CA2929837A1 - Polymorph forms of pyrrolidine-2,5-dione derivatives and pharmaceutical compositions thereof - Google Patents

Abstract

Two distinct crystalline forms of a 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione are provided. The compound 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione is an inhibitor. The crystalline forms may be used in the preparation of pharmaceutical compositions.

Description

POLYMORPH FORMS OF PYRROLIDINE-2,5-DIONE DERIVATIVES AND
PHARMACEUTICAL COMPOSITIONS THEREOF
FIELD OF INVENTION
The present invention relates to crystalline forms of pyrrolidine-2,5-dione derivatives.
BACKGROUND OF INVENTION
Indoleamine 2,3-dioxygenase 1 (IDOI) is an intracellular monomeric, heme-containing enzyme that catalyzes the first and rate limiting step of L-tryptophan (Trp) catabolism along the kynurenine pathway, leading to the production of N-formylkynurenine.
95% of Trp is metabolized through this kynurenine pathway. The kynurenine pathway (KYN) initiates the production of neuroactive and immunoregulatory metabolites, collectively known as kynurenines and provides precursors that supplement dietary niacin for the biosynthesis of NAD+ and NADP+.
By locally depleting tryptophan and increasing kynurenines, ID01 expressed by antigen presenting cells (APCs) such as dendritic cells (plasmacystoid DCs in tumor draining lymph nodes) can greatly affect T-cell proliferation and survival and activate regulatory T cells thereby reducing proinflammatory responses. IDO1 can thus provide "immune privilege" to tissues subject to chronic inflammations such as infectious and allergic diseases, transplantation and cancer. Because such tolerogenic responses can be expected to operate in a variety of physiopathological conditions, tryptophan metabolism and kynurenine production through IDO1 might represent a crucial interface between the immune and nervous system. Expression of IDO1 is upregulated by proinflammatory cytokines and can be detected in a variety of tissues, including placenta, spleen, thymus, lung, digestive tract, and central nervous system (reviewed in Munn et al. Trends lmmunol, 2013, 34, 137-43).
IDO1 has emerged as a promising molecular target of new therapeutic agents for treating cancer as well as other diseases characterized by the reduction of local Trp levels and/or to imbalances in the level of cytotoxic metabolites produced by the kynurenine pathway (reviewed in Munn et at. Trends Immunol, 2013, 34, 137-43).

2 Indeed, inhibition of IDO1 activity as a therapeutic strategy has been tested in preclinical models of many diseases, with the most widely used IDO1 inhibitor, the tryptophan analogue L-1-methyltryptophan (L-1MT). Treatment with L-1MT, alone or in combination with other agents, attenuated disease severity in animal models of arthritis, ischemia-reperfusion injury, endotoxin shock, human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, airway inflammation, and cancer (Uyttenhove et at., Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210, 7, 1389-1402), among others. For cancer, IDO1 induction has been observed in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process (Uyttenhove et at., Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210, 7, 1389-1402). Cervical carcinoma cells (or HeLa cells) co-cultured with peripheral blood lymphocytes (PBLs) acquire an immuno-inhibitory phenotype through up-regulation of ID01 activity. A
reduction in PBL
proliferation upon treatment with interleukin-2 (IL2) was believed to result from IDO1 released by the tumor cells in response to gamma interferon (IFN)-g (y) secretion by the PBLs. IDO1 activity in tumor cells may thus serve to impair anti-tumor responses, a process in which IFNy plays a central role. Further evidence for a tumoral immune resistance mechanism based on tryptophan degradation by 001 comes from the observation that most human tumors constitutively express ID01, and that expression of IDO1 by immunogenic mouse tumor cells prevents their rejection (reviewed in Munn et at., Front Biosci, 2012, 4, 734-45; Godin-Ethier et al. Clin Cancer Res 2011, 17, 6985-6991; Johnson et al. Immunol Invest 2012, 41, 6-7, 765-797). This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of ID01, in the absence of noticeable toxicity (Holmgaard et at., J Exp Med, 2013, 210, 7, 1389-1402).
IDO1 expression has been demonstrated by immunohistochemistry in a wide spectrum of cancer patients. ID01 mRNA, protein or modification of the ratio of tryptophan and kynurenine in the blood have been detected in patients with malignant melanoma, acute myelogenous leukemia, pancreatic, colorectal, prostate, cervical, brain, endometrial and ovarian cancers amongst others. In several malignancies, the presence of ID01 is an independent predictor of a worse clinical outcome (reviewed in Munn et at., Front Biosci, 2012, 4, 734-45)

3 Although the potential of the ID01 inhibitors as pharmaceutical agents has generated a significant interest, the initial inhibitors were identified by modification of Trp but not the discovery of molecules bearing novel structural skeleton. In the early 2000's, the best IDO1 inhibitors were mainly comprised of competitive Tip derivatives (like L-1-MT) and noncompetitive carbolines, which displayed affinities in the micromolar range.
Since 2006, some potent nanomolar ID01 inhibitors with novel structural skeleton have been discovered by high throughput screening, computational screening or natural product isolation and optimization of the core pharmacophores in the structures. Many of these ID01 inhibitors possess low micromolar activities or limited pharmacokinetics.
Two ID01 inhibitors are currently being tested in phase I/II clinical trials for the treatment of relapsed or refractory solid tumors (reviewed in Dolu id et al., Expert Opin Ther Pat.
2013, 23, 1367-81).
In parallel, the importance of awakening and solidifying tumor immune surveillance is now widely accepted as an important aspect of anti-cancer therapy (Motz et al., Immunity, 2013, 39, 1, 61-73). lmmunoscoring of infiltrating T cell subsets is under development as biomarker approach and will allow determining the patients' responsiveness to treatment (Galon et al., J Trans! Med, 2012, 10, 1). Hence, it is still of major interest to find new potent IDO1 inhibitors.
Therefore, there is a need for new ID01 inhibitors, including crystalline forms thereof.

4 SUMMARY OF THE INVENTION
The compound 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione is an ID01 inhibitor, as disclosed in US 2015-0329525 Al.
In one aspect of the present invention, a crystalline form of 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione (Form 1) is provided, which has an X-ray powder diffraction pattern which comprises characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, about 15.0 degrees two-theta, about 16.4 degrees two-theta, and about 24.4 degrees two-theta. In another embodiment, crystalline Form 1 has an X-ray powder diffraction pattern which comprises characteristic peaks at one or more of 6.7 0.2 degrees two-theta, 14.2 0.2 degrees two-theta, 15.0 0.2 degrees two-theta, 16.4 0.2, degrees two-theta, and 24.4 0.2 degrees two-theta. In a further embodiment, the crystalline Form 1 has two, three, four or more of these characteristic peaks.
In another aspect, a crystalline form of 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione (Form 1) is provided, which has a solid state (SS) nuclear magnetic resonance (NMR) of one or more 13C chemical shifts at about 39.2, about 124.7, and about 127.5 parts per million (ppm). In one embodiment, crystalline Form 1 has the SS NMR of one or more 130 chemical shifts at about 39.2 0.2 ppm, 124.7 0.2 ppm, or 127.5 .
0.2 ppm.
In yet another aspect, a crystalline form of 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione (Form 1) is provided which has the SS NMR spectra of 19F chemical shift at about -122.8 parts per million. In one embodiment, the 19F chemical shift is at -122.8 0.2 ppm.
In still another aspect, crystalline Form 1 has an X-ray powder diffraction pattern which comprises characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, and about 24.4 degrees two-theta, and a SS NMR of one or more 130 chemical shifts at about 39.2 ppm, about 124.7 ppm, and about 127.5 ppm.
In still a further aspect, crystalline Form 1 has an X-ray powder diffraction pattern which comprises characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, and about 24.4 degrees two-theta, and a SS NMR of 19F
chemical shift at about -122.8 ppm.
In one embodiment, the crystalline Form 1 comprises characteristic peaks as expressed in FIG. 1A and/or FIG 1B. In another embodiment, the crystalline Form 1 lacks peaks

5 at about 9.5 degrees two-theta and/or about 12.3 degrees two-theta. In still another embodiment, 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione Form 1 has a melting point above 195 C, or above 196 C, i.e., 197 C.
In another aspect, a crystalline form of 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione (Form 2) is provided, which has an X-ray powder diffraction pattern which comprises characteristic peaks at about 9.5 degrees two-theta, about 12.3 degrees two-theta, about 13.5 degrees two-theta, and about 14.3 degrees two-theta. In one embodiment, these characteristic peaks are as expressed in FIG. 2. In another embodiment, the compound lacks a peak at about 6.7 degrees two-theta. In still another embodiment, 3-(5-fluoro-1H-indo1-3-Apyrrolididine-2,5-dione Form 2 has a melting point above 195 C, i.e., 19600 Other aspects and advantages of the invention will be apparent from the following detailed description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG 1A is an X-ray powder diffraction spectrum of 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione Form 1 performed as described in the initial powder x-ray diffraction (PXRD) analysis technique in Example 1.
FIG 1B is an X-ray powder diffraction spectrum of 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione Form 1 performed as described in the alternative PXRD analysis technique in Example 1.
FIG. 2 is an X-ray powder diffraction spectrum of 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione Form 2.
FIG. 3 is a 130 solid state NMR spectrum of Form I prepared as described In Example 1, Part C. The peaks marked by hashed marks are spinning sidebands.

,

6 FIG. 4 is 19F solid state NMR spectrum of Form I prepared as described In Example 1, Part C. The peaks marked by hashed marks are spinning sidebands.
DETAILED DESCRIPTION OF THE INVENTION
Compounds Crystalline polymorphic Form 1 and a crystalline polymorphic Form 2 of 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione are provided herein. Also provided is a composition containing Form 1, Form 2, or combinations thereof, in a pharmaceutically acceptable carrier or excipient. Such new polymorphic forms have properties which may be advantageous in pharmacokinetics, ease of manufacturing (formulation), and dosage form stability which improve storage and/or ease of packaging.
By the term "characteristic peak" is meant that the presence of the powder x-ray diffraction peak definitively identifies the 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione as the referenced crystalline form (Form 1 or Form 2). Typically, the powder X-ray diffraction analysis is conducted using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source, or other suitable equipment.
In one embodiment, Polymorph Form 1 of 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione is characterized by: an X-ray powder diffraction pattern which comprises characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, about 15.0 degrees two-theta, about 16.4 degrees two-theta, or about 24.4 degrees two-theta. In one embodiment, Form 1 contains two or more, three or more, four or more, or all five of these characteristic peaks. For example, Form I may contain a combination of X-ray powder diffraction pattern characteristic peaks at about 6.7 and about 14.2, about 14.2 and about 15.0, about 15.0 and about 16.4, about 6.7 and about 15.0, about 6.7 and about 14.2, or about 14.2 and about 16.4. In another example, there may be three characteristic peaks at about 6.7 degrees two-theta, about 14.2 degrees two-theta, and about 24.4 degrees two-theta, which may be in further combination with a fourth peak. Optionally, all five peaks may be present.

7 For example, Polymorph Form 1 of 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione is characterized by: an X-ray powder diffraction pattern which comprises characteristic peaks at one or more of 6.7 0.2 degrees two-theta, 14.2 0.2 degrees two-theta, 15.0 0.2 degrees two-theta, 16.4 0.2 degrees two-theta, or 24.4 0.2 degrees two-theta. In one embodiment, Form 1 contains two or more, three or more, four or more, or all five of these peaks. For example, Form I may contain a combination of X-ray powder diffraction pattern characteristic peaks at 6.7 0.2 and 14.2 0.2 degrees two-theta, 14.2 0.2 and 15.0 0.2 degrees two-theta, 15.0 0.2 and 16.4 0.2, 6.7 0.2 and 15.0 0.2, 6.7 0.2 and 14.2 0.2, or 14.2 0.2 and 16.4 0.2 degrees two-theta. In another example, there may be three characteristic peaks at 6.7 0.2 degrees two-theta, 14.2 0.2 degrees two-theta, and 24.4 0.2 degrees two-theta, which may be in further combination with a fourth peak. Optionally, all five peaks may be present.
In still another embodiment, Form I is characterized by a solid state (SS) nuclear magnetic resonance (NMR) of one or more 13C chemical shifts at about 39.2 parts per million (ppm), about 124.7 ppm, or about 127.5 ppm. Form I may be characterized by two or more of these chemical shifts, or all three of these chemical shifts.
In another embodiment, Form I is characterized by a SS NMR of one or more 13C chemical shifts at 39.2 0.2 ppm, 124.7 0.2 ppm, or 127.5 0.2 ppm. Form I may be characterized by two or more of these chemical shifts, or all three of these chemical shifts.
In still a further embodiment, Form I is characterized by a SS NMR spectra of chemical shift at about -122.8 ppm. In still a further embodiment, Form I is characterized by a SS NMR spectra of 19F chemical shift at -122.8 0.2 ppm.
In yet a further embodiment, Form I may be characterized by combinations of one or more of these powder X-ray powder diffraction characteristic peaks, with one or more of the SS NMR chemical shift peaks for 13C. Form I may be characterized by two or more or three or more of the powder X-ray diffraction peaks are present. Form I may be characterized by two or more or three or more of the SS NMR chemical shift peaks are present. In one embodiment, Form I is characterized by combinations of one or more of the X-ray powder diffraction pattern characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, or about 24.4 degrees two-theta,

8 optionally in further combination with the SS NMR chemical shift peaks for 13C
provided herein.
In another embodiment, Form 1 is characterized by combinations of one or more of these characteristic X-ray powder diffraction, with the SS NMR chemical shift peak for 19F. Form I may be characterized by two or more or three or more of the powder X-ray diffraction peaks are present. In one embodiment, Form 1 is characterized by combinations of one or more of the X-ray powder diffraction pattern characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, or about 24.4 degrees two-theta, optionally in further combination with the SS NMR
chemical shift peak for 19F provided herein. In a further embodiment, Form 1 is characterized by combinations of one or more of the SS NMR chemical shift peaks for 13C and the SS
NMR chemical shift peak for 19F. Form I may be characterized by two or more or three or more of the powder X-ray diffraction peaks are present. In one embodiment of this combination, Form 1 is characterized by combinations of one or more of the X-ray powder diffraction pattern characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, or about 24.4 degrees two-theta, optionally in further combination with the one or more of the SS NMR chemical shift peaks for 130 and/or the SS NMR chemical shift peak for 19F.
In one embodiment, Form I is characterized by combinations of one or more of the X-ray powder diffraction pattern characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, or about 24.4 degrees two-theta, or combinations thereof. In a further embodiment, Form 1 is characterized by having, at a minimum, these three peaks.
In one embodiment, the compound is free of Form 2, i.e., lacks the peaks characteristic of Form 2, including, about 9.5 degrees two-theta, about 12.3 degrees two-theta, about 13.5 degrees two-theta, and about 14.3 degrees two-theta.
In one embodiment, the 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione Form 1 has a melting point above 195 C (i.e., above 195.000 to 195.9 C). In another embodiment, the 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione Form 1 has a melting point in range of about 197 C, e.g., 196.6 C to 197.99 C, or 197 C. In one embodiment,

9 Polymorph Form 1 is anhydrous, i.e., free of water, and non-hygroscopic. In another embodiment, Form I is substantially free of water and other solvents.
In one embodiment, crystalline Form 1 as prepared herein is at least 90% pure, at least 95% pure, at least 97% pure, at least 99% pure, about 99.5% pure, or about 99.7%
pure. By "pure" means free from contaminants including, e.g., solvents, other crystalline forms and/or amorphous forms. In another embodiment, a crystalline form of 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione is provided which is characterized by: an X-ray powder diffraction pattern which comprises characteristic peaks at two or more of about 9.5 degrees two-theta, about 12.3 degrees two-theta, about 13.5 degrees two-theta, and about 14.3 degrees two-theta (Form 2). In one embodiment, Form 2 is characterized by peaks at about 9.5 degrees two-theta and about 12.3 degrees two-theta, about 9.5 degrees two-theta and about 13.5 degrees two-theta, about 9.5 degrees two-theta and about 14.3 degrees two-theta, about 12.3 degrees two-theta and about 14.3 degrees two-theta, about 12.3 degrees two-theta and about 13.5 degrees two-theta, and/or about 13.5 degrees two-theta and about 14.3 degrees two-theta.
Form 2 may also contain three or more, or all four of these characteristic peaks.
Suitably, the compound lacks the peaks characteristic of Form 1, including about 6.7 degrees two-theta, about 14.2 degrees two-theta, about 15.0 degrees two-theta, about 16.4 degrees two-theta, and/or about 24.4 degrees two-theta. In a further embodiment, the powder X-ray diffraction characteristic peaks for Form 2 are at two or more of 9.5 0.2 degrees two-theta, 12.3 0.2 degrees two-theta, 13.5 0.2 degrees two-theta, and 14.3 0.2 degrees two-theta.
The 3-(5-fluoro-1H-indo1-3-yl)pyrrolididine-2,5-dione Form 2 has a melting point above 195 C (e.g., 196 or higher C), or approximately 196 C. In one embodiment, Polymorph Form 2 is anhydrous, i.e., free of water, and non-hygroscopic. In another embodiment, Form 2 is substantially free of water and other solvents.
Crystalline Form 1 and/or crystalline Form 2 may be used in pharmaceutical compositions as described herein. Reference in the discussion of these compositions and uses may refer to "compounds".
As used herein, the term "a 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione"
refers to the racemic compound having the structure:

' NH

F, N\
H
II .
As used herein, the term "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. In general, reference throughout this specification will 5 be to a polymorph of the racemic 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione compound. As described herein, a racemic compound of Formula II may contain about 50% of the R-enantiomer and about 50% of the S-enantiomer based on a molar ratio (about 48 to about 52 mol %, or about a 1:1 ratio)) of the two isomers/enantiomers.
The compounds described herein in the examples were named using ChemBioDraw

10 Ultra version 12.0 (PerkinElmer).
Process for manufacturing The compounds of the invention can be prepared by different ways with reactions known to a person skilled in the art. Illustrative schemes for preparing 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione are provided in US Provisional Patent Application No.
61/996,976, filed March 15, 2014, entitled "Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as IDO inhibitors", now incorporated by reference and its counterpart PCT and US applications, filed on the same date with the present application.
According to one embodiment, the optional separation of the enantiomers starting from the corresponding racemic compound can be achieved by chiral HPLC, such as but not limited to using a Chiralpak AS-H, Chiralcel OJ-H or Chiralpak IC column, using as eluents mixtures of appropriate solvents such as but not limited to supercritical CO2, ethanol, methanol, hexane.

11 Reaction schemes as described in the example section are illustrative only and should not be construed as limiting the invention in any way.
Uses The invention also provides pharmaceutical compositions comprising a compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to a recipient thereof in an amount used in the composition.
By means of non-limiting examples, the compounds of the invention may be formulated as a pharmaceutical preparation in a form suitable for potential oral administration, for potential parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for potential topical administration (including ocular), for potential administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such formulations ¨ which may be solid, semi-solid or liquid, depending on the manner of potential administration ¨ as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
Some non-limiting examples of such potential preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for potential administration as a bolus and/or for potential continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations may optionally contain other ,

12 substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrates, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
The polymorph compounds of the present invention may be used as IDO1 inhibitors.
In another aspect, the invention relates to the use of these compounds for the synthesis of 001 inhibitors.
DEFINITIONS
In the present invention, the following terms have the following meanings:
The term "subject" refers to a mammal. In one embodiment, a subject may be a warm-blooded animal, and may be a human.
The term "administration", or a variant thereof (e.g. "administering"), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to a subject.
By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is potentially administered.
The term "inhibitor" refers to a natural or synthetic compound that has a biological effect to inhibit or reduce or down-regulate the expression of a gene and/or a protein or that has a biological effect to inhibit or reduce the biological activity of a protein.
Consequently, an "IDO1 inhibitor" refers to a compound that has a biological effect to inhibit or reduce or down-regulate the expression of the gene encoding for I
DO1 and/or the expression of I DO1 and/or the biological activity of ID01.
"Stereoisomer" refers to both enantiomers.

13 The words "comprise", "comprises", and "comprising" are to be interpreted inclusively rather than exclusively. The works "consist", "consisting", and its variants, are to be interpreted exclusively, rather than inclusively.
As used herein, the term "about" means a variability of ( ) 10 A. from the reference given, unless otherwise specified.
EXAMPLES
The present invention will be better understood with reference to the following examples. These examples are intended to representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.
I. CHEMISTRY EXAMPLES
The MS data provided in the examples described below were obtained as followed:
Mass spectrum: LC/MS Agilent 6110 (ESI) or a Waters Acquity SQD (ESI).
The NMR data provided in the examples described below were obtained as followed:
Bruker Ultrashield TM 400 PLUS and Bruker Fourier 300 MHz and TMS was used as an internal standard.
The microwave chemistry was performed on a single mode microwave reactor Initiator Microwave System EU from Biotage.
Preparative HPLC purifications were performed with a mass directed autopurification Fractionlynx from Waters equipped with a XbridgeTM Prep C18 OBD column 19x150 mm 5 pm, unless otherwise reported. All HPLC purifications were performed with a gradient of CH3CN/H20/NH4HCO3 (5 mM), CH3CN /H2OTTFA (0.1%), or CH3CN
/H20/NH3 H20 (0.1%).

14 Compound 1: 3-(5-fluoro-1H-indo1-3-yl)pyrrolidine-2,5-dione NH

F, N\
H
A. Route A
A mixture of 5-fluoro-1H-indole (300 mg; 2.22 mmol), maleimide (646 mg; 6.65 mmol) in AcOH (2 mL) was stirred at 170 C for 2 h in a microwave reaction. The reaction mixture was concentrated in vacuo. The residue was neutralized with saturated aqueous NaHCO3 solution to pH 7-8 and extracted with Et0Ac (10 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to afford 180 mg (35%) of the title compound as a yellow solid. LC-MS for C12H9FN202-1-1- EM-H]: calcd. 231.1; found: 231Ø 1H NMR
(300 MHz, DMSO-d6) 6 [ppm]: 11.30 (brs, 1H), 11.14 (s, 1H), 7.41(d, J= 2.5 Hz, 1H), 7.36 (dd, J=
9.0, 4.6 Hz, 1H), 7.20 (dd, J = 10.1, 2.5 Hz, 1H), 6.94 (ddd, J = 9.2, 9.0, 2.5 Hz, 1H), 4.33 (dd, J = 9.5, 5.5 Hz, 1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.79 (dd, J =
18.0, 5.5 Hz, 1H).
Route B:
Alternatively, a mixture of 5-Fluoroindole (5.00 g, 5.00 g, 35.5 mmol, 96 mass%, 1.00) and Maleimide (1.5 equiv., 5.17 g, 53.3 mmol, 1.50) was charged in a 50 mL
vessel, and then Acetonitrile (3 L/kg, 15.0 mL, 11.7 g, 286 mmol, 100 mass%) and Zinc Chloride (1.05 equiv., 5.08 g, 37.3 mmol, 100 mass%) were added. The reaction was heated to 85 C over 10 min and then maintained at 85 C for 24 hrs. While still at 85 C, Water (6 L/kg, 30.0 mL, 30.0 g, 1670 mmol, 100 mass%) was added slowly, while maintaining the temperature above 80 C. Yellow solids precipitated. The reaction mixture was cooled to 50 C over 1 hour followed by stirring at 50 C for 2 hours, then cooled 10 C over 1 hour. The reaction was stirred at 10 C for 1 hour. The solids were filtered off, then the filter cake was washed 2 times with 5 ml 1:1 ACN/water to afford isolated compound (6.85 g, 6.85 g, 29.5 mmol, 83.1% Yield).

For purification, the resulting isolated compound was charged (6.85 g, 6.85 g, 29.5 mmol, 100 mass%) into a vessel, followed by addition of Tetrahydrofuran (6 L/kg, 41.1 mL, 36.4 g, 505 mmol, 100 mass%). This mixture was heated to 66 C to form a homogeneous solution. Heptane (4 L/kg, 27.4 mL, 18.7 g, 187 mmol, 100 mass%, was 5 added slowly at 66 C; solids began to precipitate after 5 volumes. The mixture was cooled to 25 C over 3 hours, then filtered and washed with heptane, followed by drying in the high vacuum oven overnight. Isolated compound (4.93 g, 4.93 g, 21.2 mmol, 100 mass%, 72.0% Yield). This isolated compound is Form 2 shown in FIG. 2.
This isolated compound is charged 2 (1.00 g, 4.3 mmol, 100 mass%,) into a 50m1 10 vessel And Tetrahydrofuran (6 L/kg, 6 mL, 100 mass%) and Heptane (6 L/kg, 6 mL, 100 mass%) were added. The slurry was stirred at 25 C for 48 hrs. The solids were filtered off and dried in the high vacuum oven overnight. The Isolated compound : (0.89 g, 0.89 g, 3.83 mmol, 100 mass%, 89.00% Yield). This isolated compound is Form shown in FIG. 1A or FIG. 1 B.
Initial Powder X-Ray Diffraction:
Powder X-ray diffraction analysis of the isolated Form 1 and 2 prepared as in Route B
was conducted using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. The divergence and scattering slits were set at 1 mm, and the receiving slit was set at 0.6 mm. Diffracted radiation was detected by a PSD-Lynx Eye detector. The X-ray tube voltage and amperage were set to 40 kV and 40 mA
respectively. Data was collected in the Theta-2Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.020 degrees and a step time of 0.3 second. Samples were prepared by placing them in a customized holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA Diffrac Plus software.
The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks were selected with a threshold value of 1 and a width value of 0.3 to make preliminary peak assignments. The output of automated assignments was visually checked to ensure validity and adjustments manually made if necessary. Peaks with relative intensity of ?. 2% were summarized in Tables 1 and 2.

A typical error associated with the peak position from PXRD stated in USP and JP is up to +1- 0.2 2-theta. The spectra from the PXRD method of this initial analysis is provided in FIG 1A.
Table 1: Form 1 PXRD Peak List. Characteristic reflections are underlined.
Relative Angle Intensity ( 2-theta) (%) 6.7 11 13.3 3 14.2 34

15.0 92

16.1 4 16.4 14

17.1 7

18.3 22

19.5 15 19.9 24

20.1 7 20.7 24

21.3 4

22.2 7

23.6 20 23.8 26

24.4 100 24.6 83 26.1 5 26.6 2 27.1 22 27.7 98 28.0 18 Relative Angle Intensity ( 2-theta) (%) 28.6 2 29.9 27 32.5 5 32.9 11 33.1 7 35.2 6 35.6 8 36.1 3 37.1 21 39.0 2 39.9 4 In one embodiment, Form 1 is characterized by at least one of the underlined characteristic peaks. In another embodiment, Form 1 is characterized by two or more of the underlined characteristic peaks.
In a further embodiment, Form 1 is characterized by three or more, four or more, or all five of the underlined characteristic peak. Optionally, Form 1 may further, or alternatively, have a powder X-ray diffraction spectra comprising a peak at one or more of: about 13.3 degrees two-theta, about 16.1 degrees two-theta, about 17.1 degrees two-theta, about 18.3 degrees two-theta, about 19.5 degrees two-theta, about 19.9 degrees two-theta, about 20.1 degrees two-theta, about 20.7 degrees two-theta, about 21.3 degrees two-theta, about 22.2 degrees two-theta, about 23.6 degrees two-theta, about 23.8 degrees two-theta, about 24.6 degrees two-theta, about 26.1 degrees two-theta, about 26.6 degrees two-theta, about 27.1 degrees two-theta, about 27.7 degrees two-theta, about 28.0 degrees two-theta, about 28.6 degrees two-theta, about 29.9 degrees two-theta, about 32.5 degrees two-theta, about 32.9 degrees two-theta, about 33.1 degrees two-theta, about 35.2 degrees two-theta, about 35.6 degrees two-theta, about 36.1 degrees two-theta, about 37.1 degrees two-theta, about 39.0 degrees two-theta, or about 39.9 degrees two-theta. In still another option, Form I may further, or alternatively, have a powder X-ray diffraction spectra comprising a peak at one or more of: 13.3 0.2 degrees two-theta, 16.1, 0.2 degrees two-theta, 17.1 0.2 degrees two-theta, 18.3 0.2 degrees two-theta, 19.5 0.2 degrees two-theta, 19.9 0.2 degrees two-theta, 20.1 0.2 degrees two-theta, 20.7 0.2 degrees two-theta, 21.3 0.2 degrees two-theta, 22.2 0.2 degrees two-theta, 23.6 0.2 degrees two-theta, 23.8 0.2 degrees two-theta, 24.6 0.2 degrees two-theta, 26.1 0.2 degrees two-theta, 26.6 0.2 degrees two-theta, 27.1 0.2 degrees two-theta, 27.7 0.2 degrees two-theta, 28.0 0.2 degrees two-theta, 28.6 0.2 degrees two-theta, 29.9 0.2 degrees two-theta, 32.5 0.2 degrees two-theta, 32.9 0.2 degrees two-theta, 33.1 0.2 degrees two-theta, 35.2 0.2 degrees two-theta, 35.6 0.2 degrees two-theta, 36.1 0.2 degrees two-theta, 37.1 0.2 degrees two-theta, 39.0 0.2 degrees two-theta, or 39.9 0.2 degrees two-theta.
Table 2: Form 2 PXRD Peak List. Characteristic reflections are underlined.
Relative Angle Intensity ( 2-theta) (%) 6.6 2 9.5 7 12.3 23 13.5 14 14.3 100 15.0 21 16.8 13 18.3 3 20.4 10 20.9 4 21.6 6 23.0 3 23.2 5 23.9 7 24.3 20 24.7 7 24.9 29 Relative Angle Intensity ( 2-theta) (%)

25.1 7 27.5 25 28.6 2 28.8 3 29.7 11 31.7 5 36.5 2 37.3 2 In one embodiment, Form 2 is characterized by at least one of the underlined characteristic peaks. In another embodiment, Form 2 is characterized by two or more of the underlined characteristic peaks.
In a further embodiment, Form 2 is characterized by three, or all four of the underlined characteristic peak.
Optionally, Form 2 may further, or alternatively, have a powder X-ray diffraction spectra comprising a peak at one or more of: about 6.6 degrees two-theta, about 15.0 degrees two-theta, about 16.8 degrees two-theta, about 18.3 degrees two-theta, about 20.4 degrees two-theta, about 20.9 degrees two-theta, about 21.6 degrees two-theta, about 23.0 degrees two-theta, about 23.2 degrees two-theta, about 23.9 degrees two-theta, about 24.3 degrees two-theta, about 24.7 degrees two-theta, about 24.9 degrees two-theta, about 25.1 degrees two-theta, about 27.5 degrees two-theta, about 28.6 degrees two-theta, about 28.8 degrees two-theta, about 29.7 degrees two-theta, about 31.7 degrees two-theta, about 36.5 degrees two-theta, or about 37.3 degrees two-theta.
Optionally, Form 2 may further, or alternatively, have a powder X-ray diffraction spectra comprising a peak at one or more of: 6.6 0.2 degrees two-theta, 15.0 0.2 degrees two-theta, 16.8 0.2 degrees two-theta, 18.3 0.2 degrees two-theta, 20.4 0.2 degrees two-theta, 20.9 0.2 degrees two-theta, 21.6 0.2 degrees two-theta, 23.0 0.2 degrees two-theta, 23.2 0.2 degrees two-theta, 23.9 0.2 degrees two-theta, 24.3 0.2 degrees two-theta, 24.7 0.2 degrees two-theta, 24.9 0.2 degrees two-theta, 25.1 0.2 degrees two-theta, 27.5 0.2 degrees two-theta, 28.6 0.2 degrees two-theta, 28.8 0.2 degrees two-theta, 29.7 0.2 degrees two-theta, 31.7 0.2 degrees two-theta, 36.5 0.2 degrees two-theta, or 37.3 degrees two-theta. Route C:
Alternatively, a mixture of 5-Fluoroindole (5.00 g, 5.00 g, 35.5 mmol, 96 mass%, 1.00) 5 and Maleimide (1.5 equiv., 5.17 g, 53.3 mmol, 1.50) was charged in a 50 ml vessel, and then Acetonitrile (3 L/kg, 15.0 ml, 11.7 g, 286 mmol, 100 mass%) and Zinc Chloride (1.05 equiv., 5.08 g, 37.3 mmol, 100 mass%) were added. The reaction was heated to 85 C over 10 min and then maintained at 85 C for 24 hrs. While still at 85 C, Water (6 L/kg, 30.0 ml, 30.0 g, 1670 mmol, 100 mass%) was added slowly, while maintaining the 10 temperature above 80 C. Yellow solids precipitated. The reaction mixture was cooled to 50 C over 1 hour followed by stirring at 50 C for 2 hours, then cooled 10 C
over 1 hour. The reaction was stirred at 10 C for 1 hour. The solids were filtered off, then the filter cake was washed 2 times with 5 ml 1:1 ACN/water to afford isolated compound (6.85 g, 6.85 g, 29.5 mmol, 83.1% Yield).
For purification, a sample of the above isolate (5.00 g, 21.5 mmol) is heated to reflux in acetonitrile (5 L/Kg, 25 ml). This is distilled at atmospheric pressure to a volume of 18 ml. To the resulting slurry is added water (25 ml), rapidly dropwise such that the reaction temperature remains at 70-75 C. After completing the addition allow to come to room temperature over -90 min. Stir at ambient another two hours and then collect by suction filtration through paper, rinsing with acetonitrile/water (1/2).
Transfer to a vacuum oven for overnight drying at 50 C to provide the product (4.72 g, 94.4%
Yield).
For additional purification, product isolated as above (5.02 g, 21.5 mmol) is heated in tetrahydrofuran (30 ml). A solution results at -55 C. Introduce heptane (30 ml), rapidly dropwise, at such a rate as to maintain the reaction temperature at 50-55 C. A
hazy precipitate begins to form after -20m1 is added. After completing the addition the mixture is allowed to come to 23 C over -2 hr. Stir at ambient another three hours and then collect by suction filtration through paper, rinsing with heptane.
Transfer to a vacuum oven for overnight drying. There is so obtained desired product, of correct Form 1 (4.65 g, 92.6% yield).

Alternative Powder X-Ray diffraction Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 ADVANCE
diffractometer equipped with a Cu radiation source (K-a average). The system is equipped with a 2.5 axial SoIler slits on the primary side. The secondary side utilizes 2.5 axial SoIler slits and motorized slits. Diffracted radiation was detected by a Lynx Eye XE detector. The X-ray tube voltage and amperage were set to 40 kV and 40 mA
respectively. Data was collected in the Theta-Theta goniometer at the Cu wavelength from 3.0 to 40.0 degrees 2-Theta using a step size of 0.037 degrees and a step time of 1920 seconds. Samples were prepared by placing them in a Bruker sample holder (part number: C79298A32446261) and rotated during collection. Data were analyzed using Bruker EVA DIFFRAC software (Version 3.1). The spectra from this PXRD analysis is provided in FIG 1B.
Solid State NMR:
Solid state NMR (ssNMR) analysis was conducted at ambient temperature and pressure on a Bruker- BioSpin CPMAS probe positioned into a Bruker-BioSpin Avance III 500 MHz (1H frequency) NMR spectrometer. The packed rotor containing approximately 80 mg of material was oriented at the magic angle and spun at 15.0 kHz.
The carbon ssNMR spectrum was collected using a proton decoupled cross-polarization magic angle spinning (CPMAS) experiment. A phase modulated proton decoupling field of 85 kHz was applied during spectral acquisition. The cross-polarization contact time was set to 2 ms and the recycle delay to 45 seconds.
The carbon ssNMR spectrum was collected for 1024 scans to obtain an adequate signal to noise ratio. The carbon chemical shift scale was referenced using a carbon CPMAS
experiment on an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm (as determined from neat TMS). The fluorine ssNMR
spectrum was collected using a proton decoupled direct polarization magic angle spinning (MAS) experiment. A phase modulated proton decoupling field of 85 kHz was applied during spectral acquisition. The recycle delay was set to 250 ms. The fluorine ssNMR
spectrum was collected for 32 scans. The fluorine chemical shift scale was referenced using a direct polarization fluorine experiment on an external standard of volume/volume of trifluoroacetic acid and water, setting its resonances to -76.54 ppm.
Automatic peak picking was performed using Bruker-BioSpin TopSpin version 3.2 software. Generally, a threshold value of 5% relative intensity was used to preliminary select peaks. The output of the automated peak picking was visually checked to ensure validity and adjustments were manually made if necessary. Although specific 130 and 19F solid state NMR peak values are reported herein there does exist a range for these peak values due to differences in instruments, samples, and sample preparation. This is common practice in the art of solid state NMR because of the variation inherent in peak values. A typical variability for a 13C and 19F chemical shift x-axis value is on the order of plus or minus 0.2 ppm for a crystalline solid. The solid state NMR peak heights reported herein are relative intensities. Solid state NMR intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample.
Table 3: 130 solid state NMR peak list for Form 1 prepared according to Route C.
Asterisked peak positions represent characteristic peaks.
13C Chemical Shifts (ppm) Relative intensity (%) 38.0 73 39.2* 75 104.2 47 110.5 60 112.4 84 124.7* 54 127.5* 41 133.3 49 157.3 16 180.3 100 Table 4:: 19F solid state NMR peak list for Form 1 prepared according to Route C.
Asterisked peak positions represent characteristic peaks.
19F Chemical Shifts (ppm) Relative intensity (%) -122.8* 100 Purity of Form I prepared according to methods B and C may be determined on an anhydrous solvent free base (ASFB) by high performance liquid chromatography (HPLC). The HPLC procedure utilizes a Waters Acquity UPLC system with a Waters HSS T3 2.1 x 150 mm, 1.8 pm column with 0.05% methanesulfonic acid in deionized water (v/v) and acetonitrile mobile phases with a gradient chromatography conditions, collecting at 220 nM UV detection. Standards and samples are prepared in 75/25 deionized water/acetonitrile (v/v). Form I assessed by this method is found to be 99.5%
pure for Form I prepared according the process of Part B of this example and 99.7%
pure for Form I prepared according to the process of Part C of this example.
All publications cited in this specification are incorporated herein by reference, as is US
Provisional Patent Application No. 62/253,478, filed November 10, 2015 and US
Provisional Patent Application No. 62/161534, filed May 15, 2015. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention.
Such modifications are intended to fall within the scope of the appended claims.

Claims (38)

1. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 1) which has a powder X-ray diffraction pattern which comprises characteristic peaks at two or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, about 15.0 degrees two-theta, about 16.4 degrees two-theta, or about 24.4 degrees two-theta.

2. The crystalline form according to claim 1, which comprises three or more of the peaks.

3. The crystalline form according to claim 2, wherein the three or more peaks comprises at least the peaks at about 6.7 degrees two-theta, about 14.2 degrees two-theta and about 24.4 degrees two-theta.

4. The crystalline form according to claim 1, which comprises four or more peaks.

5. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form I) which has a powder X-ray diffraction pattern which comprises characteristic peaks at two or more of 6.7 ~ 0.2 degrees two-theta, 14.2 ~ 0.2 degrees two-theta, 15.0 degrees ~ 0.2 two-theta, 16.4 ~ 0.2 degrees two-theta, or 24.4 ~ 0.2 degrees two-theta.

6. The crystalline form according to claim 5, which comprises three or more of the peaks.

7. The crystalline form according to claim 6, wherein the three or more peaks comprises at least the peaks at 6.7 ~ 0.2 degrees two-theta, 14.2 ~ 0.2 degrees two-theta, and 24.4 ~ 0.2 degrees two-theta.

8. The crystalline form according to any one of claims 1 to 7 having a powder X-ray diffraction pattern as shown in FIG. 1A or FIG 1B.

9. The crystalline form according to any one of claims 1 to 8, wherein said powder X-diffraction pattern further comprises a peak at one or more of: 13.3 ~ 0.2 degrees two-theta, 16.1, ~ 0.2 degrees two-theta, 17.1~ 0.2 degrees two-theta, 18.3~
0.2 degrees two-theta, 19.5~ 0.2 degrees two-theta, 19.9 ~ 0.2 degrees two-theta, 20.1 ~
0.2 degrees two-theta, 20.7 ~ 0.2 degrees two-theta, 21.3 ~ 0.2 degrees two-theta, 22.2 ~ 0.2 degrees two-theta, 23.6 ~ 0.2 degrees two-theta, 23.8 ~ 0.2 degrees two-theta, 24.6 ~ 0.2 degrees two-theta, 26.1 ~ 0.2 degrees two-theta, 26.6 ~ 0.2 degrees two-theta, 27.1 ~ 0.2 degrees two-theta, 27.7 ~ 0.2 degrees two-theta, 28.0 ~ 0.2 degrees two-theta, 28.6 ~ 0.2 degrees two-theta, 29.9 ~ 0.2 degrees two-theta, 32.5 ~
0.2 degrees two-theta, 32.9 ~ 0.2 degrees two-theta, 33.1 ~ 0.2 degrees two-theta, 35.2 ~
0.2 degrees two-theta, 35.6 ~ 0.2 degrees two-theta, 36.1 ~ 0.2 degrees two-theta, 37.1 ~ 0.2 degrees two-theta, 39.0 ~ 0.2 degrees two-theta, or 39.9 ~ 0.2 degrees two-theta.

10. The compound according to any one of claims 1 to 8, which lacks peaks at about 9.5 degrees two-theta and/or about 12.3 degrees two-theta.

11. The crystalline form according to any one of claims 1 to 10, which has a melting point from above 195 °C to 198 °C.

12. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione which has a solid state (ss) nuclear magnetic resonance (NMR) of two or more 13C chemical shifts at about 39.2 parts per million (ppm), about 124.7 ppm, or about 127.5 ppm.

13. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 1) which has a solid state (ss) nuclear magnetic resonance (NMR) of three 13C
chemical shifts at 39.2 ~ 0.2 parts per million (ppm), 124.7 ~ 0.2 ppm, or 127.5 ~ 0.2 ppm.

14. The crystalline form according to claim 12 or claim 13, which has a ssNMR
spectra of FIG 3.

15. The crystalline form according to any one of claims 12 to 14, wherein the crystalline for is further characterized by a solid state (ss) nuclear magnetic resonance (NMR) of 19F chemical shift at about -122.8 parts per million.

16. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 1) which has a solid state (ss) nuclear magnetic resonance (NMR) of 19F chemical shift at about -122.8 parts per million.

17 The crystalline form according to claim 16, which has a ssNMR spectra of FIG 4.

18. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 1) characterized by a powder X-ray diffraction pattern which comprises characteristic peaks at one or more of about 6.7 degrees two-theta, about 14.2 degrees two-theta, about 15.0 degrees two-theta, about 16.4 degrees two-theta, or about 24.4 degrees two-theta, and at least one of (a) or (b) :
(a) a solid state (ss) nuclear magnetic resonance (NMR) of one or more 13C chemical shifts at about 39.2 parts per million (ppm), about 124.7 ppm, or about 127.5 ppm, and (b) a ssNMR spectra of 19F chemical shift at about -122.8 ppm.

19. The crystalline form according claim 18, wherein the ssNMR of the one or more 13C chemical shifts is 39.2 ~ 0.2 ppm, 124.7 ~ 0.2 ppm, or 127.5 ~ 0.2 ppm.

20. The crystalline form according claim 18 or 19, wherein the ssNMR of the chemical shift is -122.8 ~ 0.2 ppm.

21. The crystalline form according to any one of claims 18 to 20, which comprises two or more of the X-ray peaks.

22. The crystalline form according to any one of claims 18 to 21, which comprises three or more of the X-ray peaks.

23. The crystalline form according to any one of claims 18 to 22, which comprises two or more of the chemical shifts of (a).

24. The crystalline form according to any one of claims 16 to 23, which comprises (a) and (b).

25. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 1) which is characterized by :
(a) a powder X-ray diffraction pattern which comprises characteristic peaks at one or more of 6.7 0.2 degrees two-theta, 14.2 0.2 degrees two-theta, or 24.4 0.2 degrees two-theta, and (b) a solid state nuclear magnetic resonance of one or more 13C chemical shifts at 39.2 0.2 parts per million (ppm), 124.7 0.2 ppm, or 127.5 ppm 0.2 ppm.

26. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 1) which has (a) a powder X-ray diffraction pattern which comprises characteristic peaks at one or more of 6.7 0.2 degrees two-theta, 14.2 0.2 degrees two-theta, or 24.4 0.2 degrees two-theta, and (b) a solid state NMR spectra of 19F chemical shift at -122.8 0.2 ppm.

27. A purified crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 1) which is characterized by being at least about 95% free of solvents and other solid forms of the compound.

28. The purified crystalline form according to claim 27, wherein the crystalline form is at least 97% pure.

29. The purified crystalline form according to claim 27, wherein the crystalline form is at least 99% pure.

30. The purified crystalline form according to claim 29, wherein the crystalline form is at least 99.5% pure.

31. The purified crystalline form according to claim 30, wherein the crystalline form is 99.7% pure.

32. A pharmaceutical composition comprising the crystal form according to any one of claims 1 to 31 and a pharmaceutically acceptable carrier or diluent.

33. A crystalline form of 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione (Form 2) having a powder X-ray diffraction pattern which comprises characteristic peaks at two or more of about 9.5, about 12.3, and/or about 13.5 degrees two-theta.

34. The crystalline form according to claim 33, which comprises three or more of the peaks.

35. The crystalline form according to claim 33 or claim 34 having a powder X-ray diffraction pattern as shown in FIG. 2.

36. The crystalline form according to any one of claims 33 to 35, which lacks characteristic peaks at about 6.7, about 15.0, and about 16.4 degrees two-theta.

37. The crystalline form according to any one of claims 33 to 36, wherein said powder X-diffraction pattern further comprises a peak at one or more of: about 6.6, about 15.0, about 16.8, about 18.3, about 20.4, about 20.9, about 21.6, about 23.0, about 23.2, about 23.9, about 24.3, about 24.7, about 24.9, about 25.1, about 27.5, about 28.6, about 28.8, about 29.7, about 31.7, about 36.5, or about 37.3 degrees two-theta.

38. The crystalline form according to any one of claims 33 to 36, wherein said powder X-diffraction pattern further comprises a peak at one or more of: 6.6 ~
0.2 degrees two-theta, 15.0 ~ 0.2 degrees two-theta, 16.8 ~ 0.2 degrees two-theta, 18.3 ~
0.2 degrees two-theta, 20.4 ~ 0.2 degrees two-theta, 20.9 ~ 0.2 degrees two-theta, 21.6 ~ 0.2 degrees two-theta, 23.0 ~ 0.2 degrees two-theta, 23.2 ~ 0.2 degrees two-theta, 23.9 ~ 0.2 degrees two-theta, 24.3 ~ 0.2 degrees two-theta, 24.7 ~ 0.2 degrees two-theta, 24.9 ~ 0.2 degrees two-theta, 25.1 ~ 0.2 degrees two-theta, 27.5 ~ 0.2 degrees two-theta, 28.6 ~ 0.2 degrees two-theta, 28.8 ~ 0.2 degrees two-theta, 29.7 ~
0.2 degrees two-theta, 31.7 ~ 0.2 degrees two-theta, 36.5 ~ 0.2 degrees two-theta, or 37.3 degrees two-theta.