WO2021249969A1 - Produit de combinaison pour le traitement de maladies cancéreuses - Google Patents

Produit de combinaison pour le traitement de maladies cancéreuses Download PDF

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WO2021249969A1
WO2021249969A1 PCT/EP2021/065216 EP2021065216W WO2021249969A1 WO 2021249969 A1 WO2021249969 A1 WO 2021249969A1 EP 2021065216 W EP2021065216 W EP 2021065216W WO 2021249969 A1 WO2021249969 A1 WO 2021249969A1
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formula
radical
ring
divalent
unsubstituted
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PCT/EP2021/065216
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Frank CZAUDERNA
Roberta FERRETTI
Ralph Lindemann
Shivapriya RAMASWAMY
Ada SALA-HOJMAN
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Merck Patent Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
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Definitions

  • the present invention relates to a product for combination therapies useful for the treatment of cancer diseases.
  • the invention relates to the combination of an anti-PD-L1 antibody and an MCT4 inhibitor.
  • the therapeutic combination may be utilized for the use in treating a subject having a cancer disease that tests positive for PD-L1 and/or MCT4 expression.
  • Cancer immune evasion is a major obstacle to effective anti-cancer therapeutic strategies.
  • Two prominent pathways that cancers exploit to escape immune surveillance are tumor-derived lactic acid excretion via the monocarboxylate transporters (MCT) and the programmed death ligand 1 (PD- L1 )/programmed death 1 (PD-1 ) immune checkpoint pathway.
  • MCT monocarboxylate transporters
  • PD- L1 programmed death ligand 1
  • PD-1 programmed death 1
  • ATP adenosine triphosphate
  • OXPHPOS mitochondrial oxidative phosphorylation
  • MCT monocarboxylate transporters
  • MCT1 shows a much higher affinity to lactate (Km at about 1 to 3.5 mM according to I. Marchiq and J. Pouyssegur, J. Mol. Med. (2016) 94:155-171 ; or at about 3.5 to 10 mM according to V. L. Payen, et al., Mol. Met. 33 (2020) 48-66) than MCT4 (Km at about 28 mM (Marchiq/Pouyssegur); or at about 22 to 28 mM (Payen)).
  • MCT4 expression levels are higher in hypoxic cells than in well- oxygenated cells while the opposite seems true for MCT1 expression.
  • MCT1 and MCT4 play a role in a metabolic mechanism called metabolic symbiosis that utilizes lactate for tumor cells of different levels of oxygen supply: a hypoxic tumor cell converts large amounts of glucose to lactate by glycolysis which lactate is then transported out of the cell via the up-regulated MCT4. A nearby aerobic tumor cell then uptakes lactate via MCT1 and utilizes the lactate for energy production via OXPHOS (I. Marchiq and J. Pouyssegur, J. Mol. Med. (2016) 94:155-171 ; V. L. Payen, et al., Mol. Met. 33 (2020) 48-66).
  • MCT may be a promising target for cancer therapy.
  • selective inhibition of MCT1 in particular in highly glycolytic and hypoxic tumors, may be compensated by upregulating MCT4 rendering the treatment with the MCT 1 inhibitor ineffective.
  • MCT1 up-regulation there are no indications that selective inhibition of MCT4 in cancer cells would be compensated by MCT1 up-regulation.
  • the selective inhibition of MCT4 or the dual inhibition of both MCT1 and MCT4 is a promising approach for the development of an effective treatment of diseases and conditions which are affected by MCT1 and/or MCT4 activity, in particular of cancer.
  • MCT4 expression is amplified in many tumor types and is a marker of poor prognosis in cancer patients (K. Renner, et al., 2019, Cell Reports 29, 135-150).
  • the tumor-derived lactic acid inhibits T and natural killer (NK) cell function, which leads to tumor immune evasion.
  • Immune checkpoints are regulators of immune activation.
  • An example of such a regulator comprises programmed cell death protein 1 (PD-1 ) and programmed death-ligand 1 (PD-L1 ).
  • PD-1 is expressed on the surface of T cells whereas PD-L1 is expressed on the surface of many more cells, including cancer cells. Binding of PD-L1 to the PD-1 receptor inhibits T cell activation and proliferation.
  • PD-L1 is overexpressed in many cancers and is often associated with poor prognosis. It is well established that cancer cells overexpress PD-L1 to evade the host’s immune system. Thus, in recent years PD-L1/PD-1 inhibitors have been advocated as cancer therapies. Anti-PD-L1 antibodies like atezolizumab, durvalumab and avelumab have been shown to overcome T cell anergy and to activate immune response and now are well-established agents in cancer immunotherapy. While MCT may be a promising target for cancer therapies, therapies targeting PD-L1 have already shown anti-tumor effects in the clinic (K. Renner, et al. , 2019, Cell Reports 29, 135-150; A. Akinleye and Z. Rasool, Akinleye and Rasool, Journal of Hematology & Oncology (2019) 12:92, 1-13
  • W denotes CR W1 , N;
  • R W1 is H, halogen, R a , -OR a ;
  • R 2 is H, halogen, -CN, R a , -OH, -OR a , NH 2 , -NH-R a , -NR a R b ;
  • R 3 is H, halogen, R a , -OH, -OR a , NH 2 , -NH-R a , -NR a R b , -NO 2 , unsubstituted or substituted phenyl; or R 2 and R 3 form together with the carbon atoms to which they are attached to an unsubstituted or substituted six-membered aromatic ring; or form together a divalent -NH-CH 2 -CH 2 -NH- radical;
  • R 4 is H, R a ;
  • R 5 is H, halogen
  • R 6 is H, halogen, R a , -OR a , NH 2 , -NHR a , -NR a R b , -NO 2 , Ar A ;
  • R 8 is H, halogen, R a ; n is an integer selected from 0 and 1 ;
  • L 1 is a divalent -CH 2 - radical
  • L 1 is a divalent-SO 2 - radical
  • L 2 is a divalent -NH- or -N(R a )- radical; and L 3 is a single bond;
  • A is a ring selected from the group consisting of Ar A , Hetar A , Cyc A or Hetcyc A ;
  • Ar A is a mono-, bi- or tricyclic aryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents R A1 , R A2 , R A3 , R A4 , R A5 , R A6 and/or R A7 which may be the same or different, with the proviso that Ar A is not 4-methylphenyl;
  • Hetar A is a mono-, bi- or tricyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents R A1 , R A2 , R A3 , R A4 , R A5 , R A6 and/or R A7 which may be the same or different;
  • Cyc A is a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with R A8 , R A 9 , R A10 and/or R A11 which may be the same or different;
  • Hetcyc A is a saturated or partially unsaturated, mono-, bi- or tricyclic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with R A8 , R A9 , R A1 ° and/or R A11 which may be the same or different;
  • Ar B is a phenyl ring, wherein that phenyl ring may be unsubstituted or substituted with substituents R B1 , R B2 and/or R B3 which may be the same or different;
  • Hetar B is a monocyclic heteroaryl with 5, 6, 7 ring atoms wherein 1 , 2, 3, 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroryl may be unsubstituted or substituted with substituents R B1 , R B2 and/or R B3 which may be the same or different;
  • Cyc B is a mono- or bicyclic saturated or partially unsaturated carbocycle with 5, 6, 7, 8, 9, 10 ring carbon atoms wherein that carbocycle may be unsubstituted or mono-, di- or trisubstituted with R B4 , R B5 and/or R B6 which may be the same or different;
  • Hetcyc 6 is a saturated or partially unsaturated monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 , 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or mono-, di- or trisubstituted with R B4 , R B5 and/or R B6 which may be the same or different;
  • Cyc c is a mono- or bicyclic saturated or partially unsaturated carbocycle with 5, 6, 7, 8, 9, 10 ring carbon atoms wherein that carbocycle is fused to Ar A or Hetar A via 2 adjacent ring atoms of said Ar A or Hetar A and wherein that carbocycle may be unsubstituted or substituted with R C1 , R c2 , R C3 , R C4 , R C5 , R C6 which may be the same or different;
  • R B1 , R B2 and/or R B3 are independently from each other H, halogen, R a , -OR a , -SR a ;
  • R B4 , R B5 , R B6 , R C1 , R C2 , R C3 , R C4 , R C5 , R C6 are independently from each other H, R a ;
  • R a , R b are independently from each other unsubstituted or substituted, straight-chain or branched C 1-6 -aliphatic or may form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 4, 5, 6, 7 ring atoms wherein 1 , 2 of said ring atoms is/are a hetero atom(s) selected from N, 0 and/or S and the remaining are carbon atoms; or any stereoisomer, solvate or tautomer thereof and/or a pharmaceutically acceptable salt of the compound of formula (I) or any of its stereoisomers, solvates or tautomers.
  • the compound of formula (I) being component (b) of the combination product of the present invention is an MCT4 inhibitor.
  • the compounds of formula (I) are first described in the international patent application with the application number PCT/EP2019/086662, filed on 20. December 2019, published as WO 2020/127960 A1 , which is herewith incorporated by reference in its entirety.
  • the compound of formula (I) as defined above being component (b) of the combination product of the present invention does not comprise any of the following compounds
  • component (a) of the combination product is an anti-PD-L1 antibody or antigen-binding fragement thereof, preferably avelumab.
  • anti-PD-L1 antibody refers to an antibody that blocks binding of PD-L1 to PD-1 .
  • the anti-PD-L1 antibody specifically binds to human PD-L1 and blocks binding of human PD-L1 to human PD-1.
  • the antibody may be a monoclonal antibody, human antibody, humanized antibody or chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the group consisting of lgG1 , lgG2, lgG3 and lgG4 constant regions, and in preferred embodiments, the human constant region is an lgG1 or lgG4 constant region.
  • the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
  • Specific anti-human PD- L1 monoclonal antibodies useful as the anti-PD-L1 antibody in the combination product, treatment method, medicaments and uses of the present invention include, for example without limitation, avelumab (MSB0010718C), MPDL3280A (atezolizumab, an lgG1 -engineered, anti-PD-L1 antibody, disclosed in WO 2010/077634), BMS-936559 (a fully human, anti-PD-L1 , lgG4 monoclonal antibody), MEDI4736 (durvalumab, an engineered lgG1 kappa monoclonal antibody with triple mutations in the Fc domain to remove antibody-dependent, cell-mediated cytotoxic activity; disclosed in WO 2011/066389), and an antibody which comprises the heavy chain and light chain variable regions of SEQ ID NO:24 and SEQ ID NO:21 , respectively, of WO 2013/019906.
  • the anti-PD-L1 antibody (component (a) of the combination product of the present invention) is avelumab (disclosed in WO 2013/079174, the disclosure of which is hereby incorporated by reference in its entirety).
  • Avelumab (formerly designated MSB0010718C; marketed as Bavencio®) is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 isotype (see, e.g., WO 2013/079174). Avelumab selectively binds to PD-L1 and competitively blocks its interaction with PD-1. The mechanisms of action rely on the inhibition of PD-1/PD-L1 interaction and on the antibody-dependent cell- mediated cytotoxicity (ADCC) activity (see e.g., Boyerinas et al. (2015) Cancer Immunol Res 3: 1148).
  • ADCC antibody-dependent cell- mediated cytotoxicity
  • Avelumab, its sequence, and many of its properties have been described in WO 2013/079174, where it is designated A09-246-2 having the heavy and light chain sequences according to SEQ ID NOs: 32 and 33 of this patent application. It is frequently observed, however, that in the course of antibody production the C-terminal lysine (K) of the heavy chain is cleaved off. This modification has no influence on the antibody-antigen binding. Therefore, in some embodiments the C-terminal lysine (K) of the heavy chain sequence of avelumab is absent.
  • one of avelumab’s properties is its ability to exert antibody-dependent cell-mediated cytotoxicity (ADCC), thereby directly acting on PD-L1 expressing tumor cells by inducing their lysis without showing any significant toxicity.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • Component (b) of the combination product of the present invention is an MCT4 inhibitor of formula (I) as described above and below.
  • the compound of formula (I) is a compound of formula (I) or any stereoisomer, solvate or tautomer thereof and/or a pharmaceutically acceptable salt of the compound of formula (I) or any of its stereoisomers, solvates or tautomers
  • W denotes CR W1 , N
  • R W1 is H, halogen, R a , -OR a ;
  • R 2 is H, halogen, -CN, R a , -OH, -OR a , NH 2 , -NH-R a , -NR a R b ;
  • R 3 is H, halogen, R a , -OH, -OR a , NH 2 , -NH-R a , -NR a R b , -NO 2 , unsubstituted or substituted phenyl; or
  • R 2 and R 3 form together with the carbon atoms to which they are attached to an unsubstituted or substituted six-membered aromatic ring; or form together a divalent -NH-CH 2 -CH 2 -NH- radical;
  • R 4 is H, R a ;
  • R 5 is H, halogen
  • R 6 is H, halogen, R a , -OR a , NH 2 , -NHR a , -NR a R b , -NO 2 , Ar A ;
  • R 8 is H, halogen, R a ; n is an integer selected from 0 and 1 ;
  • L 1 is a divalent -NH-, -N(R a )- or -CH 2 - radical
  • L 2 is a divalent -SO 2 - radical
  • L 2 is a divalent -CH 2 - radical
  • L 3 is a divalent -CH 2 - radical
  • L 1 is a divalent -CH 2 - radical
  • L 3 is a single bond
  • A is a ring selected from the group consisting of Ar A , Hetar A , Cyc A or Hetcyc A ;
  • Ar A is a mono-, bi- or tricyclic aryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents R A1 , R A2 , R A3 , R A4 , R A5 , R A6 and/or R A7 which may be the same or different, with the proviso that Ar A is not 4-methylphenyl;
  • Hetar A is a mono-, bi- or tricyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents R A1 , R A2 , R A3 , R A4 , R A5 , R A6 and/or R A7 which may be the same or different;
  • Cyc A is a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with R A8 , R A 9 R A10 and/or R A11 which may be the same or different;
  • Hetcyc A is a saturated or partially unsaturated, mono-, bi- or tricyclic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with R A8 , R A9 , R A1 ° and/or R A11 which may be the same or different;
  • Ar B is a phenyl ring, wherein that phenyl ring may be unsubstituted or substituted with substituents R B1 , R B2 and/or R B3 which may be the same or different;
  • Hetar B is a monocyclic heteroaryl with 5, 6, 7 ring atoms wherein 1 , 2, 3, 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroryl may be unsubstituted or substituted with substituents R B1 , R B2 and/or R B3 which may be the same or different;
  • Cyc B is a mono- or bicyclic saturated or partially unsaturated carbocycle with 5, 6, 7, 8, 9, 10 ring carbon atoms wherein that carbocycle may be unsubstituted or mono-, di- or trisubstituted with R B4 , R B5 and/or R B6 which may be the same or different;
  • Hetcyc B is a saturated or partially unsaturated monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 , 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or mono-, di- or trisubstituted with R B4 , R B5 and/or R B6 which may be the same or different;
  • Cyc c is a mono- or bicyclic saturated or partially unsaturated carbocycle with 5, 6, 7, 8, 9, 10 ring carbon atoms wherein that carbocycle is fused to Ar A or Hetar A via 2 adjacent ring atoms of said Ar A or Hetar A and wherein that carbocycle may be unsubstituted or substituted with R C1 , R C2 , R C3 , R C4 , R C5 , R C6 which may be the same or different;
  • R B1 , R B2 and/or R B3 are independently from each other H, halogen, R a , -OR a , -SR a ;
  • R B4 , R B5 , R B6 , R C1 , R C2 , R C3 , R C4 , R C5 , R C6 are independently from each other H, R a ;
  • R a , R b are independently from each other unsubstituted or substituted, straight-chain or branched C 1-6 -aliphatic or may form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 4, 5, 6, 7 ring atoms wherein 1 , 2 of said ring atoms is/are a hetero atom(s) selected from N, 0 and/or S and the remaining are carbon atoms; with the proviso that
  • the compound of formula (I) is a compound of formula (I) or any stereoisomer, solvate or tautomer thereof and/or a pharmaceutically acceptable salt of the compound of formula (I) or any of its stereoisomers, solvates or tautomers wherein W denotes CR W1 , N;
  • R W1 is H, R a , -OR a ;
  • R 1 is -OH, OR a , NHR a , NH-OH;
  • R 2 is H, halogen, R a , -OR a , -NH 2 , -NHR a , -NR a R b ;
  • R 3 is H, halogen, R a , -OR a , -NH 2 , -NHR a , -NR a R b , -NO 2 , phenyl; or
  • R 2 and R 3 form together with the carbon atoms to which they are attached to a benzo ring;
  • R 4 is H
  • R 5 is H
  • R 6 is is H, halogen, R a , -OR a , -NH 2 , -NHR a , -NR a R b ;
  • R 7 H halogen, R a , -OR a ;
  • R 8 is H, halogen.
  • the compound of formula (I) is a compound of formula (I) or or any stereoisomer, solvate or tautomer thereof and/or a pharmaceutically acceptable salt of the compound of formula (I) or any of its stereoisomers, solvates or tautomers wherein W is N; and
  • R 2 is H, halogen, R a , -OR a , -NH 2 , -NHR a , -NR a R b ;
  • R 3 is H, halogen, R a , -OR a , -NH 2 , -NHR a , -NR a R b , -NO 2 , phenyl; thereby forming a compound of formula (l-a) or
  • R 2 and R 3 form together with the carbon atoms to which they are attached to a benzo ring thereby forming a compound of formula (l-b) wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , n, L 1 , L 2 , L 3 and A are as defined above and below and in the claims.
  • the compound of formula (I) is a compound of formula (I) or any stereoisomer thereof and/ora pharmaceutically acceptable salt of that compound or any of its stereoisomers wherein W denotes CR W1 , N; in particular N;
  • R W1 is H, -OCH 3 ;
  • R 1 is -OH, -OC 1 -4 -alkyl, -OCH 2 CH(OH)-CH 2 OH, -O(CH 2 ) 2 O(CH 2 ) 2 OH, -
  • R 2 is H, F, Cl, CH 3 , C 2 H 5 , -CH 2 OH, -OCHS, -OC 2 H 5 , -NH 2 , -NHCHS, -NHC 2 H 5 ;
  • R 2 and R 3 form together with the carbon atoms to which they are attached to a benzo ring;
  • R 4 is H
  • R 5 is H
  • R 6 is H, F, Cl, Br, I, -CH 3 , -C 2 H 5 , -CH(CH 3 ) 2 , -OCH 3 , -N(CH 3 ) 2 ;
  • R 7 is H, F, Cl, Br, CH 3 , CF 3 , -OCH 3 ;
  • R 8 is H, F; n is 0;
  • L 1 is a divalent -NH- or -N(CH 3 )- radical
  • L 2 is a divalent -SO 2 - radical
  • L 1 is a divalent -N(CHO)- radical
  • L 2 is a divalent -CH 2 - radical
  • A is a ring selected from the group consisting of Ar A , Hetar A , Cyc A or Hetcyc A ;
  • Ar A is selected from the group consisting of 4-methoxyphenyl, 4-methoxy-2- methylphenyl, 4-methoxy-3-methylphenyl, 2,3-dimethyl-4- methoxyphenyl, 2,3,6-trimethyl-4-methoxyphenyl, 2,3-dichloro-4- methoxyphenyl, 3-acetamido-4-ethoxyphenyl, 4-(cyclohex-1 -en-1 - yl)phenyl, 1 ,1 ’-biphenyl-2 -yl, 1 , 1 ’-biphenyl-3-yl, 1 , 1 ’-biphenyl-4-yl, 2’- methyl-1 , 1 ’-biphenyl-4-yl, 2-methoxy-1 , 1 ’-biphenyl-4-yl, 3-methoxy-1 , 1 ’- biphen-4-yl, 2’-methoxy-1 , 1 ’-biphenyl
  • Hetar A is selected from the group consisting of 5-bromo-6- methoxypyhdin-3-yl, 6-phenylpyridin-3-yl, 1 -methylindol-4-yl, 1- benzofuran-2-yl, 1 -benzothiophen-3-yl, 5-chloro-1 -benzothiophen-2-yl, 5-chloro-3-methyl-1-benzothiophen-2-yl, 1 ,3-benzothiazol-4-yl, quinolin- 2-yl, quinolin-8-yl, 2-methylquinolin-8-yl, 3-methylquinolin-8-yl, 4- methylquinolin-8-yl, 6-methylquinolin-8-yl, 7-methylquinolin-8-yl, 4,7- dimethylquinolin-8-yl, 5,7-dimethylquinolin-8-yl, 5,6,7-trimethylquinolin-8- yl, 5-ethylquinolin-8-yl, 5-(n
  • Cyc A is 3,4-dihydronaphth-2-yl
  • Hetcyc A is selected from the group consisting of 2,3-dihydro-1 H-indol-1 -yl, octahydro-1 H-indol-1 -yl, decahydroquinolin-1 - yl, 4a,8a-trans-decahydroquinolin-1 -yl, 4aR,8aS-decahydroquinolin-1 -yl, decahydroquinolin-2-yl, 4-methyldecahydroquinolin-1 -yl, 1 ,2,3,4- tetrahydro-1 ,8-naphthyridin-1 -yl.
  • the compound of formula (I) is selected from the compounds of Table 1 below or any stereoisomer, solvate or tautomer thereof and/or a pharmaceutically acceptable salt of the compound of formula (I) or any of its stereoisomers, solvates or tautomers.
  • PE5 the compound of formula (I) is 5- ⁇ 2-[5- chloro-2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl ⁇ -4-methoxy- pyridine-2-carboxylic acid (Compound 367) or any pharmaceutical acceptable salt thereof.
  • aliphatic or “aliphatic group”, as used herein, means a straight- chain (i.e.
  • aliphatic groups contain 1-8 or 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 -4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (“cycloalkyl”) refers to a monocyclic C 3 -C 7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • the term “carbocycle” refers to a monocyclic or bicyclic cycloaliphatic ring system which is fused to an aromatic, heteroaromatic or heterocyclic ring or ring system via 2 adjacent ring atoms of that aromatic, heteroaromatic or heterocyclic ring or ring system; in other words, such carbocycle shares two ring atoms with the ring or ring system to which it is fused thereby having two points of attachement to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl usually refers to a saturated aliphatic and acyclic moiety
  • alkynyl usually refers to an aliphatic and acyclic moiety with one or more C ⁇ C triple bonds.
  • Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C 1 -8 -alkyl, C 1-6 -alkyl, C 1 -4 -alkyl, C 2-8 -alkenyl, C 2-6 -alkenyl, C 2-8 -alkynyl, C 2-6 -alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • C 1-3 -alkyl refers to alkyl groups, i.e. saturated acyclic aliphatic groups, having 1 , 2 or 3 carbon atoms.
  • Exemplary C 1-3 -alkyl groups are methyl, ethyl, propyl and isopropyl.
  • the term “C 1 -4 -alkyl” refers to alkyl groups having 1 , 2, 3 or 4 carbon atoms.
  • Exemplary C 1 -4 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • C 1-6 - alkyl refers to alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Exemplary C 1-6 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl.
  • C 1 -8 -alkyl refers to alkyl groups having 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Exemplary C 1 -8 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4- trimethylpentyl.
  • Each of these alkyl groups may be straight-chain or - except for C 1 -alkyl and C 2 -alkyl - branched and may be unsubstituted or substituted with 1 , 2 or 3 substituents or even 4, 5 or 6 substituents that may be the same or different and are, if not specified differently elsewhere in this specification, selected from the group comprising halogen, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino.
  • the C 1-3 -alkyl, C 1 -4 -alkyl, C 1-6 -alkyl, C 1 -8 -alkyl groups may also comprise those residues in which 1 or 2 of non-terminal and non-adjacent -CH 2 - (methylene) groups are replaced by -O-, -S- and/or 1 or 2 non-terminal and non-adjacent -CH 2 - or -CH- groups are replaced by -NH- or -N-.
  • C 3-7 -cycloalkyl refers to a cycloaliphatic hydrocarbon, as defined above, with 3, 4, 5, 6 or 7 ring carbon atoms.
  • C 3-7 -cycloalkyl groups may be unsubstituted or substituted with - unless specified differently elsewhere in this specification - 1 , 2 or 3 substituents that may be the same of different and are - unless specified differently elsewhere in this specification - selected from the group comprising C 1-6 -alkyl, O- C 1-6 -alkyl (alkoxy), halogen, hydroxy unsubstituted or mono- or di-substituted amino.
  • Exemplary C 3-7 - cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl.
  • aliphatoxy refers to saturated or unsaturated aliphatic groups or substituents as defined above that are connected to another structural moiety via an oxygen atom (-O-).
  • alkoxy refers to a particular subgroup of saturated aliphatoxy, i.e. to alkyl substituents and residues that are connected to another structural moiety via an oxygen atom (-O-).
  • O-alkyl sometimes, it is also referred to as “O-alkyl” and more specifically as “O-C 1 -4 -alkyl”, “O-C 1-6 -alkyl”, “O-C 1 -8 -alkyl”.
  • alkyl groups may be straight-chain or - except for -O-C 1 -alkyl and -O-C 2 -alkyl - branched and may be unsubstituted or substituted with 1 , 2 or 3 substituents or even 4, 5 or 6 substituents that may be the same or different and are, if not specified differently elsewhere in this specification, selected from the group comprising halogen, unsubstituted or mono- or di-substituted amino.
  • alkoxy groups are methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n- butoxy, sec-butoxy, tert-butoxy, n-pentoxy.
  • alkylene refers to a divalent aliphatic group and in particular a divalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., - (CH 2 ) X -, wherein x is a positive integer, preferably 1, 2, 3, 4, 5 or 6.
  • x is a positive integer, preferably 1, 2, 3, 4, 5 or 6.
  • C 1-3 -alkylene refers to an alkylene moiety with 1 , 2 and 3, respectively, -CH 2 - groups; the term “alkylene”, however, not only comprises linear alkylene groups, i.e. "alkylene chains", but branched alkylene groups as well.
  • C 1-6 -alkylene refers to an alkylene moiety that is either linear, i.e. an alkylene chain, or branched and has 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by (or with) a substituent. Suitable substituents include those described herein for a substituted alkyl group. In some instances 1 or 2 methylene groups of the alkylene chain may be replaced by, for instance, O, S and/or NH or N-C 1 -4 - alkyl.
  • alkylene groups are -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - CH 2 -, -O-CH 2 -O-, -O-CH 2 -CH 2 -O-, -O-CH 2 -CH 2 -CH 2 -O- -CH 2 -NH-CH 2 - CH 2 -, -CH 2 -N(CH 3 )-CH 2 -CH 2 -.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.
  • alkynylene refers to a bivalent alkynyl group.
  • a substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • heteroatom means one or more of oxygen (O), sulfur (S), or nitrogen (N), including, any oxidized form of nitrogen or sulfur, e.g. N-oxides, sulfoxides and sulfones; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic or heteroaromatic ring, for example N (as in 3 , 4-dihydro-2H-pyrrolyl ) , NH (as in pyrrolidinyl) or N-SUB with SUB being a suitable substituent (as in N-substituted pyrrolidinyl).
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, that ring members being carbon atoms, wherein at least one ring in the system is aromatic, i.e. , it has (4n+2) p (pi) electrons (with n being an integer selected from 0, 1 , 2, 3), which electrons are delocalized over the system, and wherein each ring in the system contains three to seven ring members.
  • all rings in the aryl system or the entire ring system are aromatic.
  • aryl is used interchangeably with the term “aryl ring”.
  • aryl refers to an “aromatic ring system”. More specifically, those aromatic ring systems may be mono-, bi- or tricyclic with 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 ring carbon atoms. Even more specifically, those aromatic ring systems may be mono- or bicyclic with 6, 7, 8, 9, 10 ring carbon atoms.
  • Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which may be unsubstituted or substituted with one or more identical or different substituents.
  • aryl or “aromatic ring system”, as they are used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. In the latter case the "aryl” group or substituent is attached to its pendant group via the aromatic part of the ring system.
  • benzo refers to a six-membered aromatic ring (with carbon ring atoms) that is fused via two adjacent carbon atoms to another ring, being it a cycloaliphatic, aromatic, heteroaromatic or heterocyclic (heteroaliphatic) ring; as a result a ring sytem with at least two rings is formed in which the benzo ring shares two common carbon atoms with the other ring to which it is fused. For example, if a benzo ring is fused to a phenyl ring, a napthaline ring system is formed, while fusing a benzo ring to a pyridine provides for either a quinoline or an isoquinoline.
  • heteroaryl and “heteroar-”, used alone or as part of a larger moiety refer to groups having 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 ring atoms (which atoms are carbon and hetero atoms), preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 p (pi) electrons shared in a cyclic array; and having, in addition to carbon atoms, 1 , 2, 3, 4 or 5 heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, in particular pyrrolo[2,3-b]pyridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on the heteroaromatic or, if present, the aryl ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/-/— quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl and pyrido[2,3-b]-1 ,4-oxazin-3(4/-/)-one.
  • an indolyl ring may be attached via one of the ring atoms of the six- membered aryl ring or via one of the ring atoms of the five-membered heteroaryl ring.
  • a heteroaryl group is optionally mono-, bi- or tricyclic.
  • the term “heteroaryl” is used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are unsubstituted or substituted with one or more identical or different substituents.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • a heteroaryl ring can be attached to its pendant group at any of its hetero or carbon ring atoms which attachment results in a stable structure or molecule: any of the ring atoms may be unsubstituted or substituted.
  • heteroaryl substituents as used in the present invention are depicted below: pyrrolyl furanyl thiophenyl 1-oxa-2,3- 1-oxa-2,4- diazolyl diazolyl
  • heteroaryl substituents can be attached to any pendant group via any of its ring atoms suitable for such an attachment.
  • the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable mono- bi- or tricyclic heterocyclic moiety with 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 ring atoms wherein 1 , 2, 3, 4, 5 of said ring atoms are hetero atoms and wherein that heterocyclic moiety is either saturated or partially unsaturated.
  • the heterocycle is a stable saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, or 11-membered bicyclic or 11-, 12- 13-, or 14-membered tricyclic heterocyclic moiety.
  • nitrogen When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen.
  • the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB with SUB being a suitable substituent (as in N- substituted pyrrolidinyl).
  • heterocycle In the context of the term “heterocycle” the term “saturated” refers to a completely saturated heterocyclic system, like pyrrolidinyl, piperidinyl, morpholinyl, and piperidinonyl. With regard to the term “heterocycle” the term “partially unsaturated” refers to heterocyclic systems (i) that contain one or more units of unsaturation, e.g.
  • This second class (ii) of "partially unsaturated” heterocycles may also be referred to as (bicyclic or tricyclic) "partially aromatic" heterocycles indicating that at least one of the rings of that heterocycle is a saturated or unsaturated but non-aromatic heterocycle that is fused with at least one aromatic or heteroaromatic ring system.
  • Typical examples of these "partially aromatic" heterocycles are 1 ,2,3,4-tetrahydroquinolinyl and 1 ,2,3,4- tetrahydroisoquinolinyl.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms may be unsubstituted or substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquino- linyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are unsubstituted or substituted.
  • unsaturated means that a moiety or group or substituent has one or more units of unsaturation.
  • the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation. In particular, it encompasses (i) non-saturated (mono-, bi- or tricyclic) ring systems without any aromatic or heteroaromatic moiety or part; and (ii) bi- or tricyclic ring systems in which one of the rings of that system is an aromatic or heteroaromatic ring which is fused with another ring that is neither an aromatic nor a heteroaromatic ring, e.g.
  • the first class (i) of "partially unsaturated" rings, ring systems, ring moieties may also be referred to as "non-aromatic partially unsaturated” rings, ring systems, ring moieties, while the second class (ii) may be referred to as "partially aromatic” rings, ring systems, ring moieties.
  • bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e. being partially unsaturated or aromatic, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho- fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • tricyclic “tricyclic ring” or “tricyclic ring system” refers to any tricyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e.
  • heterotricyclic is a subset of “tricyclic” that requires that one or more heteroatoms are present in one or both rings of the tricycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • certain compounds of the invention contain “substituted” or “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure. Unless otherwise indicated, a “substituted” or “optionally substituted” group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent is either the same or different at every position.
  • substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Ph means phenyl
  • -(CH 2 ) 0-4 means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1 , 2, 3 or 4 CH 2 units.
  • Ph means phenyl
  • halo means halogen
  • -(CH 2 ) 0- 2 means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1 or 2 CH 2 units.
  • R * is C 1-6 aliphatic
  • R * is optionally substituted with halogen, - R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -O(haloR ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , - NHR ⁇ , -NR ⁇ 2, or -NO 2
  • each R ⁇ is independently selected from Ci- 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently -R ⁇ , - NR ⁇ 2 , -C(O)R ⁇ , -C(O)OR ⁇ , -C(O)C(O)R ⁇ , C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or - N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstitute
  • R a and R b may be, inter alia, independently from each other unsubstituted or substituted, straight-chain or branched C 1-6 -aliphatic.
  • they may be, inter alia, C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, in each case either unsubstituted or substituted with one or more substituents, the substituents being the same or different.
  • R a and/or R b are stable C 1-6 -alkyl moieties bearing one or more substituents, the substituents being the same or different and being selected from halogen, OH, alkoxy.
  • the invention therefore, also relates to the optically active forms, enantiomers, racemates, diastereomers, mixtures thereof in all ratios, collectively: “stereoisomers” for the purpose of the present invention, of these compounds. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use a specific stereoisomer, e.g. one specific enantiomer or diastereomer.
  • a compound according to the present invention obtained as a racemate - or even intermediates thereof - may be separated into the stereoisomeric (enantiomeric, diastereoisomeric) compounds by chemical or physical meas- ures known to the person skilled in the art.
  • Another approach that may be applied to obtain one or more specific stereoisomers of a compound of the present invention in an enriched or pure form makes use of stereoselective synthetic procedures, e.g. applying starting material in a stereoisomerically enriched or pure form (for instance using the pure or enriched (R)- or (S)- enantiomer of a particular starting material bearing a chiral center) or utilizing chiral reagents or catalysts, in particular enzymes.
  • pure enantiomer usually refers to a relative purity of one enantiomer over the other (its antipode) of equal to or greater than 95%, preferably ⁇ 98 %, more preferably ⁇ 98.5%, still more preferably > 99%.
  • the compounds of formula (I) which have one or more centers of chirality and which occur as racemates or as mixtures of enatiomers or diastereoisomers can be fractionated or resolved by methods known per se into their optically pure or enriched isomers, i.e. enantiomers or diastereomers.
  • the separation of the compounds of formula (I) can take place by chromatographic methods, e.g. column separation on chiral or nonchiral phases, or by recrystallization from an optionally optically active solvent or by use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and subsequent elimination of the radical.
  • tautomer refers to compounds of the present invention that may exist in tautomeric forms and show tautomerism; for instance, carbonyl compounds may be present in their keto and/or their enol form and show keto-enol tautomerism. Those tautomers may occur in their individual forms, e.g., the keto or the enol form, or as mixtures thereof and are claimed separately and together as mixtures in any ratio. The same applies for cis/trans isomers, E/Z isomers, conformers and the like.
  • the compounds of formula (I) are in the form of free base or acid - as the case may be -, i.e. in their non-salt (or salt-free) form.
  • the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically acceptable salts.
  • acidic groups such as carboxyl groups
  • the compounds of the present invention which contain acidic groups, such as carboxyl groups can be present in salt form, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts, aluminium salts or as ammonium salts.
  • salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, diethanolamine, triethanolamine, piperdine, N-methylglutamine or amino acids.
  • a suitable base e.g. lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide or barium hydroxide.
  • base salts of compounds of the present invention include but are not limited to copper(l), copper(ll), iron(ll), iron (III), manganese(ll) and zinc salts.
  • Compounds of the present invention which contain one or more basic groups, e.g. groups which can be protonated, can be present in salt form, and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid,
  • the salts which are formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates.
  • the stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one.
  • Compounds of the present invention which contain basic nitrogen-containing groups can be quaternised using agents such as (C 1-4 )alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di( C 1-4 )alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C 10- C 18 )alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(C 1-4 )alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds according to the invention can be prepared using such salts.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines can be obtained by customary methods which are known to a person skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • a compound of formula (I) includes isotope-labelled forms thereof.
  • An isotope-labelled form of a compound of the formula (I) is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally.
  • isotopes which are readily commercially available and which can be incorporated into a compound of formula (I) by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F and 36 CI, respectively.
  • a compound of formula (I) or a pharmaceutically acceptable salt therof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.
  • An isotope- labelled compound of formula (I) can be used in a number of beneficial ways.
  • an isotope-labelled compound of the present invention into which, for example, a radioisotope, such as 3 H or 14 C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays.
  • radioisotopes i.e. tritium ( 3 H) and carbon-14 ( 14 C)
  • 3 H tritium
  • 14 C carbon-14
  • Incorporation of heavier isotopes, for example deuterium ( 2 H) into a compound of formula (I) has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound.
  • An isotope-labelled compound of formula (I) can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • Deuterium ( 2 H) can also be incorporated into a compound of formula (I) for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.
  • Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus cause a reduction in the rate in rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially.
  • the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.
  • a compound of formula (I) which has multiple potential sites of attack for oxidative metabolism for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms.
  • Half-life determinations enable favourable and accurate determination of the extent of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is deter-mined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.
  • Deuterium-hydrogen exchange in a compound of the present invention can also be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites.
  • a toxic metabolite arises through oxidative carbon- hydrogen (C-H) bond cleavage
  • C-H oxidative carbon- hydrogen
  • the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step.
  • Further information on the state of the art with respect to deuterium- hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org.
  • the compounds of formula (I) - or any stereoisomer, solvate or tautomer thereof and/or a pharmaceutically acceptable salt of the compound of formula (I) or any of its stereoisomers, solvates or tautomers - have been found to exhibit pharmacological activity by inhibiting monocarboxylate transporters (MCT).
  • MCT4 monocarboxylate transporter isoform 4
  • MCT4 selectively monocarboxylate transporter isoform 4
  • Selectivity assessment is based on cellular activity, considering different cell lines with different MCT4/MCT1 expression levels.
  • MDA-MB231 cells this ratio is 120 based on mRNA levels (MCT4: 2750; MCT1 : 23). Many compounds of the present invention show low IC50 values even down to single digit nanomolar level in this cell line when measuring lactate efflux inhibition. In SNU-398 cells on the other hand, the ratio is 0.02 (mRNA MCT4: 22; MCT 1 : 874) and the compounds of the present invention typically have IC50 values > 25 mM if they are selective MCT4 inhibitors.
  • MCT4 While there is evidence that selective inhibition of MCT 1 , in particular in highly hypoxic cancer cells, are compensated by cellular upregulating MCT4 which compensation renders the treatment of diseases that are affected by MCT activity with an MCT1 inhibitor ineffective, it is believed that selective inhibition of MCT4 may not be compensated by cellular MCT1 upregulation; this makes selective MCT4 inhibitors useful for the treatment, prevention, suppression and/or amelioration of medicinal conditions or pathologies that are affected by MCT activity. In another embodiment some compounds of formula (I) exhibit both MCT4 and MCT1 inhibitory activity, i.e. a dual inhibitory effect.
  • compounds of the present invention being MCT4 inhibitors may be combined with other compounds that exhibit MCT1 inhibition, in particular primarily or even selectively, in order to provide for a treatment, prevention, suppression and/or amelioration of medicinal conditions or pathologies that are affected by MCT activity that would benefit from the dual inhibition of both MCT4 and MCT1.
  • MCT1 inhibitors to combine with the compounds of the present invention are those known as AZD3965 (5-((S)-4-Hydroxy-4-methyl- isoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-(3-methyl-5-trifluoromethyl- 1 H-pyrazol-4-ylmethyl)-1 H-thieno[2,3-d]pyrimidine-2,4-dione), BAY-8002 ( 2- (5-Benzenesulfonyl-2-chloro-benzoylamino)-benzoic acid) and those described in J. Med. Chem. 2014, 7317; and ACS Med. Chem. Lett. 2015, 558.
  • the compounds of formula (I) being selective MCT4 or dual MCT4 and MCT1 inhibitors are useful in particular in the treatment, prevention, suppression and/or amelioration of hyperproliferative disorders and cancer, more particular adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pit
  • the compounds of formula (I) can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials, and as further exemplified by the following specific examples. They may also be prepared by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made of variants which are known per se, but are not mentioned here in greater detail.
  • the starting materials for the preparation of compounds of formula (I) can be prepared by methods as described in the examples or by methods known per se, as described in the literature of synthetic organic chemistry and known to the skilled person, or can be obtained commercially.
  • the starting materials for the processes utilized may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of formula (I) or intermediate compounds.
  • in general it is possible to carry out the reaction stepwise.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1 ,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or but
  • the reaction temperature is between about -100° C and 300° C, depending on the reaction step and the conditions used.
  • Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.
  • the compounds of the present invention can readily be synthesized by reacting other compounds of the present invention under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present invention, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person.
  • the skilled artisan will apply - whenever necessary or useful - synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).
  • TAA triethylamine
  • DIPA di- isopropylamine
  • the amino group of alkyne C may then be reacted with a suitable sulfonyl chloride CI-SO 2 -A in pyridine and in the presence of dimethylaminopyidine (DMAP) to yield sulfonamide D of the present invention.
  • DMAP dimethylaminopyidine
  • the carboxylic acid E is easily available via saponifaction of the ester D (with R 1 being an alkoxy group).
  • Alkyne derivative F is subjected to a C-C-cross coupling reaction with bromo- nitro-substituted phenyl G, for instance, under conditions typical for a Sonogashira reaction as described above for Scheme A, to yield the nitro- substituted compound H which in turn is subjected to a reduction reaction, e.g., with iron powder under heating, to yield the respective amino-substituted compound C.
  • a reduction reaction e.g., with iron powder under heating
  • the bromomethyl-substituted bromo-phenyl derivative J is reacted in a nucleophilic substitution reaction with the thiol A-SH, for instance in the presence of potassium carbonate to form thioether K.
  • Compound K is then oxidized my means of hydrogen peroxide to form the sulfone derivative M which is subsequently subjected to a C-C-cross coupling condition (e.g., Sonogashira reaction in a suitable solvent with Copper-(l)-iodide, a suitable Pd(0) complex, e.g. Pd(0)(bistriphenylphospan)-dichloride, and in the presence of a nitrogen base, e.g.
  • the alkyne derivative F may be reacted with phenyl derivative Y in a C-C-cross coupling reaction (e.g., Sonogashira reaction) to yield compound U, and after optional saponification, compound V of the present invention.
  • Y in turn is available by formylation of the amino group of compound X utilizing formyl acetic acid anhydride.
  • bromomethyl- substituted bromo-phenyl derivative J is reacted in a nucleophilic substitution reaction with the amine A-NH 2 under suitable conditions, e.g. in the presence of a sutiable base, to yield bromo-phenyl derivative KK.
  • Compound KK is in turn subjected to a C-C-cross coupling reaction with alkyne derivative F similar to the C-C-cross coupling reaction described in more detail for Scheme C thereby providing alkyne derivative MM.
  • the secondary amino moiety of MM may then be converted in a formylated or acylated moiety yielding compound NN by utilizing suitable reaction conditions, e.g.
  • NN happens to be a carboxylic acid ester, this may then be converted into the respective carboxylic acid by saponification.
  • compound MM may be converted into compound PP be applying reaction conditions described in more detail for Scheme F; again, saponification of the ester function, if present, provides the respective carboxylic acid.
  • the halogenated aromatic or heteroaromatic compound A is reacted with alkyne derivative PP under typical C-C-coupling reaction conditions to yield alkyne derivative QQ.
  • This is subjected to a C-N-Coupling reaction with the substituted imino- ⁇ 6-sulfanone derivative RR, e.g. in the presence of a base, for instance cesium carbonate, and a suitable catalyst like RuPhos (2- dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl and palladium(ll)acetate, to provide the oxo- ⁇ 6-sufanylidene-amino derivative SS of the present invention.
  • Alkyne derivative F and the iodo-phenyl derivative UU are subjected to a C-C- cross coupling reaction to yield alkyne derivative W having a BOC protecting group at the N-atom bearing substituent A.
  • This proctecting is subsequently removed by reacting W with an acid like hydrochloric acid to yield alkyne derivative WW of the present invention (with R 1 ⁇ OH) or alkyne derivative XX of the present invention (with R 1 being OH) if the carboxylic ester is already saponified under these conditions; otherwise saponification can be effected either before or after removing the BOC protecting group.
  • the invention relates to a combination product comprising
  • the combination product of the present invention comprises components (a) and (b) wherein (a1) the anti-PD-L1 antibody is avelumab; and (b1) the compound of formula (I) is selected from one of the particular embodiments of the compound of formula (I) described herein, i.e. PEO, PE1, PE2, PE3, PE4 and PE5.
  • the combination product of the present invention comprises components (a) and (b) wherein
  • the compound of formula (I) is 5- ⁇ 2-[5-chloro-2-(5-ethoxyquinoline-8- sulfonamido)phenyl]ethynyl ⁇ -4-methoxypyridine-2-carboxylic acid (Compound 367) or a pharmaceutically acceptable salt thereof.
  • Tumors can evade immune surveillance by exploiting signaling pathways associated with immunosuppression.
  • the immune checkpoint protein PD-L1 is commonly upregulated in tumors and signals through its receptor PD-1 to limit anti-tumor T cell responses by promoting T cell anergy and exhaustion.
  • high expression levels of the MCT4 transporter in the tumor microenviroment (TME) are associated with high extracellular lactate levels, suppression of anti-tumor T cell responses and poor prognosis in cancer.
  • MCT4 MCT4 inhibitor of formula (I) decreases or suppresses transport of intracellular lactate, thereby reducing extracellular lactacte levels and thus enhancing T cell activity in the TME and promoting the immune response to the tumor.
  • MCT4 and PD-L1 -targeting agents according to the invention are found to be complementary on T cells in combination therapy, which enhances anti-tumor activity over either therapy alone.
  • the present invention arises out of the discovery that the combination of component (a), i.e. the anti-PD-L1 antibody, in particular avelumab, and component (b), i.e. an MCT4 inhibitor of formula (I), in particular 5- ⁇ 2-[5-chloro- 2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl ⁇ -4-methoxypyridine-2- carboxylic acid (Compound 367), may effectively inhibit or diminish further tumor growth in a subject having cancer.
  • the present invention provides a method comprising administering to the subject an anti- PD-L1 antibody and an MCT4 inhibitor of formula (I) for treating a cancer in a subject in need thereof.
  • a method for treating an MCT4- positive cancer that induces an escape pathway to immune checkpoint inhibitor treatment in a subject in need thereof comprising administering to the subject an anti-PD-L1 antibody and an MCT4 inhibitor of formula (I).
  • the anti- PD-L1 antibody and the MCT4 inhibitor of formula (I) are administered in amounts that together are effective in treating cancer.
  • methods of inhibiting tumor growth or progression in a subject who has malignant cells are also provided.
  • methods of inhibiting metastasis of malignant cells in a subject are also provided.
  • the combination treatment results in an objective response, preferably a complete response or partial response in the subject.
  • the method provides an objective response rate of the patients under the treatment of at least about 20%, at least about 30%, at least about 40% or at least about 50%.
  • the objective response rate is improved in comparison to either therapy with an PD-L1 antagonist or an MCT4 inhibitor of formula (I).
  • the present invention provides a combination product comprising (a) an anti-PD-L1 antibody; and (b) a compound of formula (I).
  • the cancer is identified as PD-L1 -positive cancerous disease. In some embodiments, the cancer is identified as an MCT4-positive cancerous disease. In some embodiments, the cancer is an MCT4-positive cancer that induces an escape pathway to checkpoint inhibitor treatment. In some embodiments, the subject suffers from an MCT4-positive cancer whose MCT4 expression level exceeds an MCT4 expression level predetermined prior to administering to the subject the anti-PD-L1 antibody and/or the MCT4 inhibitor of formula (I). Pharmacodynamic analyses show that tumor expression of PD-L1 and/or MCT4 might be predictive of treatment efficacy.
  • the cancer is preferably considered to be PD-L1 positive if between at least 0.1 % and at least 10% of the cells of the cancer have PD-L1 present at their cell surface, more preferably between at least 0.5% and 5%, most preferably at least 1 %.
  • the PD-L1 expression is determined by immunohistochemistry (IHC). Immunohistochemistry with anti-PD-L1 primary antibodies can be performed on serial cuts of formalin fixed and paraffin embedded specimens from patients treated with a PD-L1 antagonist, such as avelumab, and an MCT4 inhibitor of formula (I).
  • the cancer is preferably considered to be an MCT4- positive cancer if its MCT4 level exceeds an MCT4 level predetermined prior to administering to a subject the anti-PD-L1 antibody and/or the MCT4 inhibitor of formula (I).
  • the MCT4-positive cancer shows an MCT4 expression that exceeds an MCT4 level predetermined prior to administering to the subject the anti-PD-L1 antibody and/or the MCT4 inhibitor.
  • the addition of an MCT4 inhibitor is particularly beneficial in subjects that show an increase in MCT4 expression compared to a baseline, i.e.
  • the cancer is innately resistant to cancer therapy, preferably immunotherapy, more preferably checkpoint inhibitor treatment, or the cancer was resistant or became resistant to prior cancer therapy, preferably immunotherapy, more preferably checkpoint inhibitor treatment, in each case either in part or completely.
  • upregulation of MCT4 in tumors induces a dominant immune resistant tumor environment and escape pathway to checkpoint inhibitor treatment.
  • the cancer is an MCT4-positive cancer (having upregulated MCT4 expression) that induces or provides an escape pathway to or escapes checkpoint inhibitor treatment.
  • MCT4- positive cancer suppresses checkpoint inhibitor activity. Inhibition of this pathway, in combination with checkpoint inhibitors, restores and enhances antitumor responses. MCT4 is therefore a useful predictive biomarker for the selection of patients that receive and respond to MCT4 inhibitor / anti-PD-L1 combination therapy.
  • the MCT4 inhibitor may efficiently induce immune cell stimulation and rescue the suppressed activity of anti-PD-L1 antibodies when used in combination therapy in patients with MCT4-high expressing cancers.
  • the cancer can be a metastatic or locally advanced unresectable solid tumor.
  • Specific types of cancer to be treated according to the invention include, but are not limited to, a cancer selected from malignant melanoma, acute myelogenous leukemia, soft tissue sarcoma, pancreatic, gastric, stomach, colorectal, lung, bladder, prostate, cervical, brain, liver, renal, Merkel cell carcinoma, squamous cell skin, head and neck, endometrial, esophageal, mesothelioma, breast, and ovarian cancers, and histological subtypes thereof.
  • the cancer is selected from bladder, stomach, mesothelioma, lung, renal, Merkel cell carcinoma, head and neck, ovarian, melanoma cervical, endometrial, esophageal, or breast cancer.
  • the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) can be administered in a first-line, second-line or higher treatment of the cancer.
  • the cancer is resistant to prior cancer therapy.
  • the combination therapy of the invention can also be used in the treatment of a subject with the cancer who has been previously treated with one or more chemo- or immunotherapies, or underwent radiotherapy but failed with any such previous treatment.
  • the subject to be treated is human.
  • the anti-PD-L1 antibody is used in the treatment of a human subject.
  • PD-L1 is human PD-L1.
  • the main expected benefit in the treatment with the therapeutic combination is a gain in risk/benefit ratio with said antibody, particularly avelumab, for these human patients.
  • the anti-PD-L1 antibody mediates antibody-dependent cell-mediated cytotoxicity (ADCC). Nevertheless, such ADCC-mediating anti- PD-L1 antibody is not toxic or does not show increased toxicity.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • the anti-PD-L1 antibody shows cross-reactivity in mice and rhesus monkeys. In some preferred embodiments, the anti-PD-L1 antibody is avelumab.
  • the anti-PD-L1 antibody is a monoclonal antibody. In one embodiment, the anti-PD-L1 antibody mediates antibody-dependent cell- mediated cytotoxicity (ADCC). In one embodiment, the anti-PD-L1 antibody is a human or humanized antibody. In one embodiment, the anti-PD-L1 antibody is an isolated antibody. In various embodiments, the anti-PD-L1 antibody is characterized by a combination of one or more of the foregoing features, as defined above.
  • the anti-PD-L1 antibody is administered intravenously (e.g., as an intravenous infusion) or subcutaneously.
  • the anti-PD- L1 antibody is administered as an intravenous infusion.
  • the inhibitor is administered for 50-80 minutes.
  • the anti-PD-L1 antibody is administered via intravenous infusion over 50-80 minutes, highly preferably as a one-hour intravenous infusion.
  • the anti- PD-L1 antibody is administered at a dose of about 10 mg/kg body weight every other week (i.e. , every two weeks, or“Q2W”).
  • the anti- PD-L1 antibody is administered at a dose of about 800 mg Q2W.
  • the MCT4 inhibitor of formula (I) is a dual MCT4/MCT1 inhibitor. In some aspects, the MCT4 inhibitor of formula (I) is a selective MCT4 inhibitor. In some aspects, MCT4 inhibitor of formula (I) is 5- ⁇ 2-[5-chloro-2-(5- ethoxyquinoline-8-sulfonamido)phenyl]ethynyl ⁇ -4-methoxypyridine-2- carboxylic acid (Compound 367) or a pharmaceutically acceptable salt thereof. In some embodiments, the MCT4 inhibitor of formula (I) is administered orally.
  • the MCT4 inhibitor of formula (I) is administered at a dose of about 0.01 to about 200 mg/kg twice daily (i.e., “BID”), e.g., for 3 or 4 weeks. In some embodiments, the MCT4 inhibitor of formula (I) is administered at a dose of about 0.01 mg/kg BID, 0.1 mg/kg BID, 1 mg/kg BID, 10 mg/kg BID, 100 mg/kg BID, 150 mg/kg BID or 200 mg/kg BID. In some embodiments, MCT4 inhibitor of formula (I) inhibitor is administered at a dose of about 10 to about 1000 mg twice daily (i.e. , “BID”), e.g., for 3 or 4 weeks.
  • the MCT4 inhibitor of formula (I) is administered at a dose of about 100 mg BID, 200 mg BID, 300 mg BID, 400 mg BID, 500 mg BID, 600 mg BID, 700 mg, 800 mg BID or 900 mg/kg BID.
  • the dose for the MCT4 inhibitor of formula (I) is about 0.01 to 200 mg/kg orally BID or about 100 to 900 mg orally BID, and the dose for avelumab is 10 mg/kg IV Q2W or about 800 mg Q2W.
  • the anti-PD-L1 antibody and MCT4 inhibitor of formula (I) or the combination product of the invention are used in combination with chemotherapy (CT), radiotherapy (RT) or chemoradiotherapy (CRT).
  • the chemotherapeutic agent can be etoposide, topotecan, irinotecan, fluorouracil, a platin, an anthracycline, and a combination thereof.
  • the radiotherapy can be a treatment given with electrons, photons, protons, alfa-emitters, other ions, radio-nucleotides, boron capture neutrons and combinations thereof. In some embodiments, the radiotherapy comprises about 35-70 Gy / 20-35 fractions.
  • first-line therapy is the first treatment for a disease or condition.
  • first-line therapy sometimes referred to as primary therapy or primary treatment, can be surgery, chemotherapy, radiation therapy, or a combination of these therapies.
  • a patient is given a subsequent chemotherapy regimen (second- or third-line therapy), either because the patient did not show a positive clinical outcome or only showed a sub-clinical response to a first- or second-line therapy or showed a positive clinical response but later experienced a relapse, sometimes with disease now resistant to the earlier therapy that elicited the earlier positive response.
  • second- or third-line therapy a subsequent chemotherapy regimen
  • the clinical benefit offered by the therapeutic combination of the invention warrants a first-line setting in cancer patients.
  • the combination may become a new standard treatment for patients suffering from a cancer.
  • the therapeutic combination of the invention is applied in a later line of treatment, particularly a second-line or higher treatment of the cancer.
  • a later line of treatment particularly a second-line or higher treatment of the cancer.
  • the round of prior cancer therapy refers to a defined schedule/phase for treating a subject with, e.g., one or more immunotherapeutic agents (e.g., an anti-PD-L1 antibody), chemotherapeutic agents (both including and excluding MCT4 and MCT1/4 inhibitors), radiotherapy or chemoradiotherapy, and the subject failed with such previous treatment, which was either completed or terminated ahead of schedule.
  • immunotherapeutic agents e.g., an anti-PD-L1 antibody
  • chemotherapeutic agents both including and excluding MCT4 and MCT1/4 inhibitors
  • radiotherapy or chemoradiotherapy radiotherapy or chemoradiotherapy
  • an anti-PD-L1 antibody / MCT4 inhibitor combination preferably avelumab and Compound 367, or a pharmaceutically acceptable salt thereof, may be as effective and better tolerated than SoC chemotherapy in patients with cancer resistant to mono- and/or poly-chemotherapy, radiotherapy or chemoradiotherapy.
  • the dosing regimen will comprise administering the anti-PD-L1 antibody, preferably avelumab, at a dose of about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg/kg at intervals of about 14 days ( ⁇ 2 days) or about 21 days ( ⁇ 2 days) or about 30 days ( ⁇ 2 days) throughout the course of treatment.
  • the dosing regimen will comprise administering the anti-PD-L1 antibody at a dose of from about 0.005 mg/kg to about 10 mg/kg, with intra-patient dose escalation.
  • the interval between doses will be progressively shortened, e.g., about 30 days ( ⁇ 2 days) between the first and second dose, about 14 days ( ⁇ 2 days) between the second and third doses.
  • the dosing interval will be about 14 days ( ⁇ 2 days), for doses subsequent to the second dose.
  • a subject will be administered an intravenous (IV) infusion of a medicament comprising any of the anti-PD-L1 antibody described herein.
  • the anti-PD-L1 antibody in the combination therapy is avelumab, which is administered in a liquid medicament at a dose selected from the group consisting of about 1 mg/kg Q2W, about 2 mg/kg Q2W, about 3 mg/kg Q2W, about 5 mg/kg Q2W, about 10 mg Q2W, about 1 mg/kg Q3W, about 2 mg/kg Q3W, about 3 mg/kg Q3W, about 5 mg/kg Q3W, and about 10 mg Q3W.
  • a treatment cycle begins with the first day of combination treatment and last for 2 weeks.
  • the combination therapy (and the combination product of the invention) is preferably administered for at least 12 weeks (6 cycles of treatment), more preferably at least 24 weeks, and even more preferably at least 2 weeks after the patient achieves a CR.
  • avelumab is administered as a flat dose of about 80, 150, 160, 200, 240, 250, 300, 320, 350, 400, 450, 480, 500, 550, 560, 600, 640, 650, 700, 720, 750, 800, 850, 880, 900, 950, 960, 1000, 1040, 1050, 1100, 1120, 1150, 1200, 1250, 1280, 1300, 1350, 1360, 1400, 1440, 1500, 1520, 1550 or 1600 mg, preferably 800 mg, 1200 mg or 1600 mg at intervals of about 14 days ( ⁇ 2 days) or about 21 days ( ⁇ 2 days) or about 30 days ( ⁇ 2 days) throughout the course of treatment.
  • the anti-PD-L1 antibody preferably avelumab
  • the anti-PD-L1 antibody will be given IV every two weeks.
  • the anti-PD-L1 antibody is administered intravenously for 50-80 minutes at a dose of about 10 mg/kg body weight every two weeks.
  • the avelumab dose will be 10 mg/kg body weight administered as 1-hour intravenous infusions every 2 weeks (Q2W). Given the variability of infusion pumps from site to site, a time window of minus 10 minutes and plus 20 minutes is permitted. Pharmacokinetic studies demonstrated that the 10 mg/kg dose of avelumab achieves excellent receptor occupancy with a predictable pharmacokinetics profile (see e.g., Heery et al. (2015) Proc ASCO Annual Meeting: abstract 3055). This dose is well tolerated, and signs of antitumor activity, including durable responses, have been observed. Avelumab may be administered up to 3 days before or after the scheduled day of administration of each cycle due to administrative reasons.
  • provided methods comprise administering a pharmaceutically acceptable composition comprising the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof, one, two, three or four times a day.
  • a pharmaceutically acceptable composition comprising the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered once daily (“QD” or “qd”), particularly continuously.
  • a pharmaceutically acceptable composition comprising the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered twice daily, particularly continuously.
  • twice daily administration refers to a compound or composition that is administered “BID”, or two equivalent doses administered at two different times in one day.
  • a pharmaceutically acceptable composition comprising the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered three times a day.
  • a pharmaceutically acceptable composition comprising Compound 367, or a pharmaceutically acceptable salt thereof is administered “TID”, or three equivalent doses administered at three different times in one day.
  • a pharmaceutically acceptable composition comprising the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered four times a day.
  • a pharmaceutically acceptable composition comprising Compound 367, or a pharmaceutically acceptable salt thereof, is administered “QID”, or four equivalent doses administered at four different times in one day.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered to a patient under fasted conditions and the total daily dose is any of those contemplated above and herein.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered to a patient under fed conditions and the total daily dose is any of those contemplated above and herein.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered orally.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof will be given orally twice daily.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered twice daily (BID), at a dose of about 0.01 to about 1000 mg/kg, particularly at a dose of about 0.01 to about 200 mg/kg.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered twice daily (BID), at a dose of about 10 to about 1000 mg, particularly at a dose of about 100 to about 900 mg.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered twice daily (BID) for 3 to 4 weeks, at a dose of about 0.01 to about 1000 mg/kg, particularly at a dose of about 0.01 to about 200 mg/kg.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is administered twice daily (BID) for 3 to 4 weeks, at a dose of about 10 to about 1000 mg, particularly at a dose of about 100 to about 900 mg.
  • the invention provides a method treatment, as described above, further comprising an additional step of administering to said patient an additional therapeutic agent that is selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating neurogenerative diseases, an agent for treating metabolic disoriders and diseases, such as diabetes, an anti-viral agent, an agent for treating blood disorders, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease being treated.
  • an additional therapeutic agent that is selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating neurogenerative diseases, an agent for treating metabolic disoriders and diseases, such as diabetes, an anti-viral agent, an agent for treating blood disorders,
  • the anti- PD-L1 antibody and the MCT4 inhibitor of formula (I) are administered in combination with chemotherapy (CT), radiotherapy (RT), or chemotherapy and radiotherapy (CRT).
  • CT chemotherapy
  • RT radiotherapy
  • CRT chemotherapy and radiotherapy
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with PD-L1 and MCT4 comprising administering to a patient in need thereof an anti-PD-L1 antibody and an MCT4 inhibitor of formula (I) in combination with an additional chemotherapeutic agent.
  • the chemotherapeutic agent is selected from the group of etoposide, topotecan, irinotecan, fluorouracil, a platin, an anthracycline, and a combination thereof. In certain embodiments, the chemotherapeutic agent is selected from the group of inhibitors of MCT1 and/or 2, such as AZD3965 and BAY-8002.
  • the additional chemotherapeutic agent is topotecan, etoposide and/or antracycline treatment, either as single cytostatic agent or as part of a doublet or triplet regiment.
  • the MCT4 inhibitor of formula (I) can be preferably given once or twice daily with the anti- PD-L1 antibody, particularly avelumab, which is given every second week.
  • the treatment with anthracycline is stopped once a maximal life-long accumulative dose has been reached (due to the cardiotoxicity).
  • the additional chemotherapeutic agent is a platin.
  • Platins are platinum-based chemotherapeutic agents.
  • the term “platin” is used interchangeably with the term “platinating agent.” Platinating agents are well known in the art.
  • the platin (or platinating agent) is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, and satraplatin.
  • the additional chemotherapeutic is a combination of both of etoposide and a platin.
  • the platin is cisplatin.
  • the provided method further comprises administration of radiation therapy to the patient.
  • the additional chemotherapeutic is a combination of both of etoposide and cisplatin.
  • the additional therapeutic agent is selected from daunomycin, doxorubicin, epirubicin, idarubicin, valrubicin, mitoxantrone, paclitaxel, docetaxel and cyclophosphamide.
  • the additional therapeutic agent is selected from a CTLA4 agent (e.g., ipilimumab (BMS)); GITR agent (e.g., MK-4166 (MSD)); vaccines (e.g., sipuleucel-t (Dendron); or a SoC agent (e.g., radiation, docetaxel, temozolomide (MSD), gemcitibine or paclitaxel).
  • the additional therapeutic agent is an immune enhancer such as a vaccine, immune-stimulating antibody, immunoglobulin, agent or adjuvant including, but not limited to, sipuleucel-t, BMS-663513 (BMS), CP-870893 (Pfizer/VLST), anti-OX40 (AgonOX), or CDX-1127 (CellDex).
  • an immune enhancer such as a vaccine, immune-stimulating antibody, immunoglobulin, agent or adjuvant including, but not limited to, sipuleucel-t, BMS-663513 (BMS), CP-870893 (Pfizer/VLST), anti-OX40 (AgonOX), or CDX-1127 (CellDex).
  • cancer therapies or anti-cancer agents that may be used in combination with the inventive agents of the present invention include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, low-dose radiotherapy, and systemic radioactive isotopes), immune response modifiers such as chemokine receptor antagonists, chemokines and cytokines (e.g., interferons, interleukins, tumor necrosis factor (TNF), and GM-CSF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g. antimetics, steroids, anti-inflammatory agents), and other approved chemotherapeutic drugs.
  • radiotherapy e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, low-dose radiotherapy, and systemic radioactive isotopes
  • immune response modifiers such as chemokine receptor antagonists, chemokines and
  • the additional therapeutic agent is selected from an antibiotic, a vasopressor, a steroid, an inotrope, an anti-thrombotic agent, a sedative, opioids or an anesthetic.
  • the additional therapeutic agent is selected from cephalosporins, macrolides, penams, beta-lactamase inhibitors, aminoglycoside antibiotics, fluoroquinolone antibiotics, glycopeptide antibiotics, penems, monobactams, carbapenmems, nitroimidazole antibiotics, lincosamide antibiotics, vasopressors, positive inotropic agents, steroids, benzodiazepines, phenol, alpha2-adrenergic receptor agonists, GABA-A receptor modulators, anti-thrombotic agents, anesthetics or opiods.
  • the MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof, and compositions thereof in combination with the anti-PD-L1 antibody and additional chemotherapeutic according to methods of the present invention, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above.
  • 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 infection, the particular agent, its mode of administration, and the like.
  • provided methods comprise administering a pharmaceutically acceptable composition comprising a chemotherapeutic agent one, two, three or four times a day.
  • a pharmaceutically acceptable composition comprising a chemotherapeutic agent is administered once daily (“QD”).
  • a pharmaceutically acceptable composition comprising a chemotherapeutic agent is administered twice daily.
  • twice daily administration refers to a compound or composition that is administered “BID”, or two equivalent doses administered at two different times in one day.
  • a pharmaceutically acceptable composition comprising a chemotherapeutic agent is administered three times a day.
  • a pharmaceutically acceptable composition comprising a chemotherapeutic agent is administered “TID”, or three equivalent doses administered at three different times in one day.
  • a pharmaceutically acceptable composition comprising a chemotherapeutic agent is administered four times a day.
  • a pharmaceutically acceptable composition comprising a chemotherapeutic agent is administered “QID”, or four equivalent doses administered at four different times in one day.
  • a pharmaceutically acceptable composition comprising a chemotherapeutic agent is administered for a various number of days (for example 14, 21 , 28) with a various number of days between treatment (0, 14, 21 , 28).
  • a chemotherapeutic agent is administered to a patient under fasted conditions and the total daily dose is any of those contemplated above and herein. In some embodiments, a chemotherapeutic agent is administered to a patient under fed conditions and the total daily dose is any of those contemplated above and herein. In some embodiments, a chemotherapeutic agent is administered orally for reasons of convenience. In some embodiments, when administered orally, a chemotherapeutic agent is administered with a meal and water. In another embodiment, the chemotherapeutic agent is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.
  • water or juice e.g., apple juice or orange juice
  • a chemotherapeutic agent when administered orally, is administered in a fasted state.
  • a chemotherapeutic agent can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the healthcare practitioner, and can depend in-part upon the site of the medical condition.
  • the anti-PD-L1 antibody and the MCT inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof are administered in combination with radiotherapy.
  • the radiotherapy comprises about 35-70 Gy / 20-35 fractions.
  • the radiotherapy is given either with standard fractionation (1 .8 to 2 Gy for day 5 days a week) up to a total dose of 50-70 Gy in once daily.
  • Other fractionation schedules could also be envisioned, for example, a lower dose per fraction but given twice daily with the MCT inhibitor of formula (I) given also twice daily. Higher daily doses over a shorter period of time can also be given.
  • stereotactic radiotherapy as well as the gamma knife are used.
  • avelumab is preferably given every second week.
  • the duration of treatment will be the time frame when radiotherapy is given.
  • the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) are administered simultaneously, separately or sequentially and in any order.
  • the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) are administered to the patient in any order (i.e. , simultaneously or sequentially) in separate compositions, formulations or unit dosage forms, or together in a single composition, formulation or unit dosage form.
  • a method of treating a proliferative disease may comprise administration of a combination of an MCT4 inhibitor of formula (I) and an anti PD-L1 antibody, wherein the individual combination partners are administered simultaneously or sequentially in any order, in jointly therapeutically effective amounts, (for example in synergistically effective amounts), e.g.
  • the individual combination partners of a combination therapy of the invention may be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the first active component which is at least one MCT4 inhibitor of formula (I), and the anti-PD-L1 antibody are formulated into separate pharmaceutical compositions or medicaments.
  • the at least two active components can be administered simultaneously or sequentially, optionally via different routes.
  • the treatment regimens for each of the active components in the combination have different but overlapping delivery regimens, e.g., daily, twice daily, vs. a single administration, or weekly.
  • the second active component may be delivered prior to, substantially simultaneously with, or after, the at least one MCT4 inhibitor of formula (I).
  • the anti-PD-L1 antibody is administered simultaneously in the same composition comprising the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I).
  • the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) are administered simultaneously in separate compositions, i.e. , wherein the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) are administered simultaneously each in a separate unit dosage form.
  • the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) are administered on the same day or on different days and in any order as according to an appropriate dosing protocol.
  • the instant invention is therefore to be understood as embracing all such regimens of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly.
  • the method comprises the steps of: (a) under the direction or control of a physician, the subject receiving the PD-L1 antibody prior to first receipt of the MCT4 inhibitor of formula (I); and (b) under the direction or control of a physician, the subject receiving the MCT4 inhibitor of formula (I). In some embodiments, the method comprises the steps of: (a) under the direction or control of a physician, the subject receiving the MCT4 inhibitor of formula (I) prior to first receipt of the PD-L1 antibody; and (b) under the direction or control of a physician, the subject receiving the PD-L1 antibody.
  • the method comprises the steps of: (a) prescribing the subject to self-administer, and verifying that the subject has self-administered, the PD-L1 antibody prior to first administration of the MCT4 inhibitor of formula (I); and (b) administering the MCT4 inhibitor of formula (I) to the subject.
  • the method comprises the steps of: (a) prescribing the subject to self-administer, and verifying that the subject has self-administered, the MCT4 inhibitor of formula (I) prior to first administration of the PD-L1 antibody; and (b) administering the PD-L1 antibody to the subject.
  • the method comprises, after the subject has received the PD- L1 antibody prior to the first administration of the MCT4 inhibitor of formula (I), administering the MCT4 inhibitor of formula (I) to the subject.
  • the method comprises the steps of: (a) after the subject has received the PD-L1 antibody prior to the first administration of the MCT4 inhibitor of formula (I), determining that an MCT4 level in a cancer sample isolated from the subject exceeds an MCT4 level predetermined prior to the first receipt of the anti-PD-L1 antibody, and (b) administering the MCT4 inhibitor of formula (I) to the subject.
  • the method comprises the steps of: (a) after the subject has received prior cancer therapy and/or the PD-L1 antibody prior to the first administration of the MCT4 inhibitor of formula (I), determining that an MCT4 level in a cancer sample isolated from the subject exceeds an MCT4 level predetermined prior to the first receipt of the prior cancer therapy and/or the anti-PD-L1 antibody, and (b) administering the MCT4 inhibitor of formula (I) to the subject.
  • the method comprises, after the subject has received the MCT4 inhibitor of formula (I) prior to first administration of the anti-PD-L1 antibody, administering the anti-PD-L1 antibody to the subject.
  • the invention relates to a method for predicting the likelihood that a subject suffering from a cancer, which is a candidate for treatment with an anti-PD-L1 antibody and an MCT4 inhibitor of formula (I), will respond to the treatment, comprising determining the MCT4 expression, e.g., by means of Western Blot analysis, immunostaining (immunohistochemistry, IHC) or determining MCT4 mRNA within a cell or tissue (utilizing techniques like RT-PCR and real-time quantitative RT-PCR) in a sample obtained from the subject, wherein a higher expression, as compared to a predetermined value, indicates that the subject is likely to respond to the treatment.
  • determining the MCT4 expression e.g., by means of Western Blot analysis, immunostaining (immunohistochemistry, IHC) or determining MCT4 mRNA within a cell or tissue (utilizing techniques like RT-PCR and real-time quantitative RT-PCR) in a sample obtained from the subject, wherein a higher expression
  • the method is particularly suited to predict the likelihood that a subject suffering from an MCT4-positive cancer, which induces an escape pathway to checkpoint inhibitor treatment and is a candidate for treatment with an anti-PD- L1 antibody and an MCT4 inhibitor of formula (I) will respond to the treatment.
  • compositions comprising an anti-PD- L1 antibody, an MCT4 inhibitor of formula (I), i.e. a combination product of the present invention, and at least a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) can be provided in a single or separate unit dosage forms.
  • a composition comprising an anti-PD-L1 antibody for use in the treatment of an MCT4-positive cancer that induces an escape pathway to checkpoint inhibitor treatment, wherein the composition is administered in combination with an MCT4 inhibitor of formula (I).
  • a composition comprising an MCT4 inhibitor of formula (I) for use in the treatment of an MCT4-positive cancer that induces an escape pathway to checkpoint inhibitor treatment, wherein the composition is administered in combination with an anti-PD-L1 antibody.
  • an anti-PD-L1 antibody in combination with an MCT4 inhibitor of formula (I) for use as a medicament, particularly for use in the treatment of cancer.
  • an MCT4 inhibitor of formula (I) is provided in combination with an anti-PD-L1 antibody for use as a medicament, particularly for use in the treatment of cancer.
  • a combination comprising an anti-PD-L1 antibody and an MCT4 inhibitor of formula (I), for any purpose, for use as a medicament (i.e. , a combination for use as a medicament, comprising an anti-PD-L1 antibody and an MCT4 inhibitor of formula (I)), or in the treatment of cancer.
  • the combination of the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) can be provided in a single or separate unit dosage forms. Also provided is the use of a combination for the manufacture of a medicament for the treatment of cancer, comprising an anti-PD-L1 antibody and an MCT4 inhibitor of formula (I). Also provided herein is a combination for use in the treatment of an MCT4-positive cancer that induces an escape pathway to checkpoint inhibitor treatment, comprising an anti-PD- L1 antibody and an MCT4 inhibitor of formula (I).
  • the invention relates in one aspect to a combination product comprising (a) an anti-PD-L1 antibody, preferably avelumab, and (b) an MCT4 inhibitor of formula (I).
  • This combination product may be in any form suitable for any of its intended uses, e.g., in utilizing it in a treatment method of the invention.
  • the combination product of the invention is a single product (single unit dosage form) containing both components (a) and (b).
  • the combination product of the invention is provided in separate unit dosage forms thereby allowing concomitant or sequential administering of the different components of the combination product.
  • the invention relates to a kit comprising (x) an anti-PD-L1 antibody and (z) a package insert comprising instructions for using the anti- PD-L1 antibody in combination with (y) an MCT4 inhibitor of formula (I) to treat or delay progression of a cancer in a subject. Also provided is a kit comprising an MCT4 inhibitor of formula (I) and a package insert comprising instructions for using the MCT4 inhibitor of formula (I) in combination with an anti-PD-L1 antibody to treat or delay progression of a cancer in a subject.
  • kits comprising (x) an anti-PD-L1 antibody and (y) MCT4 inhibitor of formula (I), and (z) a package insert comprising instructions for using the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) to treat or delay progression of a cancer in a subject.
  • the kit can comprise a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising an anti-PD-L1 antibody, the second container comprises at least one dose of a medicament comprising an MCT4 inhibitor of formula (I), and the package insert comprises instructions for treating the subject for cancer using the medicaments.
  • the instructions can state that the medicaments are intended for use in treating a subject having a cancer that tests positive for PD-L1 and/or MCT4 expression, e.g., by an immunohistochemical (IHC) assay, Western Blot analysis, mRNA determination, FACS or LC/MS/MS.
  • the kit is suited to treat and delay progression of an MCT4-positive cancer that induces an escape pathway to checkpoint inhibitor treatment.
  • the instructions can state that the medicaments are intended for use in treating a subject having a cancer that tests positive for PD-L1 expression, e.g., by an immunohistochemical (IHC) assay.
  • the present invention provides a pharmaceutically acceptable composition comprising an anti-PD-L1 antibody.
  • the present invention provides a pharmaceutically acceptable composition comprising an MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutically acceptable composition of a chemotherapeutic agent.
  • the present invention provides a pharmaceutical composition comprising an anti-PD-L1 antibody, MCT4 inhibitor of formula (I) and at least a pharmaceutically acceptable excipient or adjuvant.
  • the aforementioned pharmaceutical compositions of the anti-PD-L1 antibody and the MCT4 inhibitor of formula (I) are provided in a single or separate unit dosage forms.
  • the anti-PD-L1 antibody is avelumab.
  • a composition comprising an MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof is separate from a composition comprising an anti-PD-L1 antibody, preferably avelumab, and/or a chemotherapeutic agent.
  • an MCT4 inhibitor of formula (I), preferably Compound 367, or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody, preferably avelumab, and/or a chemotherapeutic agent are present in the same composition. Exemplary pharmaceutically acceptable compositions are described further below and herein.
  • the invention provides a composition comprising an MCT4 inhibitor of formula (I) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the amount of MCT4 inhibitor of formula (I) in compositions of this invention is such that is effective to modulate MCT4 in a biological sample or in a patient.
  • the amount of the MCT4 inhibitor of formula (I) in compositions of this invention is such that is effective to modulate MCT4 in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances 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, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate
  • compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • compositions of the MCT4 inhibitor of formula (I) are formulated for oral administration. Such formulations may be administered with or without food.
  • the anti-PD-L1 antibodies (or antigen-binding fragments) according to the invention preferably avelumab
  • the pharmaceutical composition comprises the anti-PD-L1 antibodies or antigen- binding fragments thereof, preferably avelumab, and a pharmaceutically acceptable carrier.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the anti-PD-L1 antibodies or antigen-binding fragments thereof.
  • compositions of the present invention as well as the combination products of the invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., dispersions or suspensions
  • tablets, pills, powders, liposomes, and suppositories e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., dispersions or suspensions
  • tablets e.g., pills, powders, liposomes, and suppositories.
  • Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans.
  • the preferred mode of administration is parenter
  • the anti-PD-L1 antibody or antigen-binding fragment thereof is administered by intravenous infusion or injection.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof, preferably avelumab is administered by intramuscular or subcutaneous injection.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration.
  • Sterile injectable solutions can be prepared by incorporating the active anti-PD-L1 antibody or antigen-binding fragment thereof in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active ingredient into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • avelumab is a sterile, clear, and colorless solution intended for IV administration.
  • the contents of the avelumab vials are non- pyrogenic, and do not contain bacteriostatic preservatives.
  • Avelumab is formulated as a 20 mg/mL solution and is supplied in single-use glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off seal.
  • avelumab must be diluted with 0.9% sodium chloride (normal saline solution).
  • Tubing with in-line, low protein binding 0.2 micron filter made of polyether sulfone (PES) is used during administration.
  • “About” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 10 mg/kg may vary between 9 mg/kg and 11 mg/kg.
  • administering or “administration of” a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self- administration, and/or indirect administration, which may be the act of prescribing a drug.
  • direct administration which may be administration to a patient by a medical professional or may be self- administration
  • indirect administration which may be the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drug or provides a patient with a prescription for a drug is administering the drug to the patient.
  • Antibody is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
  • a target such as a carbohydrate, polynucleotide, lipid, polypeptide, etc.
  • the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen-binding fragment or antibody fragment thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen-binding portion (e.g., antibody- drug conjugates), any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site, and antibody compositions with poly- epitopic specificity.
  • Antibody-dependent cell-mediated cytotoxicity refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins.
  • the antibodies arm the cytotoxic cells and are required for killing of the target cell by this mechanism.
  • the primary cells for mediating ADCC the NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII.
  • Fc expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991 ).
  • Biomarker generally refers to biological molecules, and quantitative and qualitative measurements of the same, that are indicative of a disease state. “Prognostic biomarkers” correlate with disease outcome, independent of therapy. For example, tumor hypoxia is a negative prognostic marker - the higher the tumor hypoxia, the higher the likelihood that the outcome of the disease will be negative. “Predictive biomarkers” indicate whether a patient is likely to respond positively to a particular therapy. E.g., FIER2 profiling is commonly used in breast cancer patients to determine if those patients are likely to respond to Flerceptin (trastuzumab, Genentech). “Response biomarkers” provide a measure of the response to a therapy and so provide an indication of whether a therapy is working.
  • decreasing levels of prostate-specific antigen generally indicate that anti-cancer therapy for a prostate cancer patient is working.
  • the marker can be measured before and/or during treatment, and the values obtained are used by a clinician in assessing any of the following: (a) probable or likely suitability of an individual to initially receive treatment(s); (b) probable or likely unsuitability of an individual to initially receive treatment(s); (c) responsiveness to treatment; (d) probable or likely suitability of an individual to continue to receive treatment(s); (e) probable or likely unsuitability of an individual to continue to receive treatment(s); (f) adjusting dosage; (g) predicting likelihood of clinical benefits; or (h) toxicity.
  • measurement of a biomarker in a clinical setting is a clear indication that this parameter was used as a basis for initiating, continuing, adjusting and/or ceasing administration of the treatments described herein.
  • Blood refers to all components of blood circulating in a subject including, but not limited to, red blood cells, white blood cells, plasma, clotting factors, small proteins, platelets and/or cryoprecipitate. This is typically the type of blood which is donated when a human patient gives blood. Plasma is known in the art as the yellow liquid component of blood, in which the blood cells in whole blood are typically suspended. It makes up about 55% of the total blood volume. Blood plasma can be prepared by spinning a tube of fresh blood containing an anti-coagulant in a centrifuge until the blood cells fall to the bottom of the tube. The blood plasma is then poured or drawn off. Blood plasma has a density of approximately 1025 kg/m 3 or 1 .025 kg/I.
  • Cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • Examples of cancer include but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma.
  • cancers include squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, hodgkin's lymphoma, non- hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, Merkel cell carcinoma (MCC), and head and neck cancer.
  • MCC Merkel cell carcinoma
  • Checkpoint inhibitors refer to a type of immunotherapy that help the immune system respond more strongly to a tumor. These drugs do not target the tumor directly but interfere with the ability of cancer cells to avoid immune system attack, thereby releasing brakes that keep T cells (a type of white blood cell and part of the immune system) from killing cancer cells.
  • Non-limiting examples of checkpoint inhibitors are immune checkpoint inhibitors, such as antibodies against CTLA-4, PD-1 (e.g., nivolumab) or PD-L1 (e.g., atezolizumab, durvalumab, and avelumab).
  • Cyhemotherapy is a therapy involving a chemotherapeutic agent, which is a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphor- amide, and trimethylolomelamine; MCT1 and/or MCT1/2 and/or MCT1/4 inhibitors, such as AZD3965, BAY-8002, diclofenac, and syrosingopine; acetogenins (especially bullatacin and bullatacinone); delta-9- tetrahydrocannabinol (dronabinol); beta-lapachone; lapachol; colchicines; betulinic
  • Combination or “combination product” as used herein refers to the provision of a first active modality in addition to another active modality.
  • any modalities within a single composition, formulation or unit dosage form i.e., a fixed-dose combination
  • the combined modalities can be manufactured and/or formulated by the same or different manufacturers.
  • the combination partners may thus be, e.g., entirely separate pharmaceutical dosage forms or pharmaceutical compositions that are also sold independently of each other.
  • Combination therapy in combination with or “in conjunction with” as used herein denotes any form of concurrent, parallel, simultaneous, sequential or intermittent treatment with at least two distinct treatment modalities (i.e., compounds, components, targeted agents or therapeutic agents).
  • the terms refer to administration of one treatment modality before, during, or after administration of the other treatment modality to the subject.
  • the modalities in combination can be administered in any order.
  • the therapeutically active modalities are administered together (e.g., simultaneously in the same or separate compositions, formulations or unit dosage forms) or separately (e.g., on the same day or on different days and in any order as according to an appropriate dosing protocol for the separate compositions, formulations or unit dosage forms) in a manner and dosing regimen prescribed by a medical care taker or according to a regulatory agency.
  • each treatment modality will be administered at a dose and/or on a time schedule determined for that treatment modality.
  • three or more modalities may be used in a combination therapy.
  • the combination therapies provided herein may be used in conjunction with other types of treatment.
  • other anti-cancer treatment may be selected from the group consisting of chemotherapy, immunotherapy, surgery, radiotherapy (radiation) and/or hormone therapy, amongst other treatments associated with the current standard of care for the subject.
  • compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the composition or method.
  • Consisting of shall mean excluding more than trace elements of other ingredients for claimed compositions and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention. Accordingly, it is intended that the methods and compositions can include additional steps and components (comprising) or alternatively including steps and compositions of no significance (consisting essentially of) or alternatively, intending only the stated method steps or compositions (consisting of).
  • Dose and “dosage” refer to a specific amount of active or therapeutic agents for administration. Such amounts are included in a “dosage form,” which refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active agent calculated to produce the desired onset, tolerability, and therapeutic effects, in association with one or more suitable pharmaceutical excipients such as carriers.
  • Enhancing T-cell function means to induce, cause or stimulate a T-cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T-cells.
  • enhancing T-cell function include: increased secretion of interferon-gamma, IL-2, TNFalpha from CD8+ T-cells, increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention.
  • the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 1 20%, 150%, 200%. The manner of measuring this enhancement is known to one of ordinary skill in the art.
  • Fc is a fragment comprising the carboxy-terminal portions of both FI chains held together by disulfides.
  • the effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain cell types.
  • Fully fragments of the antibodies of the invention comprise a portion of an intact antibody, generally including the antigen-binding or variable region of the intact antibody or the Fc region of an antibody which retains or has modified FcR binding capability.
  • functional antibody fragments include linear antibodies, single-chain antibody molecules, and multi-specific antibodies formed from antibody fragments.
  • Fv is the minimum antibody fragment, which contains a complete antigen- recognition and antigen-binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the FI and L chain) that contribute the amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. Flowever, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • Human antibody is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • Human antibodies can be produced using various techniques known in the art, including phage- display libraries (see e.g., Hoogenboom and Winter (1991 ), JMB 227: 381 ; Marks et al. (1991 ) JMB 222: 581 ). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al. (1985) Monoclonal Antibodies and Cancer Therapy, Alan R.
  • Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge but whose endogenous loci have been disabled, e.g., immunized xenomice (see e.g., U.S. Pat. Nos. 6,075,181 ; and 6,150,584 regarding XENOMOUSE technology). See also, for example, Li et al. (2006) PNAS USA, 103: 3557, regarding human antibodies generated via a human B-cell hybridoma technology.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and/or capacity.
  • donor antibody such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and/or capacity.
  • framework (“FR") residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc.
  • the number of these amino acid substitutions in the FR are typically no more than 6 in the FI chain, and no more than 3 in the L chain.
  • the humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Ig immunoglobulin
  • the basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (FI) chains.
  • An IgM antibody consists of 5 of the basic heterotetramer units along with an additional polypeptide called a J chain, and contains 10 antigen binding sites, while IgA antibodies comprise from 2-5 of the basic 4-chain units which can polymerize to form polyvalent assemblages in combination with the J chain.
  • the 4-chain unit is generally about 150,000 Daltons.
  • Each L chain is linked to an FI chain by one covalent disulfide bond, while the two FI chains are linked to each other by one or more disulfide bonds depending on the FI chain isotype.
  • Each FI and L chain also has regularly spaced intra-chain disulfide bridges.
  • Each FI chain has, at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the a and g chains and four CH domains for m and e isotypes.
  • Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain at its other end. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (CH1 ).
  • immunoglobulins There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, having heavy chains designated a, d, e, g and m, respectively.
  • the g and a classes are further divided into subclasses on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: lgG1 , lgG2A, lgG2B, lgG3, lgG4, lgA1 , and lgK1.
  • Immunotherapy refers to the treatment of a subject by a method comprising inducing, enhancing, suppressing, or otherwise modifying an immune response, including checkpoint inhibitor treatment.
  • “Infusion” or “infusing” refers to the introduction of a drug-containing solution into the body through a vein for therapeutic purposes. Generally, this is achieved via an intravenous bag.
  • isolated refers to molecules or biological or cellular materials being substantially free from other materials.
  • the term “isolated” refers to nucleic acid, such as DNA or RNA, or protein or polypeptide, or cell or cellular organelle, or tissue or organ, separated from other DNAs or RNAs, or proteins or polypeptides, or cells or cellular organelles, or tissues or organs, respectively, that are present in the natural source.
  • isolated also refers to a nucleic acid or peptide that is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.
  • an “isolated nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state.
  • isolated is also used herein to refer to polypeptides which are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides.
  • isolated is also used herein to refer to cells or tissues that are isolated from other cells or tissues and is meant to encompass both cultured and engineered cells or tissues.
  • an "isolated antibody” is one that has been identified, separated and/or recovered from a component of its production environment (e.g., natural or recombinant).
  • the isolated polypeptide is free of association with all other components from its production environment.
  • Contaminant components of its production environment such as that resulting from recombinant transfected cells, are materials that would typically interfere with research, diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.
  • the polypeptide will be purified: (1 ) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (1 ) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS- PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain.
  • the “isolated antibody” includes the antibody in-situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, an isolated polypeptide or antibody will be prepared by at least one purification step.
  • MCT4 expression means any detectable level of expression of MCT4 protein or of MCT4 mRNA within a cell or tissue, in particular in the cell membrane (plasma membrane). MCT4 protein expression may be detected by various methods, e.g., detection with an MCT4 specific antibody in an IHC assay of a tumor tissue section (T. A. Adams, et al. , Modern Pathology (2016) 31 , 288-298; A. K. Witkiewicz, et al., Cell Cycle 11 :6 11 OS- 1117 (2012)); or Western blot analysis (K. Renner, et al., 2019, Cell Reports 29, 135-150; A.
  • Techniques for detecting and measuring MCT4 mRNA expression include RT-PCR and real- time quantitative RT-PCR.
  • MCT4 inhibitor refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of the gene encoding for MCT4 and/or the expression of MCT4 and/or the biological activity of MCT4.
  • MCT4-positive cancer including a “MCT4-positive” cancerous disease, is one comprising cells, which have MCT4 present in their cells (in particular in their cell membrane).
  • MCT4-positive also refers to a cancer that produces sufficient levels of MCT4 in the cells thereof, such that an MCT4 inhibitor has a therapeutic effect, mediated by the binding of the said MCT4 inhibitor to MCT4.
  • Metalstatic cancer refers to cancer which has spread from one part of the body (e.g., the lung) to another part of the body.
  • “Monoclonal antibody”, as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. , the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translation modifications (e.g., isomerizations and amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture and uncontaminated by other immunoglobulins.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler and Milstein (1975) Nature 256: 495; Hongo et al. (1995) Hybridoma 14 (3): 253; Harlow et al.
  • the monoclonal antibodies herein specifically include chimeric antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is (are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see e.g., U.S. Patent No. 4,816,567; Morrison et al. (1984) PNAS USA, 81 : 6851 ).
  • Objective response refers to a measurable response, including complete response (CR) or partial response (PR).
  • a “patient” and “subject” are used interchangeably herein to refer to a mammal in need of treatment for a cancer. Generally, the patient is a human diagnosed or at risk for suffering from one or more symptoms of a cancer. In certain embodiments a “patient” or “subject” may refer to a non-human mammal, such as a non-human primate species, a dog, cat, rabbit, pig, cow; rodents, including mouse, rat or hamster, or animals used in screening, characterizing, and evaluating drugs and therapies.
  • a non-human mammal such as a non-human primate species, a dog, cat, rabbit, pig, cow
  • rodents including mouse, rat or hamster, or animals used in screening, characterizing, and evaluating drugs and therapies.
  • PD-L1 expression as used herein means any detectable level of expression of PD-L1 protein on the cell surface or of PD-L1 mRNA within a cell or tissue.
  • PD-L1 protein expression may be detected with a diagnostic PD-L1 antibody in an IHC assay of a tumor tissue section or by flow cytometry.
  • PD-L1 protein expression by tumor cells may be detected by PET imaging, using a binding agent (e.g., antibody fragment, affibody and the like) that specifically binds to PD-L1.
  • a binding agent e.g., antibody fragment, affibody and the like
  • Techniques for detecting and measuring PD-L1 mRNA expression include RT-PCR and real-time quantitative RT-PCR.
  • “PD-L1 -positive” cancer is one comprising cells, which have PD-L1 present at their cell surface.
  • the term “PD-L1 -positive” also refers to a cancer that produces sufficient levels of PD- L1 at the surface of cells thereof, such that an anti-PD-L1 antibody has a therapeutic effect, mediated by the binding of the said anti-PD-L1 antibody to PD-L1 .
  • “Pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprised in a formulation, and/or the mammal being treated therewith. In other words, the substance or composition must be chemically and/or toxicologically suitable for the treatment of mammals.
  • “Pharmaceutically acceptable adjuvant” refers to any and all substances which enhance the body’s immune response to an antigen.
  • Non-limiting examples of pharmaceutically acceptable adjuvants are: Alum, Freund’s Incomplete Adjuvant, MF59, synthetic analogs of dsRNA such as poly(l:C), bacterial LPS, bacterial flagellin, imidazolquinolines, oligodeoxynucleotides containing specific CpG motifs, fragments of bacterial cell walls such as muramyl dipeptide and Quil-A ® .
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable diluent” means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, compatible with pharmaceutical administration.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and, without limiting the scope of the present invention, include: additional buffering agents; preservatives; co-solvents; antioxidants, including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; salt-forming counterions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinis
  • compositions described herein may also be included in a pharmaceutical composition described herein, provided that they do not adversely affect the desired characteristics of the pharmaceutical composition.
  • Serum refers to the clear liquid that can be separated from clotted blood. Serum differs from plasma, the liquid portion of normal unclotted blood containing the red and white cells and platelets. Serum is the component that is neither a blood cell (serum does not contain white or red blood cells) nor a clotting factor. It is the blood plasma not including the fibrinogens that help in the formation of blood clots. It is the clot that makes the difference between serum and plasma.
  • Single-chain Fv also abbreviated as “sFv” or “scFv”
  • sFv Single-chain Fv
  • the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding.
  • Systemic treatment is a treatment, in which the drug substance travels through the bloodstream, reaching and affecting cells all over the body.
  • “Therapeutically effective amount” of an anti-PD-L1 antibody or antigen- binding fragment thereof, or an MCT4 inhibitor of formula (I), or a pharmaceutically acceptable salt thereof in each case of the invention refers to an amount effective, at dosages and for periods of time necessary, whereby, when administered to a patient with a cancer according to a method, combination or combination therapy, the method, combination or combination therapy, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation, or elimination of one or more manifestations of the cancer in the patient, or any other clinical result in the course of treating a cancer patient.
  • a therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • Such therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of an anti-PD-L1 antibody or antigen-binding fragment thereof, or an MCT4 inhibitor of formula (I), or a combination thereof to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of an anti-PD-L1 antibody or antigen-binding fragment thereof, or an MCT4 inhibitor of formula (I), or a combination thereof are outweighed by the therapeutically beneficial effects.
  • Treating” or “treatment of” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation, amelioration of one or more symptoms of a cancer; diminishment of extent of disease; delay or slowing of disease progression; amelioration, palliation, or stabilization of the disease state; or other beneficial results.
  • references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.
  • Treating” or “treatment” of a state, disorder or condition therefore includes: (1 ) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e. , arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • Tumor as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms.
  • a solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors.
  • Unit dosage form refers to a physically discrete unit of therapeutic formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • the compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples.
  • the compounds are shown in Table 2.
  • Analytical data of compounds made according to the following examples are shown in Table 3.
  • 1 H-NMR data is provided in Table 3 below.
  • 1 H NMR spectra were usually acquired on a Bruker Advance III 400 MHz, Bruker Fourier HD 300 MHz, Bruker DPX-300, DRX-400, AVII-400 or on a 500 MHz spectrometer, if not specified otherwise.
  • Chemical shifts (d) are reported in ppm relative to TMS signal.
  • 1 H NMR data are reported as follows: chemical shift (multiplicity, coupling constants and number of hydrogens).
  • Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets) br (broad) and coupling constants (J) are reported in Hz.
  • L 1 being a divalent -NH- or -N(R a )- radical and L 2 being a divalent -SO 2 - radical (i.e. sulfonamide derivatives) may be prepared in accordance with the following scheme and synthetic procedure described below:
  • Ester 5 (1 eq) was dissolved in THF and sodium hydroxide solution in water (2N, 1.1 eq) was added. The reaction mixture was stirred for 12 hrs at room temperature. After full conversion the mixture was acidified with 1 N HCI and diluted with ethylacetate and water. The aqueous layer was extracted with ethylacetate and the combined organic layers were washed with brine and dried with sodium sulphate, filtered and evaporated to dryness. Either crystalisation from established solvent mixtures or purification via chromatography delivered the final products usually as solid.
  • the ethynyl-aniline is not commercially available, it can be prepared by reaction of the corresponding halo-aniline with trimethylsilyl- ethyne under Sonogashira reaction conditions known to an expert in the field.
  • Step B 5-ethoxy-quinoline (15.0 g, 86.6 mmol) was mixed with pre-cooled chlorosulfonic acid (200 mL) and the temperature was kept below 10°C. The obtained mixture was stirred at 10°C for 3 h and poured onto crushed ice (1500 g). The product was extracted with ethyl acetate (3 ⁇ 300 mL). The combined organic extract was washed with water (500 mL), saturated NaHCO 3 (2 ⁇ 500 mL), and brine (500 mL), dried over Na 2 SO 4 , and evaporated under reduced pressure to obtain 8.00 g (29.4 mmol, 34%) of 5- ethoxy-quinoline-8-sulfonylchloride.
  • the crude product (50 mg) was purified by prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 5 ⁇ m,19*150mm; mobile phase: water (10 mmoL/L NH 4 HCO 3 + 0.1 % NH 3 .H 2 O) and ACN (24% ACN up to 45% in 8 min); Detector, UV 254/220nm. This resulted in 23 mg (64%) of 5-[2-[4-ethoxy-2-(quinoline-8-sulfonamido)phenyl]ethynyl]pyridine-2- carboxylic acid as a white solid. The compound exhibited a melting point of 138-140°C.
  • the aqueous layer was extracted with CH 2 CI 2 (3x30 mL). The combined organic layers were concentrated under vacuum.
  • the crude product (200 mg) was purified by prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 30*150mm, 5 urn; mobile phase, Water (10 mmoL/L NH4HCO3+0.1 %NH 3 .H 2 O ) and ACN (20% phase B up to 40% in 8 min). This resulted in 3-ethyl-5-[2-[2-(quinoline-8-sulfonamido)phenyl]ethynyl]- pyridine-2-carboxylic acid (40 mg, 23%) as a white solid. The compound exhibited a melting point of 205-210°C.
  • Methyl 3-ethyl-5-[2-[2-(7-ethylquinoline-8-sulfonamido)phenyl]ethynyl]- pyhdine-2-carboxylate 130 mg, 0.19 mmol, 1 eq, 75%) and LiOH (14.7 mg, 0.58 mmol, 3 eq, 95%) were dissolved in THF (4 mL) and H 2 O (2.0 mL). The resulting mixture was stirred for 4 h at room temperature and then concentrated under reduced pressure.
  • the crude product (120 mg) was purified by prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 30*150mm, 5um; mobile phase: water (10 mmoL/L NH 4 HCO 3 +O.1%NH 3 . H 2 O) and ACN (28% up to 40% in 8 min). The product fractions were combined and concentrated under reduced pressure to afford 3-ethyl-5-[2-[2-(7-ethylquinoline-8-sulfonamido)phenyl]ethynyl]pyridine-2- carboxylic acid (12 mg, 12%) as a white solid.
  • 2-(2-bromobenzylsulfanyl)naphthalene (382 mg; 1.1 mmol; yield 85 % as a bright beige waxy solid.
  • 2-(2-Bromophenylmethanesulfonyl)naphthalene A mixture of 2-(2-Bromobenzylsulfanyl)naphthalene (380 mg; 1.1 mmol; 1 eq.) and acetic acid (6 ml) was placed in 25 mL round bottom flask immersed in an ice bath.
  • Methyl 3-(2-trimethylsillylethynyl)benzoate was obtained as follows: methyl 4- bromobenzoate (2.5 g; 11.6 mmol; 1 eq.), ethynyltrimethylsilane (1.8 ml; 12.8 mmol; 1.1 eq.), copper (I) iodide (40 mg; 0.23 mmol; 0.02 eq.), diisopropyl- amine (1.85 ml; 12.8 mmol; 1.1 eq.) in acetonitrile (15 ml) were placed in a screw capped glass reacting tube.
  • Methyl-3-ethynylbenzoate was obtained as follows: methyl 3-(2-trimethylsilyl- ethynyl)benzoate (4.1 g; 12.3 mmol; 1 eq.) was dissolved in methanol (61 mL) and potassium carbonate (2.6 g; 18.4 mmol; 1.5 eq.) was added. RM was stirred for 20 min, then diluted with diethyl ether and subsequently washed with water and brine. The organic layer was dried over Na 2 SO 4 and evaporated.
  • Sonogashira coupling was conducted as follows: 2-(2-bromophenylmethane- sulfonyl)naphthalene (67 mg; 0.18 mmol; 1 eq.), 4-methyl ethynylbenzoate (45.4 mg; 0.22 mmol; 1.2 eq.), copper (I) iodide (3 mg; 0.02 mmol; 0.1 eq.) were placed in a sealed tube.
  • the air from the tube was evacuated in vacuo and and the tube backfilled with argon (cycle was repeated 3 times), then diisopropylamine (0.028 ml; 0.2 mmol; 1.1 eq.) and anhydrous acetonitrile (2 ml) was added dropwise by syringe.
  • the RM was stirred and heated to 65-70 °C for 18 h, cooled to RT and diluted with EtOAc and filtered by celite.
  • Ester saponification step was conducted as follows: Methyl 4-(2- ⁇ 2- [(naphthalene-2-sulfonyl)methyl]phenyl ⁇ ethynyl)benzoate (20 mg; 0.04 mmol) was dissolved in a mixture of 4 mL of methanol and 2 mL water, then lithium hydroxide (110 mg; 2,62 mmol, 14 eq.) was added. The resulting RM was stirred at RT for 3 h, diluted with waer and acidified to pH 3 with 2M HCI. The resulting solution was taken up by extraction with EtOAc. The organic layer was washed with water and brine, dried over Na 2 SO 4 and evaporated. The crude product was purified by prep. HPLC yielding 4-(2- ⁇ 2-[(naphthalene-2- sulfonyl)methyl]phenyl ⁇ ethynyl)benzoic acid (14.7 mg; 0.03 mmol; 19%) as a white solid.
  • Ester saponification step was conducted as outlined above in Example 14. Starting from 5-[2-(2- ⁇ N-[(naphthalen-2-yl)methyl]acetamido ⁇ phenyl)ethynyl]- pyridine-2-carboxylic acid methyl ester (117 mg; 0.27 mmol; 1 eq) and lithium hydroxide (56 mg; 1.33 mmol; 5 eq.) the 5-[2-(2- ⁇ N-[(naphthalen-2-yl)methyl]- acetamido ⁇ phenyl)ethynyl]pyridine-2-carboxylic acid (81 mg; 0.2 mmol; yield 72%) as a light yellow slid.
  • the resulting mixture was was bubbled with argon for 10 min, then the copper (I) iodide (6.77 mg; 0.04 mmol; 0.03 eq.) and tetrakis(triphenylphosphine)palladium(0) (41.11 mg; 0.04 mmol; 0.03 eq.) were added under Ar atm and vessel was capped.
  • RM was stirred at 65 ° C for 3h. RM was cooled down to RT, diluted with AcOEt and filtered through a pad of celite®.
  • Microwave vial was charged with 5-(2-aminophenylethynyl)-4-chloropyridine- 2-carboxylic acid methyl ester (100 mg; 0.35 mmol; 1 eq.), K 3 HOPH 2 4 (220 mg; 1 mmol; 3 eq.), potassium acetate (8.5 mg; 0.09 mmol; 0.25 eq.) and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (PdCI2(dppf)2) (25 mg; 0.03 mmol; 0.1 eq.).
  • the tube was sealed with a septum, air evacuated under vacuum, and back filled with argon (the cycle was repeated three times) and mixture of [1 ,4]-dioxane (2 ml) and 2-isopropenyl-4,4,5,5-tetramethyl-[1 ,3,2]- dioxaborolane (0.1 ml; 0.52 mmol; 1 .5 eq.) was added by syringe. The reaction was stirred at 80 ° C for 24h, cooled to room temperature and filtrated through a pad of celite®.
  • N-(2-Ethynylphenyl)-7-methylquinolin-8-ylsulfonamide (374 mg; 1.14 mmol; 1 eq.), DMAP (28 mg; 0.23 mmol; 0.2 eq.) and anhydrous acetonitrile (5 ml) was stirred at RT for 5 min. Then, the mixture was heated to 80 ° C. The solution of tert-butoxycarbonyl tert-butyl carbonate (BOC 2 O) (1 g; 4.6 mmol; 4 eq.) in acetonitrile (anhydrous) (2 ml) was added to the reaction mixture in four portions during 1 hour.
  • BOC 2 O tert-butoxycarbonyl tert-butyl carbonate
  • Methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (439 mg; 0.8 mmol; 1 eq.), anhydrous sodium acetate (982 mg; 12 mmol; 15 eq.) and glacial acetic acid (3 ml) were placed into flame dried reacting vessel.
  • the vessel content was purged with argon, capped and placed in preheated to 120 ° C an oil bath.
  • RM was stirred for 30 min at 120 ° C and cooled down to RT.
  • RM was cooled down and neutralized with saturated sodium bicarbonate, diluted with water and extracted with AcOEt. Combined organic extracts were subsequently washed with water, brine and dried over anhydrous Na 2 SO 4 and evaporated.
  • Residue was purified by FCC (SiHP, hexane/EtOAc, gradient) to give Methyl 3-[(acetyloxy)methyl]-5-bromopyridine-2-carboxylate (84 mg; 0.3 mmol; yield 37%) as orange solid.
  • Sonogashira coupling was conducted accordingly to general procedure for Sonogashira coupling described above giving methyl 3-[(acetyloxy)methyl]-5- [2-(2- ⁇ N-[(tert-butoxy)carbonyl]7-methylquinoline-8-sulfonamido ⁇ phenyl)- ethynyl]pyridine-2-carboxylate (110 mg; 0.17 mmol; yield 99%) as beige solid.
  • Methyl 3-[(acetyloxy)methyl]-5- ⁇ 2-[2-(7-methylquinoline-8-sulfonamido)- phenyl]ethynyl ⁇ pyridine-2-carboxylate (86 mg; 0.16 mmol; 1 eq.) was dissolved in THF (5 ml). Water (2 ml) was added to resulted mixture followed by lithium hydroxide hydrate (34 mg; 0.8 mmol; 5 eq.) addition. The resulting mixture was stirred for 5 hours at RT. Then RM was concentrated under reduced pressure, acidified using 1 M hydrochloric acid 6 pH and extracted with AcOEt.
  • L1 being a divalent -N(CHO)- radical; and L2 being a divalent -CH 2 - radical may be prepared in accordance with the following scheme and synthetic procedure described below for -[2-(2- ⁇ N-[(6-phenyl- pyridin-3-yl)methyl]formamido ⁇ phenyl)ethynyl]pyridine-2-carboxylic acid:
  • acetic formic anhydride was generated by the dropwise addition of formic acid (0.27 ml; 7.16 mmol) to acetic anhydride (0.81 ml; 8.59 mmol) at 0°C.
  • the mixture was added to a solution of (2-iodo-phenyl)- (6-phenyl-pyridin-3-ylmethyl)-amine (189.00 mg; 0.48 mmol) in tetrahydro- furan (3.00 ml).
  • the mixture was stirred at 70°C overnight.
  • UPLC analysis showed conversion of starting material to desire product.
  • a pressure vessel was charged with N-(2-iodo-phenyl)-N-(6-phenyl-pyridin-3- ylmethyl)-formamide (190.00 mg; 0.46 mmol), 5-ethynyl-pyridine-2-carboxylic acid methyl ester (147.84 mg; 0.92 mmol), triethylamine (anhydrous) (0.26 ml; 1.83 mmol) and N,N-dimethylformamide anhydrous, 99.8% (4.00 ml). The resulting mixture was purged with argon for 10 min.
  • step A The ester from step A was dissolved in THF (6.00 ml) and water (2.00 ml). Then lithium hydroxide monohydrate (57.74 mg; 1.38 mmol) was added and reaction mixture was stirred at RT overnight. Conversion of starting material was confirmed by TLC. The reaction mixture was partially evaporated to remove THF, then diluted with additional portion of water and neutralized with 1 M HCI. Precipitated product was extracted to ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 .
  • R 2 being either an alkoxy or amino substituent
  • a pressure reactor vessel was charged with methyl 5-bromo-3-fluoro-pyridine- 2-carboxylate (150 mg; 0.64 mmol; 1 eq.), methenamine hydrochloride (173 mg; 2.56 mmol; 4 eq.), Cesium carbonate (835 mg; 2.56 mmol; 4 eq.), then the vessel was capped and filled with argon. Then anhydrous toluene (3 ml) was added via syringe. The reaction mixture was stirred at 105°C for 16 hours with stirring.
  • Sonogashira coupling was conducted accordingl to the general procedure for Sonogashira coupling described above. Starting from methyl 3-(methylamino)- 5-bromopyridine-2-carboxylate (270 mg; 0.76 mmol; 1.1 eq.) and 2-ethynyl- phenylamine (0.08 ml; 0.69 mmol; 1 eq.) the methyl 5-[2-(2-amino- phenyl)ethynyl]-3-(benzylamino)pyridine-2-carboxylate (170 mg; 0.43 mmol; yield 62 %) was obtained as orange solid.
  • Saponification step was conducted according to the procedure described above: Starting from methyl 3-(benzylamino)-5- ⁇ 2-[2-(7-methylquinoline-8- sulfonamido)phenyl]ethynyl ⁇ pyridine-2-carboxylate (10 mg; 0.02 mmol; 1 eq.),
  • the boc deprotection step was conducted according to the procedure described above in Example 25: Starting from methyl 8-[2-(2- ⁇ N-[(tert- butoxy)carbonyl]7-methylquinoline-8-sulfonamido ⁇ phenyl)ethynyl]- 1 H,2H,3H,4H-pyrido[3,4-b]pyrazine-5-carboxylate (30 mg; 0.05 mmol; 1 eq.) methyl 8- ⁇ 2-[2-(7-methylquinoline-8-sulfonamido)phenyl]ethynyl ⁇ - 1 H,2H,3H,4H-pyrido[3,4-b]pyrazine-5-carboxylate (40 mg; 0.08 mmol) was obtained as brown solid.
  • the saponification step was conducted according to the procedure described above in Example 25: Starting from methyl 8- ⁇ 2-[2-(7-methylquinoline-8- sulfonamido)phenyl]ethynyl ⁇ -1 H,2H,3H,4H-pyrido[3,4-b]pyrazine-5- carboxylate (40 mg; 0.08 mmol; 1 eq.), the 8- ⁇ 2-[2-(7-methylquinoline-8-sulfon- amido)phenyl]ethynyl ⁇ -1 H,2H,3H,4H-pyrido[3,4-b]pyrazine-5-carboxylic acid (22 mg; 0.04 mmol; yield 58%) was obtained as green solid.
  • the crude product (80 mg) was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD Column, 19*250mm,10um; mobile phase, Water (0.05%HCI) and ACN (27% PhaseB up to 45% in 8 min); Detector, UV. This resulted in 5-(2-[2-[4- (dimethylamino)quinoline-8-sulfonamido]phenyl]ethynyl)-4-methylpyridine-2- carboxylic acid hydrochloride(34.5mg, 41%) as a white solid.
  • 2#SHIMADZU HPLC-01
  • the crude product (18 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150mm 5um; Mobile Phase A:Water(10 mmoL/L NH 4 HCO 3 +0.1 % NH 3 .H 2 O, Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:30 B to 60 B in 8 min; 254 nm; RT1:6.8) to afford 5-(2-[2-[4-(dimethylamino)quinoline-8-sulfonamido]phenyl]- ethynyl)pyridine-2-carboxylic acid (3.3 mg, 26%) as a white solid.
  • the crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 19x250mm,10um; Mobile Phase A:Water(0.05%HCI), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 46% B in 9 min; 254 nm; Rt: 7.18 min) to afford 5-(2-[2-[4-(morpholin-4-yl)quinoline-8-sulfonamido]- phenyl]ethynyl)pyridine-2-carboxylic acid (20 mg, 33%) as a light yellow solid.
  • the crude product (100 mg) was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep OBD C18 Column, 30*150mm 5 urn; mobile phase, water (10 mmoL/L NH 4 HCO 3 +0.1% NH 3 .H 2 O) and ACN (20% PhaseB up to 50% in 8 min); Detector, UV.). This resulted in 4-methyl-5-(2-[2-[4-(methylamino)quinoline-8-sulfonamido]phenyl]ethynyl)- pyridine-2-carboxylic acid hydrochloride (8.7 mg, 10%) as a white solid.
  • 2#SHIMADZU HPLC-01
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150mm,5um ; Mobile Phase A: water (10 mmoL/L NH HCO 3 +0.1% NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15 B to 35 B in 8 min; 254 nm) to afford 5-(2-[2-[4- (ethylamino)quinoline-8-sulfonamido]phenyl]ethynyl)pyridine-2 -carboxylic acid (3 mg, 4%) as a white solid.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150mm, 5um ; Mobile Phase A:Water(0.05%HCI ), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient: 15 B to 40 B in 8 min; 254 nm) to afford 5-(2-[2-[4-(isopropylamino)quinoline-8-sulfonamido]phenyl]ethynyl)pyridine-2- carboxylic acid (5 mg, 3%) as a white solid.
  • HPLC-MS showed the formation of the required product.
  • the reaction was diluted with ethyl acetate and extracted 3x with water, dried over Na 2 SO 4 and evaporated to dryness.
  • the product was obtained as brown oil in 77% yield (351 mg) and used in the next step without further purification.
  • HPLC-MS showed a not complete formation of the required product. More HCI (4.0 M in dioxane, 2 ml) was added and stirred for 16 hrs at RT. HPLC-MS showed the complete formation of the required product. The reaction was diluted with water and lyophilized. The residue was purified by prep. HPLC giving the product 5-(2- ⁇ 2-[(naphthalen-1-yl)sulfamoyl]phenyl ⁇ - ethynyl)pyridine-2 -carboxylic acid as light yellow solid in 39% yield (10 mg).
  • Table 2 shows the compounds prepared in accordance with or similar to the synthetic procedures described above:
  • Table 3 shows analytical data of the compounds depicted in Table 2 above:
  • Biological Activity of compounds of formula (I) Biological activity of the compounds of formula (I) shown in Table 2 was determined by measuring their inhibition of extracellular lactate production in a suitable assay utilizing MDA-MB-231, SNU398 and MIA PaCa-2 cell lines (see the international patent applicaton with the application number PCT/EP2019/086662, filed on 20. December 2019, published as WO 2020/127960 A1). Compounds tested in that assay exhibited IC50 values in the range of 1 nM up to 100 mM, preferably in the range of 1 nM to 1 ⁇ M, more preferably in the range of 1 nM to 100 nM; they are effective MCT4 inhibitors.
  • Murine MC38 colon carcinoma cells were obtained from Scripps Research Institute. Cells were tested and verified to be free of adventitious viruses and mycoplasma.
  • MC38 cells were cultured in DMEM containing 4.5 g/L D-glucose, 2 mM glutamine, and 110 mg/L sodium pyruvate and supplemented with 10% FBS. All cells were maintained at 37°C and 5% CO2 in aseptic conditions. Cells were passaged upon reaching 50-85% confluence for a total of 2 to 15 passages prior to in vivo implantation. Cells were harvested by trypsinization with TrypLE Express and viable cell counts were determined using a Countess or hematocrit chamber cell counter and trypan blue exclusion staining.
  • mice Female C57/BL6 mice were obtained from Charles River Laboratories. They were inoculated (s.c. in the right dorsal flank) with 1x10 6 MC38 cells in 0.1 mL sterile PBS. Treatment was initiated when tumors reached an average volume of approximately 50-80 mm 3 (Day 0).
  • Test groups of the MC38 tumor-bearing mice (10 animals in each group) were treated with both vehicle (20% Kleptose (HPB) in 50 mM Phosphate pH 7.4 buffer) and mutant PD-L1 (Group 1 ), the MCT4 inhibitor Compound 367 (5- ⁇ 2- [5-chloro-2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl ⁇ -4-methoxypyri- dine-2-carboxylic acid) (Group 2), avelumab (commercially available) (Group 3), or a combination of Compound 367 and avelumab (Group 4).
  • Group 1 Control Group the vehicle was administered at 10ml/kg animal weight, p.o. once daily and Mut PD-L1 i.v. at day 0, 3, and 6 (400 ⁇ g/animal).
  • the MCT4 inhibitor was administered at 3 mg/kg animal weight from day 0 to day 3, followed by 30 mg/kg animal weight per day until the end of the study (p.o. administration, once per day (qd)).
  • avelumab was administered 400 ⁇ g/animal at day 0, 3, and 6 (i.v. administration).
  • Efficacy of the treatment was evaluated by monitoring tumor volume over the course of the study. The results are summarized in Table 5 and shown in Figures 1 to 4.
  • Group 4 i.e. the MCT4 inhibitor/avelumab combination group was significantly different when compared to the vehicle group (Group 1) and to Group 2 (mono-treatment with MCT4 inhibitor).
  • MCT1 inhibitor AZD3965 (5-((S)-4-Hydroxy-4-methyl- isoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-(3-methyl-5-trifluoromethyl- 1 H-pyrazol-4-ylmethyl)-1 H-thieno[2,3-d]pyrimidine-2,4-dione; commercially available from, e.g., Selleck Chemicals) alone or in combination with avelumab or in triple combination with avelumab and the MCT4 inhibitor Compound 367 neither reached a comparable effect nor contributed to a further inhibition of tumor growth.

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Abstract

La présente invention concerne un produit pour polythérapies utiles pour le traitement de maladies cancéreuses. En particulier, l'invention concerne la combinaison d'un anticorps anti-PD-L1 et d'un inhibiteur de MCT4 de formule (I). La combinaison thérapeutique peut être utilisée pour le traitement d'un sujet ayant une maladie cancéreuse qui est testé positif pour l'expression de PD-L1 et/ou de MCT4.
PCT/EP2021/065216 2020-06-10 2021-06-08 Produit de combinaison pour le traitement de maladies cancéreuses WO2021249969A1 (fr)

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