as a single component or in combination with other crystalline forms of Compound I for use in pharmaceutical preparations or compositions. In a particular embodiment, the pharmaceutical formulation or composition of the invention contains from 25 to 100% or from 50 to 100% by weight of at least one crystalline form of Compound I according to the invention in the formulation or composition.

Use for treatment

The invention also provides a therapy for a cell proliferation related disease. In one aspect, the invention provides a method for selectively activating a p53 protein comprising contacting the compound with a cell proliferative phase A cell that affects the disease. In a particular embodiment, the method comprises contacting the cancer and/or tumor cells in a crystalline form of Compound 1, or a pharmaceutically acceptable salt, ester and/or solvate thereof, according to the invention. In another embodiment, the method of contacting cancer and/or tumor cells in the form of a crystalline form of Compound 1, or a pharmaceutically acceptable salt, ester and/or solvate thereof, according to the present invention, induces apoptosis Or reduce or prevent the progression of the disease.

Furthermore, methods for treating cancer, cancer cells, tumors or tumor cells are disclosed. Non-limiting examples of cancers that can be treated by the methods of the invention include the following cancers or cancer cells: large intestine, breast, lung, liver, pancreas, lymph nodes, colon, prostate, brain, head and neck, skin, ovaries, cervix, Thyroid, bladder, kidney, and blood and heart (eg, leukemia, lymphoma, and malignancy). Non-limiting examples of tumors that can be treated by the methods of the invention include the following tumor and tumor cells: large intestine, breast, lung, liver, pancreas, lymph nodes, colon, prostate, brain, head and neck, skin, kidney, and blood and heart ( For example, leukemia, lymphoma and malignant tumors).

The invention also provides methods of treating, preventing, ameliorating, and/or alleviating the progression of a disease or condition having cell proliferation characteristics in an individual. More specifically, the methods of the invention involve administering to a subject an effective amount of a crystalline form of a quinolone compound as described herein to treat a disease or condition having cell proliferation characteristics. Administration of the crystalline form can effectively activate the amount of p53 protein in cancer and/or tumor cells, which can result in cell death or apoptosis. The terms "individual" and "patient" are used interchangeably herein.

As described herein, pharmaceutical administration can be accomplished or performed using any of a variety of methods well known to those skilled in the art. The crystalline form may contain a dosage form of a generally non-toxic, physiologically acceptable carrier or vehicle, administered in the form of, for example, subcutaneous, intravenous, parenteral, intraperitoneal, Intradermal, intramuscular, topical, enteral (eg, oral), rectal, nasal, buccal, sublingual, vaginal, by inhalation spray, by a drug pump or via an implanted reservoir.

In addition, the crystalline forms disclosed herein can be administered to a localized area in need of treatment. It can be achieved by, for example but not limited to, local infusion during surgery, topical application, transdermal patch, by injection, by catheter, by suppository, or by implant (implant optional) The ground is a porous, non-porous or gel-like material) which comprises a film such as a silicone rubber film or fiber.

The form in which the crystalline form is administered (e.g., syrups, elixirs, capsules, lozenges, foams, emulsions, gels, and the like) will depend in part on the route of administration. For example, for administration to mucous membranes (for example, oral mucosa, rectum, intestinal mucosa, bronchial mucosa), nasal drops, aerosols, inhalants, nebulizers, eye drops or suppositories can be used. The crystalline form can also be used to coat bio-implantable materials to enhance axon growth, nerve survival, or interaction of cells with the implant surface. The crystalline forms disclosed herein can be administered with other bioactive agents that control the symptoms or causes of one or more diseases or conditions having cell proliferation characteristics, such as anticancer agents, analgesics, anti-inflammatory agents. , anesthetics and other agents.

In a particular embodiment, a crystalline form of Compound I of the present invention or a crystalline form of a pharmaceutically acceptable salt, ester and/or solvate of Compound I can be administered in combination with one or more therapeutically active agents. . In a specific embodiment, the one or more therapeutically active agents are anticancer agents. In some embodiments, the one or more therapeutically active anticancer agents include, but are not limited to, paclitaxel, vinblastine, vincristine, etoposide, doxorubicin, Herceptin, lapatinib, gemfibrate Nie, erlotinib, tamoxifen, fulvestrant, anastrozole, levothole, exemestane, fadrozole, cyclophosphamide, taxotere, melphalan, benzene Butyric acid mustard, nitrogen mustard, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin ,White Xiaoan, thiotepa, cisplatin, carboplatin, actinomycin D, Adriamycin, daunorubicin, idarubicin, mitoxantrone, pucamycin, silk Myostatin, C bleomycin, combinations thereof, and analogs thereof. In another specific embodiment, the one or more therapeutically active anticancer agents include, but are not limited to, a PARP (poly(DP-ribose) polymerase) inhibitor. Suitable PARP inhibitors include, but are not limited to, 4-(3-(1-(cyclopropanecarbonyl)piperidin-4-carbonyl)-4-fluorobenzyl)pyridazine-1(2H)-one (olaparib, AZD2281, Ku-0059436), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (Veliparib, ABT-888), (8S, 9R)-5- Fluorine-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4, 3,2-depyridazinyl-3H-(7H)-one (talazoparib, BMN 673), 4-iodo-3-nitrobenzamide (iniparib, BSI-201), 8-fluoro-5-( 4-((Dimethylamino)methyl)phenyl)-3,4-dihydro-2H-aza-[5,4,3-cd]indole-1(6H)-ketophosphate (Rucaparib, AG-014699, PF-01367338), 2-[4-[(Dimethylamino)methyl]phenyl]-5,6-dihydro-imidazo[4,5,1-JK][1,4 Benzodiazepine 7(4H)-one (AG14361), 3-aminobenzamide (INO-1001), 2-(2-fluoro-4-((S)-pyrrolidin-2-yl)benzene -3H-benzo[d]imidazole-4-carboxamide (A-966492), N-(5,6-dihydro-6-oxo-2-phenanthridine)-2-acetamide hydrochloride (PJ34, PJ34 HCl), MK-4827, 3,4-dihydro-4-oxo-3,4-dihydro-4-oxo-N-[(1S)-1-phenylethyl]-2 -quinazolinepropene (ME0328), 5-(2-oxo-2-phenylethyl)-1(2H)-isoquinoline (UPF -1069), 4-[[4-fluoro-3-[(4-methoxy-1-piperidyl)carbonyl]phenyl]methyl]-1(2H)-pyridazinone (AZD 2461) and Its analogues. In another specific embodiment, the one or more therapeutically active agents are immunotherapeutic agents. In some embodiments, the one or more immunotherapeutic agents include, but are not limited to, monoclonal antibodies, immune effector cells, adoptive cell transfer, immunotoxins, vaccines, cytokines, and the like.

In another embodiment, a crystalline form of Compound I as described herein or a crystalline form of Compound I in a pharmaceutically acceptable salt, ester and/or solvate can be administered in combination with radiation therapy.

In addition, administration can include administering to the individual a plurality of doses over a suitable period of time. This drug administration protocol can be determined according to conventional methods after reading this article.

The crystalline form of the invention is generally administered at a dose of from about 0.01 mg/kg/dose to about 100 mg/kg/dose. Alternatively, the dosage may be from about 0.1 mg/kg/dose to about 10 mg/kg/dose; or from about 1 mg/kg/dose to 10 mg/kg/dose. The time-controlled release formulation may be employed or the agent may be divided into multiple doses for administration. When other methods (e.g., intravenous administration) are used, the crystalline form is administered to the affected tissue at a rate of from about 0.05 to 10 mg/kg/hr or from about 0.1 to about 1 mg/kg/hr. Such rates can be readily maintained when the crystalline form is administered intravenously as discussed herein. In general, topical formulations are administered at a dose ranging from about 0.5 mg/kg/dose to about 10 mg/kg/dose. Alternatively, the topical formulation is administered at a dose of from about 1 mg/kg/dose to about 7.5 mg/kg/dose, or even at a dose of from about 1 mg/kg/dose to about 5 mg/kg/dose.

A range from about 0.1 to about 100 mg/kg is a suitable single dose. A suitable continuous administration range is from about 0.05 to about 10 mg/kg.

The drug dose can also be given as the body surface area in milligrams per square meter, rather than the body weight, as this method has a good correlation with specific metabolic and excretory functions. In addition, body surface area can be used as a common denominator of drug doses between adults and children and between different animal species (Freireich et al., (1966) Cancer Chemother Rep. 50, 219-244). Briefly, the dose is multiplied by the appropriate km factor and the mg/kg dose can be expressed as an equivalent mg/sq m dose in any given species. In adults, 100 mg/kg is equivalent to 100 mg/kg x 37 kg/sq m = 3700 mg/m ² .

The dosage form of the present invention may contain Compound I or a pharmaceutically acceptable salt, ester and/or solvate thereof as described herein in an amount of from about 5 mg to about 500 mg. That is, the dosage form of the present invention may contain the compound I in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 175mg, 180mg, 190mg, 200mg, 210mg, 220mg, 225mg, 230mg, 240mg, 250mg, 260mg, 270mg, 275mg, 280mg, 290mg, 300mg, 310mg, 320mg, 325mg, 330mg, 340mg, 350mg, 360mg, 370mg, 375mg, 380mg, 390mg, 400mg, 410mg, 420mg, 425 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 475 mg, 480 mg, 490 mg, or 500 mg. In a specific embodiment, the above dosage is administered to the patient as a single dose per day, or as multiple times daily, such as twice, three times or four times daily.

The dosage form of the invention can be administered hourly, daily, weekly or monthly. The dosage form of the invention may be administered twice daily or once daily. The dosage form of the invention may be administered with or without food.

When the crystalline form disclosed herein can take the form of a mimetic or a fragment thereof, it should be understood that its potency, and therefore, an effective amount of the dosage can be varied. However, those skilled in the art can readily analyze the efficacy of the type of crystalline form contemplated by the present invention.

In the case of a progressive disease or condition having cell proliferation characteristics, the crystalline form of the invention is administered on a consistent basis. In certain instances, the crystalline form of the invention may be administered prior to the development of the disease symptoms as part of a strategy to delay or prevent disease. In other instances, the crystalline form of the invention may be administered after the onset of the symptoms of the disease as part of a strategy to slow or reverse the progression of the disease, and/or as part of a strategy to improve cellular function and alleviate symptoms.

It will be understood by those skilled in the art that the dosage range will depend on the particular crystalline form and its effectiveness. It should be understood that the dose range is large enough to produce the desired effect, which can alleviate neurodegenerative Or other diseases and their associated symptoms, and / or achieve their cell survival, but the dose range is not so large that it causes untreated side effects. However, it will be understood that the particular dosage for any particular patient will depend on a variety of factors, including the activity of the particular crystalline form employed; the age, weight, health, sex and diet of the subject being treated; time and route of administration; rate of excretion Other previously administered drugs; and the severity of the particular disease being treated, as fully understood by those skilled in the art. The dosage can also be adjusted by an individual physician in the event of any complication. It is expected that when the crystalline form disclosed herein is used in accordance with the present invention, there is no unacceptable toxicological effect.

An effective amount of the crystalline form disclosed herein includes an amount sufficient to produce a measurable biological response. In order to administer to a particular individual and/or application an amount of the active crystalline form effective to achieve the desired therapeutic response, the actual dosage of the active ingredient of the therapeutic crystalline form of the invention may vary. Preferably, the minimum dose is administered and the dose is increased in the absence of a dose-limiting toxicity to the least effective amount. The determination and adjustment of therapeutically effective amounts, as well as the assessment of when and how to make such adjustments, are well known to those of ordinary skill in the art.

Further to the method of the invention, the preferred individual is a vertebrate individual. Preferred vertebrate animals are warm-blooded; a preferred warm-blooded vertebrate is a mammal. The subject to be treated by the methods disclosed herein is preferably a human, but it will be understood that the principles of the present invention are indicative of effectiveness for all vertebrate species and are included in the term "individual." In this regard, a vertebrate is understood to be any vertebrate species that is intended to be a treatment for a neurodegenerative disorder. The term "individual" as used herein includes both human and animal individuals. Thus, in accordance with the present invention, veterinary therapeutic uses are also provided.

In this way, the therapy provided by the present invention can be directed to mammals such as humans, to mammals of importance due to endangered species, such as Siberian tigers; economically important animals, such as human food animals raised on farms. And animals that are socially important to humans, such as Animals raised as pets or at the zoo or farm. Examples of such animals include, but are not limited to, carnivores, such as cats and dogs; pigs, including domestic pigs, pigs, and wild pigs; ruminants and/or ungulates, such as livestock, bulls, sheep, giraffes, deer, goats, Bison and camel; and horse. Bird therapy is also available, including treatments for birds that are endangered and/or preserved in zoos, as well as poultry, especially domesticated birds, ie poultry such as turkeys, chickens, ducks, geese, guinea fowls, etc. Because they are also of economic importance to humans. Accordingly, therapies for livestock are also provided, including but not limited to domesticated pigs, ruminants, ungulates, horses (including horse racing), poultry, and the like.

The following examples are intended to further illustrate the invention, but should not be construed as limiting the scope thereof.

Instance

Analytical Methods - Various analytical methods, as described hereinafter, are applied to the crystalline forms of the present invention and their precursors, respectively, to characterize their physiochemical properties.

Differential Scanning Thermal Analysis (DSC): DSC data was obtained on a DSC-system (DSC 822e-Mettler Toledo) or on a TA Instruments Q2000. In general, samples having a mass range of 1 to 5 mg are placed in a dry aluminum crucible and closed using an aluminum cap with a hole. In general, the initial temperature was 20 ° C, the heating rate was 10 ° C / min, and the final temperature was 300 ° C, using a 20 mL / min nitrogen purge stream.

Thermogravimetric Analysis (TGA): TGA data was collected on a TGA 851e device. In general, samples with a mass range of about 10 mg are placed in lean and dry alumina or aluminum pans. In general, the sample pan was scanned at a temperature of 5 ° C/min or 10 ° C/min and between -30 ° C and about 350 ° C using a nitrogen purge flow rate of 50 mL/min.

TGA analysis was also performed using a TA instrument to explore the IR thermogravimetric analyzer. Nickel and nickel alloy Alu Mel (Alumel ^TM) calibration temperature. Place the sample in an aluminum pan. The sample was hermetically sealed, the lid was pierced, and then inserted into a thermogravimetric furnace. The furnace is heated by nitrogen. The analytical sample was heated from room temperature to 350 ° C at a heating rate of 10 ° C/min. Trios software v3.1.2.3591 is used to generate the map.

Hydrogen nuclear magnetic resonance ( ¹ H NMR): ¹ H NMR spectra were obtained in a DMSO-d ₆ or CDCl ₃ using tetramethyl decane as an internal standard on a Bruker AVANCE 400 MHz NMR spectrometer.

Hot Stage Optical Microscope (HSM): Olympus BX41 and Di-Li 5MP cameras and grab&measure software for use with the Hostage Mettler Toledo FP90 with FP 82 heating station. The sample is prepared to be placed in a brush shape on the article holder. Observe polarized light using unpolarized light or using two polarized lights at 40, 100, 200 or 400 x magnification. The photo was taken by software and exported as JPEG, the size is only roughly, not verified.

X-ray powder diffraction (XRPD): The XRPD pattern was obtained using MiniFlex (Rigaku Corporation) using a low background sample holder (24 mm in diameter, 0.2 mm in hole). The collection time is usually 75 minutes. A source of 1.5406 angstroms of Cu K alpha radiation was used to illuminate the sample at 15 kV. The effective 2θ range is about 2 to 40 ° C and the sampling width is 0.02 ° C. The samples were ground in a mortar and pestle. The solid was placed in a sample holder with grease and flattened with a glass plate.

High Performance Liquid Chromatography (HPLC) Analysis: The crystalline forms of the invention (i.e., salts and free bases) were analyzed by total area normalization (TAN).

HPLC conditions:

HPLC column: Phenomenex Luna8, 3μm C18, 4.6 x 50mm

Flow rate: 1.0mL/min

Injection volume: 5μL

Detection: DAD detector, recorded at 240nm

Mobile phase: AH ₂ O+0.05% CF ₃ COOH B-CAN+0.05% CF ₃ COOH

Example 1. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia 1,11b diaza-benzo[c] Solubility of indole-6-carboxylic acid (5-methyl-pyridin-2-ylmethyl)-amide (Compound I, free base): The solubility of Compound I is heated at elevated temperatures in different solvates And then cooled to room temperature to suspend compound I to determine. The mother liquor was sampled and the concentration of Compound I was determined by HPLC.

Example 2. Preparation of Polymorph E of Compound I (Free Base): Compound I (free base) was dissolved in a mixture of solvates to form a solution which was then concentrated to a suspension. The suspension was then concentrated to dryness. An anti-solvent is added to the suspension which is concentrated to dry again. XRPD analysis confirmed the formation of polymorph E and showed that polymorph E was crystalline (Fig. 11). The dry content was measured to be 99.97% w/w. ¹ H NMR (Figure 13) confirmed the structure of the material as the free base of the compound.

Example 3. Preparation of Polymorph A of Compound I (Free Base): Polymorph E of Compound I (free base) prepared as in Example 2 was suspended in a solvate mixture. The suspension was heated and then cooled to room temperature. The suspension was filtered and the resulting filter cake was dried to give polymorph A. XRPD analysis confirmed the formation of polymorphs and showed that polymorph A was crystalline (Fig. 1). The dry content was measured to be 99.86% w/w. ¹ H NMR (Figure 5) confirmed the structure of the material as the free base of the compound.

The DSC pattern (Fig. 2) exhibited a sharp endothermic peak at about 215 ° C, followed by an exothermic peak at about 217 ° C, an endothermic peak at about 231 ° C, an exothermic peak at about 233 ° C, and an endothermic peak at about 242 ° C. Without being bound by any theory, these events are consistent with a melting and subsequent recrystallization, another melting and recrystallization, and a final melting event. The TGA map (Figure 3) shows a weight loss of about 0.3% from ambient temperature to 300 °C. Figure 4 shows an overlay of the DSC map and the TGA map.

Example 4. Preparation of Polymorph C of Compound I (Free Base): Polymorph A of Compound I is suspended in an organic solvate at elevated temperature, filtered, cooled to form a suspension, and then It was filtered to obtain a white needle solid. ¹ H NMR (Figure 9) confirmed the structure of the material as the free base of Compound I.

XRPD analysis showed polymorph C to be crystalline as shown in FIG.

Example 5. Preparation of Polymorph G of Compound I (Free Base): Polymorph A of Compound I was suspended in another organic solvate at elevated temperature. The suspension was filtered, and the mother liquid was evaporated to give a suspension which was filtered to give a pale yellow solid. ¹ H NMR (Figure 18) confirmed the structure of the material as the free base of Compound I.

XRPD analysis showed that the polymorph G was a crystalline body as shown in FIG.

Example 6. Solubility and Stability Test of Polymorphic Forms: Solubility of Polymorphs A, C, E, and G of Compound I (Free Base) by Suspending 25 mg of each polymorph in an organic solvent The solution was determined and the resulting mixture was stirred at room temperature or elevated temperature for 1 hour. The sample was filtered and concentrated and determined by HPLC. The remaining suspension was evaporated and the solid was analyzed by XRPD to confirm that the polymorph form in the suspension was the same as the polymorph type used for the experiment.

The solubility of each polymorph is shown in Figure 20. Polymorph A exhibited the lowest solubility and was confirmed to be the most stable.

Example 7. Preparation of the hydrochloride salt of Compound I: Compound I was dissolved in an elevated temperature solvate mixture followed by the addition of hydrochloric acid. The suspension was stirred overnight, then filtered and washed to give the hydrochloride salt of Compound I as a white powder (yield 62%). The characteristics of the obtained salt are shown in ¹ H NMR (Fig. 23), XRPD (Fig. 21), and TGA (Fig. 25). TGA showed that the hydrochloride salt of Compound I exhibited a loss of 0.9 wt% at 140 °C.

Example 8. Preparation of the maleate salt of Compound I: Compound I was dissolved in an elevated temperature solvate mixture and then maleic acid was added to the mixture. The obtained suspension was cooled and stirred, filtered, and washed to give the compound of Compound I as a white powder (yield 86%). The characteristics of the obtained salt are shown in ¹ H NMR (Fig. 28), XRPD (Fig. 26) and TGA (Fig. 30). TGA showed that the maleate salt of Compound I exhibited a loss of 2.9 wt% at 140 °C. Without being bound by any theory, such weight loss may be due to loss of solvate.

Example 9. Preparation of the fumarate salt of Compound I: Compound I was dissolved in an elevated temperature solvate mixture and then fumaric acid was added to the mixture. The obtained suspension was cooled and stirred, filtered, and washed to give the compound of the compound I. as a white powder (yield: 104%). The characteristics of the obtained salt are shown in ¹ H NMR (Fig. 33), XRPD (Fig. 31) and TGA (Fig. 35). TGA showed that the fumarate salt of Compound I exhibited a loss of 6.6 wt% at 140 °C.

Example 10. Preparation of Citrate of Compound I: Compound I was dissolved in a mixture of elevated temperature solvates and then citric acid was added to the mixture. The obtained suspension was cooled and stirred, filtered, and washed to give the succinate salt of Compound I as white powder (yield: 93%). The characteristics of the obtained salt are shown in ¹ H NMR (Fig. 38), XRPD (Fig. 36) and TGA (Fig. 40). TGA showed that the citrate salt of Compound I exhibited a loss of 5.2 wt% at 140 °C.

Example 11. Preparation of L-malate salt of Compound I: Compound I was dissolved in a solvate mixture at an elevated temperature, and then L-malic acid was added to the mixture. The obtained suspension was cooled and stirred, filtered, and washed to give the succinate salt of Compound I as white powder (yield: 59%). The characteristics of the obtained salt are shown in ¹ H NMR (Fig. 43), XPRD (Fig. 41) and TGA (Fig. 45). TGA showed that the L-malate salt of Compound I exhibited a loss of 4.7 wt% at 140 °C.

Example 12. Solubility and Stability of Acidic Salts of Compound I. The solubility of the hydrochloride, maleate, fumarate, citrate and L-malate salts of Compound I by suspension of about 50 mg of various The salt was determined in 0.25 mL of water (x 2, added in portions). The mixture was stirred at 42 ° C for 3 days, and each solution was subjected to concentration and purity analysis by HPLC. After 3 days of testing, the solubility and purity of various salts are shown in Table 11 below.

*The sample dissolves during the 3-day stability test; NT = not tested

The stability of the acid salt was also tested by storing the salt (solid form) at elevated temperatures of 45 ° C and 80 ° C. The results of the stability test are shown in Table 12 below.

The patents and publications set forth herein are subject to the general skill of the art in the field of the invention. All patents and publications are hereby incorporated to the same extent, as if each individual publication They were specifically and individually pointed out to be cited. . In the event of any conflict between the cited references and this specification, the present specification controls. In describing particular embodiments of the invention, the specific terminology is employed in the context of clarity. However, the invention is not intended to be limited to the specific terms selected. Nothing in this specification should be construed as limiting the scope of the invention. All examples presented are representative and not limiting. The above-described embodiments may be modified or changed without departing from the invention, as understood by those skilled in the art. Therefore, it is to be understood that the invention may be practiced otherwise than as specifically described herein.

Claims (88)

A compound I: A crystalline form thereof or a pharmaceutically acceptable salt, ester and/or solvate thereof. The crystalline form of claim 1 is the crystalline form of Compound I. As in the crystalline form of claim 2, the X-ray powder diffraction pattern (XRDP) is shown to have peaks at about 7.30 ± 0.3, 22.050 ± 0.3, and 24.550 ± 0.3 degrees at 2θ. The crystalline form of claim 3, wherein the X-ray powder diffraction pattern further comprises peaks at about 2.41 ± 0.3 and 27.700 ± 0.3 degrees at 2θ. The crystalline form of claim 2 or 3, wherein the X-ray powder diffraction pattern further comprises a peak at 2θ of about 17.950 ± 0.3 and 25.400 ± 0.3 degrees. The crystalline form of any one of claims 2-5, wherein the X-ray powder diffraction pattern further comprises one or more peaks selected from the group consisting of: peaks at 2θ about 11.230 ± 0.3, 11.630 ± 0.3, 16.900 ± 0.3 , 18.580 ± 0.3, 23.300 ± 0.3 and 26.700 ± 0.3 degrees. The crystalline form of claim 2, which exhibits an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of: peaks at 2θ of about 7.730 ± 0.3, 9.410 ± 0.3, 11.230 ±0.3, 11.630±0.3, 16.900±0.3, 17.950±0.3, 18.580±0.3, 22.050±0.3, 23.300±0.3, 24.550±0.3, 25.400±0.3, 26.700±0.3, and 27.700±0.3 degrees. The crystalline form of any one of claims 2 to 7 which exhibits a differential scanning calorimetry (DSC) pattern having peak characteristic values at about 215.41 ± 2.0 °C. The crystalline form of any one of claims 2-8, which is polymorph A, exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 1. The crystalline form of any one of claims 3-9, having a purity of about 95% or greater. The crystalline form of claim 10 shows a purity of about 97% or higher. The crystalline form of claim 11 shows a purity of about 99% or 99.5% or higher. As in the crystalline form of claim 2, the X-ray powder diffraction pattern is shown to have a peak at about 2.720 ± 0.3 degrees from 2θ. As in the crystalline form of claim 2 or 13, the DSC pattern shown has peak characteristic values at about 246.47 ± 2.0 °C. The crystalline form of claim 13 or 14 is polymorph C, which exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 7. The crystalline form of any one of claims 13-15 having a purity of about 95% or greater. The crystalline form of claim 16 shows a purity of about 97% or higher. The crystalline form of claim 17 shows a purity of about 99% or 99.5% or higher. As in the crystalline form of claim 2, the X-ray powder diffraction pattern is shown to have a peak at about 2.380 ± 0.2 degrees from 2θ. The crystalline form of claim 19, wherein the X-ray powder diffraction pattern further comprises peaks at 2θ of about 12.200 ± 0.2, 12.600 ± 0.3, 25.360 ± 0.3, and 27.560 ± 0.3 degrees. The crystalline form of claim 2, 19 or 20, which exhibits an X-ray powder diffraction pattern comprising two or more peaks selected from the group consisting of: peak at about 2.78 ± 0.2, 12.200 at 2θ. ±0.2, 12.600±0.3, 25.360±0.3, and 27.560±0.3. The crystalline form of claim 2 or 19-21, which exhibits a DSC spectrum having peak characteristic values at about 231.99 ± 2.0 °C. The crystalline form of any one of claims 19-22, which is polymorph E, exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 11. The crystalline form of any one of claims 19-23, having a purity of about 95% or greater. As in the crystalline form of claim 24, a purity of about 97% or greater is shown. The crystalline form of claim 25 shows a purity of about 99% or 99.5% or higher. As in the crystalline form of claim 2, the X-ray powder diffraction pattern is shown to have a peak at about 2.00 ± 0.3 and 6.000 ± 0.4 degrees at 2θ. As in the crystalline form of claim 2 or 27, the DSC pattern shown has a peak characteristic value at about 222.11 ± 2.0 °C. The crystalline form of claim 27 or 28, which is polymorph G, exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 16. The crystalline form of any one of claims 27-29 having a purity of about 95% or greater. As in the crystalline form of claim 30, a purity of about 97% or higher is shown. The crystalline form of claim 32 exhibits a purity of about 99% or 99.5% or greater. The crystalline form of claim 1, wherein the salt is selected from the group consisting of hydrochloride, maleate, fumarate, citrate, malate, acetate, sulfate , Phosphate, L-(+)-tartrate, D-glucuronate, benzoate, succinate, ethane sulfonate, methanesulfonate, p-toluenesulfonate, propylene Acid salt, besylate and 1-hydroxy-2-naphthoate. The crystalline form of claim 1 or 19, wherein the salt is selected from the group consisting of hydrochloride, maleate, fumarate, citrate, and L-malate. The crystalline form of claim 34 is the crystalline form of the hydrochloride salt of Compound I. As shown in the crystalline form of claim 35, the X-ray powder diffraction pattern (XRDP) is shown to have a peak at about 2.760 ± 0.3 and 24.540 ± 0.3 at 2θ. As in the crystalline form of claim 36, the X-ray powder diffraction pattern shown further comprises one or more peaks at about 19.60 ± 0.4, 20.160 ± 0.4, 24.920 ± 0.3, and 26.360 ± 0.35 degrees at 2θ. The crystalline form of X-ray powder as indicated in claim 35 or 36 further comprises one or more peaks at about 13.30 ± 0.4, 14.540 ± 0.3, 25.380 ± 0.3, and 28.940 ± 0.3 degrees at 2θ. The crystalline form of any one of claims 35-38, which exhibits a DSC pattern having peak characteristic values at about 266.27 ± 2.0 °C. The crystalline form of any of claims 35-39, which exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 21. The crystalline form of claim 34, which is the crystalline form of the maleate salt of Compound I. As in the crystalline form of claim 41, the X-ray powder diffraction pattern (XRDP) is shown to have peaks at about 2.400 ± 0.3, 18.440 ± 0.5, and 26.500 ± 0.4 degrees at 2θ. As in the crystalline form of claim 42, the X-ray powder diffraction pattern is further comprised of one or more peaks at 22.320 ± 0.4, 23.920 ± 0.3, 24.300 ± 0.4, and 25.240 ± 0.7 degrees. The crystalline form of X-ray powder as indicated in claim 41 or 42 further comprises one or more peaks at about 5.040 ± 0.3, 15.080 ± 0.3, 15.880 ± 0.4, 20.860 ± 0.4, and 28.540 ± 0.3 degrees at 2θ. . The crystalline form of any of claims 41-44, which exhibits a DSC pattern having peak characteristic values at about 217.32 ± 2.0 °C. The crystalline form of any of claims 41-45, which exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 26. The crystalline form of claim 34 is a crystalline form of the fumarate salt of Compound I. As shown in the crystalline form of claim 47, the X-ray powder diffraction pattern (XRDP) is shown to have a peak at about 2.360 ± 0.3 and 24.800 ± 0.3 degrees at 2θ. As in the crystalline form of claim 48, the X-ray powder diffraction pattern is further comprised of one or more peaks at about 19.60 ± 0.3, 20.420 ± 0.3, and 26.860 ± 0.3 degrees at 2θ. The crystalline form of X-ray powder as indicated in claim 47 or 48 further comprises one or more peaks at about 22.70 ± 0.3, 17.020 ± 0.2, 25.180 ± 0.2, and 28.280 ± 0.3 degrees. The crystalline form of any one of claims 47-50, which exhibits a DSC pattern having peak characteristic values at about 222.40 ± 2.0 °C. The crystalline form of any of claims 47-51, which exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 31. The crystalline form of claim 34 is the crystalline form of the citrate salt of Compound I. As shown in the crystalline form of claim 53, the X-ray powder diffraction pattern (XRDP) is shown to have peaks at about 2.900 ± 0.3, 25.380 ± 0.3, and 27.500 ± 0.4 degrees at 2θ. As in the crystalline form of claim 54, the X-ray powder diffraction pattern is further comprised of one or more peaks at about 22.360 ± 0.3, 18.100 ± 0.3, 19.300 ± 0.3, and 26.140 ± 0.4 degrees. The crystalline form of the X-ray powder as claimed in claim 53 or 54 further comprises one or more peaks at about 17.4 ± 0.3, 18.680 ± 0.4, 24.040 ± 0.4, and 26.740 ± 0.3 degrees. The crystalline form of any of claims 53-56, which exhibits a DSC pattern having peak characteristic values at about 196.86 ± 2.0 °C. The crystalline form of any of claims 53-57, which exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 36. The crystalline form of claim 34 which is the crystalline form of the L-malate salt of Compound I. As shown in the crystalline form of claim 59, the X-ray powder diffraction pattern (XRDP) is shown to have a peak at about 6.580 ± 0.2, 6.780 ± 0.3, and 25.560 ± 0.4 degrees. As in the crystalline form of claim 60, the X-ray powder diffraction pattern is further comprised of one or more peaks at about 19.560 ± 0.4, 23.660 ± 0.4, 26.060 ± 0.7, and 26.960 ± 0.7 degrees at 2θ. The crystalline form of X-ray powder as indicated in claim 59 or 60 further comprises one or more peaks at about 8.800 ± 0.3, 11.800 ± 0.3, 18.600 ± 0.3, 24.460 ± 0.5 and 25.080 ± 0.3 degrees at 2θ. . The crystalline form of any one of claims 59-62, which exhibits a DSC pattern having peak characteristic values at about 209.67 ± 2.0 °C. The crystalline form of any of claims 59-63, which exhibits an X-ray powder diffraction pattern substantially similar to that of Figure 41. A composition comprising the crystalline form of any one of claims 1-64. The composition of claim 65, wherein the composition comprises at least one pharmaceutically acceptable carrier. A method of stabilizing G-quadruplex (G4s) in an individual, the method comprising administering to the individual a therapeutically effective amount of the crystalline form of any one of claims 1-64. A method of modulating p53 activity in an individual, the method comprising administering to the individual a therapeutically effective amount of the crystalline form of any one of claims 1-64. A method of treating or ameliorating a cell proliferative disorder in an individual, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1-64. The method of claim 69, wherein the cell proliferative disorder is cancer. The method of claim 70, wherein the cancer is selected from the group consisting of blood cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, pancreatic cancer, lymph node cancer. Colon cancer, prostate cancer, brain cancer, head and neck cancer, skin cancer, kidney cancer and cardiac tumors. The method of claim 71, wherein the blood cancer line is selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma. The method of claim 70, wherein the cancer is a homologous recombination (HR) DNA double strand break (DSB) repair defective cancer, or a non-homologous end joining (NHEJ) DNA double strand break repair defective cancer. The method of claim 70, wherein the cancer is contained in the following defective cancer cells: breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2), and/or other members of the homologous recombination pathway . The method of claim 74, wherein the cancer cell is defective in BRCA1 and/or BRCA2. The method of claim 75, wherein the cancer cell means a genotype having a BRCA1 and/or BRCA2 mutation is a homozygote. The method of claim 75, wherein the cancer cell means a genotype having a BRCA1 and/or BRCA2 mutation is a heterozygote. The method of any one of claims 69-74, wherein the method further comprises co-administering one or more additional therapeutic agents and/or radiation therapy. The method of claim 78, wherein the one or more additional therapeutic agents are anticancer agents or immunotherapeutic agents. A method for reducing or inhibiting cell proliferation, the method comprising contacting a cell with a therapeutically effective amount of the crystalline form of any one of claims 1-64. The method of claim 80, wherein the cell is a cancer in a cancer cell strain or in a body. The method of claim 81, wherein the cancer cell is selected from the group consisting of blood cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, Head and neck cancer, skin cancer, ovarian cancer, cervical cancer, Ewing's sarcoma, kidney cancer and cardiac tumors. The method of claim 82, wherein the blood cancer line is selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma. The method of claim 81, wherein the cancer cell carries a defect in homologous recombination (HR) DNA double strand break (DSB) repair or non-homologous end joining (NHEJ) DNA double strand break repair. The method of claim 81, wherein the cancer is comprised of the following defective cancer cells: breast cancer susceptibility gene 1 (BRCA1), breast cancer susceptibility gene 2 (BRCA2), and/or other members of the homologous recombination pathway . The method of claim 85, wherein the cancer cell is defective in BRCA1 and/or BRCA2. The method of claim 86, wherein the cancer cell means a genotype having a BRCA1 and/or BRCA2 mutation is a homozygote. The method of claim 86, wherein the cancer cell means a genotype having a BRCA1 and/or BRCA2 mutation is a heterozygote.