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EP-4735113-A1 - PYRAZOLE DERIVATIVES AS PD-1/PD-L1 INTERACTION INHIBITORS

EP4735113A1EP 4735113 A1EP4735113 A1EP 4735113A1EP-4735113-A1

Abstract

The present application relates to pyrazole derivatives as PD-1/PD-L1 interaction inhibitors. The applicants designed compounds of general formula (I), wherein R', R 2 , y 3 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein, that are able to efficiently block PD-1/PD-L1 interactions in order to restore anti-tumor immune responses of subjects and eradicate dormant tumor cells and any tumors in which PD-L1 is involved in immunoevasion. The applicants confirmed that these compounds blocked the PD-1/PD-L1 interactions by carrying out physicochemical tests (MST, NanoDSF) and in vitro biological tests (FRET assay, Promega Blockade assay, T cell assay). These compounds had an affinity (Kd) of the order of pM that was higher than that of the antibody atezolizumab used in clinical use, and had a comparable or better IC50 than that observed with atezolizumab. Thus, the present invention also relates to a pharmaceutical composition comprising said compound(s) and their uses in the treatment of PD-1-PD-L1 interactions-related diseases (cancer, chronic inflammatory diseases, neurological diseases and chronic infections).

Inventors

  • THURU, Xavier
  • BAILLY, CHRISTIAN
  • QUESNEL, Bruno
  • Klupsch, Frédérique
  • LE BIANNIC, Raphaël
  • MILLET, Régis

Assignees

  • Institut National de la Santé et de la Recherche Médicale
  • Université de Lille
  • Centre National de la Recherche Scientifique
  • Centre Hospitalier Universitaire de Lille

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 1 . A compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: - (a) Wherein Y 3 represents C and R 3 represents H; and R 1 represents phenyl substituted with one Cl; R 2 represents Ci-Ce alkyl; R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or - (b) Wherein Y 3 represents C and R 3 represents halogen, preferably Cl; and R 1 represents C(O)OCi-Ce alkyl, or phenyl substituted with one Cl; R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3; R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H, halogen, CN, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, C(0)NH(CH 2 ) m -C5-Cio heterocyclyl, or C(0)-Cs-Cio heterocyclyl-C(O)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or is the following compound ALIPD347 - (c) Wherein Y 3 represents N and R 3 is absent; and R 1 represents phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, CrCe alkoxy and Ci-Ce alkyl; R 2 represents Ci-Ce alkyl; R 4 , R 5 , R 6 and R 7 are identical and represent H.
  2. 2. The compound according to claim 1 , wherein (a) Y 3 represents C and R 3 represents H; and wherein: - R 1 represents - R 2 represents CH 3 ; and - R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H, Cl, CN, OCH 3 , CH 2 NH 2 , CH 2 NH(CH 2 ) 2 C(O)OH, or CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 .
  3. 3. The compound according to claim 2, wherein: (i) - R 4 , R 6 and R 7 are identical and represent H; and - R 5 represents Cl, CN, OCH 3 , CH 2 NH 2 , CH 2 NH(CH 2 ) 2 C(O)OH, CH 2 NH(CH 2 ) 2 C(O)OCH 2 CH 3 ; preferably R 5 represents Cl, or CH 2 NH(CH 2 ) 2 C(O)OH; more preferably R 5 represents Cl; or (ii) - R 5 , R 6 and R 7 are identical and represent H; and R 4 represents Cl.
  4. 4. The compound according to claim 1 , wherein (b) Y 3 represents C and R 3 represents halogen, preferably Cl; and wherein: R 2 represents H, CH 3 , CH 2 C(O)OCH 2 CH 3 , or CH 2 C(O)OH; preferably R 2 represents CH 3 , CH 2 C(O)OCH 2 CH 3 , or CH 2 C(O)OH; more preferably R 2 represents CH 3 , or CH 2 C(O)OCH 2 CH 3 ; even more preferably R 2 represents CH 3 ; and - R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H, Cl, CN, C(O)NH 2 ,
  5. 5. The compound according to claim 4, wherein: (i) - R 4 , R 6 and R 7 are identical and represent H; and - (ii) - R 4 , R 5 and R 6 are identical and represent H; and R 7 represents Cl; or (iii) - R 4 , R 5 and R 7 are identical and represent H; and R 6 represents Cl.
  6. 6. The compound according to claim 5, wherein: (i) - R 4 , R 6 and R 7 are identical and represent H; and - R 5 represents preferably R 5 represents Cl.
  7. 7. The compound according to claim 1 , wherein (c) Y 3 represents N and R 3 is absent; and wherein: R 1 represents phenyl optionally substituted with one or two substituents selected from the group consisting of Cl, OCH 3 and CH 3 ; preferably R 1 represents - R 2 represents CH 3 ; and - R 4 , R 5 , R 6 and R 7 represent H.
  8. 8. The compound according to any one of claims 1 to 7, which is selected from the group consisting of the following compounds:
  9. 9. The compound according to claim 8, which is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, even more preferably ALIPD304, ALIPD395 and ALIPD396.
  10. 10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9, and at least one pharmaceutically acceptable excipient.
  11. 11. A compound of the following general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising at least one of said compound of the following general formula (I), and at least one pharmaceutically acceptable excipient; wherein said compound or said pharmaceutical composition is for use in a method of prevention and/or treatment of a disease in a subject, in particular a human: - Wherein (a) Y 3 represents C and R 3 represents H; and wherein: R 1 represents aryl substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; R 2 represents Ci-Ce alkyl; R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n - C(O)O-C1-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci- Ce alkyl, C(0)NH(CH 2 ) m -C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3; or - Wherein (b) Y 3 represents C and R 3 represents halogen, preferably Cl; or (c) Y 3 represents N and R 3 is absent; and wherein: R 1 represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl optionally substituted with one or two substituents selected from the group consisting of halogen, Ci-Ce alkoxy and Ci-Ce alkyl; R 2 represents H, Ci-Ce alkyl, (CH 2 ) m -C(O)OCi-C6 alkyl, or (CH 2 ) m -C(O)OH, with m representing an integer between 1 and 3; - R 4 , R 5 , R 6 and R 7 , which may be identical or different, represent H, halogen, CN, a Ci-Ce alkoxy, C(O)NH 2 , C(O)OH, (CH 2 ) m -NH 2 , (CH 2 ) m -NH-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-(CH 2 ) n - C(O)O-C1-C 6 alkyl, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)OH, (CH 2 ) m -NH-C(O)-(CH 2 ) n -C(O)O-Ci-C 6 alkyl, C(0)NH(CH 2 ) m -C5-Cio heterocyclyl, or C(0)-C5-Cio heterocyclyl-C(0)-Ci-C6 alkyl, with m representing an integer between 1 and 3 and n representing an integer between 1 and 3.
  12. 12. The compound or the composition for use according to claim 11 , as a PD-1/PD-L1 interaction inhibitor in a subject, in particular a human.
  13. 13. The compound or the composition for use according to claim 11 or 12, wherein the disease is a PD-1 -PD-L1 interactions-related disease such as cancer, chronic inflammatory disease, neurological disease and chronic infection in a subject, in particular a human.
  14. 14. The compound or the composition for use according to claim 13, wherein: the cancer is selected from the group consisting of lung carcinoma (Non small cell and Small cell), head and neck carcinoma, bladder carcinoma, kidney carcinoma, triple negative breast cancer, pancreatic carcinoma, melanoma, gastric carcinoma, colon carcinoma, oesophagus carcinoma, Hodgkin’s lymphoma, non Hodgkin lymphoma, glioblastoma, multiple myeloma, acute myeloide leukemia, Cholangiocarcinoma (gallbladder carcinoma), Merkel carcinoma, squamous cell carcinoma and endometrial carcinoma; the neurological disease is Alzheimer disease; the chronic inflammatory disease is psoriasis; and/or the chronic infections are selected from the group consisting of Human immunodeficiency virus (HIV), malaria, tuberculosis and B hepatitis.
  15. 15. The compound or the composition for use according to any one of claims 11 to 14, wherein: - R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in any one of claims 2 to 7; or - the compound is selected from the group of the following compounds ALIPD290, ALIPD304, ALIPD307, ALIPD314, ALIPD319, ALIPD321 , ALIPD322, ALIPD323, ALIPD324, ALIPD328, ALIPD330, ALIPD337, ALIPD338, ALIPD339, ALIPD340, ALIPD342, ALIPD347, ALIPD349, ALIPD350, ALIPD356, ALIPD357, ALIPD363, ALIPD370, ALIPD372, ALIPD373, ALIPD376, ALIPD381 , ALIPD382, ALIPD384, ALIPD390, ALIPD394, ALIPD395 and ALIPD396; preferably is selected from the group consisting of the following compounds ALIPD304, ALIPD307, ALIPD322, ALIPD342, ALIPD349, ALIPD350, ALIPD356, ALIPD381 , ALIPD382, ALIPD384, ALIPD394, ALIPD395 and ALIPD396, more preferably ALIPD304, ALIPD307, ALIPD381, ALIPD382, ALIPD395 and ALIPD396, even more preferably ALIPD304, ALIPD395 and ALIPD396.

Description

PYRAZOLE DERIVATIVES AS PD-1/PD-L1 INTERACTION INHIBITORS The present invention relates to novel pyrazole derivatives which act advantageously as PD-1/PD-L1 interaction inhibitors. The present invention is directed to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1, R2, Y3, R3, R4, R5, R6and R7 are as defined in the description. The present invention also relates to a pharmaceutical composition comprising at least one of said compound, and uses of said compound or pharmaceutical composition, in particular as a PD-1/PD-L1 interaction inhibitor, preferably in the prevention and/or the treatment of PD-1-PD-L1 interactions-related diseases such as cancer, chronic inflammatory diseases, neurological diseases and chronic infections. In recent years, immunotherapy has emerged as a powerful strategy for treating cancer, so much so that in 2018 the Nobel Prize in Physiology or Medicine was awarded to Allison and Honjo "for their discovery of cancer therapy by inhibiting negative immune regulation". The immunotherapeutic drugs currently on the market are monoclonal antibodies that interfere with specific modulatory systems, called immune checkpoints, acting at the interface between the tumour and cells of the immune system, particularly T cells. Immune checkpoint receptors (ICRs) are constitutively expressed on the surface of T cells to counteract hyperactive adaptive responses to self-antigens, thereby preventing autoimmune reactions. Among the immune checkpoints, programmed cell death protein 1 (PD-1 , also known as CD279) and its ligand, programmed death ligand 1 (PD-L1 , also known as CD274 or B7-H1 ) play a major role in T-cell depletion in many types of cancer, including melanoma, breast, pancreatic, kidney and non-small cell lung cancer (NSCLC). The PD-L1 (CD274/B7-H1 ) transmembrane molecule belongs to the B7 family of immunoregulatory proteins and was originally described as mediating tumor immunoescape through interaction with the PD-1 receptor on T cells (Schildberg, et al.-, Saudemont, et al.). This role has been well documented and has led to the development of several clinical grade blocking antibodies that are currently considered innovative drugs in many cancers (Nishino, et al.). Aberrant PD-L1 expression has been observed in hematologic malignancies and in a variety of solid tumor types. Tumor cells evade antitumor immunity, in part by exploiting immune checkpoints, such as the PD-1/PD-L1 axis, that induce T cell dysfunction or unresponsiveness. More than 1 ,000 clinical trials have evaluated the antitumour properties of anti-PD-1/anti- PD-L1 mAbs. As a result, some anti-PD1 (e.g., nivolumab and pembrolizumab) and anti-PD-L1 (e.g., atezolizumab, avelumab and durvalumab) mAbs have entered the market, revolutionising the treatment landscape for the above-mentioned tumours, including agents effective against other malignancies. In order to overcome the limitations of mAbs (e.g., high production costs and side effects), while improving patient compliance (e.g., oral administration), macrocyclic peptides, peptidomimetics and small non-peptidic molecules are being developed as anti-PD-L1 agents, opening a new era for drug discovery in the field of immunotherapy. However, clinical development of anti-PD-L1 small molecules is still in its infancy; in fact, there is only one organic small molecule, INCB086550, currently in phase II clinical trials for the treatment of advanced solid tumors. The patent application W02021/009384 discloses pyrazolone derivatives as PD-1/PD-L1 interaction inhibitors, and uses of said pyrazolone derivatives or a pharmaceutical composition comprising said pyrazolone derivatives in the prevention and/or treatment of PD-1-PD-L1 interactions-related diseases. There is thus a need for novel small molecules that are able to efficiently block PD-1/PD- L1 interactions, have high bioavailability, high tumor penetration, low production costs and are non-toxic. The inventors have succeeded in developing novel pyrazole derivatives that are able to efficiently block PD-1/PD-L1 interactions in order to restore anti-tumor immune responses of subjects and ultimately eradicate dormant tumor cells and any tumors in which PD-L1 is involved in immunoevasion. Thus, the present invention relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: wherein: R1 represents Ci-Ce alkyl, C(O)OCi-Ce alkyl, or aryl, in particular a phenyl, optionally substituted with one or two substituents selected from the group consisting of halogen, Ci- Ce alkoxy and Ci-Ce alkyl; R2 represents H, Ci-Ce alkyl, (CH2)m-C(O)OCi-C6 alkyl, or (CH2)m-C(O)OH, with m representing an integer between 1 and 3, preferably 1 or 2; Y3 represents C and R3 represents H or halogen; or Y3 represents N an