RU2811417C2 - Quinoline derivatives for use in treatment or prevention of cancer - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the use of a compound of formula (Ib') or a pharmaceutically acceptable salt thereof for the treatment of cancer selected from gastric cancer, gastrointestinal cancer, colorectal cancer, pancreatic cancer, lung cancer and liver cancer in a patient, wherein the said patient does not have clinically detectable metastases or wherein the said patient has clinically detectable metastases and the said compound of formula (Ib') is not directly directed against metastatic invasion, the said compound being 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2- amine.

EFFECT: obtaining quinoline derivatives for use in the treatment or prevention of cancer.

6 cl, 3 tbl

Description

TECHNICAL FIELD

The purpose of the present invention is to provide quinoline derivatives for use in the treatment of cancer.

Due to the severity of the disease, there is a constant need to find new drugs to prevent and/or treat cancer and/or improve the effectiveness of existing anticancer drugs.

There also remains a need for compounds without or with limited side effects.

BACKGROUND ART

Some quinoline derivatives are described in the following patent applications: WO 2010/143169, WO 2012/080953, WO 2016/009065 and WO 2016/009066 are effective in the treatment of AIDS or certain inflammatory diseases.

Additionally, certain quinoline derivatives that have been disclosed in WO 2010/143168 are effective in the treatment of certain types of cancer, and more particularly are effective against metastatic invasion.

BRIEF DESCRIPTION OF THE INVENTION

Within the framework of the present invention, the following definitions can be given:

• effective amount: an amount of a pharmaceutical compound that has an effect on the tumor being treated and/or an amount of a compound of the present invention that is effective in preventing, reducing, eliminating, treating or controlling the symptoms of the diseases and conditions described herein, i.e. cancer and/or dysplasia and in particular precancerous, early stage or non-metastatic cancer. The term “effective amount” includes “an effective amount for prophylaxis” as well as “an effective amount for treatment.” The term “effective amount for prophylaxis” refers to the concentration of a compound of the present invention effective in inhibiting, preventing, reducing the likelihood of cancer and/or dysplasia and, in particular, precancerous condition, early stage cancer or non-metastatic cancer or in the prevention of delayed onset cancer and/or dysplasia and, in particular, precancerous condition, early stage cancer or non-metastatic cancer. Also, the term “effective for the treatment "amount" refers to the concentration of a compound that is effective in treating cancer and/or dysplasia and, more particularly, precancerous, early-stage or non-metastatic cancer, for example, leading to a reduction in tumor size, tumor burden and/or tumor number of the precancerous tumor, early-stage tumor or non-metastatic tumor after examination upon administration of the compound after cancer and/or dysplasia has occurred.

• separate administration of a drug combination, simultaneous administration or administration distributed over time means that the elementary components of the combination can be administered simultaneously, each in one dose at different times, or repeatedly, or at different times, in particular during cycles. To achieve this, the elemental components can be formulated as mixtures only when administered simultaneously, or developed separately for other administration regimens;

• As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, excipients, carrier, adjuvant, drug-carrying vehicle, compositions or dosage forms that, within the bounds of careful medical evaluation, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problematic complications commensurate with a reasonable benefit/risk ratio.

• The term “patient” as used herein means an animal, preferably a mammal, and most preferably a human.

• “Combination” means a pharmaceutical composition or kit containing a compound as defined herein, or any of its metabolites or pharmaceutically acceptable salts thereof, particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2- an amine in any form, and at least an additional anticancer or antitumor active agent.

• In the context of this invention, the term “treatment” or “treatment” as used herein means regression, alleviation, inhibition of progression or prevention of cancer and/or dysplasia and, in particular, precancerous condition, early-stage cancer or non-metastatic cancer.

• The term “control” is intended to include all processes where slowing, interrupting, reversing or stopping the progression of the diseases and conditions described herein may occur, but does not necessarily mean complete elimination of all symptoms of the disease and condition, and is intended to include preventive treatment.

• The term “prevention” as used herein means reducing the risk of occurrence or delaying the occurrence of a given phenomenon, namely, in the present invention, cancer and/or dysplasia and, in particular, precancerous condition, early stage cancer or non-metastatic cancer. As used herein, the term “prevention” also includes “reducing the likelihood of occurrence” or “reducing the likelihood of reoccurrence.”

Therefore, the invention relates to a quinoline derivative of formulas (I), (I'), (I''), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa) , (IVb), (IVb'), (IVc) or (IVd), as defined herein below, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancer or dysplasia.

As shown in the experimental part by calculation of IC50, the compounds of the present invention, in particular the compounds of formula (Ib') or any of their metabolites or a pharmaceutically acceptable salt thereof, are effective for the treatment and/or prevention of cancer, and in particular colorectal cancer (direct and colon), stomach cancer, liver cancer, lung cancer and/or pancreatic cancer, particularly in patients with precancerous, early-stage or non-metastatic cancer. In one embodiment, the compounds of formula (Ib') or any of their metabolites or pharmaceutically acceptable salts thereof do not directly target metastatic invasion.

Additionally, the present invention relates to compounds of formulas (I), (I'), (I''), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa) , (IVb), (IVb'), (IVc) or (IVd), as defined below, or a pharmaceutically acceptable salt thereof, for use in the prevention and/or inhibition and/or treatment of cancer or dysplasia, or cancer metastasis or preneoplastic lesions.

Moreover, the present invention relates to a method of preventing, inhibiting or treating cancer or dysplasia, which includes at least one step of administering to a patient suffering therefrom an effective amount of a compound defined in formulas (I), (I'), (I''), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa), (IVb), (IVb'), (IVc) or (IVd ) below, or a pharmaceutically acceptable salt thereof.

In some embodiments, the method or use of the present invention further includes measuring the level of a compound defined in formulas (I), (I'), (I''), (Ia), (Ib), (Ic), (Id) or ( Ib') herein, or a pharmaceutically acceptable salt thereof or a metabolite thereof in a patient. In some embodiments, the level of a compound defined in formulas (I), (I'), (I''), (Ia), (Ib), (Ic), (Id) or (Ib'), or a pharmaceutically acceptable level thereof salt, or its metabolite, is measured in a biological sample from the patient. In some embodiments, the patient's biological sample is a blood, plasma, tissue, saliva, and/or serum sample. In some embodiments, the method of the present invention further includes measuring the level of a compound of formulas (IV), (IVa), (IVb), (IVb'), (IVc) or (IVd) or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method or use of the present invention further includes measuring the total level of compounds of formulas (I), (I') or (I'') and (IV) or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method or use of the present invention further includes measuring the total level of compounds of formulas (Ia) and (IVa) or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method or use of the present invention further comprises measuring the total level of compounds of formulas (Ib) and (IVb) or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method or use of the present invention further includes measuring the total level of compounds of formulas (Ib') and (IVb') or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method or use of the present invention further includes measuring the total level of compounds of formulas (Ic) and (IVc) or pharmaceutically acceptable salts thereof in a patient. In some embodiments, the method or use of the present invention further includes measuring the total level of compounds of formulas (Id) and (IVd) or pharmaceutically acceptable salts thereof in a patient.

In some embodiments, a method or use of the present invention further includes measuring and/or monitoring the presence and/or level of a biomarker in a patient. In some embodiments, the presence and/or level of the biomarker is measured in a biological sample from the patient. In some embodiments, the patient's biological sample is a blood sample. In some embodiments, the patient's biological sample is a tissue sample. In some embodiments, the biomarker measured and/or monitored in the method of the present invention is miR-124, as described in WO 2014/111892, the entire contents of which are incorporated herein by reference. In some embodiments, a method or application of the present invention further comprises measuring and/or monitoring the presence and/or expression level of miR-124 in a patient prior to administration of a compound or pharmaceutically acceptable salt or composition thereof, as described herein. In some embodiments, the method or use of the present invention further comprises measuring and/or monitoring the presence and/or expression level of miR-124 in a patient during a course of treatment with a compound or pharmaceutically acceptable salt or composition thereof, as described herein. In some embodiments, a method or use of the present invention further comprises selecting a patient for treatment with a compound or pharmaceutically acceptable salt or composition thereof, as described herein, by measuring and/or monitoring the presence and/or expression level of miR-124 in the patient. In some embodiments, a method or use of the present invention further comprises excluding a patient from treatment with a compound or pharmaceutically acceptable salt or composition thereof, as described herein, by measuring and/or monitoring the presence and/or expression level of miR-124 in the patient. In some embodiments, the method or use of the present invention further includes adjusting (e.g., increasing or decreasing) a dosage regimen (e.g., dosage amount and/or dosage schedule) of the compound or a pharmaceutically acceptable salt or composition thereof, as described herein, for administration to a patient by measuring and/or monitoring the presence and/or expression level of miR-124 in a patient.

In some embodiments, a method or use of the present invention includes comparing a measured miR-124 expression level in a patient to a control reference value. The control reference value that will be used to compare the measured miR-124 expression level in the patient is obtained from the control sample. The control sample can be taken from various sources. In some embodiments, a control sample is obtained from a patient prior to treatment or disease (such as a historical blood sample or tissue sample). In some embodiments, the control sample is taken from a set of normal, non-diseased members of the population. In some embodiments, a control sample is collected from a patient prior to treatment with a compound or pharmaceutically acceptable salt or composition thereof, as described herein. In some embodiments, a cell-based test may be performed on a biological sample.

In some embodiments, modulated presence and/or expression level of miR-124 in a patient compared to a control reference value is indicative of cancer. In some embodiments, the modulated presence and/or expression level of miR-124 in a patient compared to a control reference value indicates the effectiveness of treatment with a compound or pharmaceutically acceptable salt or composition thereof, as described herein, that is administered to the patient. The terms “modulation” or “modulated presence and/or level of expression” mean that the presence or level of expression of a biomarker is either induced or increased or, alternatively, suppressed or decreased.

In some embodiments, the measured reduced or suppressed presence or decreased expression level of miR-124 relative to a control reference value is indicative of cancer. In some embodiments, the measured induced or increased presence or increased expression level of miR-124 relative to a control reference value indicates the effectiveness of the compound or a pharmaceutically acceptable salt thereof or a composition thereof, as described herein. In some embodiments, the measured level of miR-124 expression in a patient receiving a compound or pharmaceutically acceptable salt or composition thereof, as described herein, is a two-fold, four-fold, six-fold, eight-fold, or ten-fold increase relative to the control reference value.

Also provided herein is the use of miR-124 in vitro or ex vivo as a biomarker for the activity of a quinoline derivative of formula (I), (I') or (I'') or any of its metabolites or pharmaceutically acceptable salt, as defined above, in regarding cancer.

According to one embodiment, the use and methods according to this invention may, in particular, allow the identification of cancer in a patient and, in particular, the subsequent monitoring of such cancer.

Use according to the present invention may be aimed at assessing the response of a patient to cancer treatment with a quinoline derivative in accordance with the present invention. It may also be further directed to assessing the effectiveness of said quinoline derivative in treating cancer or assessing the therapeutic efficacy of said quinoline derivative as a therapeutic agent for the prevention and/or treatment of cancer.

In addition, it can be aimed at assessing the patient's compliance with antitumor treatment with the specified quinoline derivative.

In some embodiments, the present invention provides the use of a compound of formulas (I), (I'), (I''), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa), (IVb), (IVb'), (IVc) or (IVd) or a pharmaceutically acceptable salt thereof, wherein the presence and/or expression level of miR-124 in a blood and/or tissue sample is measured for regulation, dosing or monitoring response to treatment.

In some embodiments, the present invention provides the use of a compound of formulas (I), (I'), (I''), (Ia), (Ib), (Ib'), (Ic), (Id), (IV), (IVa), (IVb), (IVb'), (IVc) or (IVd) or a pharmaceutically acceptable salt thereof, wherein the level of miR-124 methylation is measured to guide therapy.

In some embodiments, the present invention provides an algorithm combining the level of miR-124 and the level of a cytokine or other biomarker, or levels of compounds of formula (I) and/or (IV) as defined below, or pharmaceutically acceptable salts thereof, for monitoring the severity of cancer and /or to monitor the effectiveness of treatment, including without limitation treatments as described herein. In some embodiments, a treatment method described herein includes the use of an algorithm that combines the level of miR-124 and the level of a cytokine or other biomarker, or levels of compounds of formula (I) and/or (IV), as defined below, or pharmaceutically acceptable salts thereof, to monitor the severity of cancer and/or to monitor the effectiveness of treatment.

The present invention further provides a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of its enantiomers or diastereoisomers for use according to the present invention, wherein an algorithm combining the level of miR-124 and the level of a cytokine or other biomarker, or levels of a compound of formula (I'), as defined below, or any of its metabolites or pharmaceutically acceptable salts or any of their enantiomers or diastereoisomers, are used to monitor the severity of cancer and/or to monitor the effectiveness of treatment.

Further provided herein is an algorithm that combines the level of miR-124 and the level of a cytokine or other biomarker, or levels of a compound of formula (I') as defined below, or any of its metabolites or pharmaceutically acceptable salt, or any of its enantiomers or diastereoisomers to monitor the effectiveness of treatment.

Also provided herein is a quinoline derivative of formula (I), (I') or (I'') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as an antineoplastic agent intended for patients who have the presence and/or level of miR-124 expression is monitored in the blood and/or tissue sample of the specified patient before and/or during the specified use of the anticancer agent or treatment.

Also provided herein is a quinoline derivative of formula (I), (I') or (I'') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as an antitumor agent in patients for whom the presence and/or level of miR expression -124 was measured in the blood and/or tissue sample of the specified patient before, during and/or after administration.

Therefore, provided herein is a method for assessing the activity of a quinoline derivative of formula (I), (I') or (I'') for the prevention and/or treatment of cancer in a patient receiving said quinoline derivative, comprising at least the steps of:

a - measuring the presence or level of expression of at least one microRNA (miRNA), with at least one microRNA being miR-124, in a first biological sample previously obtained from said patient prior to administration of said quinoline derivative, and in a second biological sample, previously obtained from said patient after administration of said quinoline derivative; And

b - determining whether the specified presence or level of expression in the second biological sample obtained after treatment is modulated compared to the second biological sample obtained before treatment;

where the modulated presence or expression level of the specified microRNA indicates the antitumor activity of the specified quinoline derivative.

In some embodiments, the method or use of the present invention is used in combination with another active ingredient, in particular another antineoplastic agent, as described herein.

In some embodiments, a method or use of the present invention is used in combination with other therapy as described herein. In some embodiments, the other therapy is selected from chemotherapy, immunotherapy, radiation therapy, surgery, ultrasound therapy, monoclonal antibodies, and cancer vaccines.

DETAILED DESCRIPTION OF THE INVENTION

Connections

The compounds described herein can be prepared according to the synthetic approaches described in WO 2010/143169, WO 2012/080953, WO 2016/009065 and WO 2016/009066, the contents of which are incorporated herein by reference in their entirety.

In one aspect, the compound of this invention is a compound of Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, where:

Z represents C or N;

V represents C or N;

means an aromatic ring where V is C or N, and when V is N, then V is in the ortho, meta or para position relative to Z;

each R independently represents hydrogen, halogen, -CN, hydroxyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₃ )fluoroalkoxy, (C ₃ -C ₆ )cycloalkyl, -NO ₂ , -NR ₁ R ₂ , (C ₁ -C ₄ )alkoxy, phenoxy, -NR ₁ -SO ₂ -NR ₁ R ₂ , -NR ₁ -SO ₂ -R ₁ , -NR ₁ -C(=O)-R ₁ , -NR ₁ -C(=O)-NR ₁ R ₂ , -SO ₂ -NR ₁ R ₂ , -SO ₃ H, -O-SO ₂ -OR ₃ , -OP(=O)-(OR ₃ )(OR ₄ ) , -O-CH ₂ -COOR ₃ , (C ₁ -C ₃ )alkyl, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group, a group of formula (IIa): , or a group of formula (IIIa): ;

Q is N or O, provided that R" does not exist when Q is O;

each of R ₁ and R ₂ independently represents hydrogen or (C ₁ -C ₃ )alkyl;

R ₃ and R ₄ are each independently hydrogen, Li ⁺ , Na ⁺ , K ⁺ , N ⁺ (Ra) ₄ or benzyl;

n is 1, 2 or 3;

n’ equal represents but 1, 2 or 3;

each R' independently represents hydrogen, (C ₁ -C ₃ )alkyl, hydroxyl, halogen, -NO ₂ , -NR ₁ R ₂ , morpholinyl, morpholino, N-methylpiperazinyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₄ )alkoxy, -OP(=O)-(OR ₃ )(OR ₄ ), -CN, group of formula (IIa): , or a group of formula (IIIa): ;

A represents a covalent bond, oxygen or NH;

B represents a covalent bond or NH;

m represents 1, 2, 3, 4 or 5;

p is 1, 2 or 3;

Ra and Rb are each independently hydrogen, (C ₁ -C ₅ )alkyl or (C ₃ -C ₆ )cycloalkyl, or

Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, said heterocycle optionally being substituted by one or more Ra, provided that when R' is a group (IIa) or (IIIa) , n' can be 2 or 3 only if the other R' groups are different from the specified group (IIa) or (IIIa); And

R" represents hydrogen, (C ₁ -C ₄ )alkyl or a group of formula (IIa) as defined above.

As generally defined above, Z is C or N.

In some embodiments, Z is C. In some embodiments, Z is N.

In some embodiments, Z is selected from those depicted in Tables 1-3 below.

As generally defined above, V is C or N.

In some embodiments, V is C. In some embodiments, V is N.

In some embodiments, V is selected from those depicted in Tables 1-3 below.

As generally defined above, means an aromatic ring where V is C or N, and when V is N, then V is in the ortho, meta or para position relative to Z.

In some embodiments means an aromatic ring in which V represents C.

In some embodiments means an aromatic ring wherein V is N and V is in an ortho, meta, or para position with respect to Z. In some embodiments, V is N and V is in an ortho position with respect to Z. In some embodiments, V is N. and V is in a meta position with respect to Z. In some embodiments, V is N and V is in a para position with respect to Z.

In some embodiments is phenyl. In some embodiments is pyridine. In some embodiments is a pyridazine. In some embodiments is a pyrimidine. In some embodiments is a pyrazine.

In some embodiments selected from those depicted in Tables 1-3 below.

As generally described above, each R independently represents hydrogen, halogen, -CN, hydroxyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₃ )fluoroalkoxy, (C ₃ -C ₆ )cycloalkyl, -NO ₂ , -NR ₁ R ₂ , (C ₁ -C ₄ )alkoxy, phenoxy, -NR ₁ -SO ₂ -NR ₁ R ₂ , -NR ₁ -SO ₂ -R ₁ , -NR ₁ -C(=O)- R ₁ , -NR ₁ -C(=O)-NR ₁ R ₂ , -SO ₂ -NR ₁ R ₂ , -SO ₃ H, -O-SO ₂ -OR ₃ , -OP(=O)-(OR ₃ )(OR ₄ ), -O-CH ₂ -COOR ₃ , or (C ₁ -C ₃ )alkyl, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group.

In some embodiments, R is hydrogen. In some embodiments, R is halogen. In some embodiments, R is -CN. In some embodiments, R is hydroxyl. In some embodiments, R is (C ₁ -C ₃ )fluoroalkyl, wherein said alkyl is optionally mono- or disubstituted with hydroxyl. In some embodiments, R is (C ₁ -C ₃ )fluoroalkoxy. In some embodiments, R is (C ₃ -C ₆ )cycloalkyl. In some embodiments, R is -NO ₂ . In some embodiments, R is NR ₁ R ₂ . In some embodiments, R is (C ₁ -C ₄ )alkoxy. In some embodiments, R is phenoxy. In some embodiments, R is -NR ₁ -SO ₂ -NR ₁ R ₂ . In some embodiments, R is -NR ₁ -SO ₂ -R ₁ . In some embodiments, R is -NR ₁ -C(=O)-R ₁ . In some embodiments, R is -NR ₁ -C(=O)-NR ₁ R ₂ . In some embodiments, R is -SO ₂ -NR ₁ R ₂ . In some embodiments, R is -SO ₃ H. In some embodiments, R is -O-SO ₂ -OR ₃ . In some embodiments, R is -OP(=O)-(OR ₃ )(OR ₄ ). In some embodiments, R is -O-CH ₂ -COOR ₃ . In some embodiments, R is (C ₁ -C ₃ )alkyl, wherein said alkyl is optionally mono- or di-substituted with hydroxyl.

In some embodiments, each R is independently halogen, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₃ )fluoroalkoxy, -NR ₁ R ₂ , (C ₁ -C ₄ )alkoxy, or (C ₁ -C ₃ )alkyl.

In some embodiments, each R is independently hydrogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, amino, halogen, or -OP(=O)-(OR ₃ )(OR ₄ ). In some embodiments, R is methyl. In some embodiments, R is methoxy. In some embodiments, R is trifluoromethyl. In some embodiments, R is trifluoromethoxy. In some embodiments, R is amino. In some embodiments, R is -OP(=O)-(OR ₃ )(OR ₄ ).

In some embodiments, each R is independently methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy, or amino.

In some embodiments, R is selected from those depicted in Tables 1-3 below.

As generally described above, Q is N or O, with the proviso that R" is absent when Q is O.

In some embodiments, Q is N. In some embodiments, Q is O and R" is not present.

In some embodiments, Q is selected from those depicted in Tables 1-3 below.

As described generally above, R ₁ and R ₂ are each independently hydrogen or (C ₁ -C ₃ )alkyl.

In some embodiments, R ₁ is hydrogen, R ₁ is (C ₁ -C ₃ )alkyl. In some embodiments, R ₂ is hydrogen. In some embodiments, R ₂ is (C ₁ -C ₃ )alkyl.

In some embodiments, each of R ₁ and R ₂ is selected independently of those depicted in Tables 1-3 below.

As described generally above, R ₃ and R ₄ are each independently hydrogen, Li ⁺ , Na ⁺ , K ⁺ , N ⁺ (Ra) ₄ or benzyl.

In some embodiments, R ₃ is hydrogen and R ₃ is Li ⁺ . In some embodiments, R ₃ is Na ⁺ . In some embodiments, R ₃ is K ⁺ . In some embodiments, R ₃ is N ⁺ (Ra) ₄ . In some embodiments, R ₃ is benzyl.

In some embodiments, R ₄ is hydrogen and R ₄ is Li ⁺ . In some embodiments, R ₄ is Na ⁺ . In some embodiments, R ₄ is K ⁺ . In some embodiments, R ₄ is N ⁺ (Ra) ₄ . In some embodiments, R ₄ is benzyl.

In some embodiments, each of R ₃ and R ₄ is independently selected from those depicted in Tables 1-3 below.

As generally described above, n is 1, 2 or 3.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, n is selected from those depicted in Tables 1-3 below.

As generally described above, n' is 1, 2 or 3.

In some embodiments, n' is 1 or 2. In some embodiments, n' is 1. In some embodiments, n' is 2. In some embodiments, n' is 3.

In some embodiments, n' is selected from those depicted in Tables 1-3 below.

As described generally above, each R' is independently hydrogen, (C ₁ -C ₃ )alkyl, hydroxyl, halogen, -NO ₂ , -NR ₁ R ₂ , morpholinyl, morpholino, N-methylpiperazinyl, (C ₁ -C ₃ )fluoroalkyl, ((C ₁ -C ₄ )alkoxy, -OP(=O)-(OR ₃ )(OR ₄ ), -CN, group of formula (IIa): , or a group of formula (IIIa): .

In some embodiments, R' is hydrogen. In some embodiments, R' is (C ₁ -C ₃ alkyl. In some embodiments, R' is hydroxyl. In some embodiments, R' is halogen. In some embodiments, R' is -NO ₂ . In some embodiments R' is -NR ₁ R ₂ In some embodiments, R' is morpholinyl. In some embodiments, R' is morpholino. In some embodiments, R' is N-methylpiperazinyl. In some embodiments, R' is is (C ₁ -C ₃ )fluoroalkyl. In some embodiments, R' is (C ₁ -C ₄ )alkoxy. In some embodiments, R' is -OP(=O)-(OR ₃ )(OR ₄ ) In some embodiments, R' is -CN. In some embodiments, R' is a group of formula (IIa): . In some embodiments, R' is a group of formula (IIIa): .

In some embodiments, R' is amino. In some embodiments, R' is methyl. In some embodiments, R' is a group of the formula where A is O or NH, m is 2 or 3, and X ₁ is O, CH ₂ or N-CH ₃ with the proviso that when R' is such a group, n' is 1 or 2 , and when n' is 2, the other group R' is different from the specified group.

In some embodiments, R' is a group of the formula where A is O or NH, m is 2 and X ₁ is O, CH ₂ or N-CH ₃ with the proviso that when R' is such a group, n' is 1 or 2 and when n' is 2, the other group R' is different from the specified group.

In some embodiments, R' is a group of the formula where A is O or NH, m is 3, and X ₁ is O, CH ₂ or N-CH ₃ , with the proviso that when R' is such a group, n' is 1 or 2, and when n' is 2, the other group R' is different from the specified group.

In some embodiments, each R' independently represents hydrogen, halogen, amino, methyl, -OP(=O)-(OR ₃ )(OR ₄ ), or a group of the formula where A is O or NH, m is 2 or 3 and X ₁ is O, CH ₂ or N-CH ₃ , with the proviso that when R' is such a group, n' is 1 or 2 , and when n' is 2, the other group R' is different from the specified group.

In some embodiments, each R' independently represents hydrogen, halogen, methyl, or a group of the formula where A is O or NH, m is 2 and X ₁ is O, CH ₂ or N-CH ₃ with the proviso that when R' is such a group, n' is 1 or 2 and when n' is 2, the other group R' is different from the specified group.

In some embodiments, each R' is independently halogen, (C ₁ -C ₃ )alkyl, hydroxyl, -NR ₁ R ₂ , morpholinyl, morpholino, N-methylpiperazinyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ - C ₄ )alkoxy or a group of formulas (IIa) or (IIIa) as described herein.

In some embodiments, R' is halogen or methyl.

In some embodiments, each R' is selected independently of those depicted in Tables 1-3 below.

As generally described above, A represents a covalent bond, oxygen or NH.

In some embodiments, A is a covalent bond. In some embodiments, A is oxygen. In some embodiments, A is NH.

In some embodiments, A is selected from those depicted in Tables 1-3 below.

As generally described above, B represents a covalent bond or NH.

In some embodiments, B is a covalent bond. In some embodiments, B is NH.

In some embodiments, B is selected from those depicted in Tables 1-3 below.

As generally described above, m is 1, 2, 3, 4 or 5.

In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

In some embodiments, m is selected from those depicted in Tables 1-3 below.

As described generally above, p is 1, 2 or 3.

In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

In some embodiments, p is selected from those depicted in Tables 1-3 below.

As described generally above, Ra and Rb are each independently hydrogen, ((C ₁ -C ₅ )alkyl or (C ₃ -C ₆ )cycloalkyl, or Ra and Rb form together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, wherein said heterocycle is optionally replaced by one or more Ra, with the proviso that when R' is a group (IIa) or (IIIa), n' may be 2 or 3 only if the others the R' groups are different from said group (IIa) or (IIIa).

In some embodiments, Ra is hydrogen. In some embodiments, Ra is (C ₁ -C ₅ )alkyl. In some embodiments, Ra is (C ₃ -C ₆ )cycloalkyl. In some embodiments, Rb is hydrogen. In some embodiments, Rb is a (C ₁ -C ₅ )alkyl. In some embodiments, Rb is (C ₃ -C ₆ )cycloalkyl.

In some embodiments, Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, wherein said heterocycle is optionally substituted with one or more Ra, provided that when R' is a group of formulas ( IIa) or (IIIa), n' can represent 2 or 3 only if the other groups R' differ from the specified group of formulas (IIa) or (IIIa). In some embodiments, the saturated 5- or 6-membered heterocycle formed by Ra and Rb together with the nitrogen atom to which they are attached as described above optionally has an additional heteroatom selected from N, O, and S.

In some embodiments, Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle having an additional heteroatom selected from N, O, and S, wherein said heterocycle is substituted with one or more Ra, provided that when R' is a group of formulas (IIa) or (IIIa), n' can be 2 or 3 only if the other R' groups are different from said group of formulas (IIa) or (IIIa).

In some embodiments, Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5-membered heterocycle, provided that when R' represents a group of formulas (IIa) or (IIIa), n' may represent 2 or 3, only if the other groups R' differ from the specified group of formulas (IIa) or (IIIa).

In some embodiments, Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 6-membered heterocycle, provided that when R' represents a group of formulas (IIa) or (IIIa), n' may represent 2 or 3, only if the other groups R' differ from the specified group of formulas (IIa) or (IIIa).

In some embodiments, Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, optionally having an additional heteroatom selected from N, O, and S, wherein said heterocycle is optionally substituted with one or more Ra, with the proviso that when R' is a group (IIa) or (IIIa), n' may be 2 only if the other group R' is different from said group (IIa) or (IIIa).

In some embodiments, Ra and Rb are each selected independently of those depicted in Tables 1-3 below.

As described generally above, R" represents hydrogen, (C ₁ -C ₄ )alkyl or a group of formula (IIa) as defined above.

In some embodiments, R" is hydrogen or (C ₁ -C ₄ )alkyl. In some embodiments, R" is hydrogen. In some embodiments, R" is (C ₁ -C ₄ )alkyl. In some embodiments, R" is a group of formula (IIa), as described herein.

In some embodiments, "R" is a group of the formula where m represents 2 or 3 and X ₁ represents O, CH ₂ , or N-CH ₃ .

In some embodiments, "R" is selected from those depicted in Tables 1-3 below.

In some embodiments, n is 1; n' represents 1 or 2; R" represents H; R is selected from methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy and amino; and each R' independently represents a halogen, methyl or group where A is O or NH, m is 2 or 3 and X ₁ is O, CH ₂ or N-CH ₃ , provided that when n' is 2, the other group R' is different from the specified group.

In some embodiments, n is 1; n’ represents 1; R" represents H; R is selected from methyl, methoxy, trifluoromethyl, halogen and trifluoromethoxy; and R' represents halogen or methyl.

In some embodiments, a compound of this invention is a compound of formula (Ia):

(Ia)

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', R", n and n' are independently as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, a compound of this invention is a compound of formula (Ib):

(Ib)

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', R", n and n' are independently as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, a compound of this invention is a compound of formula (Ic):

(Ic)

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', R", n and n' are independently as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, a compound of the invention is a compound of formula (Ib'):

(Ib')

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', R" and n are independently as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, a compound of the invention is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein:

each R independently represents halogen, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₃ )fluoroalkoxy, -NR ₁ R ₂ , (C ₁ -C ₄ )alkoxy or (C ₁ -C ₃ )alkyl, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group;

n is 1 or 2;

n’ represents 1 or 2;

R ₁ and R ₂ are each independently hydrogen or C ₁ -C ₃ alkyl;

each of R' independently represents halogen, (C ₁ -C ₃ )alkyl, hydroxyl, -NR ₁ R ₂ , morpholinyl, morpholino, N-methylpiperazinyl, (C ₁ -C ₃ fluoroalkyl, C ₁ -C ₄ )alkoxy or group of formulas (IIa) or (IIIa) as described herein;

A represents a covalent bond, oxygen or NH;

B represents a covalent bond or NH;

m represents 1, 2, 3, 4 or 5;

p is 1, 2 or 3;

Ra and Rb are each independently hydrogen, (C ₁ -C ₅ )alkyl or (C ₃ -C ₆ )cycloalkyl, or

Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, optionally having an additional heteroatom selected from N, O and S, which heterocycle is optionally substituted by one or more Ra, provided that when R' represents a group (IIa) or (IIIa), n' can represent 2 only if the other group R' is different from the specified group (IIa) or (IIIa); And

R” represents hydrogen or (C ₁ -C ₄ )alkyl.

In some embodiments, a compound of this invention is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each R' independently represents hydrogen, halogen, (C ₁ -C ₃ )alkyl, or (C ₁ -C ₄ )alkoxy, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group; R” represents hydrogen or (C ₁ -C ₄ )alkyl; n is 1 or 2; n' represents 1 or 2; when n is 1, R is (C ₁ -C ₃ )fluoroalkoxy, NR ₁ R ₂ , or phenoxy, wherein R ₁ and R ₂ are each independently (C ₁ -C ₃ )alkyl; and when n is 2, one of the two R groups is (C ₁ -C ₃ )fluoroalkoxy and the other R group is (C ₁ -C ₃ )alkyl.

In some embodiments, the compound of this invention is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein each R independently represents (C ₁ -C ₃ )fluoroalkoxy; each R' independently represents hydrogen, halogen, (C ₁ -C ₃ )alkyl or (C ₁ -C ₄ )alkoxy; R” represents hydrogen or (C ₁ -C ₄ )alkyl; n represents 1; and n' is 1 or 2.

In some embodiments, the compound of the invention is a compound of formula (Ib') or a pharmaceutically acceptable salt thereof, wherein each R independently represents hydrogen, halogen, (C ₁ -C ₃ )alkyl, -NR ₁ R ₂ , (C ₁ -C ₃ )fluoroalkoxy, -NO ₂ , phenoxy or (C ₁ -C ₄ )alkoxy, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group; each of R ₁ and R ₂ independently represents hydrogen or (C ₁ -C ₃ )alkyl; R' is hydrogen, halogen, (C ₁ -C ₃ )alkyl or (C ₁ -C ₄ )alkoxy, with the caveat that R' is other than the methyl group at the 4-position of the quinoline group; R” represents hydrogen or (C ₁ -C ₄ )alkyl; n is 1, 2 or 3; and n' is 1 or 2.

In some embodiments, a compound of this invention is a compound of formula (Id):

(Id)

or a pharmaceutically acceptable salt thereof, wherein each of R and R' independently represents, as defined above and described in the embodiments herein, either alone or in combination, and R'” represents hydrogen or the group where A is O or NH, m is 2 or 3, and X ₁ is O, CH ₂ or N-CH ₃ .

In some embodiments, the compound of the invention is a compound of formula (Id) or a pharmaceutically acceptable salt thereof, wherein R is methyl, methoxy, trifluoromethyl, halogen, trifluoromethoxy or amino; R' represents halogen or methyl, and R''' represents hydrogen or a group where A is O or NH, m is 2 or 3, and X ₁ is O, CH ₂ or N-CH ₃ .

In some embodiments, R''' is hydrogen. In some embodiments, R''' is a group where A is O or NH, m is 2 or 3, and X ₁ is O, CH ₂ or N-CH ₃ . In some embodiments, R''' is a group where A is O, m is 2 or 3, and X ₁ is O, CH ₂ or N-CH ₃ . In some embodiments, R''' is a group where A is NH, m is 2 or 3, and X ₁ is O, CH ₂ or N-CH ₃ .

Moreover, the present invention provides a quinoline derivative of formula (I')

(I'),

Where:

R independently represents a halogen atom or a group selected from (C ₁ -C ₃ )fluoroalkyl group, (C ₁ -C ₃ )fluoroalkoxy group, a -NR ₁ R ₂ group, (C ₁ -C ₄ )alkoxy group and (C ₁ -C ₃ )alkyl group, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group,

n represents 1 or 2,

n’ represents 1 or 2,

R ₁ and R ₂ independently represent a hydrogen atom or a (C ₁ -C ₃ )alkyl group,

R' independently represents a halogen atom or a group selected from (C ₁ -C ₃ )alkyl group, hydroxyl group, -NR ₁ R ₂ group, morpholinyl or morpholino group, N-methylpiperazinyl group, (C ₁ -C ₃ )fluoroalkyl group groups and (C ₁ -C ₄ )alkoxy groups, and may additionally be a group selected from:

, ,

A represent a covalent bond, an oxygen atom or NH,

B - covalent bond or NH,

m represent 2, 3 or 4,

p represent 1, 2 or 3,

Ra and Rb independently represent a hydrogen atom, a (C ₁ -C ₅ )alkyl group or a (C ₃ -C ₆ )cycloalkyl group,

Ra and Rb may further form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, optionally containing an additional heteroatom selected from N, O and S, which heterocycle is optionally replaced by one or more Ra, provided that when R' is (IIa) or (IIIa), n' can be 2 only if the other R' groups are different from said group (IIa) or (IIIa).

R'' is a hydrogen atom or an alkyl group (C ₁ -C ₄ ),

or any of its metabolites or pharmaceutically acceptable salts or any of their enantiomers or diastereoisomers,

for use in the treatment or prevention of cancer or dysplasia.

In one aspect, the present invention provides a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of its enantiomers or diastereoisomers for use in accordance with the present invention, wherein R independently represents a methyl group, a methoxy group, a trifluoromethyl group, a halogen atom and in particular a fluorine or chlorine atom, a trifluoromethoxy group and an amino group.

According to a further aspect, provided herein is a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of its enantiomers or diastereoisomers for use in accordance with the present invention, wherein R' independently represents a halogen atom and, in in particular, a fluorine or chlorine atom, a -NR ₁ R ₂ group and preferably an amino group, a hydroxyl group, an alkyl group (C ₁ -C ₃ ), preferably a methyl group or group where A is O or NH, m is 2 or 3 and X ₁ is O, CH ₂ or N-CH ₃ , with the proviso that when R' is such a group, n' is 1 or 2 , and when n' is 2, the other group R' is different from the specified group.

According to a further aspect, provided herein is a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of its enantiomers or diastereoisomers for use in accordance with the present invention, wherein R' independently represents a halogen atom and, in in particular, a fluorine or chlorine atom, a methyl group or group where A is O or NH, m is 2 or 3 and X ₁ is O, CH ₂ or N-CH ₃ , with the proviso that when R' is such a group, n' is 1 or 2 , and when n' is 2, the other group R' is different from the specified group.

According to a further aspect, provided herein is a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of its enantiomers or diastereoisomers for use in accordance with the present invention, wherein n is 1, n' is 1 or 2, R" represents H, R is selected from a methyl group, a methoxy group, a trifluoromethyl group, a halogen atom and in particular a fluorine or chlorine atom, a trifluoromethoxy group and an amino group, and R' represents a halogen atom and in particular a fluorine atom or chlorine, methyl group or group where A is O or NH, m is 2 or 3 and X ₁ is O, CH ₂ or N-CH ₃ , provided that when n' is 2, the other R' group is different from the specified group .

According to a further aspect, provided herein is a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of its enantiomers or diastereoisomers for use in accordance with the present invention, wherein n is 1, n' is 1 , R" represents H, R is selected from a methyl group, a methoxy group, a trifluoromethyl group, a halogen atom and in particular a fluorine or chlorine atom and a trifluoromethoxy group, and R' represents a halogen atom and in particular a fluorine or chlorine atom or chlorine or methyl group.

According to a further aspect, provided herein is a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of its enantiomers or diastereoisomers for use in accordance with the present invention, wherein it is defined by formula (I')

(I''),

Where

R is selected from a methyl group, a methoxy group, a trifluoromethyl group, a halogen atom and in particular a fluorine or chlorine atom, a trifluoromethoxy group and an amino group, and

R' represents a halogen atom and in particular a fluorine or chlorine atom or a methyl group, and

R'' represents a hydrogen atom or group where A represents O or NH, m represents 2 or 3 and X ₁ represents O, CH ₂ or N-CH ₃ and in particular represents a hydrogen atom.

In some embodiments, a compound of the present invention is a compound of the formula: (“ABX464”) or a pharmaceutically acceptable salt thereof. In some embodiments, compound ABX464 or a pharmaceutically acceptable salt thereof is in amorphous form. In some embodiments, compound ABX464 or a pharmaceutically acceptable salt thereof is in crystallized form. In some embodiments, a crystallized form of compound ABX464 or a pharmaceutically acceptable salt thereof has a melting point of 120.5°C (±2°C). In some embodiments, a crystallized form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits XRPD (X-ray powder diffractogram) peaks at angles of 7.3, 14.6, 18.4, and 24.9. In some embodiments, a crystallized form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits one or more XRPD peaks at angles selected from 18.0, 24.2, 28.3, and 29.5. In some embodiments, a crystallized form of compound ABX464 or a pharmaceutically acceptable salt thereof exhibits one or more XRPD peaks at angles selected from 18.6, 22.3, 23.0, and 23.5.

According to a further aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, wherein said compound is 8-chloro-N-(4-(trifluoromethoxy) phenyl)quinoline-2-amine and is a crystalline polymorphic form characterized by the following major peaks, expressed as degrees 2-theta angles in XRPD analysis: 7.3, 14.6, 23.5 and 28.4 (each time ±0 ,2), and may additionally show the following additional peaks expressed as degrees of 2-theta angles in XRPD analysis: 12.1, 17.3, 18.4, 23.0; 24.2, 24.9, 27.4 and 29.1 (each time ±0.2) and even optionally the following peaks expressed as degrees of 2-theta angles: 13.7, 16.3, 16.9 , 18.1, 22.4, and 29.6 (±0.2 each time).

In some embodiments, a compound of the invention is selected from Table 1:

Table 1 (compounds of formula Ia as defined above)

1 2 3 4 5 6 7 8 9 10 eleven 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 thirty 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of this invention is selected from Table 2:

Table 2 (compounds of formula Ib defined above)

95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of the invention is selected from Table 3:

Table 3 (Compounds of formula (I) other than compounds (Ia) and (Ib))

165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183

or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of cancer and/or dysplasia

(Ib'),

Where:

each R independently represents hydrogen, halogen, -CN, hydroxyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₃ )fluoroalkoxy, (C ₃ -C ₆ )cycloalkyl, -NO ₂ , -NR ₁ R ₂ , (C ₁ -C ₄ )alkoxy, phenoxy, -NR ₁ -SO ₂ -NR ₁ R ₂ , -NR ₁ -SO ₂ -R ₁ , -NR ₁ -C(=O)-R ₁ , -NR ₁ -C(=O)-NR ₁ R ₂ , -SO ₂ -NR ₁ R ₂ , -SO ₃ H, -O-SO ₂ -OR ₃ , -OP(=O)(OR ₃ )(OR ₄ ), -O-CH ₂ -COOR ₃ , (C ₁ -C ₃ )alkyl, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group, an -A-(CH ₂ ) _m -B-NRaRb group (formula IIa) or a -( group O-CH ₂ -CH ₂ ) _p -O-Ra (formula IIIa),

each of R ₁ and R ₂ independently represents hydrogen or (C ₁ -C ₃ )alkyl,

R ₃ and R ₄ are each independently hydrogen, Li+, Na+, K+, N+(Ra) ₄ or benzyl,

n represents 1, 2 or 3,

each R' independently represents hydrogen, (C ₁ -C ₃ )alkyl, hydroxyl, halogen, -NO ₂ , -NR ₁ R ₂ , morpholinyl, morpholino, N-methylpiperazinyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₄ ) alkoxy, -OP(=O)(OR ₃ )(OR ₄ ), -CN, -NH-SO ₂ -N(CH ₃ ) ₂ group, -A-(CH ₂ )mB-NRaRb group (formula IIa) or the group -(O-CH ₂ -CH ₂ ) _p -O-Ra (formula IIIa),

A represents a covalent bond, oxygen or NH; B is a covalent bond or NH;

m represents 1, 2, 3, 4 or 5;

p is 1, 2 or 3;

Ra and Rb are each independently hydrogen, (C ₁ -C ₅ )alkyl or (C ₃ -C ₆ )cycloalkyl, or

Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, optionally containing an additional heteroatom selected from N, O and S, which heterocycle is optionally substituted by one or more Ra, and

R” represents hydrogen, (C ₁ -C ₄ )alkyl or an A-(CH ₂ ) _m -B-NRaRb group (formula IIa).

In one aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, wherein:

R independently represents a halogen atom or a group selected from (C ₁ -C ₃ )fluoroalkoxy group, -NR ₁ R ₂ group, (C ₁ -C ₄ )alkoxy group, -OP(=O)(OR ₃ )(OR ₄ ), a (C ₁ -C ₃ )alkyl group, NO ₂ group, -A-(CH ₂ ) _m -B-NRaRb group (formula IIa) and -(O-CH ₂ -CH ₂ ) _p -O group -Ra Ra (formula IIIa),

n represents 1 or 2,

R' represents a hydrogen atom, a halogen atom or a group selected from -NR ₁ R ₂ group, -OP(=O)(OR ₃ )(OR ₄ ) group, -NH-SO ₂ -N(CH ₃ ) ₂ group and groups -A-(CH ₂ ) _m -B-NRaRb (IIa),

R' represents a hydrogen atom, an alkyl group (C ₁ -C ₄ ) or a -A-(CH ₂ ) _m -B-NRaRb group (formula IIa),

R ₁ and R ₂ independently represent a hydrogen atom or a (C ₁ -C ₃ )alkyl group,

R ₃ and R ₄ are independently hydrogen, Li+, Na+, K+, N+(Ra)4 or benzyl,

A represents a covalent bond, an oxygen atom or NH,

B represents a covalent bond,

m represents 2, 3 or 4,

p represents 1, 2 or 3,

Ra and Rb independently represent a hydrogen atom or an alkyl group (C ₁ -C ₅ ),

Ra and Rb may further form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, optionally containing an additional heteroatom selected from N, O and S, which heterocycle is optionally substituted by one or more Ra.

According to a further aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, in which:

R independently represents F, Cl, -NH ₂ , -N(CH ₃ ) ₂ , -OCH ₃ , -O-(CH ₂ ) ₃ -CH ₃ , -OCF ₃ , -CH ₃ , -O-(CH ₂ ) ₂ -OH, -O-(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -OCH ₃ , -NO ₂ group, -OP(=O)(OH)(OH) group, -O-(CH ₂ ) ₂ -morpholine group or -O-(CH ₂ ) ₂ -piperidino group,

n represents 1 or 2,

R' represents a hydrogen atom, Cl, -CH _{2 -CH 2} -CH ₃ , a -O-(CH ₂ ) ₂ -morpholine group, -O-(CH ₂ ) ₂ -piperidino group, -O-(CH ₂ ) ₃ -piperidino group, -N-(CH ₂ ) ₃ -morpholine group, -NH-SO ₂ -N(CH ₃ ) ₂ group, NH ₂ or -OP(=O)(OH)(OH) group,

R' represents a hydrogen atom, -CH ₃ , -(CH ₂ ) ₃ -piperidino group, -(CH ₂ ) ₂ -morpholine group, -(CH ₂ ) ₄ -morpholine group or -(CH ₂ ) ₂ -pyrrolidino group .

According to a further aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, wherein:

R represents a (C ₁ -C ₃ )fluoroalkoxy group, and

n represents 1,

both R' and R'' are defined in this text.

According to a further aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, wherein:

R represents a (C ₁ -C ₃ )fluoroalkoxy group,

n represents 1,

R' represents a hydrogen atom, and

R'' represents a hydrogen atom.

According to a further aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, wherein:

R' represents a hydrogen atom.

and R, n and R' are as defined herein.

According to a further aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, wherein said compound is selected from compounds 96, 98, 108, 109, 111, 115, 122, 125, 128, 129, 130, 132, 133, 135, 138-141, 143 and 145-164.

According to a further aspect, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, wherein said compound is 8-chloro-N-(4-(trifluoromethoxy) phenyl)quinoline-2-amine (compound 111).

As shown in the experimental section, the compounds of formula (Ib') or any metabolites thereof or a pharmaceutically acceptable salt thereof as defined herein, in particular compound ABX464, are effective for the treatment and/or prevention of cancer, in particular colorectal cancer, gastric cancer, liver cancer, lung cancer and/or pancreatic cancer (see IC50 values), particularly in patients with precancerous, early-stage or non-metastatic cancer. In one embodiment, the compounds of formula (Ib') or any metabolite thereof or a pharmaceutically acceptable salt thereof suitable for the present invention do not directly target metastatic invasion.

In addition, from the results disclosed in the experimental part, it follows that the compounds of formula (Ib') or any metabolite or pharmaceutically acceptable salt thereof are unexpectedly more effective for the treatment and/or prevention of cancer, in particular in patients having a precancerous condition, cancer on early stage or non-metastatic cancer than the comparison compound 26, which refers to formula (Ia) as defined herein and in WO 2010/143168.

Moreover, in WO 2010/143168, compound 26 corresponds to compound 37. And in WO 2010/143168, the compound was demonstrated to have an anti-invasive effect predictive of its activity against cancer. Therefore, it was unexpected that compound 26, as defined herein, was less potent than the compounds of formula (Ib'). These results also demonstrate that a compound having anti-invasive properties does not necessarily have equally effective activity against pre-cancer, early-stage cancer or non-metastatic cancer.

In some embodiments, a compound described herein is in the form of a salt selected from sulfate, hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetate, fumarate, and sulfonate. In some embodiments, a compound described herein is in salt form as an alkyl sulfonate or arylsulfonate. In some embodiments, a compound described herein is in the form of a mesylate, triflate, edisylate, besylate, and tosylate salt.

In one aspect, the present invention provides a metabolite of a compound described herein. In some embodiments, the present invention provides an N-glucuronide metabolite of a compound described herein.

In some embodiments, a compound of this invention is a compound of formula (IV):

(IV)

or a pharmaceutically acceptable salt thereof, wherein each of the variables V, Z, R, R', n and n' is as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, a compound of this invention is a compound of formula (IVa):

(IVa)

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', n, and n' are independently as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, the compound of the invention is a compound of formula (IVb):

(IVb)

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', n, and n' are independently as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, the compound of the invention is a compound of formula (IVc):

(IVc)

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', n, and n' are independently as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, the compound of the invention is a compound of formula (IVb'):

(IVb')

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R' and n are independently as defined above and described in the embodiments herein, either alone or in combination.

Thus, the present invention further provides a compound of formula (IVb') or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of cancer and/or dysplasia. In one embodiment, said compounds of formula (IVb') or a pharmaceutically acceptable salt thereof do not directly target metastatic invasion.

In some embodiments, the compound of the invention is a compound of formula (IVd):

(IVd)

or a pharmaceutically acceptable salt thereof, wherein each of the variables R, R', R'” are independent as defined above and described in the embodiments herein, either alone or in combination.

In some embodiments, the present invention provides a method of treating an inflammatory disease, disorder, or condition, comprising administering to a patient in need thereof a compound of any of formulas (IV), (IVa), (IVb), (IVc), (IVb'), and (IVd) or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of the invention is a compound of the formula:

or a pharmaceutically acceptable salt thereof.

Thus, in a further aspect, provided herein is a compound of formula (IVb') or a pharmaceutically acceptable salt thereof for use as defined herein, wherein said compound has the following formula:

.

The compounds of the present invention may exist in the form of free bases or addition salts with pharmaceutically acceptable acids. Suitable physiologically acceptable acid addition salts of the compounds of the present invention include sulfate, hydrobromide, citrate, trifluoroacetate, ascorbate, hydrochloride, triflate, tartrate, maleate, formate, acetate, fumarate and sulfonate, in particular alkyl sulfonate or arylsulfonate, and more particularly mesylate, triflate, edisylate , besylate and tosylate.

The compounds of the present invention and/or their salts may form solvates or hydrates, and the present invention includes all such solvates and hydrates. The terms "hydrates" and "solvates" literally mean that the compounds of this invention may be in the form of a hydrate or solvate, i.e. bound or associated with one or more water or solvent molecules. This is only a chemical characterization of such compounds, which can be applied to all organic compounds of the indicated type.

The compounds of the present invention may contain one or more asymmetric carbon atoms. Thus, they may exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, are within the scope of the present invention.

In the context of the present invention, the term:

- “halogen” is understood to mean chlorine, fluorine, bromine or iodine and in particular the term means chlorine, fluorine or bromine,

- “(C ₁ -C ₅ )alkyl” as used herein respectively refers to a normal, secondary or tertiary saturated C ₁ -C ₅ hydrocarbon. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, pentyl,

- “(C ₃ -C ₆ )cycloalkyl” as used herein appropriately refers to a cyclic saturated hydrocarbon. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

- “(C ₁ -C ₄ )alkoxy” as used herein accordingly refers to the O-(C ₁ -C ₄ )alkyl moiety, where alkyl is as defined above. Examples include, without limitation, methoxy, ethoxy, 1-propoxy, 2-propoxy, butoxy,

- “fluoroalkyl group” and “fluoroalkoxy group” refer, respectively, to an alkyl group and an alkoxy group as defined above, said groups being substituted by at least one fluorine atom. Examples are perfluoroalkyl groups such as trifluoromethyl or perfluoropropyl,

- “saturated 5- or 6-membered heterocycle” as used herein respectively refers to a saturated ring containing at least one heteroatom. Examples include, but are not limited to, morpholine, piperazine, thiomorpholine, piperidine, pyrrolidine.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the framework of careful medical evaluation, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, or the like, and are commensurate with a reasonable ratio benefit/risk. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference

Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate , phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like.

Salts derived from corresponding bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

Unless otherwise noted, structures depicted herein should also include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, the double bond isomers Z and E, and the conformational isomers Z and E. Therefore, individual stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds, are included within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of this invention are included within the scope of the invention. In addition, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, including the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays or as therapeutic agents according to the present invention.

Forms of cancer

The compound or any of its metabolites or pharmaceutically acceptable salts thereof, as defined above, may be effective in the treatment or prevention of various types of cancer.

As used herein, the term “cancer (cancerous disease)”, and unless otherwise specified, may refer to any disorder associated with abnormal cell growth, which thus includes malignant tumors and benign tumors, metastatic tumors and non-metastatic tumors, solid tumors and non-solid tumors such as blood cancers, which may thus include leukemia, lymphoma and myeloma; it may also refer to cancers of the central nervous system (CNS) and cancers that do not involve the CNS. Unless otherwise noted, the term “cancer (cancer disease)” also includes juvenile and non-juvenile cancers, recurrent and non-recurrent cancers, and recurrent cancers.

When the cancer in question is a blood cancer, it can be selected from: small cell lymphocytic lymphoma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (iNHL - indolent non-Hodgkin's lymphoma), refractory iNHL, mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunobl astonic large cell lymphoma, lymphoblastic lymphoma, splenic marginal zone B-cell lymphoma (+/- monocytoid B cells), nodal marginal zone lymphoma (+/- monocytoid B cells), extranodal marginal zone B-cell lymphoma MALT (mucosal lymphoid tissue) , cutaneous T-cell lymphoma, extranodal T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, granuloma fungoides, B-cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, small cell lymphoma with undissected nuclei, Burkitt lymphoma, multiple myeloma, plasmacytoma, acute lymphocytic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, acute myeloid leukemia , chronic lymphocytic leukemia, juvenile myelomonocytic leukemia, minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, or Waldenström's macroglobulinemia.

In other embodiments, the cancer is pancreatic cancer, urologic cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, thyroid cancer, gallbladder cancer, lung cancer (eg , non-small cell lung cancer, small cell lung cancer), ovarian cancer, cervical cancer, stomach cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, central nervous system cancer, brain tumors (eg, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasias, hemangiopericytomas, Kaposi sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, squamous esophageal carcinoma, oral carcinoma, adrenocortical cancers or ACTH-producing tumors.

In one embodiment, the cancer is selected from head and neck cancer, head and neck squamous cell carcinoma, neck squamous cell carcinoma, adult or pediatric acute lymphocytic leukemia (ALL), adult or pediatric acute myeloid leukemia (AML), acute lymphoblastic leukemia, adrenal cancer , anal cancer, astrocytic glioma, astrocytoma (grades I, II and III, or IV), B- or NK/T-cell lymphoma, basal and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer brain, adult brain and spinal cord tumors, pediatric brain and spinal cord tumors, anaplastic astrocytoma, breast cancer, gastrointestinal cancer, female breast cancer, young female breast cancer, male breast cancer, recurrent breast cancer breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer with lymphatic metastasis, ER (estrogen receptor) alpha breast cancer, adolescent cancer, childhood cancer, young adult cancer, cancer of unknown primary site , Castleman disease, cervical cancer, cervical intraepithelial neoplasia, cholangiocarcinoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, colon adenoma, squamous cell carcinoma of the skin, endometrial cancer, epithelial ovarian cancer, epithelial ovarian cancer associated with metastases, esophageal cancer, squamous cell esophageal cancer, Ewing's sarcoma, Ewing tumor family, lymphoblastic leukemia (ALL), eye cancer such as ocular melanoma and ocular lymphoma, gallbladder cancer, stomach cancer, gastrointestinal cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioblastoma, glioblastoma multiforme (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma of the breast, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharynx cancer, leiomyosarcoma, leukemia, childhood leukemia, liver cancer, lung cancer, lung carcinoid tumor, lymphoma, cutaneous lymphoma, malignant mesothelioma, mantle cell lymphoma, medulloblastoma , melanoma skin cancer, malignant melanoma, meningioma, Merkel cell skin cancer, multiple myeloma, multiple myeloma with osteonecrosis of the jaw, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, recurrent or metastatic nasopharyngeal carcinoma, neuroblastoma, neuroglioma, non-Hodgkin's lymphoma, non-Hodgkin's lymphoma in children, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cavity cancer, oral and oropharyngeal cancer, osteosarcoma, pulmonary metastatic osteosarcoma, ovarian cancer, pancreatic cancer, thyroid carcinoma, papillary thyroid carcinoma, childhood spinal ependymoma, penile cancer, pituitary tumors, pituitary adenoma, proneural tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the tongue, stomach cancer , testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, kidney cancer, retinoblastoma, Waldenström's macroglobulinemia and Wilms' tumor.

According to one particular embodiment, further provided herein is a compound or any metabolite or pharmaceutically acceptable salts thereof as defined herein, and in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use in the prevention or treatment of cancer selected from squamous cell carcinoma of the head and neck, squamous cell carcinoma of the neck, acute lymphocytic leukemia (ALL) in adults or children, acute myeloid leukemia (AML) in adults or children, acute lymphoblastic leukemia, adrenal cancer, anal cancer , astrocytic glioma, astrocytoma (grades I, II and III or IV), B- or NK/T-cell lymphomas, basal and squamous cell skin cancer, bile duct cancer, bone cancer, brain cancer, adult brain and spinal cord tumors, pediatric brain and spinal cord tumors, anaplastic astrocytoma, gastrointestinal cancer, female breast cancer, young female breast cancer, male breast cancer, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer , lymph node metastatic breast cancer, ER (estrogen receptor) alpha positive breast cancer, adolescent cancer, childhood cancer, young adult cancer, cancer of unknown primary site, Castleman disease, cervical intraepithelial neoplasia, cholangiocarcinoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, metastasis-associated epithelial ovarian cancer, esophageal squamous cell carcinoma, Ewing's sarcoma, tumor family Ewing's lymphoblastic leukemia (ALL), eye cancer such as ocular melanoma and ocular lymphoma, stomach cancer, gastrointestinal cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioblastoma multiforme glioblastoma (GBM), hairy cell leukemia, glioma, high-grade glioma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal carcinoma of the breast, Hodgkin's lymphoma, Kaposi's sarcoma, laryngeal and hypopharynx cancer, leiomyosarcoma, leukemia, childhood leukemia, carcinoid lung tumors , lymphoma, cutaneous lymphoma, malignant mesothelioma, mantle cell lymphoma, medulloblastoma, malignant melanoma, meningioma, Merkel cell skin cancer, multiple myeloma, multiple myeloma with osteonecrosis of the jaw, myelodysplastic syndrome, cancer of the nasal cavity and paranasal sinuses, cancer of the nasopharynx, recurrent or metastatic nasopharyngeal carcinoma, neuroblastoma, neuroglioma, non-Hodgkin's lymphoma, pediatric non-Hodgkin's lymphoma, gefitinib-resistant non-small cell lung cancer, oral cavity cancer, oral and oropharyngeal cancer, osteosarcoma, pulmonary metastatic osteosarcoma, thyroid carcinoma, papillary thyroid carcinoma, pediatric spinal ependymoma, penile cancer, pituitary tumors, pituitary adenoma, proneural tumors, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the tongue, testicular cancer, thymus cancer, uterine sarcoma , vaginal cancer, vulvar cancer, kidney cancer, retinoblastoma, Waldenström's macroglobulinemia and Wilms' tumor.

In another embodiment, the metastasis is located in the brain, head or neck, lungs, trachea, stomach, small intestine, colon, liver, bones, peritoneum, ovaries, kidneys, bladder, lymph nodes, muscle or skin.

In one embodiment, the compound or any of its metabolites or pharmaceutically acceptable salts thereof, as defined herein, and in particular, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, also referred to as ( 8-Chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine, are more specifically indicated for the treatment or prevention of any metastasis of any of the above cancers in the brain, bones, liver, lungs, kidneys, muscles, abdominal cavities or other tissues.

In one embodiment, the compound or any of its metabolites or pharmaceutically acceptable salts as described herein, and in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, also referred to as ( 8-Chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine is more specifically indicated for the treatment or prevention of the following types of cancer: head and neck cancer, gastric cancer, breast cancer, basal and squamous cell skin cancer, liver cancer, brain cancer, lung cancer, pancreatic cancer, eye cancer, gastrointestinal cancer, colorectal cancer, bladder cancer, bone cancer and kidney cancer.

In one specific embodiment, the compound or any of its metabolites, or pharmaceutically acceptable salts thereof, as described herein, and in particular, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, also called (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine, are particularly indicated for the treatment and prevention of the following types of cancer: nasopharyngeal carcinoma (recurrence and metastasis), astrocytic gliomas, cancer, prostate cancer gland, non-small cell lung cancer (NSCLC), cholangiocarcinoma (with lymph node involvement and distant metastasis), bladder cancer, head and neck squamous cell carcinoma (HNSCC), oral cancer, Ewing's sarcoma, metastatic Ewing's sarcoma, gefitinib-resistant non-small cell lung cancer, squamous cell carcinoma of the skin, osteosarcoma, malignant melanoma, osteosarcoma associated with pulmonary metastases, colorectal carcinoma, breast cancer, colorectal cancer (CRC), gastric cancer (GC), glioblastoma multiforme, glioma, glioblastoma, retinoblastoma, nasopharyngeal carcinoma (NPC), colorectal cancer, bladder cancer, acute myeloid leukemia, astrocytomas (grades I-II-II-IV), B- or NK/T-cell lymphomas, bladder cancer (advanced tumor), gastric dysplasia, gastric cancer associated with metastases to lymph nodes, gliomas, myelodysplastic syndrome, pancreatic ductal adenocarcinoma (associated with lymph node metastases and/or tumors, node, metastasis), HER2-positive breast cancer, lung adenocarcinoma, medulloblastoma, non-small cell lung cancer (associated with lymph node metastases and/or tumor node metastases), breast cancer (tumor node-associated metastases and lymph node metastases), endometrial cancer, medulloblastoma, squamous cell carcinoma of the skin, intrahepatic cholangiocarcinoma (ICC), gallbladder cancer, colorectal adenoma (CRA), acute lymphoblastic leukemia (ALL ), glioblastoma multiforme (GBM), pancreatic ductal adenocarcinoma (PDAC), bladder cancer (BC), ovarian cancer (OC), leukemia, myelodysplastic syndrome (MDS), proneural tumors, head and neck squamous cell carcinoma (HNSCC), primary tumor, renal cell carcinoma (RCC), uveal melanoma, malignant prostate cancer, oral squamous cell carcinomas (OSCC), anaplastic astrocytomas, esophageal cancer, astrocytomas, cholangiocarcinomas, breast cancer (associated with lymph node metastases), childhood spinal ependymoma , pancreatic cancer, epithelial ovarian cancer, breast cancer (associated with bone metastasis), hepatocarcinoma, myelodysplastic syndrome, malignant melanoma (nodal metastasis), small intestinal neuroendocrine neoplasms (SI-NEN), epithelial ovarian cancer (associated with lymph node metastasis , peritoneum, and distant organs), myelodysplastic syndrome, infantile ependymoma, gastric carcinoma, breast cancer (ER-alpha positive), hepatocellular carcinoma (HCC), ovarian cancer, esophageal squamous cell carcinoma (ESCC), invasive ductal carcinoma of the breast (related with lymph node metastases), lymphoma, myeloma (MM), lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), B- or NK/T-cell lymphoma, carcinoma cervical, carcinosarcoma, cervical cancer, cervical intraepithelial neoplasia (CIN2 and CIN3 grades), metachronous gastric cancer, clear cell renal cancer, myelodysplastic syndrome (MDS), bladder cancer (BCA), pancreatic cancer, CCRCC (clear cell renal cancer ), tumor tissues of ulcerative colitis (UC) (colitis-associated cancer (CAC), dysplasia and sporadic colorectal cancer (S-CRC)), cervical intraepithelial neoplasia, head and neck cancer.

According to a further embodiment, the cancer is selected from head and neck cancer, head and neck squamous cell carcinoma, neck squamous cell carcinoma, malignant melanoma, gastric cancer, breast cancer, female breast cancer, young female breast cancer, basal and squamous cell skin cancer, liver cancer, brain cancer, anaplastic astrocytomas, lung cancer, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, eye cancer, stomach cancer, gastrointestinal cancer, astrocytic gliomas, astrocytomas ( grade I, II, III, or IV), colorectal cancer, colorectal adenoma, squamous cell carcinoma of the skin, bladder cancer, bone cancer, recurrent breast cancer, hereditary breast cancer, HER2-positive breast cancer, breast cancer associated with metastases in the lymph node, ER-alpha-positive cancer of the mammary gland, RAC kidneys, intraepithelial neoplasia of the cervix, cholangiocarcinoma, leiomiosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloidal leukemia (CML), chronic myelomonocyte leukemia (CMMMML), acute myelo, acute mymor I have leukemia (AML) in adults or children, acute lymphoblastic leukemia, B- or NK/T-cell lymphomas, cervical cancer, glioblastoma, glioblastoma multiforme (GBM) hairy cell leukemia, gliomas, high-grade gliomas, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, invasive ductal breast cancer, kidney cancer, endometrial cancer, ovarian cancer, epithelial ovarian cancer, epithelial ovarian cancer associated with metastasis, esophageal cancer, squamous cell carcinoma of the esophagus, Ewing's sarcoma, lymphoblastic leukemia (ALL), mantle cell lymphoma, medulloblastoma, lymphoma, myelodysplastic syndrome, meningioma, multiple myeloma (MM), multiple myeloma with osteonecrosis of the jaw, nasopharyngeal cancer, recurrent or metastatic nasopharyngeal cancer, neuroblastoma, neuroglioma, papillary thyroid cancer, childhood spinal ependymoma, osteosarcoma, osteosarcoma with pulmonary metastases, pancreatic cancer, thyroid cancer, sarcoma, pituitary tumor, pituitary adenoma, proneural tumors, squamous cell carcinoma of the tongue, retinoblastoma and prostate cancer.

In accordance with a further embodiment of the present invention, the cancer is selected from head and neck cancer, head and neck squamous cell carcinoma, neck squamous cell carcinoma, malignant melanoma, astrocytic glioma, glioma, gastric cancer, breast cancer, cholangiocarcinoma, recurrent or metastatic nasopharyngeal carcinoma, basal and squamous cell skin cancer, liver cancer, brain cancer, anaplastic astrocytomas, lung cancer, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, oral cancer, glioblastoma, osteosarcoma, osteosarcoma with pulmonary metastases, pancreatic cancer, eye cancer, cancer gastrointestinal tract, colorectal cancer, colorectal adenoma, squamous cell carcinoma of the skin, endometrial cancer, epithelial ovarian cancer, esophageal cancer, Ewing's sarcoma, gastric cancer, hepatocellular carcinoma, HER2-positive breast cancer, bladder cancer, bone cancer, prostate cancer gland, retinoblastoma and kidney cancer.

In a specific embodiment, the cancers specifically contemplated are selected from: anaplastic astrocytomas, astrocytic gliomas, bladder cancer, breast cancer, cholangiocarcinoma, colorectal cancer, colorectal adenoma, cutaneous squamous cell carcinoma, endometrial cancer, epithelial ovarian cancer, esophageal cancer , Ewing's sarcoma, gastric cancer, gefitinib-resistant non-small cell lung cancer, glioblastoma, glioma, hepatocellular carcinoma, HER2-positive breast cancer, squamous cell carcinoma of the head and neck, malignant melanoma, nasopharyngeal carcinoma (recurrence or metastasis), squamous cell carcinoma of the neck, non-small cell - lung cancer, oral cancer, osteosarcoma, osteosarcoma associated with pulmonary metastasis, prostate cancer and retinoblastoma.

In one aspect, the present invention relates to 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine for use in the prevention and/or treatment of cancer, particularly selected from head and neck cancer, gastric cancer, breast cancer, basal and squamous cell skin cancer, liver cancer, brain cancer, lung cancer, eye cancer, gastrointestinal cancer, colorectal cancer, bladder cancer, bone cancer, kidney cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), B- or NK/T-cell lymphomas, cervical cancer, kidney cancer, endometrial cancer, ovarian cancer, esophageal cancer, lymphoblastic leukemia (ALL ), lymphoma, myelodysplastic syndrome, multiple myeloma (MM), nasopharyngeal cancer, neuroblastoma, osteosarcoma, osteosarcoma with pulmonary metastasis, pancreatic cancer, thyroid carcinoma, sarcoma, pituitary tumors and prostate cancer.

According to a particular embodiment, 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine may be effective in the treatment or prevention of head and neck cancer, gastric cancer, breast cancer, basal and squamous cell skin cancer, cancer liver, brain cancer, lung cancer, eye cancer, gastrointestinal cancer, colorectal cancer, bladder cancer, bone cancer or kidney cancer.

Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (eg, Hodgkin's disease or non-Hodgkin's disease), Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma , adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma and retinoblastoma).

In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma or retinoblastoma.

In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I - Pilocytic astrocytoma, grade II - low grade astrocytoma, grade III - Anaplastic Astrocytoma, or grade IV - glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brainstem glioma brain, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), or schwannoma. In some embodiments, the cancer is a type more common in children than in adults, such as brainstem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET) ) or rhabdoid tumor. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or pediatric patient.

Cancer includes in another embodiment, without limitation, mesothelioma, hepatobiliary cancer (liver and bile duct cancer), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or melanoma inside the eye, ovarian cancer, colon cancer , rectal cancer, anal cancer, stomach cancer, gastrointestinal cancer (gastric, colorectal and duodenal), uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, cancer esophagus, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas , bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, non-Hodgkin's lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, adrenal cortex cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma , retinoblastoma, or a combination of one or more of the above cancers.

In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or papillary serous carcinoma of the uterus (UPSC - uterine papillary serous carcinoma), prostate cancer, testicular cancer, gallbladder cancer, hepatocholangiocarcinoma, synovial sarcoma of soft tissues and bones, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, anaplastic thyroid cancer prominent gland , adrenal cortical adenomas, pancreatic cancer, pancreatic ductal carcinoma or pancreatic adenocarcinoma, gastrointestinal/stomach cancer (GIST), lymphoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, glioma or brain cancer, NF1-associated (NF1, neurofibromatosis type 1), malignant peripheral nerve sheath tumors (MPNST), Waldenström's macroglobulinemia or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, synovial sarcoma soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenal adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, NF1-associated glioma (NF1, neurofibromatosis type 1), malignant peripheral nerve sheath tumors ( MPNST), Waldenström's macroglobulinemia or medulloblastoma.

In another embodiment, the cancer is selected from anal cancer, bile duct cancer, gastrointestinal cancer, cholangiocarcinoma, colorectal cancer, colorectal adenoma, esophageal cancer, esophageal squamous cell carcinoma, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor intestinal tract (GIST), hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer, lung cancer, lung carcinoid tumor, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, pulmonary metastatic osteosarcoma, gastric cancer, pancreatic cancer, small cell lung cancer and small cell lung cancer intestines.

According to another embodiment, the cancer is selected from stomach cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, pancreatic cancer, lung cancer and liver cancer.

According to one particular embodiment, further provided herein is a compound of formula (Ib') or any metabolite thereof or a pharmaceutically acceptable salt thereof, and in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2- amine, for use in the prevention and/or treatment of cancer selected from anal cancer, bile duct cancer, gastrointestinal cancer, cholangiocarcinoma, colorectal, colorectal adenoma, esophageal cancer, squamous cell carcinoma of the esophagus, gastric cancer, gastrointestinal carcinoid tumors tract, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer, lung cancer, lung carcinoid tumor, non-small cell lung cancer, gefitinib-resistant non-small cell lung cancer, metastatic osteosarcoma of the lung, gastric cancer, pancreatic cancer, small cell lung cancer and small bowel cancer.

According to another particular embodiment, further provided herein is a compound of formula (Ib') or any metabolite thereof or a pharmaceutically acceptable salt thereof, and in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine, for use in the prevention and/or treatment of cancer selected from gastric cancer, stomach cancer, gastrointestinal cancer, colorectal cancer, pancreatic cancer, lung cancer and liver cancer.

In some embodiments, the present disclosure provides a method of treating a cancer that is a solid tumor, such as a sarcoma, carcinoma, or lymphoma, including the step of administering a disclosed compound or a pharmaceutically acceptable salt thereof to a patient in need thereof. Solid tumors are usually an abnormal mass of tissue that usually does not include cysts or fluid areas. In some embodiments, the cancer is selected from renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal carcinoma or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, epithelial ovarian cancer, ovarian carcinoma or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; synovial sarcoma of soft tissues and bones; rhabdomyosarcomas; osteosarcomas; chondrosarcomas; Ewing's sarcoma; anaplastic thyroid cancer; adrenal cortex carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach cancer (GIST); lymphomas; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; NF1-associated (neurofibromatosis type 1), malignant peripheral nerve sheath tumors (MPNST); Waldenström's macroglobulinemia; or medulloblastoma.

In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian cancer tubes, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenal cortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, adenocarcinoma pancreas , glioma, NF1-associated brain cancer (neurofibromatosis type 1), malignant peripheral nerve sheath tumors (MPNST), Waldenström's macroglobulinemia or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma , synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenal cortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, NF1-associated glioma (NF1, neurofibromatosis type 1), meningeal malignancies peripheral nerves (MPNST), Waldenström's macroglobulinemia or medulloblastoma.

In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian carcinoma. In some embodiments, the cancer is epithelial ovarian cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is a synovial sarcoma of soft tissue and bone. In some embodiments, the cancer is a rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is an adrenal cortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is a glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is NF1-associated MPNST (NF1, neurofibromatosis type 1). In some embodiments, the cancer is Waldenström's macroglobulinemia. In some embodiments, the cancer is a medulloblastoma.

The present invention further demonstrates methods and compositions for the diagnosis, prognosis and treatment of virus-associated cancers, including human immunodeficiency virus (HIV)-associated solid tumors, incurable human papillomavirus (HPV)-16 positive solid tumors and T-cell adult leukemia caused by human T-cell leukemia virus type I (HTLV-I), which is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I into leukemia cells (see https://clinicaltrials.gov/ct2/show /study/NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (see https://clinicaltrials.gov/ct2/show/study/NCT02488759; see also https://clinicaltrials.gov/ct2/show/study/NCT0240886; https://clinicaltrials.gov/ct2/show/ NCT02426892).

In some embodiments, the present invention provides a method of treating a tumor in a patient in need thereof, comprising administering to the patient any of the compounds, salts, or pharmaceutical compositions described herein. In some embodiments, the tumor includes any of the types of cancer described herein. In some embodiments, the tumor is, in particular, a melanoma cancer. In some embodiments, the tumor is, in particular, breast cancer. In some embodiments, the tumor is, in particular, lung cancer. In some embodiments, the tumor is, in particular, small cell lung cancer (SCLC). In some embodiments, the tumor is, in particular, non-small cell lung cancer (NSCLC).

In some embodiments, the tumor is treated by stopping further growth of the tumor. In some embodiments, a tumor is treated by reducing the size (e.g., volume or weight) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% relative to the size of the tumor before treatment. In some embodiments, tumors are treated by reducing the number of tumors in a patient by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% relative to the number of tumors before treatment.

This text also describes a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, or a compound of formula (IVb') or a pharmaceutically acceptable salt thereof for use as defined herein wherein the cancer is a precancerous condition, an early stage cancer, or a non-metastatic cancer.

In one embodiment, a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, or a compound of formula (IVb') or a pharmaceutically acceptable salt thereof for use as defined herein , do not directly target metastatic invasion.

Also disclosed herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, or a compound of formula (IVb') or a pharmaceutically acceptable salt thereof for use as defined herein wherein the use is to reduce or prevent the occurrence of a precancerous condition, early-stage cancer, or non-metastatic cancer in a subject with a family history of cancer or a hereditary cancer syndrome where the subject has never had a clinically detectable cancer.

This text also describes a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, or a compound of formula (IVb') or a pharmaceutically acceptable salt thereof for use as defined herein wherein the presence and/or expression level of miR-124 in a blood and/or tissue sample is measured to select a patient.

According to another embodiment, provided herein is a compound of formula (Ib') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, or a compound of formula (IVb') or a pharmaceutically acceptable salt thereof for use in a patient , as defined in this text,

where the specified patient does not have clinically detectable metastases, in particular, the specified patient has a precancerous condition, early stage cancer or non-metastatic cancer, or

wherein said patient has clinically detectable metastases, and said compounds of formula (Ib') or formula (IVb') are not directly directed at metastatic invasion.

In a particular embodiment, provided herein is ABX464 or any of its metabolites or a pharmaceutically acceptable salt thereof for use as defined herein, or a compound of formula or a pharmaceutically acceptable salt thereof for use in a patient as defined herein,

where the specified patient does not have clinically detectable metastases, in particular, the specified patient has a premalignant condition, early stage cancer or non-metastatic cancer, or

wherein said patient has clinically detectable metastases, and said ABX464 or any of its metabolites, or a pharmaceutically acceptable salt thereof, or said compound of formula does not directly target metastatic invasion.

As mentioned above, said compounds of formulas (Ib') and (IVb') can be used for the prevention and/or treatment of precancerous, early stage or non-metastatic cancer. These compounds may also be effective in preventing and/or reducing the likelihood of cancer recurrence.

In some embodiments, administration of the compounds prevents the transformation of a precancerous, early-stage, or non-metastatic cancer into an invasive or metastatic cancer. For example, the precancerous condition, early stage cancer, or non-metastatic cancer may be stage 0, stage I, or stage II cancer, and in some embodiments, administration of the compounds prevents the progression of the precancerous condition, early stage cancer, or non-metastatic cancer to the next stage(s), for example, stage I, stage II, stage III or stage IV cancer. In some embodiments, the compounds are administered for a time and in an amount sufficient to treat a precancerous tumor, early stage tumor, or non-metastatic tumor in a subject or to prevent a precancerous tumor, early stage tumor, or non-metastatic tumor from becoming an invasive or metastatic cancer. In some embodiments, administration of these compounds reduces tumor size, tumor weight, or the number of tumors of a precancerous tumor, an early stage tumor, or a non-metastatic tumor. These compounds may also be administered in an amount and over a period of time to reduce vascular density in a precancerous tumor, an early stage tumor, or a non-metastatic tumor.

The terms “early stage cancer” or “early stage tumor” mean cancer that is not invasive or metastatic or is classified as stage 0, I or II cancer.

The term "precancerous" refers to a condition or growth that usually precedes or develops into cancer. "Precancerous" growth will be cells that are characterized by abnormal regulation of cell cycle, proliferation or differentiation, which can be determined by markers of cell cycle regulation, cell proliferation or differentiation.

"Dysplasia" refers to any abnormal growth or development of tissue, organ or cells. Preferably, the dysplasia is high grade dysplasia or precancerous.

“Tumor weight” refers to the number of cancer cells, the size of the tumor, or the size of the cancer in the body. Tumor weight is also called tumor burden.

By "number of tumors" is meant the number of tumors.

“Metastasis” refers to the spread of cancer from its primary site to other places in the body. Cancer cells can break away from the primary tumor, enter lymphatic and blood vessels, circulate through the bloodstream, and grow at a distant site (metastasize) to normal tissue in other parts of the body. Metastases can be local or distant. Metastasis is a sequential process dependent on tumor cells detaching from the primary tumor, traveling through the bloodstream, and stopping at a distant site. In their new location, the cells form a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways in the tumor cell regulate this behavior, and interactions between the tumor cell and host cells at a distant site are also significant.

By "non-metastatic" cancer is meant a cancer that is benign or remains at the primary site and does not invade the lymphatic or blood vessel systems or tissues other than the primary site. In general, non-metastatic cancer is any cancer stage 0, I or II.

Reference to a tumor or cancer as "Stage 0", "Stage I", "Stage II", "Stage III" or "Stage IV" indicates classification of the tumor or cancer by overall stage, or by Roman numeral staging methods known from the level technology. Although the actual stage of the cancer depends on the type of cancer, in general, stage 0 cancer is an in situ lesion, stage I cancer is a small localized tumor, stage II is a localized tumor at an advanced stage, stage III cancer is invasion of the lymph nodes or surrounding tissues, and stage IV cancer is metastatic cancer. The specific stages for each tumor type are known to a qualified clinician.

Generally, the TNM classification of malignant tumors (TNM, see ^8th edition in 2017) is the internationally accepted standard for classifying the extent of cancer. Indeed, TNM is a notation system that describes the stage of cancer arising from a solid tumor using alphanumeric codes:

• T describes the size of the original (primary) tumor and whether it has invaded nearby tissue,

• N describes the nearby (regional) lymph nodes involved,

• M describes distant metastasis (spread of cancer from one part of the body to another).

The term "tumor" as used herein refers to all growth and proliferation of neoplastic cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues.

By "primary tumor" or "primary cancer" is meant the original cancer and not a metastatic lesion located in another tissue, organ or location in the subject's body.

The term “cancer recurrence” as used herein refers to the return of cancer after treatment and includes the return of cancer to the primary organ, as well as distant recurrence, where the cancer returns outside the primary organ.

The compounds and compositions according to the method of the present invention can be administered using any amount and any route of administration effective for treating or reducing the severity of cancer, autoimmune disorder, primary immunodeficiency, proliferative disorder, inflammatory disease, neurodegenerative or neurological disease, schizophrenia, disease, bone related, liver disease or heart disease. The exact amount required will vary from subject to subject depending on the species, age and general condition of the subject, the severity of the disease or condition, the specific agent, its route of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent suitable for the patient being treated. It should be understood, however, that the overall daily use of the compounds and compositions of the present invention will be determined by the attending physician as part of a thorough medical evaluation. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the particular compound used; the specific composition used; the patient's age, weight, general health, gender, and diet; timing of administration, route of administration, and rate of elimination of the particular compound used; duration of treatment; drugs used in combination or coincident with the particular compound used, and similar factors well known in the medical field.

The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally, as an oral or nasal spray or the like, depending depending on the severity of the disease or disorder being treated.

Liquid dosage forms for oral administration contain, without limitation, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert solvents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be prepared in accordance with the prior art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable drug-carrying media and solvents that can be used are water, Ringer's solution, U.S.P. (US Pharmacopeia - US Pharmacopoeia)) and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as a solvent or suspending medium. Any light, fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injection solutions.

Injectables may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

In order to prolong the effect of the compound of the present invention, it is often desirable to slow down the absorption of the compound when administered subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a given compound then depends on the rate of its dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered form of the compound is achieved by dissolving or suspending the compound in an oily drug-carrying vehicle. Injectable depot forms are prepared by forming microencapsulating matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot dosage forms are also prepared by entrapping the compound in liposomes or microemulsions compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore dissolve in the rectum or vaginal cavity and release the active compound.

Solid oral dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) excipients or diluents, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, f) wetting agents such as cetyl alcohol and glycerol monostearate, g) absorbents such such as kaolin and bentonite clay, and h) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and tablets, the dosage form may also contain buffering agents.

Solid compositions of the same type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical manufacturing. They may optionally contain opacifying agents and may also be of a composition in which they release the active ingredient(s) only or preferentially in a specific part of the intestinal tract, optionally with a delay. Examples of potting compositions that can be used include polymeric substances and waxes. Solid compositions of the same type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings, and other coatings well known in the field of pharmaceutical manufacturing. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as is standard practice, additional substances other than inert diluents, for example tableting lubricants and other tabletting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may also be of a composition in which they release the active ingredient(s) only or preferentially in a specific part of the intestinal tract, optionally with a delay. Examples of potting compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, volatile formulations or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic dosage form, ear drops and eye drops are also considered to be within the scope of the present invention. Also, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound into the body. Such dosage forms can be prepared by dissolving or dosing the compound in an appropriate medium. Absorption enhancers can also be used to enhance the passage of a compound through the skin. The rate can be controlled either by providing a control membrane or by dispersing the compound in a polymer matrix or gel.

Treatment of cancer or dysplasia

Types and methods of application are considered within the meaning of the invention.

The invention further relates to a method of treating or preventing cancer or dysplasia, comprising at least the step of administering to a patient in need thereof an effective amount of a compound as defined above, or any of its metabolites or a pharmaceutically acceptable salt thereof, or any of their enantiomers or diastereoisomers , in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine.

The present invention also relates to the use of at least a compound as defined above, or any of its metabolites or a pharmaceutically acceptable salt thereof, or any of its enantiomers or diastereoisomers, and in particular 8-chloro-N-(4-(trifluoromethoxy )phenyl)quinoline-2-amine in amorphous or crystalline form, or one of its metabolites or pharmaceutically acceptable salts thereof, in particular an N-glucuronide metabolite as defined above, according to the present invention for the preparation of a pharmaceutical composition intended for the treatment of cancer or dysplasia .

The present invention further relates to a method of treating patients suffering from cancer or dysplasia, which includes at least the step of administering to the patient suffering from the above-mentioned an effective amount of a compound as defined above, or any of its metabolites or a pharmaceutically acceptable salt thereof, or any of its enantiomers or diastereoisomers, and in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine in amorphous or crystalline form, or one of its metabolites or pharmaceutically acceptable salts thereof, in particular N- chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine in amorphous or crystalline form, or one of its metabolites or pharmaceutically acceptable salts thereof, in particular the N-glucuronide metabolite as defined above.

Human cancer cells from various cancer sources are used to evaluate the antitumor activity of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine in any form or in the form of one of its pharmaceutically acceptable salts, e.g. on cell proliferation , viability and invasive activity. The cells are cultured in a specific medium for each type of cancer cell in the presence or absence of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine in any form or one of its pharmaceutically acceptable salts for various periods of time, e.g. 48 and 72 hours. At the end of culture, cell cytotoxicity, proliferation and viability can be assessed using a luminescent or colorimetric test such as CellTiter-Glo or MTT. The invasiveness of cancer cells can be studied by a membrane insert migration test or a wound healing test.

Doses and treatment regimen

The present invention further relates to a method for the prevention and/or treatment of cancer or dysplasia, the method comprising the step of administering to the host an effective amount of a compound as defined above, or a pharmaceutically acceptable salt thereof, particularly at varying frequencies, in doses ranging from 10 to 1000 mg, in in particular from 25 to 800 mg, or even from 30 to 600 mg, and, for example, from 30 to 200 mg.

In one embodiment, the frequency of treatment may be once or twice a day, once every three days, once a week, once every 2 weeks, or once a month.

According to a particular embodiment, the treatment is long-term or intermittent.

The term “long-term treatment” means long-term treatment, which can be carried out at various frequencies of administration, for example once every three days, or once a week, or once every two weeks, or once a month.

Treatment period, i.e. when treatment is intermittent, may range from 1 week to three years, which includes 2 to 6 weeks, 3 months, 6 months, 1 year and three years.

In one embodiment, the compound or any of its pharmaceutically acceptable salts as described herein is administered at a dose ranging from 25 to 300 mg, in particular from 25 to 200 mg, for example from 25 to 150 mg and, in particular, from 25 to 100 mg. Doses in the range of 25 to 300 mg include doses of about 25, 50, 75, 100, 150, 200, 250 and 300 mg.

The dosages indicated may be adapted depending on whether the treatment is long-term or intermittent. It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on numerous factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of elimination, drug combination, and also the discretion of the treating physician and the severity of the specific disease being treated. The amount of the quinoline compound of the present invention in the composition will also depend on the particular compound in the composition.

All combinations of doses, frequencies and treatment periods are covered within the scope of the present invention.

In a specific embodiment, a compound of the present invention, and in particular 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine or any pharmaceutically acceptable salt thereof, can be administered in various dosages and treatment regimens, in particular , once a day in doses of 10 to 1000 mg, in particular 25 to 800 mg and, in particular, 25 to 400 mg for prolonged treatment or during the treatment period.

The treatment period can vary from one week to three years, which includes 2 to 6 weeks, 3 months, 6 months, 1 year and three years.

The quinoline derivative can be administered every day, once every three days, once a week, once every two weeks or once a month.

Some examples of doses and treatment regimens are given below.

More particularly, the present invention relates to a dosage and treatment regimen, wherein a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof, administered 25 mg once daily during the treatment period or for long-term treatment

More particularly, the present invention relates to a dosage and treatment regimen in which a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof , administered 50 mg once daily during the treatment period or during continuous treatment

More particularly, the present invention relates to a dosage and treatment regimen in which a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof , administered 75 mg once daily during the treatment period or during continuous treatment

More particularly, the present invention relates to a dosage and treatment regimen in which a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof , administered 100 mg once daily during the treatment period or during continuous treatment

More particularly, the present invention relates to a dosage and treatment regimen in which a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof , administered 150 mg once daily during the treatment period or during continuous treatment

More particularly, the present invention relates to a dosage and treatment regimen in which a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof , administered 300 mg once daily during the treatment period or during continuous treatment

More particularly, the present invention relates to a dosage and treatment regimen in which a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof , administered 400 mg once daily during the treatment period or during continuous treatment

More particularly, the present invention relates to a dosage and treatment regimen in which a compound of the present invention or a pharmaceutically acceptable salt thereof, and more particularly 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine or a pharmaceutically acceptable salt thereof , administered 600 mg once daily during the treatment period or during continuous treatment

More specifically, the invention relates to a dosage and treatment regimen wherein the N-glucuronide metabolite of formula (1) as defined above, or a pharmaceutically acceptable salt thereof, is administered at 50 mg once daily during the treatment period or during continuous treatment.

More specifically, the invention relates to a dosage and treatment regimen wherein the N-glucuronide metabolite of formula (1) as defined above, or a pharmaceutically acceptable salt thereof, is administered at 150 mg once daily during the treatment period or during continuous treatment.

More specifically, the invention relates to a dosage and treatment regimen wherein the N-glucuronide metabolite of formula (1) as defined above, or a pharmaceutically acceptable salt thereof, is administered at 300 mg once daily during the treatment period or during continuous treatment.

More particularly, the invention relates to a dosage and treatment regimen wherein the N-glucuronide metabolite of formula (1) as defined above, or a pharmaceutically acceptable salt thereof, is administered at 500 mg once daily during the treatment period or during continuous treatment.

More specifically, the invention relates to a dosage and treatment regimen wherein the N-glucuronide metabolite of formula (1) as defined above, or a pharmaceutically acceptable salt thereof, is administered at 700 mg once daily during the treatment period or during continuous treatment.

More specifically, the invention relates to a dosage and treatment regimen wherein the N-glucuronide metabolite of formula (1) as defined above, or a pharmaceutically acceptable salt thereof, is administered at 1000 mg once daily during the treatment period or during continuous treatment.

Thus, the compound of the present invention may be formulated in a pharmaceutical composition, which may contain an effective amount of the compound as defined above, or a metabolite thereof in all forms as described above, and one or more pharmaceutically acceptable excipients.

The composition may contain a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier, adjuvant or drug-carrying medium. In certain embodiments, a composition of this invention is prepared for administration to a patient in need of such a composition.

The above-mentioned excipients, carriers, adjuvants or drug-carrying media are selected according to the dosage form and the desired route of administration.

Pharmaceutically acceptable carriers, adjuvants or drug-carrying vehicles that can be used in the compositions of this invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates , glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, substances on cellulose based, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, block copolymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin.

Said pharmaceutical form may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or through an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be an aqueous or oily suspension. These suspensions can be prepared according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable drug-carrying media and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as a solvent or suspending medium.

Any light, fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are effective in the preparation of injection solutions, as are natural pharmaceutically acceptable oils such as olive or castor oil, especially in their polyoxyethylene variants. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents, which are commonly used in the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for production purposes. The pharmaceutical form may in particular be suitable for enteral or parenteral administration in combination with appropriate excipients, for example in the form of plain or coated tablets, hard gelatin capsules, soft-shell capsules and other capsules, suppositories or drinkable forms , such as suspensions, syrups or injection solutions or suspensions.

More specifically, the route of administration may be oral or parenteral (IM intramuscular, SC subcutaneous, IV intravenous) or intratumoral or in-situ administration.

Sustained release pharmaceutical compositions can be used.

For example, the compound or any of its metabolites or a pharmaceutically acceptable salt thereof, as described herein, can be administered orally, parenterally, intravenously, transdermally, intramuscularly, rectally, sublingually, mucosally, nasally or otherwise. In addition, the compound or any of its or metabolites or a pharmaceutically acceptable salt thereof, as described herein, can be administered in the form of a pharmaceutical composition and/or in the form of a dosage unit.

In particular, the pharmaceutical compositions of the present invention can be administered orally and/or parenterally.

According to one illustrative embodiment, the pharmaceutical compositions of this invention can be administered orally. The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including, without limitation, capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are usually also added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. They can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the target for treatment includes areas or organs readily accessible for topical administration, including diseases of the eye, skin or lower intestinal tract. Suitable topical dosage forms can be easily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be in the form of rectal suppositories (see above) or a suitable enema dosage form. Topical transdermal patches can also be used.

For topical application, the provided pharmaceutically acceptable compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more vehicles. Carriers for topical administration of the compounds of this invention include, but are not limited to: mineral oil, liquid petrolatum, medicinal petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions provided may be formulated as finely divided suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted, sterile saline, either with or without a preservative such as benzylalkonium chloride. . Alternatively, for ophthalmic use, pharmaceutically acceptable compositions may be provided in the form of an ointment such as petroleum jelly.

The pharmaceutically acceptable compositions of the present invention can also be administered as a nasal aerosol or by inhalation. Such compositions are prepared according to methods well known in the art of pharmaceutical manufacturing and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents. .

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such drugs can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

Suitable dosage forms include, but are not limited to: capsules, tablets (including fast-dissolving and delayed-release tablets), powder, syrups, oral suspensions and parenteral solutions, and in particular capsules.

The pharmaceutical composition may also contain another drug for the treatment of cancer, well known to a person skilled in the art, in combination with a compound of the present invention.

Preferably, the compound or any of its metabolites or a pharmaceutically acceptable salt thereof, as described herein, may be administered in combination with one or more other anticancer drugs and/or radiotherapy.

Therefore, the present invention further relates to a pharmaceutical combination of formula (I) or any of its metabolites or pharmaceutically acceptable salts or any of their enantiomers or diastereoisomers, as defined above, and another anticancer drug.

When a compound or any of its metabolites or a pharmaceutically acceptable salt thereof, as described herein, is administered in combination with another active ingredient, such as another anticancer drug, it may be administered in a unique dosage form.

Alternatively, such a combination may be administered separately or simultaneously, for example, as a bolus. According to this particular embodiment, said combination may be in the form of at least two pharmaceutical preparations. In other words, the combination may be in the form of a combination kit or product. The form of such combinations will depend on the route of administration of each compound.

In such an embodiment, the two pharmaceuticals may be administered sequentially (at different times) or simultaneously (at the same time).

In other words, the administration of a compound of formula (I) or (I') or any of its metabolites or a pharmaceutically acceptable salt thereof and said additional antitumor therapy is simultaneous, separate or distributed over time.

For example, in some embodiments, each compound of the combination or composition thereof is administered by the same route of administration (ie, strictly orally). In other embodiments, certain compounds are administered by various routes of administration (ie, orally and parenterally).

The combination can be repeated over multiple cycles according to a protocol that depends on the nature and stage of the prostate cancer being treated, as well as the patient being treated (age, weight, previous treatment(s), etc.). The protocol can be determined by any medical practitioner specializing in oncology.

According to a specific embodiment of the present invention, radiotherapy treatment procedures can also be carried out simultaneously or sequentially.

Other anticancer drugs include the following:

- Androgen receptor inhibitors such as enzalutamide (Xtandi®, Astellas/Medivation), abiraterone (Zytiga®, Centocor/Ortho), gonadotropin-releasing hormone (GnRH) receptor antagonist such as degaralix (Firmagon®, Ferring Pharmaceuticals)

- Antiapoptotic agents such as venetoclax (Venclexta®, AbbVie/Genentech), blinatumomab (Blincyto®, Amgen), navitoclax (ABT-263, Abbott);

- Antiproliferative and antimitotic agents, such as vinca alkaloids (including vinblastine, vincristine);

- Antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin;

- L-asparaginase;

- Antiplatelet agents;

- Antiproliferative/antimitotic alkylating agents such as nitrogen mustard, cyclophosphamide and analogs (which include melphalan, chlorambucil, hexamethylmelamine and thiotepa), alkyl nitrosoureas (which include carmustine) and analogs, streptozocin and triazenes (including dacarbazine);

- Antiproliferative/antimitotic antimetabolites such as folic acid analogues (which include methotrexate), aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; active microtubule junctions; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target/reduce protein or lipid kinase activity and additional antiangiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal ^® ); spindle kinesin protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as Array BioPharma's ARRY142886, AstraZeneca's AZd _6,244 , Pfizer's PD181461, and leucovorin;

- Anti-migration agents;

- Angiogenesis inhibitors such as TNP-470;

- Aromatase inhibitors such as letrozole and anastrozole, exemestane;

- Angiotensin

- Antisense oligonucleotides, such as antisense nucleic acids against miR-124;

- Anticoagulants such as heparin, synthetic heparin salts and other thrombin inhibitors;

- Arginine inhibitors such as AEB1102 (PEGylated recombinant arginase, Aeglea Biotherapeutics) and CB-1158 (Calithera Biosciences);

- Bone resorption inhibitors such as denosumab (Xgeva®, Amgen), bisphosphonates such as zoledronic acid (Zometa®, Novartis);

- CC chemokine receptor type 4 (CCR4) inhibitors such as mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan);

- CDK inhibitors, such as CDK4/CDK6 inhibitors such as palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics);

- Cell cycle inhibitors and differentiation inducers such as tretinoin;

- Corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone and prednisolone;

- DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide ( ^CYTOXAN® ), dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere , teniposide, etoposide and triethylene thiophosphoramide;

- Fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine and clopidogrel;

- Folic acid antagonists;

- FLT3 receptor inhibitors, such as enzalutamide, abiraterone, apalutamide, erlotinib, crizotinib, niraparib, olaparib, osimertinib, regorafenib, sunitinib, lestaurtinib, midostaurin, gilteritinib, semaxinib, linifanib, fostamatinib, pexidartinib, sora fenib, cabozantinib, ponatinib, ilorasertib, pacritinib , famitinib, pexidartinib, quizartinib;

- Glutaminase inhibitors such as CD-839 (Calithera Biosciences);

-Growth factor signal transduction kinase inhibitors;

- Growth factor inhibitors, such as vascular endothelial growth factor inhibitors and fibroblast growth factor inhibitors, such as olaratumab (Lartrovo®; Eli Lilly), cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca);

- Hedgehog signaling pathway inhibitors, such as sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech);

- Histone deacetylase (HDAC) inhibitors such as vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China);

- Hormones and their analogues, such as estrogen, tamoxifen, goserelin, bicalutamide and nilutamide);

- Isocitrate dehydrogenase (IDH) inhibitors such as AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010)

- Isoflavones such as genistein;

- Immunosuppressants such as tacrolimus, sirolimus, azathioprine and mycophenolate;

- Inhibitors of p53 suppressor proteins, such as ALRN-6924 (Aileron);

- Transforming growth factor-beta (TGF-beta or TGFß) inhibitors, such as NIS793 (Novartis), frezolimumab (GC1008; Sanofi-Genzyme), M7824 (Merck KGaA - formerly MSB0011459X);

- iNKT cell agonists such as ABX196 (Abivax)

- mTOR inhibitors such as everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer) and sirolimus (Rapamune®, Pfizer);

- Microtubule inhibitory drugs such as taxanes (which include paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine (NAVELBINE ^® ) and epipodophyllotoxins (etoposide, teniposide);

- Nitric oxide donors;

- Nucleoside inhibitors such as trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (a prodrug to the alkylating agent 5-(3-methyltriazen-1-yl)-imidazol-4-carboxamide (MTIC) Temodar®, Merck); injection of cytarabine (ara-C, an antimetabolic analogue of cytidine, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analogue of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxin ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); Erwinia chrysanthemi asparaginase (asparagine depletion enzyme, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (a bifunctional derivative of mechlorethamine, suspected of forming cross-links between DNA strands, Treanda®, Cephalon/Teva); ixabepilone (semi-synthetic analogue of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (deoxyguanosine analogue prodrug, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (ribonucleotide reductase inhibitor prodrug, deoxycytidine competitive inhibitor, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analogue and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology);

- PI3K inhibitors, such as idelizib (Zydelig®, Gilead), alpelizib (BYL719, Novartis), tazelisib (GDC-0032, Genentech/Roche); pictilizib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelizib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics);

- Platinum coordination complexes (such as cisplatin, oxyloplatin, carboplatin, nedaplatin, picoplatin, procarbazine, mitotane, satraplatin and aminoglutethimide);

- Poly(ADP-ribose) polymerase (PARP) inhibitor, for example selected from: olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.);

- Proteasome inhibitors such as everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer), bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda);

- Pyrimidine and purine analogs such as floxuridine, capecitabine and cytarabine;

- Receptor blockers, Antisecretory agents such as breveldine;

- Selective estrogen receptor modulator (SERM) such as raloxifene (Evista®, Eli Lilly);

- Therapeutic antibodies, for example selected from: anti-TNF antibodies, anti-VEGF antibodies, anti-EGFR antibodies, anti-PD-1 antibodies, anti-HER2 antibodies, anti-CD20 antibodies, anti-IL17 antibodies and anti-CTLA4 antibodies, anti-PDL1 antibodies, anti-CD25 antibodies , antibodies to α4integrin, antibodies to IL6R, antibodies to C5, antibodies to IL1, antibodies to TPO, antibodies to IL12/23, antibodies to EPCAM/CD3, antibodies to CD30, antibodies to CD80/86, antibodies to anthrax, antibodies to CCR4, anti-CD6, anti-CD19, anti-α4β7, anti-IL6, anti-VEGFR-2, anti-SLAMF7, anti-GD2, anti-IL17A, anti-PCSK9, anti-IL5, anti-CD22, anti- IL4, anti-PDGFRα antibodies, anti-IL17RA antibodies and anti-TcdB antibodies, and such as selected from: abagovomab, abatacept, abciximab, abituzumab, abrilumab, actoxumab, adalimumab, adecatumab, aducanumab, aflibercept, afutuzimab, alacizumab, alefacept, alemtuzumab, aliroq umaba, altumomab, amaticsumab, anatumomab, anetumab, anifromumab, anrukinzumab, apolizumab, arcitumomab, askrinvakumab, azelizumab, atezolizumab, atinumab, altizumab, atorolimumab, bapineizumab, basiliximab, bavituximab, bektumomab, begeloma ba, belatacept, belimumab, benralizumab, bertilimumab, besilezomab, bevacizumab, bezlotoxumab, bicirumab, bimagrumab, bimekizumab, bivatuzumab, blinatumumab, blosozumab, bococizumab, brentuximab, briakimumab, brodalumab, brolucizumab, bronticizumab, canakinumab, cantuzumab, caplacizumab, capromab, carlumab, catumaxomab, zedel izumab, cetrolizumab, cetixumab, citizumab, cixutumumab, clazakizumab, clenoliximab, clivatuzumab, codrituzumab, coltuximab, conatumumab, concizumab, crenezumab, dacetuzumab, daclizumab, dalotuzumab, dapirolizumab, daratumimab, dectrecumab, demcizumab, denintuzumab, denosumab, derlotixumab, detumomab, dinutuximab, diri davumab, dorlinomab, drozitumab, dupilumab, durvalumab, duzigitumab, ecromeximab, eculizumab, edobacomab, edrecolomab, efalizumab, efungumab, eldelumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emibetuzumab, enavatuzumab, enfortumab, enlimomab, enoblituzumab, enokizumab, enoticumab, ensitu ximab, epitumomab, epratozumab, erlizumab, ertumaxomab, etanercept, etaracizumab, 'etrolizumab, evinacumab, evolocumab, exbivirumab, fanolezomab, faralimomab, farletuzomab, fazimumab, felvizumab, fezkimumab, ficlatuzumab, figitumumab, firivumab, flanvotumab, fleticumab, fontolizumab, foralumab, foravirumab, fresolimumab, fulramum ba, futuximab, galiximab, ganitumab, gantenerumab, gavilimomab , gemtuzumab, gevokizumab, girentuximab, glembatumumab, golimumab, gomiliximab, guselkumab, ibalizumab, ibritumomab, icrucumab, idarucizumab, igovomab, imalumab, imkiromab, imgatuzumab, inclacumab, indatuximab, indusatumab, inflixim aba, intetumumab, inolimomab, inotuzumab, ipilimumab, iratumumab, isatuximab , itolizumab, ixekizumab, keliximab, labetuzumab, lambrolizumab, lampalizumab, lebrikizumab, lemalesomab, lenzilumab, lerdelimumab, lexatumumab, libivirumab, lifastuzumab, ligelizumab, lilotomab, lintuzumab, lirilumab, lodelzumab, lokivetmab , lorvotuzumab, lucatumumab, lulizumab, lumiliximab, lumretuzumab, mapatumumab , margetuximab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minetumumab, mirvetuximab, mitumomab, mogamulizumab, morolimumab, motavizumab, moxetumomab, muromonab CD3, nacolomab, namilumab, naptumomab, narnat umab, natalizumab, nebatsumab, necituzumab, nemolizumab, nerelimomab, nesvacumab, nimotuzumab, nivolumab, nofetumomab, obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, olokizumab, omalizumab, onartuzumab, ontuxizumab, opicinumab, oportuzumab, oregovomab, orticumab, from elixizumab, oltertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, panitumumab, pancomab, panobakumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab, pintumomab, polatuzumab, ponezumab, prilic simab, pritumumab, quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranibizumab, raxibacumab, refanezumab, regavirumab, rezlizumab, rilonacept, rilotumumab, rinucumab, rituximab, robatumumab, roledumab, romosozumab, rontalizumab, rovelizumab, ruplizumab, sacituzumab, samalizumab, with arilumab, satumomab, secukimumab, seribantumab, setoxaximab, sevirumab, sibrotuzumab, sifalimumab, siltuximab, siplizumab, sirukumab, sophytuzumab, solanezumab, solitomab, sonepcizumab, sontuzumab, stamulumab, sulesomab, suvizumab, tabalumab, takatuzumab, tadocizumab, talizumab, tanezumab, taplitumomab, tarext umab, tefibazumab, telimomab aritoxa, tenatumomab, teneliximab, teplizumab , tesidolumab, TGN 1412, ticlimumab, tildrakizumab, tigatuzumab, TNX-650, tocilizumab, toralizumab, tosatoxumab, tositimumab, tovetumab, tralokimumab, trastuzumab, TRBS07, tregalizumab, tremelimumab, alarmrumab, tucotuzumab, tuvirumab , ublituximab, ulocuplumab, urelumab, urtoxazumab, ustekimumab, vandortuzumab, vandictumab, vanucizumab, vapaliximab, varlimumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, visilizumab, volocixumab, vorsetuzumab, votumumab, zalutumimab, zanolimumab, zatuximab, ziralimumab , ziv-aflibercept and zolimomab;

- Topoisomerase inhibitors such as doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan and irinotecan;

- Toxins such as cholera toxin, ricin, exotoxin from Pseudomonas, adenylate cyclase toxin from Bordetella pertussis, diphtheria toxin and caspase activators;

Kinase or VEGF inhibitors such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech/Roche); MEK inhibitors such as cobimetanib (Cotellic®, Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors such as cabozanitib (Cometriq®, Exelexis); and multikinase inhibitors such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinase inhibitors such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); and Flt3 receptor inhibitors such as midostaurin (Rydapt®, Novartis), tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen/Takeda);

Without limitation, the compounds of this invention may be combined, individually or in kit form, with one or more of the following anticancer drugs or compounds: ABVD, AC, ACE, Abiraterone (Zytiga®), Abraxane, Abstral, Actinomycin D, Actic, adriamycin, afatinib (Giotrif®), afinitor, aflibercept (Zaltrap®), Aldara, aldesleukin (IL-2, proleukin or interleukin 2), alemtuzumab (MabCampath), alkeran, amsacrine (Amsidine, m-AMSA), amsidine, anastrozole ( Arimidex®), Ara C, Aredia, Arimidex, Aromasin, Arsenic trioxide (Trisenox®, ATO), Asparaginase (Crisantaspase®, Erwinase®), Axitinib (Inlyta®), Azacitidine (Vidaza®), BEACOPP, BEAM, Bendamustine (Levact ®), bevacizumab (Avastin), bexarotene (Targretin®), bicalutamide (Casodex®), bleomycin, etoposide and platinum (BEP), bortezomib (Velcade®), bosulif, bosutinib (Bosulif), brentuximab (Adcetris®), brufen, buserelin (Suprefact®), busilvex, busulfan (Myleran, Busilvex), CAPE-OX, CAPOX, CAV, CAVE, CCNU, CHOP, CMF, CMV, CVP, cabacitaxel (Jevtana®), cabozantimib (Cometriq®), caelix, calpol , campto, capecitabine (Xeloda®), caprelsa, carbo MB (Carboplatin, methotrexate, vinblastin), carbotaxol, carboplatin, carboplatin and etoposide, carboplatin and paclitaxel, carmustine (BCNU, Gliadel®), casodex, ceritinib (Zykadia®), cerubidine , cetuximab (Erbitux®), ChlVPP, chlorambucil (Leukeran®), cisplatin, cisplatin and teisuno, cisplatin and capecitabine (CX), cisplatin, etoposide and ifosfamide (PEI), cisplatin, fluoruturacil (5-FU) and trastuzumab, cladribine ( Leustat®, LITAK), Clasteon, clofarabine (Evoltra®), co-codamol (Kapake®, Solpadol®, Tilex®), cometric, cosmegen, crizantaspase, crizotinib (Xalkori®), cyclophosphamide, thalidomide and dexamethasone (CTD), cyprostat , cyproterone acetate (Cyprostat®), cytarabine (Ara C, cytosine arabinoside), cytarabine in cerebrospinal fluid, cytosine arabinoside, DHAP, DTIC, dabrafenib (Tafinlar®), dacarbazine (DTIC), dacogen, dactinomycin (actinomycin D, Cosmegen®) , dasatinib (Sprycel), daunorubicin, De Gramont, decapeptyl SR, decitabine (Dacogen®), degarelix (Firmagon®), denosumab (Prolia®, Xgeva®), depot, dexamethasone, diamorphine, disodium pamidronate, disprole, docetaxel (Taxotere® ), docetaxel, cisplatin and fluorouracil (TPF), doxiphos, doxil, doxorubicin (Adriamycin), doxorubicin and ifosfamide (Doxiphos), drogenil, durogesic, EC, ECF, EOF, EOX, EP, ESHAP, effentora, efudix, eldisin, eloxatin , enzalutamide, epirubicin (Pharmorubicin®), epirubicin cisplatin and capecitabine (ECX), epirubicin, carboplatin and capecitabine (ECarboX), eposine, erbitux, eribulin (Halaven®), erlotinib (Tarceva®), ervinase, estracite, etopophos, etoposide ( Eposin®, Etopophos®, Vepesid®), everolimus (Afinitor®), evoltra, exemestane (Aromasin®), FAD, FEC, FEC-T chemotherapy, FMD, FOLFIRINOX, FOLFOX, faslodex, femara, fentanyl, firmagon, fludara, fludarabine (Fludara®), fludarabine, cyclophosphamide and rituximab (FCR), fluorouracil (5FU), flutamide, folinic acid, fluorouracil and irinotecan (FOLFIRI), fulvestrant (faslodex®), G-CSF, gefitinib (Iressa), GemCarbo (gemcitinib and carboplatin), GemTaxol, gemcitabine (Gemzar), Gemcitabine and capecitabine (GemCap), Gemcitabine and cisplatin (GC), Gemcitabine and paclitaxel (GemTaxol®), gemza, giotrif, Gliadel, Gleevec, gonapeptyl, depot, goserelin (Zoladex®), goserelin (Zoladex®, Novgos®), granulocyte colony stimulating factor (G-CSF), galaven, herceptin, hycamtin, hydrea, hydroxyurea (Hydrea®), hydroxyurea, I-DEX, ICE, IL-2, IPE, ibandronic acid, ibritumomab (Zevalin®), ibrutinib (Imbruvica®), ibuprofen (Brufen®, Nurofen®), iclusig, idarubicin (Zavedos®), idarubicin and dexamethasone, idelalisib (Zydelig®), ifosfamide (Mitoxana®), imatinib (Glivec®) , imiquimod cream (Aldara®), imnovid, instanil, interferon (Intron A), interleukin, intron A, ipilimumab (Yervoy®), Iressa, irinotecan (Campto®), irinotecan and capecitabine (Xeliri®), irinotecan de Gramona, irinotecan modified de Gramont, yavlor, evtana, kadcyla, capake, keytruda, lanreotide (Somatuline®), lanvis, lapatinib (Tyverb®), lenalidomide (Revlimid®), letrozole (Femara®), leukeran, leuprorelin (Prostap®, Lutrate®) , leistat, levact, liposomal doxorubicin, litac, lomustine (CCNU), lynparza, lysodren, MIC, MMM, MPT, MST continuus, MVAC, MVP, MabCampath, Mabthera, Maxtrex, medroxyprogesterone acetate (Provera), Megace, megestrol acetate (Megace ®), melphalan (Alkeran®), mepact, mercaptopurine (Xaluprine®), methotrexate (Maxtrex), methyl prednisolone, mifamurtide (Mepact®), mitomycin C, mitotane, mitoxana, mitoxantrone (Mitozantrone®), morphesic SR, morphine, mileran , myocet, Nab-paclitaxel, Nab-paclitaxel (Abraxane®), navelbine, nelarabine (Atriance®), nexavar, nilotinib (Tasigna®), nintedanib (Vargatef®), nipent, nivolumab (Opdivo®), Novgos, nurofen, obinutuzumab (Gazyvaro®), octreotide, ofatumumab (Arzerra®), olaparib (Lynparza®), Oncovin, Oncotron, Opdivo, Oramorph, oxaliplatin (Eloxatin), oxaliplatin and capecitabine (Xelox®), PAD, PC (paclitaxel and carboplatin, carbotaxol) , PCV, PE, PMitCEBO, POMB/ACE, paclitaxel (Taxol®), paclitaxel and carboplatini, pamidronate, panadol, panitumumab (Vectibix®), paracetamol, pazopanib (Votrient®), pembrolizumab (Keytruda), pemetrexed (Alimta®), pemetrexed and carboplatin, pemetrexed and cisplatin, pentostatin (Nipent®), Perjeta, pertuzumab (Perjeta®), pixantrone (Pixuvri®), pixuvri, pomalidomide (Imnovid®), ponatinib, potactazole, prednisolone, procarbazine, proleukin, prolia, prostap, Provera, Purinetol, R-CHOP, R-CVP, R-DHAP, R-ESHAP, R-GCVP, RICE, Raloxifene, Raltitrexed (Tomudex®), Regorafenib (Stivarga®), Revlimid, Rituximab, (Mabthera®), Severdol , sodium clodronate (Bonefos®, Clasteon®, Loron®), solpadol, sorafenib (Nexavar®), steroids (dexamethasone, prednisolone, methylprednisolone), streptozocin (Zanosar®), sunitinib (Sutent®), Sutent, TAC, TIP, tafinlar , tamoxifen, tarceva, targretin, tasigna, taxol, taxotere, taxotere and cyclophosphamide (TC), temodal, temozolomide, (Temodal®), temsirolimus (Torisel®), tepadina, teisuno, thalidomide, thiotepa (Tepadina®), thioguanine (thioguanine ®, 6-TG, 6-thioguanine), tomudex, topotecan (hycamtin, protactazole), torisel, trabactedin (Yondelis), trastuzumab (Herceptin®), trastuzumab emtansine (Kadcyla®), tresulfan, tretinoin (Vesanoid®, ATRA), triptorelin (Decapeptyl SR®, Gonapeptyl Depot®), trisenox, Tilex, Tiverb, VIDE, vandetanib (Caprelsa®), vargatef, VeIP, Vectibix, Velbe, Velcade, vemurafenib (Zelboraf®), Vepesid, Vesanoid, Vidaza, vinblastine (Velbe ®), vincristine, vincristine, actinomycin D (dactinomycin®) and cyclophosphamide (VAC), vincristine, actinomycin and ifosfamide (VAI), vincristine, doxorubicin and dexamethasone (VAD), vindesine (Eldisine®), vinflunine (Javlor®), vinorelbine (Navelbine®), vismodegib (Erivedge®), votrient, xelox, xalkori, xeloda, ixgeva, istandi, ervoy, yondelis, Z-DEX, zaltrap, zanosar, zavedos, zelboraf, zevalin, zoladex (breast cancer), zoladex ( prostate cancer), zoledronic acid (Zometa®), Zometa, Zomorph, Zidelig, Zitiga.

In a particular embodiment, the compound or any of its metabolites or a pharmaceutically acceptable salt thereof, as described herein, can be combined with various therapies: chemotherapy, immunotherapy (eg, inhibitors, monoclonal antibodies), tumor vaccines, RNA vaccines , magnetic particles, intravascular microrobots, radiotherapy, surgery, ultrasound or other types of antitumor therapy.

Therefore, the present invention further provides a compound of formula (I) or (I') or any of its metabolites or a pharmaceutically acceptable salt thereof for use as an antitumor agent intended for patients who are also being treated by any of immunotherapy, antitumor vaccines, RNA -vaccines, radiotherapy, surgery, ultrasound therapy or other antitumor treatments.

Where a method of preventing and/or treating is provided, the present invention also provides corresponding use for preventing and/or treating cancer or dysplasia. Likewise, if use is provided for the prevention and/or treatment of cancer or dysplasia, the present invention also provides a corresponding method of prevention and/or treatment. In some embodiments, the present invention provides a method of preventing and/or treating cancer or dysplasia as described herein, comprising administering a compound or a pharmaceutically acceptable salt thereof as described herein. In some embodiments, the present invention provides a method for preventing and/or treating cancer or dysplasia as described herein, comprising measuring the presence and/or expression level of miR-124 as described herein.

Further provided herein is a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of their enantiomers or diastereoisomers for use in accordance with the present invention, where the use is intended for a patient whose level of the compound of formula (I' ) or a pharmaceutically acceptable salt thereof in patient blood, plasma, tissue, saliva and/or serum samples is measured at the time of use.

Further provided herein is a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of their enantiomers or diastereoisomers for use according to the present invention, where the use is intended for a patient whose level of the compound of formula (IVa) or its pharmaceutically acceptable salt in a sample of the patient's blood, plasma, tissue, saliva and/or serum is measured at the time of use.

This document further provides a quinoline derivative of formula (I') or any of its metabolites or a pharmaceutically acceptable salt or any of their enantiomers or diastereoisomers for use according to the present invention, where the use is intended for a patient whose level of the compound of formulas (I') and (IVa) or a pharmaceutically acceptable salt thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient is measured at the time of use.

Additional Examples of Embodiments

1. Compound of Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, where:

Z represents C or N;

V represents C or N;

means an aromatic ring where V is C or N, and when V is N, V is in the ortho, meta or para position relative to Z;

each R independently represents hydrogen, halogen, -CN, hydroxyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₃ )fluoroalkoxy, (C ₃ -C ₆ )cycloalkyl, -NO ₂ , -NR ₁ R ₂ , (C ₁ -C ₄ )alkoxy, phenoxy, -NR ₁ -SO ₂ -NR ₁ R ₂ , -NR ₁ -SO ₂ -R ₁ , -NR ₁ -C(=O)-R ₁ , -NR ₁ -C(=O)-NR ₁ R ₂ , -SO ₂ -NR ₁ R ₂ , -SO ₃ H, -O-SO ₂ -OR ₃ , -OP(=O)-(OR ₃ )(OR ₄ ) , -O-CH ₂ -COOR ₃ , (C ₁ -C ₃ )alkyl, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group, a group of formula (IIa): , or a group of formula (IIIa): ;

Q is N or O, with the proviso that R" is absent when Q is O;

each of R ₁ and R ₂ independently represents hydrogen or (C ₁ -C ₃ )alkyl;

R ₃ and R ₄ are each independently hydrogen, Li ⁺ , Na ⁺ , K ⁺ , N ⁺ (Ra) ₄ or benzyl;

n is 1, 2 or 3;

n' represents 1, 2 or 3;

each R' independently represents hydrogen, (C ₁ -C ₃ )alkyl, hydroxyl, halogen, -NO ₂ , -NR ₁ R ₂ , morpholinyl, morpholino, N-methylpiperazinyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₄ )alkoxy, -OP(=O)-(OR ₃ )(OR ₄ ), -CN, group of formula (IIa): , or a group of formula (IIIa): ;

A represents a covalent bond, oxygen or NH;

B represents a covalent bond or NH;

m represents 1, 2, 3, 4 or 5;

p is 1, 2 or 3;

Ra and Rb are each independently hydrogen, (C ₁ -C ₅ )alkyl or (C ₃ -C ₆ )cycloalkyl, or

Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, said heterocycle optionally being substituted by one or more Ra, provided that when R' represents a group (IIa) or (IIIa ), n' can be 2 or 3 only if the other R' groups are different from the specified group (IIa) or (IIIa); And

R" represents hydrogen, (C ₁ -C ₄ )alkyl or a group of formula (IIa) as defined herein,

for use in the treatment or prevention of cancer or dysplasia.

2. The compound of embodiment 1, wherein the compound has formula (Ia):

(Ia)

or a pharmaceutically acceptable salt thereof.

3. The compound of embodiment 1, wherein the compound has formula (Ib):

(Ib)

or a pharmaceutically acceptable salt thereof.

4. The compound of embodiment 1, wherein the compound has formula (Ic):

(Ic)

or a pharmaceutically acceptable salt thereof.

5. The compound of embodiment 1, wherein the compound has formula (Ib'):

(Ib')

or a pharmaceutically acceptable salt thereof.

6. The compound of embodiment 1, wherein the compound has the formula (Id):

(Id)

or a pharmaceutically acceptable salt thereof.

7. Compound of formula (IV):

(IV)

or a pharmaceutically acceptable salt thereof, wherein each of the variables V, Z, R, R', n and n' is as described in Embodiment 1 for use in the treatment or prevention of cancer or dysplasia.

8. The compound of embodiment 7, wherein the compound has formula (IVa):

(IVa)

or a pharmaceutically acceptable salt thereof.

9. The compound of embodiment 7, wherein the compound has formula (IVb):

(IVb)

or a pharmaceutically acceptable salt thereof.

10. The compound of embodiment 7, wherein the compound has formula (IVc):

(IVc)

or a pharmaceutically acceptable salt thereof.

11. The compound of embodiment 7, wherein the compound has formula (IVb'):

(IVb')

or a pharmaceutically acceptable salt thereof.

12. The compound of embodiment 7, wherein the compound has formula (IVd):

(IVd)

or a pharmaceutically acceptable salt thereof.

13. A compound for use according to any of embodiments 1-12, wherein the use is for a patient in whom the level of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a sample of the patient's blood, plasma, tissue, saliva and/or serum is measured during applications.

14. A compound for use in accordance with any of embodiments 1-13, wherein the use is for a patient in whom the level of a compound of formula (IV) or a pharmaceutically acceptable salt thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient is measured during use.

15. A compound for use in accordance with any of embodiments 1-14, wherein the use is for a patient whose level of compounds of formula (I) and (IV) or a pharmaceutically acceptable salt thereof in a sample of blood, plasma, tissue, saliva and/ or patient serum is measured at the time of application.

16. A compound for use in accordance with any of embodiments 1-15, wherein the use is for a patient in whom the presence and/or expression level of miR-124 in a blood and/or tissue sample of the patient is measured before and during use.

17. A compound for use in accordance with any of embodiments 1-16, wherein the use is for a patient selected by the measured presence and/or expression level of miR-124 in a blood and/or tissue sample of the patient.

18. A compound for use in accordance with any of embodiments 1-17, wherein an algorithm combining the miR-124 level and a cytokine level or other biomarker level is used to monitor the severity of a disease, disorder or condition and/or to monitor the effectiveness of the application.

19. A compound for use according to any one of embodiments 1-18, wherein an algorithm combining the miR-124 level and a cytokine level or other biomarker level is used to select patients for use.

20. An algorithm that combines the level of miR-124 and the level of cytokines or other biomarker to monitor the severity of cancer or dysplasia and/or to monitor the effectiveness of treatment.

21. A method of treating cancer or dysplasia in a patient in need thereof, comprising administering to the patient a compound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof, where:

Z represents C or N;

V represents C or N;

means an aromatic ring where V is C or N, and when V is N, V is in the ortho, meta or para position relative to Z;

each R independently represents hydrogen, halogen, -CN, hydroxyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₃ )fluoroalkoxy, (C ₃ -C ₆ )cycloalkyl, -NO ₂ , -NR ₁ R ₂ , (C ₁ -C ₄ )alkoxy, phenoxy, -NR ₁ -SO ₂ -NR ₁ R ₂ , -NR ₁ -SO ₂ -R ₁ , -NR ₁ -C(=O)-R ₁ , -NR ₁ -C(=O)-NR ₁ R ₂ , -SO ₂ -NR ₁ R ₂ , -SO ₃ H, -O-SO ₂ -OR ₃ , -OP(=O)-(OR ₃ )(OR ₄ ) , -O-CH ₂ -COOR ₃ , (C ₁ -C ₃ )alkyl, wherein said alkyl is optionally mono- or disubstituted with a hydroxyl group or a group of formula (IIa): , or a group of formula (IIIa): ;

Q is N or O, with the proviso that R" is absent when Q is O;

each of R ₁ and R ₂ independently represents hydrogen or (C ₁ -C ₃ )alkyl;

R ₃ and R ₄ are each independently hydrogen, Li ⁺ , Na ⁺ , K ⁺ , N ⁺ (Ra) ₄ or benzyl;

n is 1, 2 or 3;

n' represents 1, 2 or 3;

each R' independently represents hydrogen, (C ₁ -C ₃ )alkyl, hydroxyl, halogen, -NO ₂ , -NR ₁ R ₂ , morpholinyl, morpholino, N-methylpiperazinyl, (C ₁ -C ₃ )fluoroalkyl, (C ₁ -C ₄ )alkoxy, -OP(=O)-(OR ₃ )(OR ₄ ), -CN, group of formula (IIa): , or a group of formula (IIIa): ;

A represents a covalent bond, oxygen or NH;

B represents a covalent bond or NH;

m represents 1, 2, 3, 4 or 5;

p is 1, 2 or 3;

Ra and Rb are each independently hydrogen, (C ₁ -C ₅ )alkyl or (C ₃ -C ₆ )cycloalkyl, or

Ra and Rb form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocycle, said heterocycle optionally being substituted by one or more Ra, provided that when R' represents a group (IIa) or (IIIa ), n' can represent 2 or 3 only if the other R' groups are different from the specified group (IIa) or (IIIa); And

R" represents hydrogen, (C ₁ -C ₄ )alkyl or a group of formula (IIa) as defined herein.

22. Method of implementation 21, where the compound has formula (Ia):

(Ia)

or a pharmaceutically acceptable salt thereof.

23. Method of implementation 21, where the compound has formula (Ib):

(Ib)

or a pharmaceutically acceptable salt thereof.

24. Method of implementation 21, where the compound has formula (Ic):

(Ic)

or a pharmaceutically acceptable salt thereof.

25. Method of implementation 21, where the compound has the formula (Ib’):

(Ib')

or a pharmaceutically acceptable salt thereof.

26. Method of implementation 21, where the compound has the formula (Id):

(Id)

or a pharmaceutically acceptable salt thereof.

27. A method of treating cancer or dysplasia in a patient in need thereof, comprising administering to the patient a compound of formula (IV):

(IV)

or a pharmaceutically acceptable salt thereof, wherein each of the variables V, Z, R, R', n and n' are as described in Embodiment 21.

28. Method of implementation 27, where the compound has the formula (IVa):

(IVa)

or a pharmaceutically acceptable salt thereof.

29. Method of implementation 27, where the compound has formula (IVb):

(IVb)

or a pharmaceutically acceptable salt thereof.

30. Method of implementation 27, where the compound has the formula (IVc):

(IVc)

or a pharmaceutically acceptable salt thereof.

31. Method of implementation 27, where the compound has the formula (IVb’):

(IVb')

or a pharmaceutically acceptable salt thereof.

32. Method of implementation 27, in which the compound has the formula (IVd):

(IVd)

or a pharmaceutically acceptable salt thereof.

33. The method of any one of embodiments 21 to 32, further comprising measuring the level of a compound of formula I or a pharmaceutically acceptable salt thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient.

34. The method of any one of embodiments 21 to 33, further comprising measuring the level of a compound of formula IV or a pharmaceutically acceptable salt thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient.

35. The method of any one of embodiments 21 to 34, further comprising measuring the total level of compounds of formulas I and IV or pharmaceutically acceptable salts thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient.

36. The method of any one of embodiments 21 to 35, further comprising measuring the presence and/or expression level of miR-124 in a sample of blood and/or tissue from the patient before and during treatment.

37. The method of any one of embodiments 21 to 36, further comprising selecting a patient based on the measured presence and/or expression level of miR-124 in a blood and/or tissue sample of the patient.

38. The method of any one of embodiments 21 to 37, further comprising using an algorithm that combines the level of miR-124 and the level of cytokines or other biomarker to monitor the severity of the cancer or dysplasia and/or to monitor the effectiveness of treatment.

39. The method of any one of embodiments 21 to 38, further comprising using an algorithm that combines the level of miR-124 and the level of cytokines or other biomarker to select patients for treatment.

40. An algorithm that combines the level of miR-124 and the level of cytokines or other biomarker to monitor the severity of cancer or dysplasia and/or to monitor the effectiveness of treatment.

41. The method of any one of embodiments 21 to 40, further comprising measuring the level of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient.

42. The method of any one of embodiments 21 to 40, further comprising measuring the level of a compound of formula (IV) or a pharmaceutically acceptable salt thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient.

43. The method of any one of embodiments 21 to 40, further comprising measuring the total level of compounds of formulas (I) and (IV) or pharmaceutically acceptable salts thereof in a sample of blood, plasma, tissue, saliva and/or serum of the patient.

EXAMPLES

MATERIAL AND METHODS

Material and reagents

All cell lines are primary human cell lines cultured in DMEM/F12 + 10% FBS + additional growth factors at 37°C with 5% CO ₂ as explained below. The cell lines originate from the colon/rectum, stomach, liver, lungs, or pancreas (see table below).

• DMEM/F12 (High Glucose) (Gibco, Cat#11320033)

• FBS (Cat#FND500, ExCell Bio)

• CellTiter-Glo® Luminescent Cell Viability Assay (Cat#G7571, Promega. Storage temperature -20°C).

• 96-well plate (Cat#3610, Corning)

• DMEM/F12 medium: 1:1 mixture of DMEM (low glucose) (Gibco, Cat#11885076) and F-12K (Gibco, Cat#21127022)

Test compounds

1. Compound 111 according to the invention:

20 mg of compound 111 (also called ABX464) (MW=338.7 g/mol, purity=100%) was used. This compound was stored at room temperature (18-25°C) and the solvent was DMSO.

111

2. Comparative compound 26: 8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine

Compound 26 is a compound that belongs to formula (Ia) as defined in the present invention and in WO 2010/143168 (under the name compound 37).

20 mg of compound 26 (MW=323.71 g/mol, purity=100%) was used. This compound was stored at room temperature (18-25°C) and the solvent was DMSO.

26

For compound 26, two types of cell lines were tested, namely CR3085 (colon/colorectum) and GA0060 (stomach), as shown below.

Equipment

BMRP004; CO ₂ incubator, SANYO Electric Co., Ltd (02100400059).

Inverted microscope, Chongguang XDS-1B, Chongqing Guangdian Corp. (TAMIC0200)

Envision multichannel device (TAREA0011)

Vi-Cell XR, Beckman Coulter (TACEL0030)

Way

Day 1: Cell seeding

1. Each well of a 96-well plate contains 90 µl of cell suspension with cells. The number of cells to be seeded is determined based on an optimized cell density assay.

2. All 96-well cell plates are placed in an incubator overnight at 37°C with 5% CO ₂ .

Day 2: Compound Treatment

3. ABX464 is diluted and 10 µl/well of ABX464 is added at the indicated concentrations (see plate diagram below). The final volume is 100 µl/well.

Em (Empty): Empty well containing PBS

M: Environmental Control (form)

Em (Empty): Empty well containing PBS

M: Environmental Control (form)

Day 5: Drug/Media Replenishment

4. Replace old media with pre-prepared fresh media containing ABX464 at the same concentrations indicated. The final volume is 100 µl/well.

Day 9: Plate Reading (7 days of drug treatment)

5. The cells are observed under a microscope to ensure that the cells treated with the control medium are in good condition.

6. Add 50 µl CellTiter-Glo® Reagent to each well.

7. Mix the contents for 2 minutes on an orbital shaker to facilitate cell lysis.

8. Allow the plate to incubate at room temperature for 10 minutes to stabilize the fluorescent signals.

9. Record luminescence using an EnVision multi-channel reader.

Data analysis

Data analysis is performed using GraphPad Prism 7.0.

To calculate the IC50, a dose response curve is generated using a nonlinear regression model with a sigmoid dose response. The survival formula is shown below and the IC50 will be automatically generated by GraphPad Prism 7.0.

The difference "Raw Lum - Countermedium Lum" is set to 100%.

Results:

Cell lines IC50 (µM)
ABX464 IC50 (µM)
Comparison compound 26 CR0205
Large intestine/colon and rectum (colorectum) 7.26 Not verified CR3085
Large intestine/colon and rectum (colorectum) 0.08 0.17 CR3150
Large intestine/colon and rectum (colorectum) 0.87 Not verified GA0060
Stomach 0.6 above 10 LI0612
Liver 4.75 Not verified LU0387
Lungs 9.49 Not verified LU2511
Lungs 7.11 Not verified PA0692
Pancreas 9.63 Not verified PA1266
Pancreas 3.44 Not verified PA1405
Pancreas 6.2 Not verified PA3060
Pancreas 3.71 Not verified

Thus, the compounds of the present invention, in particular the compounds of formula (Ib') or any of their metabolites or pharmaceutically acceptable salts thereof, are effective for the treatment and/or prevention of cancer, and in particular colorectal cancer, gastric cancer, liver cancer, cancer lung and/or pancreatic cancer, particularly in patients with precancerous, early-stage or non-metastatic cancer. In particular, the compounds of formula (Ib') or any metabolites thereof or a pharmaceutically acceptable salt thereof do not directly target metastatic invasion.

In addition, from these results it follows that the compounds according to the invention, in particular the compounds of formula (Ib') or any metabolites thereof or a pharmaceutically acceptable salt thereof, are more effective for the treatment and/or prevention of cancer, in particular in patients with precancerous condition, early stage cancer or non-metastatic cancer than the comparison compound 26 belonging to formula (Ia) (for Colon/Colorectum cell line CR3085: IC50=0.08 vs. 0.17; and for stomach cell line GA0060: IC50=0.6 vs. above 10).

Claims (13)

1. Use of a compound of formula (Ib') or a pharmaceutically acceptable salt thereof for the treatment of cancer selected from gastric cancer, gastrointestinal cancer, colorectal cancer, pancreatic cancer, lung cancer and liver cancer in a patient (Ib'), wherein said compound is 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinoline-2-amine of the following formula or a pharmaceutically acceptable salt thereof: where the specified patient does not have clinically detectable metastases, or wherein said patient has clinically detectable metastases and said compound of formula (Ib') is not directly directed against metastatic invasion. 2. Application according to paragraph 1, wherein said patient has no clinically detectable metastases and wherein said patient has a precancerous condition, early-stage cancer, or non-metastatic cancer. 3. Use according to claim 1, where the presence and/or expression level of miR-124 in a sample of blood and/or tissue of the patient is measured before and/or during use. 4. Use according to claim 1, where the presence and/or expression level of miR-124 in a blood and/or tissue sample is measured to adjust the dose or monitor the response to treatment. 5. Use according to claim 1, wherein to monitor the severity of cancer and/or to monitor the effectiveness of treatment, an algorithm is used that combines the level of miR-124 and the level of cytokines or other biomarker or levels of a compound of formula (Ib') or a pharmaceutically acceptable salt thereof, as determined in paragraph 1. 6. Use according to claim 1, wherein at the time of use in a patient, the level of a compound of formula (Ib') or a pharmaceutically acceptable salt thereof as defined in claim 1 is measured in a sample of the patient's blood, plasma, tissue, saliva and/or serum.