OA18111A

OA18111A - Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as IDO1 inhibitors

Info

Publication number: OA18111A
Application number: OA1201600410
Authority: OA
Inventors: Sandra CAUWENBERGHS; Frederik Deroose; Gregory DRIESSENS; Stefano Crosignani
Original assignee: Iteos Therapeutics
Priority date: 2014-05-15
Filing date: 2015-05-14
Publication date: 2018-06-14

Abstract

The present invention relates to compound of or pharmaceutically acceptable enantiomers, salts, solvates or prodrugs thereof. The invention further relates to the use of the compounds of Formula I as ID01 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or prevention of cancer and endometriosis. The invention also relates to a process for manufacturing compounds of Formula I.

Description

BACKGROUND OF INVENTION

Indoleamine 2,3-dioxygenase 1 (IDO1) 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 15 Trp is metabolized through this kynurenine pathway. The kynurenine pathway (KYN) initiâtes the production of neuroactive and immunoregulatory métabolites, collectively known as kynurenines and provides precursors that supplément dietary niacin for the biosynthesis of NAD+ and NADP+.

By locally depleting tryptophan and increasing kynurenines, IDO1 expressed by antigen 20 presenting cells (APCs) such as dendritic cells (plasmacystoid DCs in tumor draining lymph nodes) can greatly affect T-cell prolifération and survival and activate regulatory T cells thereby reducing proinflammatory responses. IDO1 can thus provide “immune privilège” to tissues subject to chronic inflammations such as infectious and allergie 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 Immunol, 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 réduction of local Trp levels and/or to imbalances in the level of cytotoxic métabolites produced by the kynurenine pathway (reviewed in Munn étal. Trends Immunol, 2013, 34, 137-43). 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, ischemiareperfusion injury, endotoxin shock, human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, airway inflammation, and cancer (Uyttenhove et al., Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210, 7, 13891402), among others. For cancer, IDO1 induction has been observed in v/Voduring rejection of allogeneic tumors, indicating a possible rôle for this enzyme in the tumor rejection process (Uyttenhove et al., Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210, 7, 1389-1402). Cervical carcinoma cells (or HeLa cells) cocultured with peripheral blood lymphocytes (PBLs) acquire an immuno-inhibitory phenotype through up-regulation of IDO1 activity. A réduction in PBL prolifération upon treatment with interleukin-2 (IL2) was believed to resuit from IDO1 released by the tumor cells in response to gamma interferon (IFN)-g (γ) sécrétion by the PBLs. IDO1 activity in tumor cells may thus serve to impair anti-tumor responses, a process in which IFNg plays a central rôle. Further evidence for a tumoral immune résistance mechanism based on tryptophan dégradation by IDO1 cornes from the observation that most human tumors constitutively express IDO1, and that expression of IDO1 by immunogenic mouse tumor cells prevents their rejection (reviewed in Munn et al., Front Biosci, 2012, 4, 734-45; Godin-Ethier et al. Clin Cancer Res 2011,17, 6985-6991 ; Johnson et al. Immunol lnvest2012, 41, 6-7, 765-797). This effect is accompanied by a lack of accumulation of spécifie T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO1, in the absence of noticeable toxicity (Holmgaard étal., J Exp Med, 2013, 210, 7, 1389-1402).

ID01 expression has been demonstrated by immunohistochemistry in a wide spectrum of cancer patients. IDO1 mRNA, protein or modification of the ratio of tryptophan and kynurenine in the blood hâve been detected in patients with malignant melanoma, acute myelogenous leukemia, pancreatic, colorectal, prostate, cervical, brain, endométrial and 5 ovarian cancers amongst others. In several malignancies, the presence of IDO1 is an independent predictor of a worse clinical outcome (reviewed in Munn et al., Front Biosci,

2012, 4, 734-45)

Although the potential of the IDO1 inhibitors as pharmaceutical agents has generated a significant interest, the initial inhibitors were identified by modification of Trp but not the 10 discovery of molécules bearing novel structural skeleton. In the early 2000’s, the best

IDO1 inhibitors were mainly comprised of compétitive Trp dérivatives (like L-1-MT) and noncompetitive carbolines, which displayed affinities in the micromolar range. Since 2006, some potent nanomolar IDO1 inhibitors with novel structural skeleton hâve been discovered by high throughput screening, computational screening or natural product isolation and optimization of the core pharmacophores in the structures. Many of these

IDO1 inhibitors possess low micromolar activities or limited pharmacokinetics. Two

IDO1 inhibitors are currently being tested in phase l/ll clinical trials for the treatment of relapsed or refractory solid tumors (reviewed in Dolusic 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). Immunoscoring of infiltrating T cell subsets is under development as biomarker approach and will allow to détermine the patients’ responsiveness to treatment (Galon et al., J Transi Med, 2012, 10, 1). Hence, it is still of major interest to find new potent IDO1 inhibitors.

Therefore, there is a need for new IDO1 inhibitors with improved efficacy for cancer treatment and/or prévention.

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SUMMARY OF THE INVENTION

The compounds, compositions and methods herein help meet the current need for IDO1 inhibitors which can be administered to any patient diagnosed with cancer, or any subject at risk of developing a cancer.

In one aspect, a pharmaceutical composition or a médicament comprising a compound of Formula la is provided:

R la or a pharmaceutically acceptable enantiomer, sait, solvaté or prodrug thereof, wherein:

X^a represents -NH- or-CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl, preferably Q²and Q³ each independently represent H or methyl, more preferably Q² and Q³represent H;

R¹ and R² each independently represent H, halo, cyano, C1 to C6 alkyl or C1 to C6 alkoxy, preferably R¹ and R² each independently represent H or halo.

In another aspect, a pharmaceutical composition comprising a compound of Formula la is provided:

la or a pharmaceutically acceptable enantiomer, sait, solvaté or prodrug thereof, wherein:

X^a represents -NH- or -CQ²=CQ³-;

R¹ and R² each independently represent H, halo, cyano, C1 to C6 alkyl or C1 5 to C6 alkoxy, preferably R¹ and R² each independently represent H or halo;

and at least one pharmaceutically acceptable carrier.

Also provides is a compound of Formula la

or a pharmaceutically acceptable enantiomer, sait, solvaté or prodrug thereof, wherein:

X^a represents -NH- or -CQ²=CQ³-;

R¹ and R² each independently represent H, halo, cyano, C1 to 06 alkyl or C1 to 06 alkoxy, preferably R¹ and R² each independently represent H or halo.

In one embodiment, the compound of Formula I and/or Formula la has a deuterium atom substituted for a hydrogen atom therein, i.e., is optionally deuterated. In one embodiment, the compound of Formula I is deuterated at the chiral carbon and may be used to préparé deuterated compounds of Formula I’ and/or Formula I”. The compounds described herein, including those of Formula I, Formula la, Formula Ib, Formula I’ and Formula I”, and their deuterated counterparts are useful in the treatment and/or prévention of cancer and endometriosis, and/or for use as ID01 inhibitor.

Also provided is a compound of Formula la

181

la' or a pharmaceutically acceptable enantiomer, sait, solvaté or prodrug thereof, wherein:

X^a represents -NH- or -CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl, preferably Q² and Q³ each independently represent H or methyl, more preferably Q² and Q³ represent H;

In one embodiment, a compound of Formula I and/or la is deuterated at the chiral center, as in the structure of Formula la’

la' or a pharmaceutically acceptable enantiomer, sait, solvaté or prodrug thereof, wherein: X^a represents -NH- or -CQ²=CQ³-;

R¹ and R² each independently represent H, halo, cyano, C1 to C6 alkyl or C1 to C6 alkoxy, preferably R¹ and R² each independently represent H or halo. In one embodiments, racemic compounds of Formula I and/or la may be deuterated using the techniques described herein and/or those known to one of skill in the art. Such compounds may be used in a médicament or pharmaceutical composition, and/or production of a deuterated R-enantiomer and/or a deuterated S-enantiomer. Such a deuterated enantiomer may itself be used in a médicament or pharmaceutical composition as described herein.

Further, a compound of Formula I’, Formula I”, or a mixture thereof is provided:

and pharmaceutically acceptable salts, solvatés and prodrugs thereof, wherein

X représente -NQ¹- or -CQ²=CQ³-;

Q¹, Q² and Q³ each independently represent H or C1 to C6 alkyl, preferably

Q¹ is H, and Q² and Q³ each independently represent H or methyl, more preferably Q¹, Q² and Q³ each represent H;

In another embodiment, Q¹ is H and X represents -NH- or -CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl, preferably Q²and Q³ each independently represent H or methyl, more preferablyQ² and Q³each represent H;

In another embodiment, a composition comprising a compound of Formula I’ and/or Formula I” is provided. The composition may contain a racemic compound.

Alternatively, the composition may contain a mixture of a compounds of Formula I’ and Formula I”, which are produced separately. Such compounds may contain a 1:1 ratio of 20 Formula Γ to Formula I”, as is présent in the racemate, or the R-enantiomer may be présent in an amount of greater than 50%. In another alternative, a composition may contain more than 50% ofthe S-enantiomer. Optionally, the racemate, orone orboth of the enantiomers, may be deuterated, e.g., atthe chiral carbon.

181

la

The invention further discloses a compound of Formula Ib

and pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, wherein:

X represents -NQ¹- or -CQ²=CQ³-;

Q¹, Q² and Q³ each independently represent H or alkyl, preferably Q¹ is H, Q²and Q³ each independently represent H or methyl, more preferably Q¹, Q²and Q³ represent H;

R^1b and R^2b each independently represent H, halo, cyano, alkyl or alkoxy, preferably R^1b and R^2b each independently represent H or halo;

under the condition that when X represents -NQ¹-, then R^1b and R^2b are not both H, and R^1b and R^2bare not both F; in one embodiment, Q1 is H.

when X represents -CQ²=CQ³-, then R^1b and R^2b are not both H.

In another embodiment, when Q1 is H, X represents -NH- or -CQ²=CQ³Q² and Q³ each independently represent H or alkyl, Q² and Q³ each independently represent H or methyl, more preferably Q² and Q³ represent H;

under the condition that ι -swhen X represents -NH-, then R^1b and R^2b are not both H, and when X represents -NH-, R^1b and R^2b are not both F; when X represents -CQ²=CQ³-, then R^1b and R^2b are not both H.

According to one embodiment, the compound of Formula l’is selected from the group consisting of:

(a) (-)-(R)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(b) (-)-(R)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(c) (-)-(R)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(d) (R)-3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; or (e) (R)-3-(6-bromo-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable sait or solvaté thereof. In another embodiment, the compound of Formula II’ is selected from the group consisting of:

(a”) (S)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(b”) (S)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(c”) (S)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(d”) (S)-3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; or (e”) (S)-3-(6-bromo-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable sait or solvaté thereof. In still another embodiment, the compound of:

3-(6-chloro-5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione; (F?)-3-(6-chloro-5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione;

3-(6-bromo-5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione; (F?)-3-(6-bromo-5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione,

3-(naphthalen-1-yl)pyrrolidine-2,5-dione;

3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione; 3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; or 3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione or a pharmaceutically acceptable sait or solvaté thereof, or a deuterated form thereof.

-10The invention also discloses a process for manufacturing a compound of Formula I’, I” or Ib, comprising: reacting maleimide with a compound of Formula (i) or (ib)

wherein X, R¹ and R² are as defined in Formula I’ or I” and R^1b and R^2bare as defined in Formula Ib, and optionally separating enantiomers.

In another aspect, a compound having the structure of Formula II’:

II'

J or a pharmaceutically acceptable sait or solvaté thereof is provided. In one embodiment, the compound is a free base, i.e., is in neither sait nor solvaté form. Also provided a pharmaceutical compositions containing a compound of Formula ΙΓ alone, or optionally mixed or blended with a compound having the structure of Formula II”:

¹¹ , or a pharmaceutically acceptable sait thereof.

Other aspects and advantages of the invention will be apparent from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG 1 is a graph showing the effect of increasing amounts of compound 2 of the invention on T-cell prolifération (as measured by Thymidine incorporation) in a SKOV-3 - PBMC co-culture assay.

FIG. 2 is a graph showing the circulating Kynurenine concentration in healthy mouse blood after treatment with compound 2 of the invention or with a vehicle.

FIG 3 is a graph of different studies showing the tumor growth of 4T1 tumors in a mouse breast cancer model after treatment with compound 1 or with a vehicle. FIG 3 shows the tumor growth of 4T1 tumors after treatment with compound 1 at a dose of 100 mg/kg 10 BID. The upper line represents vehicle and the lôwer line represents compound 1.

FIG 4 is a graph showing the tumor growth of PanCO2 tumors in mice after treatment with test compounds. The upper line represents vehicle and the lower line represents compound 1.

FIG 5 is a graph showing the concentration of Kynurenine within a 4T1 tumor in mice after treatment with compound 2 of the invention or with a vehicle.

FIG 6 is a graph showing the concentration of Kynurenine within a CT26 tumor in mice after treatment with compound 2 of the invention or with a vehicle.

FIG 7 is a graph showing the tumor growth of CT26 tumors in Balb/c mice in test

Compound 1 at200 mg/kg BID (open circle), 600 mg/kg BID (closed triangle), as 20 compared to vehicle (square).

DETAILED DESCRIPTION OF THE INVENTION

Compounds

Compounds of Formula I

X represents -NQ¹- or -CQ²=CQ³-;

Q¹, Q² and Q³ each independently represent H or alkyl, preferably Q¹, Q² and Q³each independently represent H or methyl, more preferably Q¹, Q² and Q³represent H;

R¹ and R² each independently represent H, halo, cyano, alkyl or alkoxy, preferably R¹ and R² each independently represent H or halo.

In another embodiment, Q¹ is H, X represents -NH- or -CQ²=CQ³- ;

Q² and Q³ each independently represent H or alkyl, preferably Q² and Q³ each independently represent H or methyl, more preferably Q² and Q³ represent H; R¹and R² each independently represent H, halo, cyano, alkyl or alkoxy, preferably R¹ and R² each independently represent H or halo.

Also provided herein are compound of Formula I, and pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, which hâve at least one deuterium atom substituted for a hydrogen atom. In one embodiment, a compound of Formula I, or any of its subformulae provided herein, including la, Ib, I’, I , II, II’, II”, atthe chiral center, as illustrated below in the structure of Formula la’

Rla' or a pharmaceutically acceptable enantiomer, sait, solvaté or prodrug thereof.

- 13Formulae I, la and Ib are drawn without reference to stereochemistry, and thus each encompasses a racemic compound, and separate stereoisomers, i.e., the R- and/or Sstereoisomer. In one embodiment, these stereoisomers may hâve the structure of Formula I’ (R-stereoisomer) and Formula II’ (S-enantiomer).

Illustrative compounds of Formula I are shown in the table and examples herein and

include:

3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (-)-(R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (+)-(S)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(1H-indol-3-yl)pyrrolidine-2,5-dione; (-)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione; (+-)-(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (-)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (+)-(S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (R) -3-(6-chloro-5-fluoro-1H-indol-3-yi)pyrrolidine-2,5-dione; (S) -3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (R) -3-(6-bromo-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; (S) -3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(5-bromo-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile; 3-(5,6-difluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-bromo-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-methoxy-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile;

I -143-(naphthalen-1 -yl)pyrrolidine-2,5-dione; 3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione; 3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; and

3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione.

Optionally, these compounds of Formula I may be deuterated, e.g., at the chiral center. An illustrated deuterated compound (3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5dione is provided in the examples below. Other deuterated compounds may include, e.g., (-)-(R)-(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(+)-(S)- (3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;

(-)-(R)- (3-²H)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(+-)-(S)- (3-²H)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(-)-(R)- (3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(+)-(S)- (3-²H)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(R)- (3-²H)-3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(S)- (3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(R) -3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(S) - (3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-bromo-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione; 3-(2,5-dioxopyrrolidin-3-yl)-1 H-indole-5-carbonitrile; (3-²H)-3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(6-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;

181

(3-²H)-3-(6-methyl-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile;

(3-²H)-3-(naphthalen-1-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-chloronaphthalen-1 -yl)pyrrolidine-2,5-dione; and (3-²H)-3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione,

In one embodiment, preferred compounds of Formula I are those of Formula I’ or I”

and pharmaceutically acceptable, salts, solvatés and prodrugs thereof, wherein X, R¹and R²are as defined in Formula I.

As described herein , a racemic compound of Formula I may contain about 50% of a compound of Formula Γ and about 50% of Formula I” based on a molar ratio (about 48 to about 52 mol %, or about a 1:1 ratio)) of one of the isomers. In another embodiment, a composition, médicament, or method of treatment may involve combining separately produced compounds of Formula Γ and Formula I” in an approximately equal molar ratio (about 48 to 52 %). In another embodiment, a médicament or pharmaceutical composition may contain a mixture of separate compounds of Formula I’ and Formula I” in different ratios. In one embodiment, the pharmaceutical composition contains an excess (greater than 50%) of the R-enantiomer (Formula Γ). Suitable molar ratios of R/S may befrom about 1.5 :1,2 :1, 3 :1, 4 :1, 5 :1, 10 :1, orhigher. In another embodiment, a pharmaceutical composition may contain an excess of the S-enantiomer (Formula I”), with the ratios provided for R/S reversed. Other suitable amounts of R/S may be selected. For example, the R- enantiomer may be présent in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. In other embodiments, the S-enantiomer

181

may be présent in a higher percentage, e.g., in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. Ratios between ail these exemplary embodiments as well as greater than and less than them while still within the invention, ail are included. (The term “ratio” as used herein (above and below) refers always to the molar ratio). Compositions may contain a mixture of the racemate and a separate compound of Formula I’ and/or Formula I”, in free base and/or in sait form.

Optionally, the racemate, or one or both of the enantiomers, may be deuterated. Such deuterated compounds may be in sait form. For example, the deuterated stereoisomers may be characterized by the structure:

la' wherein X(or X^a), R¹, and R² are as defined above in Formula I and la. Without wishing to be bound by theory, it has been described in the literature generally that one enantiomer (isomer or stereoisomer) can convert in plasma to the racemate and/or to the other enantiomer. It is believed that deutération at the chiral center of these compounds slows the conversion of the individual stereoisomers to the racemate and/or the other stereoisomer in plasma.

In one embodiment, preferred compounds of Formula I are those of Formula la

181

X^a represents -NH- or -CQ²=CQ³-;

Q² and Q³ each independently represent H or alkyl, preferably Q² and Q³ each independently represent H or methyl, more preferably Q² and Q³ represent H;

In one embodiment, preferred compounds of Formula I are those of Formula Ib

Ib and pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, wherein:

X represents -NQ¹- or -CQ²=CQ³-;

Q¹, Q² and Q³ each independently represent H or alkyl; optionally, the alkyl is C1 to C6 alkyl, preferably Q¹, Q² and Q³ each independently represent H or methyl, more preferably Q¹, Q² and Q³ represent H;

R^1b and R^2b each independently represent H, halo, cyano, alkyl or alkoxy; optionally, the alkyl is C1 to C6 alkyl and the alkoxy is C1 to C6 alkoxy, preferably R^1b and R^2b each independently represent H or halo;

under the condition that when X represents -NQ¹-, then R^1b and R^2b are not both H, and R^1b and R^2b are not both F;

when X represents -CQ²=CQ³-, then R^1b and R^2b are not both H.

in another embodiment, Q¹ is H and X represents -NH¹- or -CQ²=CQ³-;

Q² and Q³ each independently represent H or alkyl; optionally, the alkyl is C1 to C6 alkyl, preferably Q² and Q³ each independently represent H or methyl, more preferablyQ² and Q³ represent H;

-18R^1b and R^2b each independently represent H, halo, cyano, alkyl or alkoxy; optionally, the alkyl is C1 to C6 alkyl and the alkoxy is C1 to C6 alkoxy, preferably R^1b and R^2b each independently represent H or halo;

under the condition that when X represents -NH-, then R^1b and R^2b are not both H, and R^1b and R^2b are not both F;

when X represents -CQ²=CQ³-, then R^1b and R^2b are not both H.

Particularly preferred compounds of Formula I of the invention are those listed in Table 1 hereafter.

TABLE 1

Cpd n°	Structure	Chemical name
1	0 U^NH H	3-(5-fluoro-1 /-/-indol-3- yl)pyrrolidine-2,5-dione
1a	0 A-nh H	(3-²H)-3-(5-fluoro-1 /7-indol- 3-yl)pyrrolidine-2,5-dione
2	0 ^NH H	(-)-(R)-3-(5-fluoro-1 /-/-indol- 3-yl)pyrrolidine-2,5-dione

Cpd n°	Structure	Chemical name
3	k œ H	3-(1 H-\ ndol-3-y I) pyrrol idine- 2,5-dione
4	O Anh A H	(-)-(/3)-3-(1 H-indol-3- yl)pyrrolidine-2,5-dione
5	0 Anh H	3-(5-chloro-1 /-/-indol-3- yl)pyrrolidine-2,5-dione
6	0 Anh ciy^A° H	(-)-(/?)-3-(5-chloro-1 H-indol- 3-yl)pyrrolidine-2,5-dione
7	0 Anh	3-(6-chloro-5-fluoro-1 Hindol-3-yl)pyrrolidine-2,5dione
8	0 Anh XA°	(R)-3-(6-chloro-5-fluoro-1 Hindol-3-yl)pyrrolidine-2,5dione

Cpd n°	Structure	Chemical name
			0	3-(6-bromo-5-fluoro-1 H-
			Λ-νη	indol-3-yl)pyrrolidine-2,5-
9	P		/%	dione
			ï)
	Br'		'U H
			0 Λ	(R)-3-(6-bromo-5-fluoro-1 H-
			Œ	indol-3-yl)pyrrolidine-2,5-
10			7°	dione
	Γ X	T	O
	Br'	U	U-N H
			0	3-(5-bromo-1 H-indol-3-
			Λ-ΝΗ	yl)pyrrolidine-2,5-dione
11	Br-,

		U	A-n H
			0	3-(5-methyl-1 /-/-indol-3-
			Λ-ΝΗ	yl)pyrrolidine-2,5-dione
12			/Ί3
		A	rS
			U H
			0	3-(5-methoxy-1 /7-indol-3-
			Λ-ΝΗ	yl)pyrrolidine-2,5-dione
13	H₃CO	/Ί3 Ar$
			Un H
			0	3-(2,5-dioxopyrrolidin-3-yl)-
			Z-NH	1 H-indole-5-carbonitrile
14
	IW	Y	v$
			Y-n H

Cpd n°	Structure	Chemical name
15	0 Λ-ΝΗ ’xxV” ^r H	3-(5,6-d if luoro-1 /7-indol-3- yl)pyrrolidine-2,5-dione
16	0 Unh 'W H	3-(5-fluoro-6-methyl-1 Hindol-3-yl)pyrrolidine-2,5dione
17	0 ANH ^r H	3-(6-fluoro-1 /7-i ndol-3- yl)pyrrolidine-2,5-dione
18	0 Anh c,VAn	3-(6-chloro-1 /7-i ndol-3- yl)pyrrolidine-2,5-dione
19	0 A-nh bAV	3-(6-bromo-1 /7-i ndol-3- yl)pyrrolidine-2,5-dione
20	0 Λ-ΝΗ H	3-(6-methyl-1 /7-i ndol-3- yl)pyrrolidine-2,5-dione

Cpd n°	Structure	Chemical name
			0	3-(6-methoxy-1 /-/-indol-3-
			Anh	yl)pyrrolidine-2,5-dione
21			yx)
			ϊΛ
	H₃CO'^>^	II / ^•N H
			0	3-(2,5-dioxopyrrolidin-3-yl)-
			Anh	1 /-/-indole-6-carbonitrile
22			/Ά
		AA
	NC		Ά H
		o_x		3-(naphthalen-1-
		y—Ni-i	yl)pyrrolidine-2,5-dione
23		H*	k_7

		o	-NH	3-(6-fluoronaphthalen-1 - yl)pyrrolidine-2,5-dione
24
			A,
	A	AA
		0	-NH	3-(7-fluoronaphthalen-1 - yl)pyrrolidine-2,5-dione
25			Ύ
	F^	A/	A
		AA
		o„	Y~ NH	3-(6-chloronaphthalen-1 - yl)pyrrolidine-2,5-dione
26
		AA	A
	CI	KJ	\A

Cpd n°	Structure	Chemical name
27	o — /7 ¹ o	3-(7-chloronaphthalen-1 - yl)pyrrolidine-2,5-dione

or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof.

In Table 1, the term “Cpd” means compound.

The compounds of Table 1 were named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

According to a preferred embodiment, particularly preferred compounds of Formula I of the invention are compounds of Table 1 n° I, la, 2, 4, 6, 7, 8, 9, 10, 14, 16, 22, 24, 25, 26, 27.

The compounds of Formula I and subformulae thereof contain an asymmetric center and thus exist as different stereoisomeric forms. Accordingly, the présent invention 10 includes ail possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographie methods as each are known in the art. Resolution of the final product, 15 an intermediate, or a starting material may be performed by any suitable method known in the art.

The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of Formula I include base salts, which form non-toxic salts including, e.g., aluminum, calcium, choline, magnésium, potassium, sodium, zinc, and tétraméthylammonium hydroxide. Although less desired, other bases may be selected, including, e.g., ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, N,N’-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine,

piperazine, tris(hydroxymethyl)aminomethane, benzathine, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, and 4-(2-hydroxyethyl)morpholine . Hemisalts of bases may also be formed, for example, hemicalcium salts.

Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods:

(i) by reacting the compound of Formula I and its subformulae with the desired base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I (or its subformulae) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or (iii) by converting one sait of the compound of Formula I (or its subformulae) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

Ail these reactions are typically carried out in solution. The sait, may precipitate from solution and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionization in the sait may vary from completely ionized to almost nonion ized.

The compounds of the présent invention may be administered in the form of pharmaceutically acceptable salts. The term pharmaceutically acceptable sait is intended to include ail acceptable salts such as can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the présent invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnésium, zinc, and from bases such as, and tétraméthylammonium hydroxide.

These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is présent, such as amino, an acidic sait, i.e. hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.

Also, in the case of an alcohol group being présent, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

Ail references to compounds of Formula I include references to enantiomers, salts, solvatés, polymorphs, multi- component complexes and liquid crystals thereof.

The compounds of the invention include compounds of Formula I as hereinbefore defined, including ail polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, géométrie and tautomeric isomers) and isotopically-labeled 10 compounds of Formula I.

In addition, although generally, with respect to the salts of the compounds ofthe invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification ofthe compounds of 15 the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the séparation of optically active isomers of the compounds of Formula I above.

As used herein, the term “free base” refers to the non-salt form of a compound of Formula I.

Unless otherwise specified, reference to Formula I herein includes its subformulae, such as Formula la, Ib, la’, I’, I”, II, II’, and II”.

The invention also generally covers ail pharmaceutically acceptable predrugs and prodrugs ofthe compounds of Formula I.

Process for manufacturing

The compounds of Formula I can be prepared by different ways with reactions known to a person skilled in the art.

181

The invention further relates to a first process for manufacturing of compounds of Formula I

and pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, wherein X, R¹ and R² are as defined in Formula I;

comprising reacting a compound of Formula (i)

wherein X, R¹ and R² are as defined in Formula I with maleimide to provide compound of Formula I;

and optionally separating enantiomers of Formula I’ and I”.

According to one embodiment, the process may be performed in the presence of a suitable solvent such as but not limited to acetic acid, acetonitrile, DMSO, dichloroethane, DMF, water or mixtures thereof, preferably in acetic acid or acetonitrile. According to one embodiment, the process may be performed in the presence or absence of a suitable catalyst, such as but not limited to protic acids such as but not limited to acetic acid, hydrochloric acid or sulfuric acid; or Lewis acids such as but not limited to zinc chloride, zinc acetate, zinc triflate, aluminum chloride, cobalt chloride, cobalt acetate or iron chloride

According to one embodiment, the process may be performed at a température ranging from 20 °C to about 200 °C, preferably at a température ranging from 60 °C to 200 °C, or about 150 °C to about 200 °C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, e.g. 10 minutes to 48 h.

181

According to one embodiment, the optional séparation ofthe enantiomers of Formula I’ and I” starting from the corresponding compound of Formula I 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, éthanol, methanol, hexane.

According to one embodiment, the optional séparation ofthe enantiomers of Formula I’ and I” starting from the corresponding compound of Formula I can be achieved by resolution using optically pure acids, such as but not limited to camphosulfonic acid or tartaric acid, or with optically pure bases, such as but not limited to brucine, depending on the nature ofthe compound of Formula I.

The invention further relates to a second process of manufacturing of compounds of Formula I

and pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, wherein X, R¹ and R²are as defined in Formula I;

comprising reacting a compound of Formula (ii)

wherein X, R¹ and R² are as defined in Formula I; and

Z¹ and Z² represent H or alkyl groups, with the possibility for Z¹ and Z²to form a ring;

with maleimide to provide compound of Formula I;.

and optionally separating enantiomers of Formula I’ and I”.

181

According to one embodiment, the process may be performed with or without a catalyst such as but not limited to [RhOH(cod)]2.

According to one embodiment, the process may be performed in the presence of bases such as but not limited to trimethylamine (TEA), diethylisopropylamine (DIEA), sodium hydroxide (NaOH), potassium hydroxide (KOH), tripotassium phosphate (K3PO4), dipotassium carbonate (K2CO3), disodium carbonate (Na2CO3), preferably TEA or DIEA.

According to one embodiment, the process may be performed in the presence of a suitable solvent such as but not limited to dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), water or mixtures thereof, preferably in dioxane or THF.

According to one embodiment, the process may be performed at a température ranging from 20 °C to about 150 °C, with orwithout microwave irradiation, fora period ranging from 10 minutes to a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, the optional séparation of the enantiomers of Formula I’ and I” starting from the corresponding compound of Formula I 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, éthanol, methanol, hexane.

According to one embodiment, the optional séparation of the enantiomers of Formula Γ and I” starting from the corresponding compound of Formula I can be achieved by resolution using optically pure acids, such as but not limited to camphosulfonic acid or tartaric acid, or with optically pure bases, such as but not limited to brucine, depending on the nature of the compound of Formula I.

The invention further relates to a third process of manufacturing of compounds of Formula I

-29and pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, wherein X, R¹ and R² are as defined in Formula I;

comprising (a) reacting a compound of Formula (iii)

wherein X, R¹ and R² are as defined in Formula I;

so as to obtain a compound of Formula (iv)

wherein X, R¹ and R² are as defined in Formula I;

(b) reacting compound of Formula (iv) with maleic anhydride so as to obtain compound of Formula (v)

wherein X, R¹ and R² are as defined in Formula I;

and (c) reacting compound of Formula (iv) with urea so as to obtain compound of Formula I (d) optionally separating enantiomers of Formula Γ and I”.

According to one embodiment, step (a) may be performed in the presence of a nitrite, such as but not limited to NaNCte, KNO2, tert-butyl nitrite or isoamyl nitrite.

According to one embodiment, step (a) may be performed in the presence of a suitable acid, such as but not limited to HBF4.

According to one embodiment, step (a) may be performed in the presence of a suitable solvent such as but not limited to water.

According to one embodiment, step (a) may be performed at a température ranging from -20 °C to about 20 °C, preferably at 0 °C.

According to one embodiment, step (a) may be performed for a period ranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, step (b) may be performed in the presence of a suitable 10 catalyst, such as but not limited to T1CI3.

According to one embodiment, step (b) may be performed in the presence of a suitable base, such as but not limited to NaOH or KOH.

According to one embodiment, step (b) may be performed in the presence of a suitable solvent such as but not limited to acetone, methyl ethyl ketone.

According to one embodiment, step (b) may be performed at a température ranging from -20 °C to about 20 °C, preferably at 0 °C.

According to one embodiment, step (b) may be performed for a period ranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, step (c) may be performed in the absence or presence of 20 a suitable solvent, at a température ranging from 100 °C to about 200 °C, preferably at 180 °C.

According to one embodiment, step (c) may be performed for a period ranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, the optional séparation of the enantiomers of Formula I’ 25 and I” starting from the corresponding compound of Formula I can be achieved by chiral

HPLC, such as but not limited to using a Chiralpak® AS-H, Chiralcel® OJ-H or φ -31Chiralpak® IC column, using as eluents mixtures of appropriate solvents such as but not limited to supercritical CO2, éthanol, methanol, hexane.

According to one embodiment, the optional séparation of the enantiomers of Formula I’ and I” starting from the corresponding compound of Formula I can be achieved by resolution using optically pure acids, such as but not limited to camphosulfonic acid or tartaric acid, or with optically pure bases, such as but not limited to brucine, depending on the nature of the compound of Formula I.

In general, the synthesis pathways for any individual compound of Formula I will dépend on the spécifie substituents of each molécule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.

According to a further general process, compounds of Formula I can be converted to alternative compounds of Formula I, employing suitable interconversion techniques well known by a person skilled in the art.

Compounds of the Formula I and related formulae can furthermore be obtained by liberating compounds of the Formula I from one of their functional dérivatives by treatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the Formula I and related formulae, but contain corresponding protected amino and/or 20 hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R*-N group, in which R* dénotés an aminoprotecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to 25 the Formula I, but carry a -COOR** group, in which R** dénotés a hydroxyl-protecting group, instead of a -COOH group.

It is also possible for a plurality of - identical or different - protected amino and/or hydroxyl groups to be présent in the molécule of the starting material. If the protecting groups présent are different from one another, they can in many cases be cleaved off 30 selectively.

φ -32The term “amino-protecting group” is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molécule. Typical of such groups are, in particular, unsubstituted or 5 substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term “acyl group” is to be understood in the broadest sense in connection with the présent process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,215 trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ (carbobenzoxy), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general terms and relates to 20 groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molécule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms. Examples of hydroxylprotecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, ptoluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.

The compounds of the Formula I and related formulae are liberated from their functional dérivatives - depending on the protecting group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid orsulfuric acid, strong organic

-33carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzeneor p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as THF or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, éthanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. Trifluoracetic acid (TFA) is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction températures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room température).

The BOC, OtBu and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30°C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°C.

Protecting groups which can be removed hydrogenolytically (for example CBZ, benzyl or the libération of the amidino group from the oxadiazole dérivative thereof) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or éthanol, or amides, such as DMF. The hydrogenolysis is generally carried out at températures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably at20-30°C and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°C.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, éthanol, isopropanol, n-propanol, nbutanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether

or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethyl-formamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid;

nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.

Esters can be hydrolysed, for example, using HCl, H2SO4, or using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at températures between 0 and 100°C.

Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at températures between -60°C and +30°C.

For ail the protection and deprotection methods, see Philip J. Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in Organic Synthesis”, Wiley Interscience, 3rd Edition 1999.

Reaction schemes as described in the example section are illustrative only and should 20 not be construed as limiting the invention in any way.

Uses

The invention is further directed to a médicament comprising at least one compound of the invention, or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof, or a deuterated form thereof, as active ingrédient.

In the présent invention, the expression “compound of the invention” encompasses compounds of Formula I and its subformulae, or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof, or a deuterated form thereof. Examples are identified in Table 1 and in the examples. Illustrative compounds include: 3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

-35(-)-(R)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; (+)-(S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(1H-indol-3-yl)pyrrolidine-2,5-dione;

(-)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;

(+-)-(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(-)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(+)-(S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(R) -3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(S) -3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; 3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(R) -3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(S) -3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile;

3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(6-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile;

3-(naphthalen-1-yi)pyrrolidine-2,5-dione;

3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; and

3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione.

Optionally, these compounds of Formula I may be deuterated, e.g., at the chiral center. An illustrated deuterated compound is (3-²H)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5dione.

In one embodiment, the compound has the structure of Formula II:

¹¹ , or a pharmaceutically acceptable sait thereof. The compound may be a racemate, wherein each stereoisomer is présent an amount of about 50 mol% (48% to 52%). Alternatively or additionally, a separate enantiomer ofthe compound is used in a pharmaceutical composition. In one embodiment, the enantiomer is characterized by structure of Formula II’:

which is présent in free base (not sait) form. Optionally, the compound is présent as a pharmaceutically acceptable sait or solvaté thereof. In another embodiment, the (S)enantiomer is additionally or alternatively présent in the composition. This enantiomer is 15 characterized by the structure of Formula II”:

which is in free base form, or optionally may be sait form. Pharmaceutical compositions may contain mixtures of the compounds of Formula II’ and Formula II”. A variety of ratios of the two compounds may be selected. For example, the ratio may be about 1:1, 5 or the compound of Formula II· may be présent in greater than 50%, greater than 95%, greaterthan 90%, or about 95% to 100%. Similarly, in other compositions, the compound of Formula II” may be présent in greater than 50%. The discussion of suitable ratios and molar percentages of enantiomers relating to the compounds of Formula I and its subformulae earlier in the spécification, is hereby incorporated by reference.

*

The invention also provides pharmaceutical compositions comprising a compound of the é·invention or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof 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 ingrédients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the récipient thereof in an amount used in the médicament.

According to one embodiment, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the présent invention or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof as active ingrédient, additional 20 therapeutic agents and/or active ingrédients.

By means of non-limiting examples, the compounds of the invention may be formulated as a pharmaceutical préparation in a form suitable for oral administration, for parentéral administration (such as by intravenous, intramuscularorsubcutaneous injection or intravenous infusion), fortopical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the

manner of administration - as well as methods and carriers, diluents and excipients for use in the préparation thereof, will be clear to the skilled person; référencé is made to the latest édition of Remington’s Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such préparations include tablets, pills, powders, lozenges, sachets, cachets, élixirs, suspensions, émulsions, solutions, syrups, aérosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, stérile injectable solutions and stérile packaged powders (which are usually reconstituted priorto use) for administration as a bolus and/or for 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, (stérile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnésium stéarate, edible oils, vegetable oils and minerai oils or suitable mixtures thereof. The formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, désintégrants, 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 pharmaceutical préparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.

Depending on the condition to be prevented or treated and the route of administration, the active compound of the invention may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.

The invention also relates to the use of compounds of the invention, or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, in the treatment and/or

prévention of cancer and endometriosis. In one embodiment, the invention relates to the use of compounds ofthe invention, or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, in the treatment and/or prévention of cancer. In another embodiment, the invention relates to the use of compounds of the invention, or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, in the treatment and/or prévention of endometriosis.

In one embodiment, compounds ofthe invention orpharmaceutically acceptable enantiomers, salts, solvatés or prodrugs thereof are for use in the treatment and/or prévention of cancer and endometriosis. According to one embodiment, compounds of 10 the invention, or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, are for use in the treatment and/or prévention of cancer. According to another embodiment, compounds ofthe invention, or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, are for use in the treatment and/or prévention of endometriosis.

The invention further relates to a method for treatment or prévention of cancer and endometriosis, which comprises administering to a subject in need thereof a therapeutically effective amount ofthe compound according to the invention or a pharmaceutically acceptable enantiomers, salts, solvatés or prodrugs thereof. In one embodiment, the invention relates to a method for treatment or prévention of cancer, 20 which comprises administering to a subject in need thereof a therapeutically effective amount ofthe compound according to the invention or a pharmaceutically acceptable enantiomers, salts, solvatés or prodrugs thereof. In another embodiment, the invention relates to a method for treatment or prévention of endometriosis, which comprises administering to a subject in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts, solvatés or prodrugs thereof.

In one embodiment, compounds ofthe invention or pharmaceutically acceptable enantiomers, salts, solvatés or prodrugs thereof are for use in increasing immune récognition and destruction of the cancer cells.

The compounds ofthe invention are therefore useful as médicaments, in particular in the prévention and/or treatment of cancer.

The invention further provides the use of a compound according to the invention or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof for the manufacture of a médicament for treating and/or preventing cancer.

Various cancers are known in the art. The cancer may be metastatic or non-metastatic.

The cancer may be may be familial or sporadic. In some embodiments, the cancer is selected from the group consisting of: leukemia and multiple myeloma. In one embodiment, the cancer is leukemia. In one embodiment, the cancer is multiple myeloma.

Additional cancers that can be treated using the methods ofthe invention include, for 10 example, benign and malignant solid tumors and benign and malignant non-solid tumors. In one embodiment, the cancer is benign solid tumors. In one embodiment, the cancer is malignant solid tumors. In one embodiment, the cancer is benign non-solid tumors. In one embodiment, the cancer is malignant non- solid tumors.

Examples of solid tumors include, but are not limited to: biliary tract cancer, brain cancer 15 (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endométrial cancer, esophageal cancer, gastric cancer, intraepithélial neoplasms (including Bowen’s disease and Paget’s disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from épithélial cells, stromal cells, germ cells and 20 mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, rénal cancer (including adenocarcinoma and Wilms tumour), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi’s sarcoma, basocellular cancer and squamous cell cancer), testicular cancer including germinal tumors (seminomas, and non-seminomas 25 such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, and thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma).

In one embodiment, the cancer is biliary tract cancer. In one embodiment, the cancer is brain cancer, including glioblastomas and medulloblastomas. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is cervical cancer. In one embodiment, the cancer is choriocarcinoma. In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is endométrial cancer. In one embodiment, the

-41 cancer is esophageal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is intraepithélial neoplasms, including Bowen’s disease and Paget’s disease. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is neuroblastomas. In one embodiment, the cancer is oral cancer, including squamous cell carcinoma. In one embodiment, the cancer is ovarian cancer, including those arising from épithélial cells, stromal cells, germ cells and mesenchymal cells. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is rectal cancer. In one embodiment, the cancer is rénal cancer, including adenocarcinoma and Wilms tumour. In one embodiment, the cancer is sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma. In one embodiment, the cancer is skin cancer, including melanoma, Kaposi’s sarcoma, basocellular cancer and squamous cell cancer. In one embodiment, the cancer is testicular cancer including germinal tumors (seminomas, and nonseminomas such as teratomas and choriocarcinomas). In one embodiment, the cancer is stromal tumors. In one embodiment, the cancer is germ cell tumors. In one embodiment, the cancer is thyroid cancer, including thyroid adenocarcinoma and medullary carcinoma.

Examples of non-solid tumors include but are not limited to hematological neoplasms. As used herein, a hématologie neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.

Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliférative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, nonHodgkin’s lymphoma lymphomas, and lymphocytic lymphomas). Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.

In one embodiment, the lymphoid disorder is acute lymphocytic leukemia. In one embodiment, the lymphoid disorder is chronic lymphoproliférative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). In one embodiment, the lymphoma is Hodgkin’s disease. In one embodiment, the lymphoma is non-Hodgkin’s

-42lymphoma. In one embodiment, the lymphoma is lymphocytic lymphoma. In one embodiment, the chronic lymphoid leukemia is T cell chronic lymphoid leukemia. In one embodiment, the chronic lymphoid leukemia is B cell chronic lymphoid leukemia.

The invention also provides for a method for delaying in a subject the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound according to the invention or pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof to a subject in need thereof.

The invention is further directed to the use of compounds of the invention, or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof as IDO1 inhibitors.

Accordingly, in a particularly preferred embodiment, the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts, solvatés and prodrugs thereof, as IDO1 inhibitors.

Accordingly, in another aspect, the invention relates to the use of these compounds or enantiomers, salts, solvatés and prodrugs thereof for the synthesis of IDO1 inhibitors.

According to a further feature of the présent invention there is provided a method for modulating IDO1 activity, in a subject in need of such treatment, which comprises administering to said subject an effective amount of compound of the présent invention, or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof.

According to a further feature of the présent invention there is provided the use of a compound of the invention or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof for the manufacture of a médicament for modulating IDO1 activity in a subject in need of such treatment, which comprises administering to said subject an effective amount of compound of the présent invention, or a pharmaceutically acceptable enantiomer, sait, solvaté and prodrug thereof.

DEFINITIONS

In the présent invention, the following terms hâve the following meanings:

Where groups may be substituted, such groups may be substituted with one or more substituents, and preferably with one, two or three substituents. Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, 5 oxo, nitro, amido, carboxy, amino, cyano, haloalkoxy, and haloalkyl.

The term halogen or halo means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferred halo groups are fluoro and chloro.

The term alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C_nH2n+i wherein n is a number greater than or equal to 1. Generally, alkyl 10 groups of this invention comprise from 1 to 6 carbon atoms (C1, C2, C3, C4, C5, or C6 carbons, inclusive), preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl 15 and its isomers (e.g. n-hexyl, iso-hexyl). Optionally, an alkyl may be substituted with 1, 2 or 3 substituents. Such a substituent may be a hydroxy, amino-, halogen, or C1-C3 alkyl group. In one embodiment, a halogen substituent is a F or Br. In another embodiment, an alkyl substituent is a methyl group.The term alkoxy refers to any group O-alkyl.

The term amino refers to a -NH2 group or any group derived thereof by substitution of one nortwo hydrogen atom by an organic aliphatic or aromatic group. Preferably, groups derived from -NH2 are “alkylamino” groups, i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino. According to a spécifie embodiment, the term amino refers to NH2, NHMe or NMe2.

The term amino-protecting group refers to a protecting group for an amine function. According to a preferred embodiment, the amino-protecting group is selected in the groups comprising: arylsulphonyl, tert-butoxy carbonyl, methoxymethyl, para-methoxy benzyl or benzyl.

The term solvaté is used herein to describe a compound in this invention that contains 30 stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically

acceptable solvent molécule such as éthanol. The term hydrate refers to when the said solvent is water.

The compounds ofthe invention include compounds of Formula I as hereinbefore defined, including ail polymorphs and crystal habits thereof, prodrugs and prodrugs thereof and isotopically- labeled compounds of Formula I.

The term prodrug as used herein means the pharmacologically acceptable dérivatives of compounds of Formula I, such as for example amides, whose in vivo biotransformation product generates the biologically active drug. Prodrugs are generally characterized by increased bio-availability and are readily metabolized into biologically active compounds in vivo.

The term predrug, as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the 15 body, and either before or after the predrug reaches the area of the body where administration ofthe drug is indicated.

The term subject refers to a mammal, preferably a human. In one embodiment, a subject may be a patient, i.e. a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or was/is/will be the 20 object of a medical procedure, or is monitored for the development of a disease.

The term human refers to a person of both genders and at any stage of development (i.e. neonate, infant, juvénile, adolescent, adult).

The terms treat, treating and treatment, as used herein, are meant to include alleviating, attenuating orabrogating a condition or disease and/or its attendant symptoms.

The terms prevent, preventing and prévention, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant

-45symptoms, barring a subject from acquiring a condition or disease, or reducing a subject’s risk of acquiring a condition or disease.

The term therapeutically effective amount (or more simply an effective amount) as used herein means the amount of active agent or active ingrédient that is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which/whom it is administered.

The term administration, or a variant thereof (e.g. administering), means providing the active agent or active ingrédient, alone or as part of a pharmaceutically acceptable composition, to the subject in whom/which the condition, symptom, or disease is to be treated or prevented.

By pharmaceutically acceptable is meant that the ingrédients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered.

The term inhibitor refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of a gene and/or a protein or that has a biological effect to inhibit or significantly reduce the biological activity of a protein. Consequently, an “IDO1 inhibitor” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of the gene encoding for IDO1 and/or the expression of IDO1 and/or the biological activity of IDO1.

“D and d both refer to deuterium. dx.y refers to substitution with from x to y number of deuterium atoms. Stereoisomer refers to both enantiomers and diastereomers. A group is substituted with a substituent when one or more hydrogen atoms of the group are replaced with a corresponding number of substituent atoms (if the substituent is an atom) or groups (if the substituent is a group). For example, substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

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 % from the reference given, unless otherwise specified.

EXAMPLES

The présent invention will be better understood with reference to the following examples. These examples are intended to représentative of spécifie embodiments of the invention, and are not intended as limiting the scope ofthe 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 ™ 400 PLUS and Bruker Fourier 300 MHz and TMS was used as an internai standard.

The microwave chemistry was performed on a single mode microwave reactor Initiator 15 Microwave System EU from Biotage.

Préparative HPLC purifications were performed with a mass directed autopurification Fractionlynx from Waters equipped with a Xbridge™ Prep C18 OBD column 19x150 mm 5 pm, unless otherwise reported. Ail HPLC purifications were performed with a gradient of CH3CN/H2O/NH4HCO3 (5 mM), CHsCN /H2O/TFA (0.1%), or CH3CN /H2O/NH3 H2O 20 (0.1%).

Compound 1: 3-(5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione

A. Route A »

A mixture of 5-fluoro-1/7-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 EtOAc (10 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by préparative HPLC to afford 180 mg (35 %) of the title compound as a yellow solid. LCMS for C12H9FN2O2-H- [M-H]: calcd. 231.1; found: 231.0.¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.30 (brs, 1 H), 11.14 (s, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 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, 1 H), 3.17 (dd, J = 18.0, 9.5 Hz, 1 H), 2.79 (dd, J = 18.0, 5.5 Hz, 1 H).

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 tempearture above 80°C. Yellow solids precipitated. The reaction mixture was cooled to 50°C over 1 hourfollowed 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 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).

-48This isolated compound is charged 2 (1.00 g, 4.3 mmol, 100 mass%,) into a 50ml 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).

Compound 1 a: (3-²H)-3-(5-fluoro-1 /7-indol-3-yl)pyrrolidine-2,5-dione

To a solution of of 3-(5-Fluoro-1 H-indol-3-yl)-pyrrolidine-2,5-dione (Compound 1,200 mg, 0.87 mmol) in D₂O (3 mL) was added K2CO3 (300 mg, 2.2 mmol). The reaction was stirred at 40 °C overnight. The mixture was extracted with EtOAc. The organic layer was dried, filtered, concentrated and purified by préparative HPLC to afford the Title Compound (20 mg, 10%) as a yellow solid. LC-MS for C12H8DFN2O2-H· [M-H]^-: calcd. 232.1; found: 232.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.28 (s, 1 H), 11.15 (s, 1 H), 7.41 (d, J = 2.1 Hz, 1 H), 7.36 (dd, J = 8.7, 4.5 Hz, 1 H), 7.20 (dd, J = 10.2, 2.4 Hz, 1H), 6.97-6.90 (m, 1H), 3.19-3.13 (m, 1H), 2.80-2.74 (m, 1H).

Compound 2: (-)-(R)-3-(5-fluoro-1 /7-indol-3-yl)pyrrolidine-2,5-dione

mg of the title compound was obtained as a yellow solid by chiral préparative HPLC séparation of 150 mg of compound 1. Préparative chiral HPLC: Chiralpak® AS-H 250mmx20mm 5pm; Mobile phase: CO2/IPA = 60/40; Flow: 50 mL/min 214 nm ambient température. Analytical chiral HPLC: Chiralpak® IC 250mmx4.6mm 5pm; Mobile phase: Hexane/EtOH = 70/30; Flow: 1.0 mL/min 230 nm ambient température; Rétention time:

-496.25 min. P1: 96.3% e.e. [a]²⁵⁴ _D = -75.4 (c = 0.0014, MeOH). LC-MS for Ci2H9FN₂O₂+H⁺[M+H]⁺: calcd. 233.1; found: 233.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.30 (brs, 1 H), 11.14 (s, 1 H), 7.41 (d, J = 2.5 Hz, 1 H), 7.36 (dd, J = 9.0, 4.6 Hz, 1 H), 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).

Compound 2a: (+)-(S)-3-(5-fluoro-1 /7-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral séparation described for

Compound 2a. Chiral HPLC rétention time: 6.96 min. 98.5% e.e. [o]²⁵⁴d= 70 (c =

0.0014, MeOH).

Compound 3: 3-(1/7-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 1H-indole (2.00 g; 17.1 mmol) and maleimide (4.96 g; 51.1 mmol), 2.50 g (68%) of the title compound was obtained as a yellow solid after purification by siiica gel chromatography (petroleum ether/EtOAc = 1/1). LC-MS for Ci2HioFN₂02+H⁺ [M+H]⁺: calcd. 215.1; found: 215.1. ¹H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.29 (s, 1H), 11.02 (s, 1H), 7.42 (d, J =8.0 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.12-7.07 (m, 1H), 7.02-6.97 (m, 1H), 4.33 (dd, J = 9.5, 5.3 Hz, 1H), 3.18 (dd, J = 18.0, 9.5 Hz, 1H), 2.76 (dd, J = 18.0, 5.3 Hz, 1H).

-50Compound 4: (-)-(F?)-3-(1/7-indol-3-yl)pyrrolidine-2,5-dione o

N H

100 mg ofthe title compound was obtained as a yellowsolid by chiral préparative HPLC séparation of 250 mg of compound 3. Préparative chiral HPLC: Chiralcel OJ-H

250mmx4.6mm 5pm; Mobile phase: CO2/MeOH = 60/40; Flow: 50 mL/min 230 nm ambient température. Analytical chiral HPLC: Chiralcel IC 250mmx4.6mm 5pm; Mobile phase: Hexane/EtOH = 70/30; Flow: 1.0 mL/min 230 nm ambient température; Rétention time: 7.632 min. P1: 99.7% e.e. [a]²⁵⁴D= -64.6 (c=0.01, MeOH). LC-MS for Ci₂HioFN20₂+H⁺ [M+H]⁺: calcd. 215.1; found: 215.1.¹H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.29 (s, 1H), 11.02 (s, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.1 Hz, 1H),

7.32 (d, J = 2.4 Hz, 1 H), 7.12-7.07 (m, 1 H), 7.02 - 6.97 (m, 1 H), 4.33 (dd, J = 9.5, 5.3 Hz, 1H), 3.18 (dd, 7=18.0, 9.5 Hz, 1H), 2.76 (dd, 7=18.0, 5.3 Hz, 1H).

Compound 4a: (+)-(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral séparation described for

Compound 4a. Chiral HPLC rétention time: 9.028 min. 99.6% e.e. [o]²⁵⁴d= 64.5 (c=0.01, MeOH).

-51 Compound 5: 3-(5-chloro-1/7-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 5-chloro-1Hindole (2.00 g; 13.2 mmol) and maleimide (3.84 g; 39.6 mmol), 160 mg (4.9%) of the title compound was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/EtOAc = 3/1). LC-MS for C12H9CIN2O2-I+ [M-H]^-: calcd. 247.0; found: 247.0. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.30 (brs, 1H), 11.25 (brs, 1H), 7.49 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.39 (d, J = 8.6 Hz, 1 H), 7.10 (dd, J = 8.6, 2.0 Hz, 1 H), 4.36 (dd, J = 9.5, 5.5 Hz, 1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.80 (dd, J = 18.0, 5.5 Hz, 1H).

Compound 6: (-)-(R)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione

mg of the title compound was obtained by chiral préparative HPLC séparation of 120 mg of compound 5. Préparative chiral HPLC: Chiralpak® IC 250mmx20mm 5pm; Mobile phase: Hexane/EtOH = 70/30; Flow: 15 mL/min 214 nm ambient température. Analytical chiral HPLC: Chiralpak® IC 250mmx4.6mm 5pm; Mobile phase: Hexane/EtOH = 70/30; Flow: 1.0 mL/min 230 nm ambient température; Rétention time: 6.073 min. P1: 99.5% e.e. [o]²⁵⁴d = -69.0 (c=0.0042, MeOH). LC-MS for 0ΐ2Η9θΝ₂0₂+Η⁺ [M+H]⁺: calcd. 249.0; found: 249.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.29 (brs, 1H), 11.25 (brs, 1H), 7.49 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.39 (d, J = 8.6 Hz, 1 H), 7.10 (dd, J = 8.6, 2.0 Hz, 1 H), 4.36 (dd, J = 9.5, 5.5 Hz, 1 H), 3.17 (dd, J = 18.0, 9.5 Hz, 1 H), 2.80 (dd, J = 18.0, 5.5 Hz, 1H).

Compound 6a: (+)-(S)-3-(5-chloro-1 /7-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral séparation described for Compound 6a. Chiral HPLC rétention time: 6.868 min. P1: 99.6% e.e. [o]²⁵⁴d = 67.4 (c=0.0038, MeOH).

Compound 7: 3-(6-chloro-5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 6-chloro-5fluoro-1/7-indole (300 mg; 1.77 mmol) and maleimide (513 mg; 5.28 mmol), 110 mg (23%) of the title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for C12H8CIFN2O2-H- [M-H]': calcd. 265.1; found: 265.0. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.30 (br s, 1 H), 11.27 (br s, 1 H), 7.54 (d, J = 6.4 Hz, 1H), 7.47 (s, 1H), 7.46 (d, J = 10.2 Hz, 1H), 4.35 (dd, J = 9.4, 5.8 Hz, 1H), 3.16 (dd, J= 18.0, 9.4 Hz, 1H), 2.81 (dd, J = 18.0, 5.8 Hz, 1H).

Compound 8: (R)-3-(6-chloro-5-fluoro-1 /-/-indol-3-yl)pyrrolidine-2,5-dione

mg of the title compound was obtained by chiral préparative HPLC séparation of 70 mg of compound 7. Préparative chiral HPLC: Chiralpak® AS-H 250mmx20mm 5pm; Mobile phase: CO2/IPA = 60/40; Flow: 50 mL/min 220 nm ambient température. Analytical chiral HPLC: Chiralpak® IA 250mmx4.6mm 5pm; Mobile phase:

-53CO2/IPA/DEA = 70/30/0.2; Flow: 1.0 mL/min 230 nm ambient température; Rétention time: 3.72 min. P1: >99.5% e.e. LC-MS for C12H8CIFN2O2-H· [M-Hp: calcd. 265.1; found:

265.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.30 (br s, 1 H), 11.27 (br s, 1 H), 7.54 (d, J = 6.4 Hz, 1 H), 7.47 (s, 1 H), 7.46 (d, J = 10.2 Hz, 1 H), 4.35 (dd, J = 9.4, 5.8 Hz, 1 H),

3.16 (dd, J= 18.0, 9.4 Hz, 1H), 2.81 (dd, J= 18.0, 5.8 Hz, 1H).

Compound 8a: (S)-3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomerfrom the chiral séparation described for Compound 8a. Chiral HPLC rétention time: 5.48 min. 99.6% e.e.

Compound 9: 3-(6-bromo-5-fluoro-1 /7-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 6-bromo-5fluoro-1 H-indole (213 mg; 1.00 mmol) and maleimide (388 mg; 4.00 mmol), 70 mg (23%) ofthe title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for Ci2H₈BrFN2O2-H’ [M-H]^-: calcd. 309.0; found: 308.9. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.31 (s, 1 H), 11.27 (s, 1 H), 7.66 (d, J = 6.0 Hz, 1 H), 7.48 (d, J = 1.7 Hz, 1 H), 7.44 (d, J = 9.8 Hz, 1 H), 4.36 (dd, J = 9.2, 5.6 Hz, 1 H),

3.17 (dd, J = 18.0, 9.2 Hz, 1 H), 2.82 (dd, J = 18.0, 5.6 Hz, 1 H).

Compound 10: (R)-3-(6-bromo-5-fluoro-1 /7-indol-3-yl)pyrrolidine-2,5-dione

-5422 mg of the title compound was obtained by chiral préparative HPLC séparation of 60 mg of compound 9. Préparative chiral HPLC: Chiralpak® AD-H 250mm*20mm 5pm; Mobile phase: CO2/MeOH = 60/40; Flow: 50 mL/min 214 nm ambient température. Analytical chiral HPLC: Chiralpak® ID 250mmx4.6mm 5pm; Mobile phase: CCte/MeOH = 60/40; Flow: 3.0 mL/min 230 nm ambient température; Rétention time: 2.14 min. P1: >99.5% e.e. LC-MS for Ci2H₈BrFN₂O2-H- [M-Hp: calcd. 309.0; found: 308.8. ¹H NMR (300 MHz, DMSO-de) δ [ppm]: 11.31 (s, 1 H), 11.27 (s, 1 H), 7.66 (d, J = 6.0 Hz, 1 H), 7.48 (d, J = 1.7 Hz, 1 H), 7.44 (d, J = 9.8 Hz, 1 H), 4.36 (dd, J = 9.2, 5.6 Hz, 1 H),

3.17 (dd, J =18.0, 9.2 Hz, 1 H), 2.82 (dd, J = 18.0, 5.6 Hz, 1 H).

Compound 10a: (S)-3-(6-bromo-5-fluoro-1 /7-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral séparation described for Compound 10a. Chiral HPLC rétention time: 4.20 min. 98.9% e.e.

Compound 11: 3-(5-bromo-1/7-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 5-bromo-1Hindole (500 mg; 2.56 mmol) and maleimide (666 mg; 6.86 mmol), 160 mg (21%) of the title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for Ci₂H9BrN₂O2+H⁺ [M+H]⁺: calcd. 293.0; found: 293.0. ¹H NMR (400 MHz,

181

DMSO-cfe) δ [ppm]: 11.29 (s, 1 H), 11.26 (s, 1 H), 7.64 (d, J = 1.8 Hz, 1 H), 7.40 (d, J = 2.4

Hz, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.21 (dd, J = 8.6, 1.8 Hz, 1 H), 4.36 (dd, J = 9.5, 5.5

Hz, 1H), 3.17 (dd, J= 18.0, 9.5 Hz, 1H), 2.80 (dd, J= 18.0, 5.5 Hz, 1H).

Compound 12: 3-(5-methyl-1/-/-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 5-methyl-1 Hindole (300 mg; 2.29 mmol) and maleimide (670 mg; 6.87 mmol), 200 mg (38%) of the title compound was obtained as a yellow solid after recrystallization in MeOH. LC-MS for Ci3Hi2N₂O₂+H⁺ [M+H]⁺: calcd. 229.1; found: 229.1. ¹H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.27 (s, 1 H), 10.88 (s, 1 H), 7.26 (dd, J = 8.3, 2.0 Hz), 7.25 (d, J = 2.0 Hz, 1 H), 7.19 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.29 (dd, J = 9.5, 5.3 Hz, 1H), 3.16 (dd, J= 18.0, 9.5 Hz, 1H), 2.74 (dd, J= 18.0, 5.3 Hz, 1H), 2.36 (s, 3H).

Compound 13: 3-(5-methoxy-1/-/-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 5-methoxy-1/-/indole (200 mg; 1.36 mmol) and maleimide (407 mg; 4.19 mmol), 170 mg (51%) of the title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for Ci3Hi₂N₂O₃+H⁺ [M+H]⁺: calcd. 245.1; found: 245.1. ¹H NMR (400 MHz, DMSO-de) δ [ppm]: 11.25 (brs, 1 H), 10.86 (s, 1 H), 7.27 (d, J = 2.2 Hz 1 H), 7.26 (d, J = 8.6 Hz, 1 H), 6.91 (d, J = 2.2 Hz, 1 H), 6.76 (dd, J = 8.6, 2.2 Hz, 1 H), 4.30 (dd, J = 9.6,

5.3 Hz, 1H), 3.74 (s, 3H), 3.18 (dd, J= 17.9, 9.6 Hz, 1H), 2.75 (dd, J= 17.9, 5.3 Hz, 1H).

Compound 14: 3-(2,5-dioxopyrrolidin-3-yl)-1 /7-indole-5-carbonitrile

A mixture of 3-(5-bromo-1/7-indol-3-yl)pyrrolidine-2,5-dione (compound 11; 500 mg; 1.71 mmol) and CuCN (231 mg; 2.58 mmol) in NMP (3 mL) was stirred at 200 °C for 1.5 h in a microwave reactor. The reaction mixture was purified by préparative HPLC to afford

110 mg (27%) ofthe title compound as a green solid. LC-MS for C13H9N3O2+H⁴· [M+H]⁺: calcd. 240.1; found: 240.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.63 (brs, 1H), 8.04 (s, 1 H), 7.57 (d, J = 1.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.45 (dd, J = 8.6, 1.8 Hz, 1 H),

4.44 (dd, J = 9.5, 5.8 Hz, 1H), 3.18 (dd, J= 17.8, 9.5 Hz, 1H), 2.87 (dd, 7= 17.8, 5.8 Hz, 10 1H).

Compound 15: 3-(5,6-difluoro-1 /-7-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 5,6-difluoro-1/7indole (200 mg; 1.31 mmol) and maleimide (380 mg; 3.91 mmol), 15 mg (5%) ofthe title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for C12H8F2N2O2+H⁴· [M+H]⁺: calcd. 251.1; found: 251.0. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.27 (brs, 1H), 11.21 (brs, 1H), 7.45 (dd, 7=11.5, 8.0 Hz, 1H), 7.41 (d, 7=1.8

Hz, 1H), 7.37 (dd, 7= 11.2, 7.0 Hz, 1H), 7.48-7.34 (m, 3H), 4.34 (dd, 7 = 9.3, 5.6 Hz,

1H), 3.16 (dd, 7=18.0, 9.3 Hz, 1H), 2.80 (dd, 7= 18.0, 5.6 Hz, 1H).

-57Compound 16: 3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione

O

o

Following the general method as outlined for compound 1, starting from 5-fluoro-6methyl-1H-indole (1.00 g; 6.70 mmol) and maleimide (2.10 g; 21.6 mmol), 4.2 mg (0.2%) 5 of the title compound was obtained as a yellow solid after purification by préparative

HPLC. LC-MS for Ci3HnFN₂O2+H⁺ [M+H]⁺: calcd. 247.1; found: 247.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.28 (s, 1 H), 10.99 (s, 1 H), 7.31 (d, J = 2.5 Hz, 1 H), 7.22 (d, J = 6.4 Hz, 1H), 7.13 (d, J= 10.8 Hz, 1H), 4.29 (dd, J = 9.4, 5.4 Hz, 1H), 3.16 (dd, J = 18.0, 9.4 Hz, 1H), 2.76 (dd, J= 18.0, 5.4 Hz, 1H), 2.30 (d, , J = 1.6 Hz, 3H).

Compound 17: 3-(6-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione

O

Following the general method as outlined for compound 1, starting from 6-fluoro-1/7indole (4.00 g; 29.6 mmol) and maleimide (8.80 g; 90.7 mmol), 3.0 g (44%) of the title compound was obtained as an orange solid after purification by silica gel chromatography (petroleum ether/EtOAc = 3/1 - 2/3). LC-MS for C12H9FN2O2-H' [M-H]^-:

calcd. 231.1; found: 231.1.¹H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.10 (s, 1 H), 7.43 (dd, J = 8.7, 5.4 Hz, 1 H), 7.33 (d, J = 2.0 Hz, 1 H), 7.14 (dd, J = 10.1, 2.3 Hz, 1 H), 6.87 (td, J = 9.8, 8.7, 2.3 Hz, 1H), 4.34 (dd, J = 9.5, 5.4 Hz, 1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.77 (dd, J = 18.0, 5.4 Hz, 1H).

-58Compound 18: 3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione o

o

Following the general method as outlined for compound 1, starting from 6-chloro-1/7indole (0.50 g; 3.3 mmol) and maleimide (0.96 g; 9.9 mmol), 100 mg (12%) of the title compound was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/EtOAc = 5/1). LC-MS for C12H9CIN2O2-H· [M-H]’: calcd. 247.0; found: 247.0. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.27 (brs, 1 H), 11.17 (s, 1H), 7.45 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 1.8 Hz, 1 H), 7.38 (d, J = 2.4 Hz, 1 H), 7.03 (dd, J = 8.4, 1.8 Hz, 1 H), 4.34 (dd, J = 9.5, 5.5 Hz, 1 H), 3.17 (dd, J = 18.0, 9.5 Hz, 1 H), 2.77 (dd, J =

18.0, 5.5 Hz, 1 H).

Compound 19: 3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione o

Br

H

Following the general method as outlined for compound 1, starting from 6-bromo-1Hindole (2.00 g; 10.2 mmol) and maleimide (2.96 g; 30.5 mmol), 1.5 g (50%) of the title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for Ci2H9BrN2O₂+H⁺ [M+H]⁺: calcd. 293.0; found: 293.0. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.30 (brs, 1H), 11.18 (s, 1H), 7.56 (d, J= 1.6 Hz, 1H), 7.41 (d, 7 = 8.5 Hz, 1H),

7.37 (d, 7 = 2.4 Hz, 1 H), 7.14 (dd, 7 = 8.5, 1.7 Hz, 1 H), 4.34 (dd, 7 = 9.5, 5.4 Hz, 1 H),

3.17 (dd, 7= 18.0, 9.5 Hz, 1H), 2.77 (dd, 7= 18.0, 5.4 Hz, 1H).

Compound 20: 3-(6-methyl-1/7-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 6-methyl-1 Hindole (0.20 g; 1.52 mmol) and maleimide (0.44 g; 4.53 mmol), 0.22 g (63%) of the title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for C13H12N2O2-H- [M-H]-: calcd. 227.1; found: 227.1.¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 10.85 (brs, 2H), 11.18 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H),

7.16 (s, 1H), 6.83 (d, J =8.0 Hz, 1H), 4.28 (dd, J= 9.5, 5.3 Hz, 1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.73 (dd, J = 18.0, 5.3 Hz, 1H), 2.38 (s, 3H).

Compound 21: 3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from 6-methoxy-1 Hindole (0.20 g; 1.36 mmol) and maleimide (0.40 g; 4.12 mmol), 80 mg (24%) of the title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS for C13H12N2O3-H- [M-H]-: calcd. 243.1; found: 243.1. ¹H NMR (400 MHz, DMSO-cfe) δ [ppm]: 11.26 (s, 1H), 10.81 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H),

6.86 (d, J = 2.2 Hz, 1 H), 6.66 (dd, J = 8.7, 2.2 Hz, 1 H), 4.27 (dd, J = 9.5, 5.2 Hz, 1 H),

3.75 (s, 3H), 3.16 (dd, J= 18.0, 9.5 Hz, 1H), 2.73 (dd, J= 18.0, 5.2 Hz, 1H).

-60Compound 22: 3-(2,5-dioxopyrrolidin-3-yl)-1 H-indole-6-carbonitrile

Following the general method as outlined for compound 14, starting from 3-(6-bromo1/7-indol-3-yl)pyrrolidine-2,5-dione (compound 19; 0.20 g; 0.68 mmol) and CuCN (90 mg; 1.00 mmol), 14 mg (8.6%) ofthe title compound was obtained as a yellow solid after purification by préparative HPLC. LC-MS forCi3H9N3O2+H⁺ [M+H]⁺: calcd. 240.1; found:

240.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.63 (brs, 1H), 11.32 (s, 1H), 7.88 (s, 1 H), 7.68 - 7.62 (m, 2H), 7.35 (dd, J = 9.5, 5.6 Hz, 1 H), 4.42 (dd, J = 17.8, 9.5 Hz, 1 H),

3.18 (dd, J = 18.0, 9.9 Hz, 1H), 2.82 (dd, J= 17.8, 5.6 Hz, 1H).

Compound 23: 3-(naphthalen-1-yl)pyrrolidine-2,5-dione

To a solution of naphthalen-1-ylboronic acid (0.27 g; 1.57 mmol) in 1,4-dioxane (9 mL) and water (1.4 mL) was added Et3N (0.10 g; 0.99 mmol), [RhOH(cod)]2 (23 mg; 0.05 mmol) and maleimide (100 mg; 1.03 mmol).The dark brown mixture was heated at 50 °C for 2.5 h, cooled to room température, and concentrated in vacuo. The residue was diluted with H2O (10 mL) and extracted with DCM (20 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by préparative HPLC to afford 136 mg (59 %) ofthe title compound as a white solid. LC-MS for C14H11NO2-H- [M-H]-: calcd. 224.1; found: 224.1. ¹H NMR (300 MHz, DMSO-cfe) δ [ppm]: 11.50 (s, 1 H), 8.02-7.95 (m, 2H), 7.89 (d, J = 9.1 Hz, 1 H), 7.63 - 7.53 (m, 2H), 7.53 - 7.46 (m, 1 H), 7.41 (d, J = 7.1 Hz, 1 H), 4.96 (dd, J = 9.6, 5.7 Hz, 1 H), 3.32 (dd, J = 18.0, 9.6 Hz, 1H), 2.71 (dd, J= 18.0, 5.7 Hz, 1H).

Compound 24: 3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione

181

ο.

Ό

Step 1: 6-fluoronaphthalene-1-diazonium tetrafluoroborate +

To a solution of 6-fluoronaphthalen-1 -amine (500 mg; 3.10 mmol) and HBF4(40 %; 2 mL; 12.6 mmol) in H2O (2 mL) at 0°C was added a cold solution of NaNCte (214 mg;

3.10 mmol) in H2O (0.5 mL) dropwise. The reaction was stirred at room température for 1 h. The precipitate was collected by filtration, washed with EtOH (5 mL), Et2O (5 mL), and dried under vacuum to afford 0.40 g (50%) of the title compound as a pale solid, which was used to directly in the next step without further purification.

Step 2: 2-(6-fluoronaphthalen-1-yl)succinic acid

COOH

L -COOH

Maleic anhydride (150 mg; 1.54 mmol) was added with to an aqueous NaOH solution (4 M; 0.70 mL; 2.8 mmol). The resulting solution was added at 0-5 °C to an aqueous TiCh solution (15%; 3.2 g; 3.11 mmol), followed by acetone (2 mL). The cooling bath was removed and 6-fluoronaphthalene-1-diazonium tetrafluoroborate (Step 1: 400 mg; 1.54 mmol) was added slowly over 0.7 h. The suspension was stirred at room température for 1.5 h, concentrated to remove acetone, and extracted with Et2Û (10 mLx3). The aqueous layer was acidified to pH~1 with HCl (1 M) and extracted with EtOAc (10 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 190 mg (47%) of the title compound as a brown solid, which was used directly in the next step without further purification. LC-MS for Ci4HnFO4+NH4⁺[M+ ΝΗ₄]⁺: calcd. 280.1; found: 280.0.

181

Step 3:

A mixture of 2-(6-fluoronaphthalen-1-yl)succînic acid (190 mg; 0.72 mmol) and urea (170 mg; 2.83 mmol) was stirred at 180°C for 1 h. The reaction mixture was purified by siiica gel chromatography (petroleum ether/EtOAc = 1/1) to give a yellow solid, which was further purified by préparative HPLC to afford 63 mg (36%) the title compound as a white solid. LC-MS for Ci4HioFN0₂+H⁺ [M+H]⁺: calcd. 244.1; found:243.9. ¹H NMR (300 MHz, DMSO-c/e) δ [ppm]: 8.08 (dd, J = 9.3, 5.6 Hz, 1H), 7.87 (d, J =8.2 Hz, 1H), 7.76 (dd, J = 10.2, 2.7 Hz, 1 H), 7.56 - 7.46 (m, 2H), 7.38 (d, J = 6.6 Hz, 1 H), 4.95 (dd, J = 9.4, 5.6 Hz, 1H), 3.30 (dd, J =18.0, 9.4 Hz, 1H), 2.71 (dd, J =18.0, 5.6 Hz, 1H).

Compound 25: 3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione

Step 1: 7-fluoronaphthalene-1-diazonium tetrafluoroborate

Nz BF₄

Following the general method as outlined for compound 24 - Step 1, starting from 7fluoronaphthalen-1-amine (300 mg; 1.86 mmol), HBF4(40 %; 1.5 mL; 9.4 mmol), H₂O (5 mL), NaNO₂ (260 mg; 3.77 mmol) in H₂O (4 mL), 300 mg (62%) of the title compound was obtained as a pale solid, which was used to directly in the next step without further purification. LC-MS for CioHeFN₂ ⁺ [M]⁺: calcd. 173.1; found: 173.0.

Step 2: 2-(7-fluoronaphthalen-1-yl)succinic acid

181

Following the general method as outhned for compound 24 - Step 2, starting from maleic anhydride (110 mg; 1.12 mmol), aqueous NaOH solution (4 M; 0.7 mL; 2.8 mmol), aqueous TiCh solution (15%; 2.36 g; 2.32 mmol), acetone (2 mL), and 7fluoronaphthalene-1-diazonium tetrafluoroborate (Step 1: 300 mg; 1.15 mmol), 200 mg (66%) of the title compound was obtained as a brown solid, which was used directly in the next step without further purification.

Step 3:

Following the general method as outlined for compound 24 - Step 3, starting from 2-(7fluoronaphthalen-1-yl)succinic acid (Step 2; 200 mg; 0.76 mmol) and urea (180 mg; 3.00 mmol), 3.3 mg (1.8%) of the title compound was obtained as a white solid after purification by silica gel chromatography (petroleum ether/EtOAc = 1/1) and préparative HPLC. LC-MS for C14H10FNO2-H- [M-H]’: calcd. 242.1; found: 242.0.¹H NMR (300 MHz, MeOH-cta) δ [ppm]: 7.99 (dd, J = 9.0, 5.9 Hz, 1H), 7.88 (dd, J = 5.8, 2.0 Hz, 1H), 7.70 (d, J= 11.1, 2.0 Hz, 2H), 7.50-7.42 (m, 1H), 7.41 -7.32 (m, 1H), 4.88 (dd, J = 9.5, 5.1 Hz, 1H), 3.43 (dd, J = 18.2, 9.5 Hz, 1H), 2.72 (dd, J = 18.2, 5.1 Hz, 1H).

Compound 26: 3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione

Step 1: 6-chloronaphthalene-1-diazonium tetrafluoroborate

Following the general method as outlined for compound 24 - Step 1, starting from 6chloronaphthalen-1-amine (1.00 g; 5.63 mmol), HBF4(40 %; 4 mL; 25.2 mmol), H2O (4 mL), and NaNCte (390 mg; 5.65 mmol) in H2O (1 mL), 1.50 g (96%) of the title compound as a purple solid, which was used to directly in the next step without further purification. LC-MS for CioH₆CIN2⁺ [M]⁺: calcd. 189.0; found: 188.9.

-64Step 2: 2-(6-chloronaphthalen-1-yl)succinic acid COOH )OOH

Following the general method as outlined for compound 24 - Step 2, starting from maleic anhydride (216 mg; 2.20 mmol), aqueous NaOH solution (4 M; 6.0 mL; 24 mmol), aqueous TiCh solution (15%; 4.5 g; 4.4 mmol), acetone (2 mL), and 6chloronaphthalene-1-diazonium tetrafluoroborate (Step 1: 600 mg; 2.17 mmol), 600 mg (99%) of the title compound was obtained as a black solid, which was used directly in the next step without further purification.

Step 3:

Following the general method as outlined for compound 24 - Step 3, starting from 2-(6chloronaphthalen-1-yl)succinic acid (Step 2; 600 mg; 2.15 mmol) and urea (600 mg; 9.99 mmol), 10 mg (2%) of the title compound was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/EtOAc = 2/1) and préparative HPLC. LC-MS for C14H10CINO2-H- [M-H]-; calcd. 258.0; found: 257.9. ¹H NMR (400 MHz, MeOH-c/4) δ [ppm]: 8.02 (d, J = 9.0 Hz, 1 H), 7.96 (d, J = 1.8 Hz, 1 H), 7.81 (d, J =

8.3 Hz, 1 H), 7.57 - 7.49 (m, 2H), 7.42 (d, J = 7.3 Hz, 1 H), 4.96 (dd, J = 9.8, 5.3 Hz, 1 H),

3.44 (dd, J = 18.3, 9.8 Hz, 1 H), 2.77 (dd, J = 18.2, 5.3 Hz, 1 H).

Compound 27: 3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione

O.

ci

Step 1: 7-chloronaphthalene-1-diazonium tetrafluoroborate n₂ bf₄

Cl

-65Following the general method as outlined for compound 24 - Step 1, starting from 7chloronaphthalen-1-amine (0.45 g; 2.53 mmol), HBF4(40 %; 2.5 mL; 15.7 mmol), H2O (2 mL), and NaNO₂ (190 mg; 2.75 mmol) in H₂O (4 mL), 400 mg (57%) ofthe title compound as a pale solid, which was used to directly in the next step without further purification. LC-MS for CioH6CIN2⁺ [M]⁺: calcd. 189.0; found: 188.9.

Step 2: 2-(7-chloronaphthalen-1-yl)succinic acid

COOH

L JDOOH ci

Following the general method as outlined for compound 24 - Step 2, starting from maleic anhydride (213 mg; 2.17 mmol), aqueous NaOH solution (4 M; 0.7 mL; 2.8 mmol), aqueous TiCh solution (15%; 4.46 g; 4.3 mmol), acetone (2 mL), and 7chloronaphthalene-1-diazonium tetrafluoroborate (Step 1: 600 mg; 2.17 mmol), 500 mg (83 %) ofthe title compound was obtained as a brown solid, which was used directly in the next step without further purification.

Step 3:

Following the general method as outlined for compound 24 - Step 3, starting from 2-(7chloronaphthalen-1-yl)succinic acid (Step 2; 500 mg; 1.79 mmol) and urea (430 mg;

7.16 mmol), 2.5 mg (0.5%) ofthe title compound was obtained as a white solid after purification by silica gel chromatography (petroleum ether/EtOAc = 1/1) and préparative HPLC. LC-MS for C14H10CINO2+H⁴· [M+H]⁺: calcd. 260.0; found: 260.0. ¹H NMR (300 MHz, MeOH-d4) δ [ppm]: 8.08 (s, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.59 - 7.53 (m, 3H), 4.94 (dd, J = 9.6, 5.4 Hz, 1 H), 3.44 (dd, J = 18.3, 9.6 Hz, 1 H), 2.75(dd, J= 18.3, 5.4 Hz, 1H).

II. BIOLOGY EXAMPLES

11.1. Assay for IDO1 enzymatic activity détermination

The compounds ofthe présent invention inhibit the enzymatic activity of human IDO1.

To measure enzymatic activity of human IDO1, the reaction mixture contained (final concentrations) potassium phosphate buffer (50 mM, pH 6.5), ascorbic acid (10 mM), methylene blue (5 μΜ) and human recombinant IDO1 enzyme (prepared as described in Rohrig et al. J Med Chem, 2012, 55, 5270-5290; final concentration 5 pg/mL) without or with the compounds of the présent invention at the indicated concentrations (total volume 112.5 pL). The reaction was initiated by the addition of 37.5 pL of L-Trp (final concentration 100 pM) at room température. The reaction was conducted at room température during 15 minutes and stopped by the addition of 30 pL of 30% (w/v) trichloroacetic acid.

To convert /V-formylkynurenine into kynurenine, the reaction mixture was incubated at 65 °C for 30 min. Then 120 pL of 2.5% (w/v) 4-(dimethylamino)-benzaldehyde in acetic acid were added and the mixture incubated for 5 min at room température. Kynurenine concentrations were determined by measuring the absorbance at 480 nm. A standard curve was made with pure kynurenine. The IDO1 activity was measured as described above using ten serial concentrations of the compounds of the présent invention. Data were fitted using the Prism software (GraphPad Software, Inc.).

The biological activity of représentative compounds is summarized in the following table:

Compound	ICso (pM)
1	0.15
1a	0.21
2	0.12
2a	>50
3	3.0
4	1.8
4a	>50
5	2.1
6	2.2
6a	>50
7	0.49
9	0.29
10	0.62

Compound	IC50 (pM)
10a	8.0
11	0.37
12	53
13	53
14	12
15	1.8
16	46
17	3.4
18	2.1
19	0.42
20	54
22	1.7
23	18
24	1.7
25	4.6

In one embodiment, compounds with an IC50 below 5 μΜ are generally désirable to be selected for further study.

II.2.A Cellular Assay for IDO Activity détermination: hlDO1 P815 cells

The compounds of the présent invention inhibit the activity of human IDO in hlDO1 P815 cells [(ATCC® TIB-64™), Mus musculus mastocytoma cell)], available from American Type Culture Collection (ATCC), Manassas VA],

The assay was performed in 96-well fiat bottom plates seeded with P815 cells overexpressing hlDO1 (prepared as described in Rohrig et al. J Med Chem, 2012, 55, 5270-5290), at a concentration of 2 χ 10⁵ cells/well in a final volume of 200 pL. To détermine IDO1 activity, the cells were incubated 24 hours at 37 °C at 5% CO2 in IMDM (Invitrogen) supplemented with 2% FBS and 2% penicillin/streptomycin in the presence ofthe compounds ofthe présent invention, at different concentrations.

The plates were then centrifuged 5 min at 1000 rpm, and 100 pl_ of the supernatant were collected in a conical plate, 30 uL of TCA 30% were added and a further centrifugated at 3000 x g for 10 minutes. 100 pL of the supernatant were collected in a fiat bottomed plate and 100 pL of 2% (w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5 min at room température. Kynurenine concentrations were determined by measuring the absorbance at 480 nm. A standard curve was made with pure kynurenine. The IDO1 activity was measured as described above using ten different concentrations of the compounds of the présent invention. Data were fitted using the Prism software (GraphPad Software, Inc.).

Compound	IC50 (DM)
1	0.094
2	0.009
2a	0.45
3	0.92
4	0.24
4a	3.30
5	0.59
15	0.26
18	0.50

In one embodiment, compounds with an IC50 below 5 pM are generally désirable to be selected for further study.

II.2.B Cellular Assay for IDO1 Activity détermination: HeLa cells

The compounds of the présent invention inhibit the activity of human IDO1 in HeLa cells [human adenocarcinoma cells, ® CCL-2™].

The assay was performed in 96-well fiat bottom plates seeded with the human cervical cancer HeLa cell line with stimulation with IFND.

Φ -69Το adhéré HeLa cells (concentration of 5 χ 10³ cells/well) were incubated overnight at 37 °C at 5% CO2 in EMEM (Lonza) supplemented with 10% FBS, 2% penicillin/streptomycin and 2mM Ultraglutamin, in a final volume of 200 pL.

To stimulate the expression of IDO1, cells were then incubated two days at 37 °C at 5% 5 CO2 in EMEM (Lonza) supplemented with 2% FBS, 2% penicillin/streptomycin and 2mM

Ultraglutamine and 100 ng/mL IFNy (R&D).

To détermine IDO1 activity, medium was removed then the cells were incubated one day at 37 °C at 5% CO2 in EMEM (Lonza) supplemented with 2% FBS and 2% penicillin/streptomycin in the presence of the compounds of the présent invention, at different concentrations. Then 100 pL of the supernatant were collected in a conical plate, 30 uL of TCA 30% were added and a centrifugation was made at 3000 x g for 10 minutes. 100 pL of the supernatant were collected in a fiat bottom plate and 100 pL of 2% (w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5 min at room température. Kynurenine concentrations were determined by measuring the absorbance at 480 nm. A standard curve was made with pure kynurenine. Data were fitted using the Prism software (GraphPad Software, Inc.).

Compound	IC50 (pM)
1	1.0
2	0.77
6	3.4
8	3.6
9	7.0
11	5.9

In one embodiment, compounds with an IC50 below 5 pM are generally désirable to be 20 selected for further study.

Il.2.0 Assay for IDO1 activity détermination in human blood: whole blood leukocyte concentrate

-70The compounds of the présent invention inhibit the activity of human IDO1 in a human whole blood assay (whole blood leukocyte concentrate).

The human whole blood leukocyte concentrate was obtained as a byproduct in the manufacturing of red blood cell and platelet concentrate from a whole blood donation (as described in van der Meer étal., Vox Sang, 1999, 76(2), 90-99).

The assay was performed in 96-well fiat bottom plates containing undiluted human whole blood leukocyte concentrate (with 2% penicillin/streptomycin) stimulated with lipopolysaccharide (LPS) (12.5 pg/mL) and recombinant human gamma interferon (rhIFNg) (50 ng/mL) for 18 hours to induce conversion of tryptophan to kynurenine. Plasma was collected after centrifugation and plasma kynurenine levels were determined LC-MS/MS (HPLC column Unison™ UK-Phenyl, 75 x 4.6, 3 pm, flow rate 0.8 mL/min, 4 minutes gradient from water + 0.2% acetic acid to methanol + 0.1% formic acid, rétention time 2.7 min; API 4000™ MS-MS System from AB Sciex, ESI+ mode, parent ion 209.2, daughter ion 94.1).

To détermine the effect of 1DO1 inhibition on kynurenine production, the compounds of the présent invention were co-incubated at different concentrations. Data were fitted using the Prism software (GraphPad Software, Inc.).

The biological activity of représentative compounds is summarized in the following table (results are the average of the results with blood from several different donors):

Compound	IC50 (pM) ± Standard Déviation	Number of individual blood donors
1	3.36±0.51	13
2	3.26±0.71	15

II.2.D Cellular Assay for IDO1-dépendent T cell prolifération détermination: SKOV-3

PBMC co-culture * -71 The compounds of the présent invention restore T-cell prolifération in a SKOV-3 PBMC co-culture assay.

The assay was performed in 96-well fiat bottom plates seeded with the human ovarian adenocarcinoma SKOV-3 cell line [SKOV-3; SKOV3] (ATCC® HTB-77™)] and co5 cultured with human peripheral blood mononuclear cells (PBMC) stimulated with CD3/CD28 beads and rhlL-2.

To adhéré, irradiated SKOV-3 cells (concentration of 150 χ 10³ cells/well) were incubated overnight at 37 °C at 5% CO2 in Iscove’s Modified Dulbecco’s Medium (IMDM) (Lonza) supplemented with 50% FBS, 2% penicillin/streptomycin and 2mM

Ultraglutamin, in a final volume of 150 pL. Isolated PBMCs (stimulated with CD3/CD28 beads and rhlL-2 (30U/mL)) were added in a ratio of 1:1. After 24h of co-culture ³HThymidine (1pCurie/10 uL) was added to assess prolifération (TopCount counter, Perkin Elmer) after overnight incubation in the presence of 50% sérum.

To détermine the effect of IDO1 inhibition on restoration of T cell prolifération, the compounds of the présent invention were co-incubated at different concentrations.

Compound 2 showed an EC50 of 0.074 μΜ in this assay (average of three independent experiments). FIG 1 shows the effect of increasing concentrations of Compound 2 on Thymidine incorporation.

II.3. In-vivo inhibition of blood kynurenine levels in healthy mice

The compounds of the présent invention reduce the amount of Kynurenine in healthy mouse blood.

Briefly, mice were treated with either a suspension of one of the compounds of the présent invention in 0.5% hydroxypropyl methylcellulose (HPMC) K4M / 0.25% Tween 25 20 at different doses, or with a vehicle control (0.5% HPMC K4M / 0.25% Tween 20), by the oral route by gavage (dosing volume 5 mL/kg, 10 mice per group). After two hours, blood was harvested, plasma was prepared and the amount of Kynurenine présent was determined by LC-MS-MS (HPLC column Unison UK-Phenyl, 75 x 4.6, 3 pm, flow rate ♦ -720.8 mL/min, 4 minutes gradient from water + 0.2% acetic acid to methanol + 0.1% formic acid, rétention time 2.7 min; API4000™ MS-MS System from AB Sciex, ESI+ mode, parent ion 209.2, daughter ion 94.1).

Compound 1 inhibited circulating Kynurenine by 41% at 100 mg/kg (p<0.0001) and by

59% at 200 mg/kg (p<0.0001): see table below.

	Vehicle	Cpd. 1 100 mg/kg	Cpd. 1 200 mg/kg
Kynurenine concentration in plasma (average ± standard error of the mean)	187.6±17.8 ng/mL	111.1+27.0 ng/mL	77.7+9.2 ng/mL

Compound 2 inhibited circulating Kynurenine by 39% at 10 mg/kg (p<0.0001), by 55% at mg/kg (p<0.0001) and by 68% at 100 mg/kg (p<0.0001): see table below and FIG 2.

	Vehicle	Cpd. 2 10 mg/kg	Cpd. 2 30 mg/kg	Cpd. 2 100 mg/kg
Kynurenine concentration in plasma (average ± standard error of the mean)	201±15.7 ng/mL	122±3.5 ng/mL	91.0+4.4 ng/mL	64.0±3.8 ng/mL

Example II.4: in vivo efficacy studies in 4T1 breast cancer syngeneic model

In vivo efficacy studies for Compounds of the présent invention were performed on 4T1 syngeneic tumor model of Balb/c mice implanted orthotopically in the mammary gland. One hundred thousand 4T1 breast cancer cells (ATCC® CRL-2539™)] were implanted orthotopically within the mammary gland of 7 weeks old Balb/c mice (day 0). Animais were randomized based on tumor size when tumor average reached 60mm³ (between day 7 and 11 ) into different treatment cohorts. The Compound of the présent invention • -73was administered orally twice per day (approximately at 9 am and 5 pm) starting the day of randomization. The Compounds were suspended into Methocel™ cellulose ether vehicle and sonicated before oral administration to animais using gavage needles. Treatment was administered daily until the end of the study. Ail experimental animais were monitored for body weight changes twice weekly. Tumor volume was measured twice a week by a caliper device and calculated with the following formula: Tumor volume = 0.5 X (length x width²). Studies were terminated before tumor volumes (Tx-T(A -—— I) * LX LU/

100. The table below and FIG 3A show that Compound 1 inhibits 4T1 tumor growth in vivo.

T reatment	Mean tumor volume (mm³) on day 25	TGI (Tumor growth inhibition)
Vehicle Methocel	736.4	0%
Compound 1 100mg/kg BID	443.7	43.4%

Example II.5: In vivo efficacy studies with PancO2 pancreatic cancer syngeneic model

In vivo efficacy studies of the Compounds of the présent invention were performed on PancO2 syngeneic tumor model of C57/BI6 mice implanted sub-cutaneously. Five millions PancO2 pancréas cancer cells were implanted sub-cutaneously to 7 weeks old C57/BI6 mice (day 0). Animais were randomized based on tumor size when tumor average reached 60mm³ (between day 10 and 12) into different treatment cohorts. The Compound was administered orally twice per day (approximately at 9 am and 5 pm) starting the day of randomization. The Compound was suspended into Methocel vehicle and sonicated before oral administration to animais using gavage needles. Treatment was administered daily until the end of the study. Ail experimental animais were monitored for body weight changes weekly. Tumor volume was measured weekly using a caliper device and calculated with the following formula: Tumor volume = 0.5 X (lengh

-74x width²). Studies were terminated before tumor volumes reached 2000 mm. TGI (% (Τχ—T0\

- _ l) * 100. The table below and

Cx C07

FIG 4 show that Compound 1 inhibits PancO2 tumor growth in vivo.

T reatment	Mean tumor volume (mm³) on day 42	TGI (Tumor growth inhibition)
Vehicle Methocel	598.2	0%
Compound 1 200mg/kg BID	457.0	26.2%

In a separate study performed underthe same conditions, Compound 2 (100 mg/kg BID) was studied. Methocel vehicle or 100mg/kg of Compound 2 was administered orally twice per day (8 hours apart) starting the day of randomization. Compound 2 was resuspended into Methocel vehicle and sonicated before oral administration to animais using gavage needles. Treatmentwas administered daily until the end ofthe study.

Tumor volume was measured weekly using a caliper device and calculated with the following formula: Tumor volume = 0.5 X (length x width²). Mice were considered as dead when tumor size reached 400mm³. The table below show that Compound 2 inhibits PancO2 tumor growth in vivo. SEM refers to standard error of measurement.

Treatment	Mean tumor volume (mm³) +/- SEM on day 55	TGI +/- SEM (Tumor growth inhibition)
Vehicle Methocel®	677.6 +/- 39.2	0%
Compound 2-100 mg/kg BID	586.6 +/- 48.4	16.8% +/- 8.2

* -75Example II.6: In vivo efficacy studies on inhibition of Tryptophan dégradation in 4T1 tumor tissue

Compounds of this invention are capable of lowering kynurenine concentration within mouse tumors, for example 4T1 syngeneic tumors of Balb/c mice implanted orthotopically in the mammary gland. One hundred thousand 4T1 breast cancer cells were implanted orthotopically within the mammary gland of 7 weeks old Balb/c mice (day 0). Animais were randomized based on tumor size when tumor average reached 60 mm³ (day 6) into different treatment cohorts (n=10/group). Animais were treated with Methocel vehicle from day 6 to 26 until tumors reached a size comprised between 1500 and 2000 mm³. Compound 1 was suspended into Methocel vehicle and sonicated before oral administration to animais using gavage needles. Methocel vehicle or 200mg/kg of Compound 1 was administered orally twice per day (approximately at 9 am and 5 pm) on day 26 and 27 days. The next morning, treatment was administered and mice were sacrificed 4h after Compound 1 administration. The tumor was removed, weighted and frozen on dry ice. Tumors were analyzed by LC/MS-MS for Kynurenine concentration. Compound 1 reduced Kynurenine concentration by 47% (p<0.0001): see Table below and FIG 5.

Treatment	Kynurenine concentration (ng / g tumor) Average ± S EM
Vehicle Methocel	787.5 ± 46.2
Compound 1 200mg/kg	417.2 ±55.7

Example II.7: In vivo efficacy studies on inhibition of Tryptophan dégradation in CT26 tumor tissue

A. Compounds of this invention are capable of lowering kynurenine concentration within mouse tumors φ -76In the présent study, CT26 syngeneic tumors were implanted subcutaneously in Balb-c mice. More particularly, Five hundred thousand (500,000) CT26 colon carcinoma cancer cells [CT26.WT, available from the ATCC® CRL-2628™] were implanted subcutaneously in 7 weeks old Balb/c mice (day 0). Animais were randomized based on tumor size when tumor average reached 150mm³ (day 11 ) into different treatment cohorts (n=10/group). Compound 1 was suspended into Methocel™ (methylcellulose) vehicle and sonicated before oral administration to animais using gavage needles. Methocel vehicle or Compound 1 was administered orally twice per day (approximately at 9 am and 5 pm) at 200 mg/kg for 2 days to the mice, once the tumor reached a size comprised between 1500 and 2000mm³. The next morning, treatment was administered and mice were sacrificed 2h after Compound 1 administration. The tumor was removed, weighted and frozen on dry ice. Tumors were analyzed by LC/MS-MS for Kynurenine concentration.

Compound 1 reduced Kynurenine concentration by 59% (p<0.0001): see Table below and FIG. 6.

T reatment	Kynurenine concentration (ng / g tumor) Average ± SEM
Vehicle Methocel	2124 ±272
Compound 1 200mg/kg	876 ± 68

B. Compound 1 inhibits tumor growth in vivo.

In a separate study, anti-tumor efficacy of IDO-1 inhibition was tested in the colon syngeneic mouse tumor model CT26 with a range of different treatment regimens. The model was essentially as described above, except that 1x 10⁶ cells in phosphate buffered saline (PBS) were implanted subcutaneously in the fiank of 8 week old Balb/c females on day 0 (10 in each group). Mice were randomized into treatment groups (100

-77mg/kg BID, 200 mg/kg BID or 600 mg/kg BID) based on tumor size on day 9 when treatment started. The results are shown the following table and in FIG 7.

Group	Dose mg/kg	Schedule	%TGl (D15)	%TGI (D17)	%TGI (D20)	N
Vehicle	-	BID	-	-	-	10
Compound 1	100	BID	29	33	20	10
Compound 1	200	BID	38	41	34	10
Compound 1	600	BID	36	51	38	10

At the highest dose of 600 mg/kg, BID a significant tumor growth inhibition (TGI) of up to 51%. At lower doses of 100 and 200 mg/kg BID, TGIs based on the group averages of tumor measurements are slightly lower and thus suggest a dose proportionality.

φ -78Ail publications cited in this spécification and priority applications including US

Provisional Patent Application No. 61/996,976, filed May 15, 2014, are incorporated herein by reference. While the invention has been described with reference to particular 5 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

1. A pharmaceutical composition comprising a compound of Formula I’, a compound of Formula I”, or a mixture thereof:

X represents -NH- or -CQ²=CQ³-;Q² and Q³ each independently represent H or C1 to C6 alkyl;

R¹ and R² each independently represent H, halo, cyano, C1 to C6 alkyl or C1 to C6 alkoxy;

and at least one pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein Q² and Q³ each independently represent H or methyl.

(3-²H)-3-(6-chloronaphthalen-1 -yl)pyrrolidine-2,5-dione; and (3-²H)-3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable sait or solvaté thereof.

(3-²H)-3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(2,5-dioxopyrrolidin-3-yl)-1 H-indole-6-carbonitrile;

(3-²H)-3-(6-methyl-1 H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-bromo-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile; (3-²H)-3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yi)pyrrolidine-2,5-dione;

(R) -3-(6-bromo-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(S) - (3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(R) - (3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(S) - (3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(-)-(R)- (3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(+)-(S)- (3-²H)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(3-²H)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; (-)-(R)-(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

(+)-(S)- (3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;

(-)-(R)- (3-²H)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

• -85(+-)-(S)- (3-²H)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

Φ -81 - (iv) 3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(v) 3-(6-bromo-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(vi) 3-(5-bromo-1 H-indol-3-yl)py rrolidine-2,5-dione;

(vii) 3-(5-methyl-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(viii) 3-(5-methoxy-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(ix) 3-(2,5-dioxopyrrolidin-3-yl)-1 H-indole-5-carbonitrile;

(x) 3-(5,6-difluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(xi) 3-(5-fluoro-6-methyl-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(xii) 3-(6-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(xiii) 3-(6-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(xiv) 3-(6-bromo-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(xv) 3-(6-methyl-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(xvi) 3-(6-methoxy-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(xvii) 3-(2,5-dioxopyrrolidin-3-yl)-1 H-indole-6-carbonitrile;

(xviii) 3-(naphthalen-1 -yl)pyrrolidine-2,5-dione;

(xix) 3-(6-fluoronaphthalen-1 -yl)pyrrolidine-2,5-dione;

(xx) 3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;

(xxii) 3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; or (xxiii) 3-(7-chloronaphthalen-1 -yl)pyrrolidine-2,5-dione.

3-(1H-indol-3-yl)pyrrolidine-2,5-dione;

3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;

3. The pharmaceutical composition according to claim 1 or claim 2, wherein Q² and Q³ each are H.

4. The pharmaceutical composition according to any one of daims 1 to 3, wherein R¹ and R² each independently represent H or halo.

5. The pharmaceutical composition according to claim 1, wherein the composition comprises a racemate which comprises approximately equal molar amounts of the compound of Formula I’ and the compound of Formula I”.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition comprises different molar amounts of the compound of Formula I’ and the compound of Formula I”.

7. The pharmaceutical composition according to claim 6, wherein the composition comprises a mixture of the compound of Formula I’ and the compound of Formula I”, wherein the composition comprises greaterthan 50% of a compound of Formula Γ.

8. The pharmaceutical composition according to claim 7, wherein the composition comprises at least 95% to 100% of the compound of Formula Γ.

9. The pharmaceutical composition according to claim 1, wherein the compound is of Formula Γ is selected from the group consisting of:

(a) (-)-(R)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(b) (-)-(R)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(c) (-)-(R)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(d) (R)-3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; and (e) (R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable sait or solvaté of any of (a) to (e).

10. The pharmaceutical composition according to claim 1, which comprises a racemic mixture of a compound of Formula I’ and Formula I”, wherein the racemate is selected from the group consisting of:

(i) (H) (iii)

¹¹ , or a pharmaceutically acceptable sait thereof.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein at least one of the hydrogen atoms of the compound of Formula Γ, one of the hydrogen atoms of the compound of Formula I”, or a hydrogen atom in both the compound of Formula I and the compound of Formula I” are replaced with a deuterium atom.

12. The pharmaceutical composition according to claim 11, wherein the compound of formula I” is selected from the group consisting of:

(a”) (S)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(b”) (S)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(c”) (S)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(d”) (S)-3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; and (e”) (S)-3-(6-bromo-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable sait or solvaté thereof.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the compound is a free base.

14. The pharmaceutical composition according to any one of claims 1 to 11, which is a sait.

15. The pharmaceutical composition according to claim 14, wherein the sait is selected from the group consisting of: an aluminium, calcium, choline, potassium, sodium or zinc sait.

16. The pharmaceutical composition according to any one of claims 1 to 12, 14 or 15, which is a solvaté.

17. The pharmaceutical composition according to any one of claims 1 to 12 which is a prodrug.

18. A compound of Formula I’or I” or a pharmaceutically acceptable sait, solvaté or prodrug thereof, wherein

X represents -NH- or-CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl;

R¹ and R² each independently represent H, halo, cyano, C1 to C6 alkyl or C1 to C6 alkoxy.

19. The compound according to claim 18, whereinQ2 and Q3 each independently represent H or methyl.

20. The compound according to claim 18 or 19, wherein Q2 and Q3 each represent H.

21. The compound according to any one of claims 18 to 20, wherein R¹ and R² each independently represent H or halo.

22. The compound according to any one of claims 18 to 21, wherein at least one of the hydrogen atoms ofthe compound of Formula Γ orthe compound of Formula I” is replaced with a deuterium atom.

23. The compound according to claim 18, wherein the compound of Formula Γ is selected from the group consisting of:

(a) (-)-(R)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(b) (-)-(R)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(c) (-)-(R)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

24. The compound according to claim 18, wherein the compound of Formula I” is selected from the group consisting of:

(a”) (S)-3-(5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(b”) (S)-3-(1 H-indol-3-yl)pyrrolidine-2,5-dione;

(c”) (S)-3-(5-chloro-1 H-indol-3-yl)pyrrolidine-2,5-dione;

(d”) (S)-3-(6-chloro-5-fluoro-1 H-indol-3-yl)pyrrolidine-2,5-dione; and (e”) (S)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable sait or solvaté of any of (a) to (e).

25. The compound according to any one of claims 18 to 24, which is a free base.

26. The compound according to any one of claims 18 to 24, which is a sait.

27. A deuterated compound having the Formula la’:

or a pharmaceutically acceptable enantiomer or sait thereof, wherein:

X represents -NH- or -CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl;

28. The deuterated compound according to claim 27, wherein Q² and Q³ each independently represent H or methyl.

29. The deuterated compound according to claim 27 or claim 28, wherein Q² and Q³each represent H.

30. The deuterated compound according to any one of claims 27 to 29, wherein R¹and R² each independently represent H or halo.

31. The deuterated compound according to claim 27, wherein the compound of Formula la, or the enantiomer thereof, is selected from the group of:

32. The deuterated compound according to claim 27, wherein the compound is (3²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione.

33. The deuterated compound according to any one of claims 27 to 32, which is a free base.

34. The deuterated compound according to any one of daims 27 to 32 which is a pharmaceutically acceptable sait.

35. The deuterated compound according to any one of daims 27 to 32, or claim 34 which is a solvaté.

36. A compound of Formula lb ^H n R^1b 0= y R²° 'X lb

X represents -NH- or -CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl;

R^1b and R^2b each independently represent H, halo, cyano, C1 to C6 alkyl or C1 to C6 alkoxy;

under the condition that when X represents -NH-, R^1b and R^2b are not both H; when X represents -NH-, then R^1b and R^2b are not both F; and further provided that when X represents CQ²=CQ³, then R^1b and R^2b are not both H.

37. The compound according to claim 36, wherein Q² and Q³ each independently represent H or methyl.

38. The compound according to claim 36 or 37, wherein Q² and Q³ each represent H.

39. The compound according any one of daims 36 to 38, wherein R^1b and R^2b are independently H or halo.

40. The compound according to claim 36, selected from the group consisting of:

(a) 3-(6-chloro-5-fluoro-1 /7-indol-3-yl)pyrrolidine-2,5-dione;

(b) (R)-3-(6-chloro-5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione;

(c) 3-(6-bromo-5-fluoro-1 /7-indol-3-y I) py rro lidine-2,5-d ione ;

(d) (F?)-3-(6-bromo-5-fluoro-1/7-indol-3-yl)pyrrolidine-2,5-dione;

(e) 3-(6-fluoronaphthalen-1 -yl)pyrrolidine-2,5-dione;

(f) 3-(7-fluoronaphthalen-1 -yl)pyrrolidine-2,5-dione;

(g) 3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; or (h) 3-(7-chloronaphthalen-1 -yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable sait or solvaté thereof.

41. The compound according to any one of claims 36 to 40 which is a free base.

42. The compound according to any one of claims 36 to 40 which is a sait.

43. The compound according to any one of claims 36 to 40, or claim 42 which is a solvaté.

44. Médicament comprising a compound of Formula Γ, a compound of Formula I”, or a mixture thereof:

or a pharmaceutically acceptable sait, solvaté or prodrug thereof, wherein:

R¹ and R² each independently represent H, halo, cyano, C1 to C6 alkyl or C1 to

C6 alkoxy, wherein said compound is optionally deuterated.

45. Médicament according to claim 44, wherein Q² and Q³ each independently represent H or methyl.

46. Médicament according to claim 44 or 45, wherein Q² and Q³ each represent H.

47. Médicament according to any one of claims 44 to 46, wherein R¹ and R² each independently represent H or halo.

48. A compound of Formula I’, a compound of Formula I”, or a mixture thereof:

or a pharmaceutically acceptable sait, solvaté or prodrug thereof, wherein:

X représente -NH- or-CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl;

C6 alkoxy; wherein said compound is optionally deuterated, for use in the treatment and/or prévention of cancer and endometriosis.

49. A compound according to claim 48, wherein Q² and Q³ each independently represent H or methyl.

50. A compound according to claim 48 or claim 49, wherein Q² and Q³ each represent H.

51. A compound according to any one of claims 48 to 50, wherein R¹ and R² each independently represent H or halo.

52. The compound of any one of claims 48 to 51, wherein the cancer is selected from maliganant melanoma, acute myelogenous leukemia, pancreatic, colorectal, prostate, cervical, brain, endométrial and ovarian cancers.

53. A compound of a compound of Formula Γ, a compound of Formula I”, or a mixture thereof:

or a pharmaceutically acceptable sait, solvaté or prodrug thereof, wherein:

X represents -NH- or -CQ²=CQ³-;

Q² and Q³ each independently represent H or C1 to C6 alkyl;

R¹ and R² each independently represent H, halo, cyano, C1 to C6 alkyl or

C1 to C6 alkoxy, wherein said compound is optionally deuterated;

for use as IDO1 inhibitor.

54. A compound according to claim 53, wherein Q² and Q³ each independently represent H or methyl.

55. A compound according to claim 53 or 54, wherein Q² and Q³ each represent H.

56. A compound according to any one of claims 53 to 55, wherein R¹ and R² each independently represent H or halo.

57. Process for manufacturing a compound according to anyone of claims 17 to 40, comprising: reacting maleimide with a compound of Formula (i) or (ib) (i) (ib) wherein X, R¹ and R² are as defined in claim 19 and R^1b and R^2b are as defined in claim 35; and optionally separating enantiomers.

58. A compound having the structure of Formula II’:

il' or a pharmaceutically acceptable sait or solvaté thereof.

59. The compound according to claim 58, wherein the compound is a free base.

60. A compound having the structure of Formula II”:

61. The compound according to claim 60, wherein the compound is a free base.

62. A pharmaceutical composition comprising a compound according to claim 58 and a pharmaceutically acceptable carrier.

63. A pharmaceutical composition comprising a compound according to claim 60 and a pharmaceutically acceptable carrier.

64. A pharmaceutical composition comprising a mixture of compounds of Formula II’ and Formula II”

II' acceptable sait thereof.

, or a pharmaceutically

65. The pharmaceutical composition according to claim 64, wherein the compound of Formula II’ and the compound of Formula II” are présent in a molar ration of about at a ratio of about 1:1.

66. The pharmaceutical composition according to claim 64, wherein the compound of Formula ΙΓ is présent in an amount of at least about 75 mol% .

67. The pharmaceutical composition according to claim 64, wherein the compound of Formula ΙΓ is présent in amount of at least about 90 mol%.

68. A pharmaceutical composition comprising a compound of the structure:

, or a pharmaceutically acceptable sait or solvaté thereof, or a deuterated form thereof, and a pharmaceutically acceptable carrier.

69. The composition according to claim 68, wherein the compound of Formula II is in free base form.