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WO2025172573A1 - Combinations of par2 inhibitors and immune checkpoint inhibitors for the treatment of cancer - Google Patents

Combinations of par2 inhibitors and immune checkpoint inhibitors for the treatment of cancer

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Publication number
WO2025172573A1
WO2025172573A1 PCT/EP2025/054098 EP2025054098W WO2025172573A1 WO 2025172573 A1 WO2025172573 A1 WO 2025172573A1 EP 2025054098 W EP2025054098 W EP 2025054098W WO 2025172573 A1 WO2025172573 A1 WO 2025172573A1
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Prior art keywords
inhibitor
cancer
carbonyl
use according
par2
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PCT/EP2025/054098
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French (fr)
Inventor
Thibaut BRUGAT
John Stagg
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Domain Therapeutics SA
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Domain Therapeutics SA
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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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to a protease-activated receptor-2 (PAR2) inhibitor in combination with an immune checkpoint inhibitor for use in the treatment of cancer via a specific administration/dosage regimen, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier (e.g., 3 to 7 days earlier) than the administration of the immune checkpoint inhibitor.
  • PAR2 protease-activated receptor-2
  • protease-activated receptors (PARs) family The protease-activated receptors (PARs) family
  • G Protein-Coupled Receptors form the largest family of human membrane proteins ( ⁇ 800 members) and are involved in many physiological processes. Compounds targeting GPCRs also represent approximately 27% of the global market for therapeutic drugs (Hauser et al., Nat. Rev. Drug Discov., 2017, 16(12):829-842).
  • proteases also called proteinases
  • proteases also called proteinases
  • PARs Protease-Activated Receptors
  • the PARs family is composed of four members (PAR-1 , PAR-2, PAR-3 and PAR-4) and belongs to the class A GPCR-receptor sub-family (Marcfarlane et al., Pharmacological Reviews, 2001 , 475(7357):519-23).
  • PAR-2 is activated by several host and pathogen-derived serine proteases such as trypsin, mast cell tryptase, kallikreins and members of the coagulation cascade TF-FVIla and FVa-FXa. These proteases cleave at R 34 J,S 35 LIGKV and unmask the tethered ligand SLIGKV in humans. Artificially, in vitro, synthetic peptides corresponding to the TL (SLIGKV) can activate the receptor without cleavage. Activation of PAR-2 induces several signalling cascades involving a number of G proteins such as G q , G, and G12/13.
  • G proteins such as G q , G, and G12/13.
  • PAR-2 is involved in the function of the cardiovascular system. Indeed, its activation can induce the relaxation or contraction of some vessels such as pulmonary arteries, coronary and intramyocardial arteries, therefore regulating the blood flow. It also controls inflammation and repair of the endothelium which influences vascular permeability.
  • PAR-2 is involved in airways function since it is expressed by epithelial and endothelial cells in the lungs. Its activation has been shown to regulate bronchodilatation or bronchoconstriction (depending on the experimental system used), ion transport in the airway epithelium, proliferation and activation of airway smooth muscle cells and lung fibroblasts. PAR-2 can thus regulate airway resistance, lung inflammation and lung fibrosis.
  • PAR-2 expression has been detected in keratinocytes, microvasculature and immune cells. Its activation has been involved in skin pigmentation, skin inflammation, and wound healing.
  • PAR-2 expression has been detected in immune cells such as macrophages where it influences cell maturation and cytokine secretion, thereby regulating inflammation.
  • the expression of PAR-2 on other cells of the tumor microenvironment can also control the immune response to cancer cells, fibrosis, as well as angiogenesis and cancer-induced pain (Mubbach et al., Mol cancer, 2016, 15(1):54; Uusitalo-Jarvinen et al., Arieriocler Thromb Vase Biol, 2007, 27(6): 1456-62; D’Andrea et al., Am J Pathol, 2001 , 158(6):2031-41 ; Graf et al., Sci Immunol, 2019, 4(39):eaaw8405; Qian at al., Oncol Lett, 2018, 16(2): 1513-20; Tu et al., J Neurosci, 2021 , 41 (1):193-210).
  • PAR2 loss of function mutation or inhibition of one of its ligands led to reduced infiltration of immune-suppressive Tumor Associated Macrophages and regulatory T cells while increasing cytotoxic T cells in the tumor in several syngeneic mouse models; this unleashed the anti-tumoral immune response and increased the potency of immune-checkpoint inhibitors currently used in the clinic (Graf et al., Sci Immunol, 2019, 4(39):eaaw8405).
  • PAR-2 therefore constitutes a promising therapeutic target in oncology and immuno-oncology.
  • the present invention provides a PAR2 inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides a combination of a PAR2 inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of a PAR2 inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with an immune checkpoint inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of a PAR2 inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • FIG. 1 B is a diagram showing the progression free survival rate in MC38 bearing wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD1 or isotype control (Iso).
  • Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • C Mean tumor growth.
  • Fig. 1C is a diagram showing mean MC38 tumor volume changes in wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso). 10 mice per group were treated.
  • FIG. 1 D is a set of diagrams showing MC38 tumor volume changes in each wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso). The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 16 (D16).
  • FIG. 1 E is a diagram showing individual MC38 tumor volume in wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso) at day 16 (last day at which all mice were still alive in every group). Average tumor volume (mm 2 ) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • FIG. 2 Influence of pharmacological inhibition of PAR2 on anti-tumor efficacy of anti-PD1 according to the timing of administration.
  • FIG. 2A is a schematic diagram showing the design of the experiment performed to determine the effect of pharmacological PAR2 inhibition on the anti-tumor efficacy of immune checkpoint inhibitors according to timing of administration.
  • MC38 cells were subcutaneously injected into groups of 15 syngeneic C57BL/6 mice.
  • Anti-PD1 antibody or isotype control were intraperitoneally injected at days 6, 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 (at a 30mg/kg dose) or vehicle were given once a day by oral gavage for 21 days.
  • Fig. 2B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti- PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD1 therapy is indicated.
  • Fig. 2C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD 1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD1 therapy is indicated. Average tumor volume (mm 3 ) and SD bars were plotted for each group.
  • 2E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti- PD1 , 1-117 or a combination of both anti-PD1 and 1-117 at day 20 (last day at which all mice were still alive in every group). Average tumor volume (mm 3 ) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups (taking all groups into account), p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****. (F) Progression-free survival. Fig.
  • FIG. 2F is a diagram showing the progression free survival rate in MC38 bearing mice treated with anti-PD1 or a combination of both anti-PD1 and 1-117.
  • start of 1-117 treatment compared to anti-PD1 therapy is indicated.
  • Log-rank (Mantel-Cox) test was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • G Mean tumor growth.
  • Fig. 2G is a diagram showing mean MC38 tumor volume changes in mice treated with anti-PD1 or a combination of both anti-PD1 and 1-117.
  • start of 1-117 treatment compared to anti-PD 1 therapy is indicated.
  • Fig. 2H is a diagram showing individual MC38 tumor volume in mice treated with anti-PD1 or a combination of both anti-PD 1 and 1-117 at day 20 (last day at which all mice were still alive in every group). Average tumor volume (mm 3 ) and SD bars were also plotted for each group. Mann-Whitney test was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • Fig. 3B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1, 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start and end days of 1-117 treatment are indicated.
  • FIG. 3D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 18 (D18).
  • 3F is a diagram showing the progression free survival rate in MC38 bearing mice treated with anti-PD1 or a combination of anti-PD1 and 1-117.
  • start and end days of 1-117 treatment are indicated.
  • Log-rank (Mantel-Cox) test was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : ****.
  • G Mean tumor growth.
  • Fig. 3G is a diagram showing mean MC38 tumor volume changes in mice treated with anti- PD1 or a combination of anti-PD1 and 1-117.
  • start and end days of 1-117 treatment are indicated.
  • FIG. 4A is a schematic diagram showing the design of the experiment performed to determine the effect of priming doses of Compound 207 on the anti-tumor efficacy of immune checkpoint inhibitors.
  • MC38 cells were subcutaneously injected into groups of 12 syngeneic C57BL/6 mice.
  • Anti-PD1 antibody or isotype control were intraperitoneally injected at days 6, 9 and 12 post tumor inoculation.
  • the PAR2 inhibitor Compound 207 (207) or vehicle were given once a day by oral gavage from day 2 post tumor inoculation to day 6.
  • Compound 207 was given at a 30mg/kg dose.
  • Fig. 4B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207.
  • doses of Compound 207 used are indicated.
  • FIG. 4C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207. For the combination groups, doses of Compound 207 used are indicated. Average tumor volume (mm 2 ) and SD bars were plotted for each group.
  • Fig. 4D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207. For the combination groups, doses of Compound 207 used are indicated. The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 25 (D25). Fig.
  • 4E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD 1 and Compound 207 at day 25 (last day at which all mice were still alive in every group).
  • Iso isotype control
  • 207 Compound 207
  • Average tumor volume (mm 2 ) and SD bars were also plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a one-way ANOVA.
  • FIG. 5A is a schematic diagram showing the design of the experiment performed to determine if the benefit of a combination between PAR2 inhibitors and immune-checkpoint inhibitors could also be observed at later stages of the tumor development.
  • MC38 cells were subcutaneously injected into groups of 10 syngeneic C57BL/6 mice.
  • Anti-PD 1 antibody or isotype control were intraperitoneally injected at days 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 (at a 30mg/kg dose) or vehicle were given once a day by oral gavage from day 5 post tumor inoculation to day 9.
  • FIG. 5B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p ⁇ 0.05: *, p ⁇ 0.01 : **, p ⁇ 0.005: ***, p ⁇ 0.001 : **** (C) Mean tumor growth. Fig.
  • 5C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD 1 and 1-117.
  • Iso isotype control
  • 5D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated when applicable.
  • E Mean tumor volume at day 15 (D15).
  • Fig. 5E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117 at day 15 (last day at which all mice were still alive in every group). For the combination groups start and end days of 1-117 treatment are indicated.
  • FIG. 6A is a schematic diagram showing the design of the experiment performed to determine the effect of the timing of priming doses of 1-117 on the anti-tumor efficacy of immune checkpoint inhibitors.
  • MC38 cells were subcutaneously injected into groups of 10 syngeneic C57BL/6 mice.
  • Anti-PD1 antibody or isotype control were intraperitoneally injected at days 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 or vehicle were given once a day by oral gavage at a 30mg/kg dose at different timings.
  • Fig. 6B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated.
  • Fig. 6C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1, or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated. Average tumor volume (mm 2 ) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a mixed effect model test .
  • FIG. 6D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated.
  • Iso isotype control
  • CR rate of complete response
  • the present invention provides a PAR2 inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides an immune checkpoint inhibitor for use in the treatment of cancer, wherein the immune checkpoint inhibitor is administered in combination with a PAR2 inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides a combination of a PAR2 inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PAR2 inhibitor and an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of an immune checkpoint inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with a PAR2 inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the invention relates to the use of a PAR2 inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor can be provided in the form of a pharmaceutical composition comprising the PAR2 inhibitor and optionally one or more pharmaceutically acceptable excipients.
  • the immune checkpoint inhibitor can be provided in the form of a pharmaceutical composition comprising the immune checkpoint inhibitor and optionally one or more pharmaceutically acceptable excipients.
  • the present invention also provides a pharmaceutical composition comprising a PAR2 inhibitor (and optionally one or more pharmaceutically acceptable excipients), for use in the treatment of cancer, wherein the pharmaceutical composition comprising the PAR2 inhibitor is administered in combination with a pharmaceutical composition comprising an immune checkpoint inhibitor (and optionally one or more pharmaceutically acceptable excipients), wherein the administration of the pharmaceutical composition comprising the PAR2 inhibitor is started at least 1 day earlier than the administration of the pharmaceutical composition comprising the immune checkpoint inhibitor.
  • Such different/separate pharmaceutical compositions i.e. the (first) pharmaceutical composition comprising the PAR2 inhibitor and the (second) pharmaceutical composition comprising the immune checkpoint inhibitor, can also be provided in the form a kit that comprises the corresponding pharmaceutical compositions.
  • the administration of the PAR2 inhibitor is started at least 1 day earlier than (or, in other words, prior to) the administration of the immune checkpoint inhibitor. Accordingly, the PAR2 inhibitor is administered at least 1 day before the first administration/dose of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor is started at least 2 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor may be started from 2 to 30 days earlier than the administration of the immune checkpoint inhibitor, or from 2 to 21 days earlier than the administration of the immune checkpoint inhibitor, or 2 to 14 days earlier than the administration of the immune checkpoint inhibitor, or 2 to 7 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor may be started, e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor is started at least 3 days earlier than the administration of the immune checkpoint inhibitor.
  • the administration of the PAR2 inhibitor may be started 3 to 14 days (e.g., 3, 5, 7, 10 or 14 days), particularly 3 to 7 days (e.g., 3 or 5 days), earlier than the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor is a small molecule (e.g., any one of the compounds described in WO 2022/117882 or WO 2023/233033), it is particularly preferred that it is administered once daily. If the PAR2 inhibitor is an antibody (or an antigen-binding fragment thereof or an antibody construct), it is preferably administered weekly or biweekly, particularly once every 1 or 2 weeks, more preferably once every 2 weeks.
  • the PAR2 inhibitor may be continued to be administered (preferably at a regular dosing interval, as described above) until the first administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor may be administered daily (preferably once daily) up until the day when the first dose of the immune checkpoint inhibitor is administered.
  • the administration of the PAR2 inhibitor may be discontinued (or, in other words, may be halted) or may be further continued.
  • the administration of the PAR2 inhibitor may also be discontinued/halted shortly (e.g., 1 day) before the first administration of the immune checkpoint inhibitor.
  • the present invention particularly relates to the sequential administration of the PAR2 inhibitor followed by the immune checkpoint inhibitor, whereby the administration of the PAR2 inhibitor is discontinued/halted when the administration of the immune checkpoint inhibitor is started.
  • the administration of the PAR2 inhibitor may be started, e.g., 3 to 5 days earlier than the administration of the immune checkpoint inhibitor, whereby the PAR2 inhibitor may be administered daily (preferably once daily) over a period of at least 3 days before the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor to be used in accordance with the present invention may be, in principle, any compound/substance that decreases, reduces, prevents, blocks, antagonizes or inhibits the activity, function or gene expression of protease-activated receptor-2 (PAR2).
  • the PAR2 inhibitor may be a small molecule, a peptide, or an antibody (or an antigen-binding fragment thereof, or an antibody construct; e.g., a monoclonal antibody).
  • the PAR2 inhibitor may be a PAR2 inhibitor that is known in the art, including, e.g., any one of the compounds disclosed in: Yau et al., Expert Opin Ther Pat, 2016, 26(4):471-83; Jiang et al., J Pharmacol Exp Ther, 2018, 364(2):246-57;
  • the PAR2 inhibitor may be, e.g., a compound disclosed in any one of the aforementioned documents (e.g., in the examples section of any one of the aforementioned patent documents), wherein said compound may be used in non-salt form or in the form of a pharmaceutically acceptable salt or solvate.
  • the PAR2 inhibitor may also be an anti-PAR2 antibody, e.g., any one of the antibodies (or antigen-binding fragments thereof) that are disclosed in WO 2018/167322 or WO 2022/040345, each of which is incorporated herein by reference in its entirety.
  • Preferred examples of the PAR2 inhibitor to be used in accordance with the present invention include any one of the compounds described in WO 2022/117882 or WO 2023/233033, particularly any one of the PAR2 inhibitors described in the examples section of WO 2022/117882 or in the examples section of WO 2023/233033, either in non-salt form and/or non-solvated form or as a pharmaceutically acceptable salt or solvate of the respective compound.
  • the PAR2 inhibitor may also be an antibody.
  • Corresponding preferred examples include, in particular, MEDI-0618 or PaB670129 (as described, e.g., in WO 2018/167322 which is incorporated herein by reference), or P24E1102 (as described, e.g., in WO 2022/040345 which is incorporated herein by reference).
  • the PAR2 inhibitor may also be a peptide, particularly a pepducin, e.g., any one of the PAR2 pepducins disclosed in WO 2012/139137 (which is incorporated herein by reference).
  • a pepducin e.g., any one of the PAR2 pepducins disclosed in WO 2012/139137 (which is incorporated herein by reference).
  • Corresponding preferred examples include any of PZ-235, OA-235i, OA-235c, or P2pal-18S (as described, e.g., in WO 2012/139137).
  • the PAR2 inhibitor to be used in accordance with the present invention is any one of the following compounds:
  • This compound has been described in Example 207 of WO 2023/233033 and is also referred to herein as "Compound 207”.
  • This compound has been described in Example 1.19 of WO 2018/057588 and is also referred to as compound "1-117”.
  • This compound has been described in Example 10 of EP 3 508 487 A1.
  • the PAR2 inhibitor may also be a stereoisomer of the aforementioned compound, e.g., (1 R)-[7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1 H-imidazol-2-yl)methanol or a pharmaceutically acceptable salt or solvate thereof, or (1 S)- [7-fl uoro-3- ( 1 -methy I cy cl opropy I) benzofu ran-4-y I] -( 1 H-i mi d azol-2- yl)methanol or a pharmaceutically acceptable salt or solvate thereof.
  • This compound has been described in Example 10 of WO 2019/124567.
  • This compound has been described in WO 2019/199800 (see, e.g., the synthesis disclosed on pages 35 to 37) and is also referred to as compound "0781”.
  • the PAR2 inhibitor is any one of the following compounds:
  • the PAR2 inhibitor to be used in accordance with the present invention is 6-(4-(5'-(4-chloro-3- fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid or a pharmaceutically acceptable salt or solvate thereof, or 6-[4-[7-tert-butyl-5-(4-chloro-3- fluoro-phenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-2,4-dimethyl-pyridine-3-carboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
  • the immune checkpoint inhibitor to be used in accordance with the present invention may be, in principle, any immune checkpoint inhibitor known in the art.
  • the immune checkpoint inhibitor may be an antibody (or an antigenbinding fragment thereof, or an antibody construct), typically a monoclonal antibody.
  • the immune checkpoint inhibitor is a monoclonal antibody (or an antigen-binding fragment thereof, or an antibody construct) directed against PD-1 , PD-L1 , CTLA-4, TIGIT, TIM3, VISTA, BTLA, CD47, LAG3, 0X40, or IGOS.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti- CD47 antibody, an anti-LAG3 antibody, an anti-OX40 antibody, or an anti-ICOS antibody.
  • Corresponding preferred examples include, but are not limited to, any one of the anti-PD-1 antibodies nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX- 4014, or APE02058, any one of the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301 , BMS-936559, MEDI4736,
  • the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, particularly an anti-PD-1 antibody.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, tislelizumab, toripalumab, penpulimab, cadonilimab, serplulimab, envafolimab, pucotenlimab, adebrelimab, camrelizumab, prolgolimab, retifanlimab, sintilimab, socazolimab, sugemalimab, zimberelimab, spartalizumab, and dostarlimab.
  • the PAR2 inhibitor for use according to item 1 the immune checkpoint inhibitor for use according to item 2, the combination for use according to item 3, the method according to item 4, or the use according to any one of items 5 to 7, wherein the administration of the PAR2 inhibitor is started 2 to 14 days earlier than the administration of the immune checkpoint inhibitor.
  • the PAR2 inhibitor is 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1,7'- pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid or a pharmaceutically acceptable salt or solvate thereof.
  • the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti- CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti-CD47 antibody, an anti-LAG3 antibody, an anti-OX40 antibody, or an anti-
  • the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, which is selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, tislelizumab, toripalumab, penpulimab, cadonilimab, serplulimab, envafolimab, pucotenlimab, adebrelimab, camrelizumab, prolgolimab, retifanlimab, sintilimab, socazolimab, sugemalimab, zimberelimab, spartalizumab, and dostarlimab.
  • an anti-PD-1 antibody or an anti-PD-L1 antibody which is selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplima
  • Example 1 Effect of PAR2 knock out on the anti-tumor efficacy of immune checkpoint inhibitors
  • the same MC38 model was used (see Example 1 above).
  • the compound 1-117 described in patent application WO 2018/057588, was used as it is a potent and selective PAR2 inhibitor with proven in vivo activity.
  • 0.5x10 6 MC38 cells were subcutaneously injected into groups of 15 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 100 g of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected at days 6, 9, 12 and 15 post tumor inoculation.
  • the PAR2 inhibitor 1-117 in 10% Ethanol- 100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water was given once a day by oral gavage.
  • 1-177 was administered at a 30mg/kg dose. For the monotherapy, treatment with 1-117 started at day 6 post tumor inoculation and lasted for 21 days.
  • MC38 model was used.
  • 0.5x10 6 MC38 cells (ATCC) were subcutaneously injected into groups of 10 syngeneic wild type female C57BL/6 mice (Jackson Laboratory).
  • 200pig of anti-PD 1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 6 days post tumor inoculation and 10Opig after 9 and 12 days.
  • the PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage.
  • 1-177 was administered at a 30mg/kg dose.
  • both 5 days and 21 days administration of PAR2 inhibitor improved the anti-tumor efficacy of anti-PD-1 treatment in a similar way. Indeed, increased progression-free survival rate and a decreased tumor growth were observed in both combination groups compared to monotherapies. When compared head-to- head, the differences in progression-free survival and tumor growth observed between anti-PD1 alone and the combination of anti-PD1 and a 5 day treatment with 1-117 are statistically significant. Furthermore, tumors were rejected in 50% of animals when treated with anti-PD1 alone. In the combination groups, the rate of complete response increased to 90% and 80% when 1-117 was administered for 5 days and 21 days respectively.
  • Compound 207 This small molecule is structurally different from 1-117 but with similar pharmacokinetic properties and potency on PAR2 inhibition.
  • MC38 cells 0.5x10 6 MC38 cells (ATCC) were subcutaneously injected into groups of 12 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 6 days post tumor inoculation and 10Opig after 9 and 12 days.
  • the PAR2 inhibitor Compound 207 or vehicle (1 ,2% methylcellulose, 0, 1 % tween80) were given once a day by oral gavage. This treatment started at day 2 post tumor inoculation and lasted for 5 days (days 2 to 6 post tumor inoculation). For the monotherapy, Compound 207 was given at a 30mg/kg dose.
  • Compound 207 was given at a 30mg/kg or 100mg/kg dose. Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm 2 . A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
  • priming doses of Compound 207 increased the anti-tumor efficacy of anti-PD1 in a similar way as 1-117. Indeed, as seen in the previous experiments, increased progression-free survival rate and a decreased tumor growth were observed in the combination group with the highest dose of Compound 207 (1 OOmg/kg) compared to monotherapies. Furthermore, tumors were rejected in 50% of animals when treated with anti-PD1 alone. In the combination groups, the rate of complete response increased in a dose dependent manner to 58% and 70% when Compound 207 was administered at 30mg/kg and 100mg/kg respectively.
  • Example 4 Effect of priming doses of PAR2 inhibitors on the anti-tumor efficacy of immune checkpoint inhibitors at later stages of tumor development
  • 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 9 days post tumor inoculation and 10Opig after 12 and 15 days.
  • the PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage.
  • 1-177 was administered at a 30mg/kg dose from day 5 to day 9 post tumor inoculation. Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm 2 .
  • a complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
  • priming doses of 1-117 increased the anti-tumor efficacy of anti-PD 1 at later stages of tumor development. Indeed, similarly to previous experiments, increased progression-free survival rate and a decreased tumor growth were observed in the combination group compared to monotherapies when both treatments were delayed. Furthermore, tumors were rejected in 40% of animals when treated with anti-PD 1 alone. In the combination groups, the rate of complete response increased to 70%.
  • Example 5 Influence of the timing of priming doses of PAR2 inhibitors on the anti-tumor efficacy of immune checkpoint inhibitors
  • MC38 cells 0.5x10 6 MC38 cells (ATCC) were subcutaneously injected into groups of 10 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 9 days post tumor inoculation and 10Opig after 12 and 15 days.
  • the PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage at a 30mg/kg dose.
  • priming doses of 1-117 increased the anti-tumor efficacy of anti-PD1 treatment even when a 2-day washout period was allowed between the 2 treatments.
  • an increased progression-free survival rate and a decreased tumor growth were observed in the combination group compared to monotherapies when 1-117 was administered from day 5 to day 9 or from day 3 to day 7 post tumor inoculation.
  • tumors were rejected in 50% of animals when treated with anti-PD 1 alone.
  • the rate of complete response increased to 70-80% with both regimens.
  • a similar rate of complete response (70%) was also observed when 1-117 was administered for 3 days (from day 5 to day 7 post tumor inoculation) instead of 5 days.

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Abstract

The present invention relates to a protease-activated receptor-2 (PAR2) inhibitor in combination with an immune checkpoint inhibitor for use in the treatment of cancer via a specific administration/dosage regimen, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier (e.g., 3 to 7 days earlier) than the administration of the immune checkpoint inhibitor.

Description

COMBINATIONS OF PAR2 INHIBITORS AND IMMUNE CHECKPOINT INHIBITORS FOR THE TREATMENT OF CANCER
The present application claims the benefit of priority of European patent application EP24305275.0 filed on February 16, 2024, which is incorporated herein by reference in its entirety.
Field of the invention
The present invention relates to a protease-activated receptor-2 (PAR2) inhibitor in combination with an immune checkpoint inhibitor for use in the treatment of cancer via a specific administration/dosage regimen, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier (e.g., 3 to 7 days earlier) than the administration of the immune checkpoint inhibitor.
Background of the invention
The protease-activated receptors (PARs) family
G Protein-Coupled Receptors (GPCRs) form the largest family of human membrane proteins (~ 800 members) and are involved in many physiological processes. Compounds targeting GPCRs also represent approximately 27% of the global market for therapeutic drugs (Hauser et al., Nat. Rev. Drug Discov., 2017, 16(12):829-842).
2% of the human genome code for proteases (also called proteinases) which suggests their importance in the correct functioning of the body (Hollenberg et al., Br. J. Pharmacol., 2014, 171 (5): 1180-94). Indeed, it has been shown that certain soluble and membrane-bound proteinases can regulate cell function by cleaving GPCRs at the cell surface to activate or inactivate receptors such as the Protease-Activated Receptors (PARs). The PARs family is composed of four members (PAR-1 , PAR-2, PAR-3 and PAR-4) and belongs to the class A GPCR-receptor sub-family (Marcfarlane et al., Pharmacological Reviews, 2001 , 475(7357):519-23). They are expressed in widely diverse cells such as platelets, immune cells, endothelial cells, myocytes, astrocytes, neurons, epithelial cells and fibroblasts and involved in a large set of physiological and pathophysiological functions (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579- 621).
PAR-2: mechanism of action
Activation of PARs involves the cleavage of the extracellular N-terminal part of the receptor by proteases at a specific site. This unmasks an amino-acid sequence in the amino terminus that folds back to act as a "tethered ligand” (TL): it binds to a conserved region in the second extracellular loop of the cleaved receptor and triggers intra-cellular signalling (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579-621 ; Hollenberg et al., Br. J. Pharmacol., 2014, 171 (5): 1180-94).
PAR-2 is activated by several host and pathogen-derived serine proteases such as trypsin, mast cell tryptase, kallikreins and members of the coagulation cascade TF-FVIla and FVa-FXa. These proteases cleave at R34J,S35LIGKV and unmask the tethered ligand SLIGKV in humans. Artificially, in vitro, synthetic peptides corresponding to the TL (SLIGKV) can activate the receptor without cleavage. Activation of PAR-2 induces several signalling cascades involving a number of G proteins such as Gq, G, and G12/13. The pathway best described so far involves its interaction with Gq and the mobilization of intracellular calcium that influences the function of several cell types. After repeated activations, PAR2 is rapidly desensitized via its endocytosis by a p-arrestin-dependent mechanism and its targeting to the lysosomes (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579-621 ).
PAR-2 in physiological conditions
PAR-2 has been shown to have a key function in multiple organs (Ossovskaya et al., Physiol. Rev., 2004, 84(2):579- 621). PAR-2 is expressed in the brain within neurons and glial cells. It is also found in the periphery in spinal afferent neurons and nociceptive DRG neurons. PAR-2 signalling has been involved in the survival, sensitization of these cells and their signal transmission, thereby controlling neuronal damage, inflammation and pain.
PAR-2 is involved in the function of the cardiovascular system. Indeed, its activation can induce the relaxation or contraction of some vessels such as pulmonary arteries, coronary and intramyocardial arteries, therefore regulating the blood flow. It also controls inflammation and repair of the endothelium which influences vascular permeability.
PAR-2 expression has been detected within the gastrointestinal system in the small intestine, colon, liver, pancreas and stomach. Its activation has been involved in the regulation of ion transport from the intestinal mucosa, contraction of gastric longitudinal muscle, pancreatic, salivary and gastric secretions, excitation of myenteric neurons, intestinal barrier integrity, release of prostaglandins from enterocytes. PAR-2 therefore plays a key role in controlling fluid secretion, intestinal inflammation, and gastro-intestinal hyperalgesia.
PAR-2 is involved in airways function since it is expressed by epithelial and endothelial cells in the lungs. Its activation has been shown to regulate bronchodilatation or bronchoconstriction (depending on the experimental system used), ion transport in the airway epithelium, proliferation and activation of airway smooth muscle cells and lung fibroblasts. PAR-2 can thus regulate airway resistance, lung inflammation and lung fibrosis.
In the skin, PAR-2 expression has been detected in keratinocytes, microvasculature and immune cells. Its activation has been involved in skin pigmentation, skin inflammation, and wound healing.
Finally, PAR-2 expression has been detected in immune cells such as macrophages where it influences cell maturation and cytokine secretion, thereby regulating inflammation.
PAR-2 in cancer
The expression of PAR-2 and proteases is significantly increased in many cancer types such as cervical squamous cell carcinoma, endocervical adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, glioblastoma multiforme, acute myeloid leukemia, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, testicular germ cell tumors, uterine corpus endometrial carcinoma, uterine carcinosarcoma, hepatocellular carcinoma, and breast cancer, which can be associated to poor prognosis (Kaufmann et al., Carcinogenesis, 2009, 30(9):1487-96; Su et al., Oncogene, 2009, 28(34):3047-57; Arakaki et al., Int. J. Mol. Sci. 2018, 19, 1886). The activation of this receptor in cancer cells can lead to several signalling cascades such as calcium, p-arrestin and Gi signalling (Kaufmann et al., J Cancer Res Clin Oncol, 2011, 137 (6): 965-73; Wu et al., Mol Med Rep, 2014, 10(6):3021 -6; Ge et al., J Biol Chem, 2004, 279(53):55419-24). This ultimately controls cancer cell migration, proliferation, survival, and expression of inflammatory cytokines (Jiang et al., J Pharmacol Exp Ther, 2018, 364(2):246-257; Darmoul et al., British J Cancer, 2001 , 85(5)772-9; Quan et al., Oncol Res., 2019, 27(7)779-788). The expression of PAR-2 on other cells of the tumor microenvironment, such as immune cells, fibroblasts, endothelial cells and DRG neurons, can also control the immune response to cancer cells, fibrosis, as well as angiogenesis and cancer-induced pain (Mubbach et al., Mol cancer, 2016, 15(1):54; Uusitalo-Jarvinen et al., Arieriocler Thromb Vase Biol, 2007, 27(6): 1456-62; D’Andrea et al., Am J Pathol, 2001 , 158(6):2031-41 ; Graf et al., Sci Immunol, 2019, 4(39):eaaw8405; Qian at al., Oncol Lett, 2018, 16(2): 1513-20; Tu et al., J Neurosci, 2021 , 41 (1):193-210). In vivo, the inhibition of PAR-2 has been shown to be an efficient way of reducing tumor growth and increasing survival in mouse models of different cancers such as breast cancer, liver cancer and colon cancer (Versteeg et al., Cancer Res, 2008, 68(17)7219-27; Sun et al., World J Gastroenterol, 2018, 24(10):1120-1133; Quan et al., Oncol Res., 2019, 27(7)779-788). Importantly, PAR2 loss of function mutation or inhibition of one of its ligands led to reduced infiltration of immune-suppressive Tumor Associated Macrophages and regulatory T cells while increasing cytotoxic T cells in the tumor in several syngeneic mouse models; this unleashed the anti-tumoral immune response and increased the potency of immune-checkpoint inhibitors currently used in the clinic (Graf et al., Sci Immunol, 2019, 4(39):eaaw8405). PAR-2 therefore constitutes a promising therapeutic target in oncology and immuno-oncology.
Considering the role of PAR-2 in several pathophysiological conditions, inhibitors of this receptor can have therapeutic applications in a wide variety of human diseases. This has drawn a great interest from pharmaceutical industries to develop such compounds. Various PAR-2 inhibitors and therapeutic uses thereof have been proposed, for example, in: Yau et al., Expert Opin Ther Pat, 2016, 26(4):471-83; Jiang et al., J Pharmacol Exp Ther, 2018, 364(2):246-57; WO 2004/002418; WO 2005/030773; WO 2012/012843; WO 2012/026765; WO 2012/026766; WO 2012/101453; WO 2015/048245; WO 2016/154075; WO 2017/194716; WO 2017/197463; WO 2018/043461 (EP 3508 487); WO 2018/057588; WO 2019/124567; WO 2019/163956 (EP 3 760 631); WO 2019/199800; JP 2020/007262; WO 2021/106864; WO 2022/117882; and WO 2023/233033. However, despite the efforts made, no PAR-2 inhibitor has reached the market yet (Yau et al., Expert Opin TherPat, 2016, 26(4):471 -83) and most of these inhibitors have been developed against auto-immune diseases. Furthermore, publicly available in vivo data demonstrating the role of PAR2 in tumor growth has been obtained either through genetic engineering (Nag et al., FASEB J, 2023, 37(1):e22675; Kancharla et al., Nat Commun, 2015, 6:8853; Graf et al., Sci Immunol, 2019, 4(39):eaaw8405; Versteeg et al., Cancer Res, 2008, 68(17)7219-27; Sun et al., World J Gastroenterol, 2018, 24(10): 1120-1133; Schaffner et al., Blood, 2010, 116(26):6106-13; MuBbach et al., Mol Cancer, 2016, 15(1):54; Shi et al., J Pathol, 2014, 234(3):398-409), the use of PAR-2 inhibitors alone in immuno-compromised mice (Versteeg et al., Blood, 2008, 111 (1):190-9) and/or in combination with chemo- or targeted therapies (Quan et al., Oncol Res, 2019, 27(7)779-788; Li et al., Cancer Lett, 2021 , 517:14-23; Jiang et al., Front Pharmacol, 2021 , 12:625289; Jiang et al., Biochim Biophys Acta Mol Cell Res, 2022, 1869(1): 119144). However, the use of PAR2 inhibitors in combination with checkpoint inhibitors in cancer has not been described. There is therefore an unmet need to determine if and how PAR2 inhibitors could be used to increase the efficacy of existing immune checkpoint inhibitors against cancer.
The present invention addresses this need and provides a new and unexpected mode and timing of administration necessary to unravel the therapeutic effect of PAR2 inhibitors in immuno-oncology when used in combination with immune checkpoint inhibitors. In particular, the present invention provides a specific administration/dosage regimen using a PAR2 inhibitor in combination with an immune checkpoint inhibitor, which has surprisingly been found to yield remarkably enhanced therapeutic effects against cancer, as also demonstrated in the examples described herein below.
Summary of the invention
In a first aspect, the present invention provides a PAR2 inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a second aspect, the invention provides an immune checkpoint inhibitor for use in the treatment of cancer, wherein the immune checkpoint inhibitor is administered in combination with a PAR2 inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a third aspect, the invention provides a combination of a PAR2 inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a fourth aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PAR2 inhibitor and an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a fifth aspect, the invention relates to the use of a PAR2 inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with an immune checkpoint inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a sixth aspect, the invention relates to the use of an immune checkpoint inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with a PAR2 inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a seventh aspect, the invention relates to the use of a PAR2 inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor. Brief description of the drawings
Figure 1: Influence of PAR2 knock out (KO) on anti-tumor efficacy of anti-PD1. (A) Experimental design. Fig. 1A is a schematic diagram showing the design of the experiment performed to determine the effect of PAR2 knock out on the anti-tumor efficacy of immune checkpoint inhibitors. MC38 cells were subcutaneously injected into groups of 10 syngeneic PAR2 knock out female C57BL/6 mice (PAR2-/-) or wild type litter mates (WT). Anti-PD 1 antibody or isotype control were intraperitoneally injected at days 6, 9 and 12 post tumor inoculation. Anti-tumor efficacy was determined by assessing progression-free survival rate and tumor growth. (B) Progression-free survival. Fig. 1 B is a diagram showing the progression free survival rate in MC38 bearing wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD1 or isotype control (Iso). Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (C) Mean tumor growth. Fig. 1C is a diagram showing mean MC38 tumor volume changes in wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso). 10 mice per group were treated. Average tumor volume (mm2) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a mixed effect model test, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (D) Individual tumor growth. Fig. 1 D is a set of diagrams showing MC38 tumor volume changes in each wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso). The rate of complete response (CR) is indicated when applicable. (E) Mean tumor volume at day 16 (D16). Fig. 1 E is a diagram showing individual MC38 tumor volume in wild type (WT) or PAR2 knock out (PAR2-/-) mice treated with anti-PD 1 or isotype control (Iso) at day 16 (last day at which all mice were still alive in every group). Average tumor volume (mm2) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****.
Figure 2: Influence of pharmacological inhibition of PAR2 on anti-tumor efficacy of anti-PD1 according to the timing of administration. (A) Experimental design. Fig. 2A is a schematic diagram showing the design of the experiment performed to determine the effect of pharmacological PAR2 inhibition on the anti-tumor efficacy of immune checkpoint inhibitors according to timing of administration. MC38 cells were subcutaneously injected into groups of 15 syngeneic C57BL/6 mice. Anti-PD1 antibody or isotype control were intraperitoneally injected at days 6, 9, 12 and 15 post tumor inoculation. The PAR2 inhibitor 1-117 (at a 30mg/kg dose) or vehicle were given once a day by oral gavage for 21 days. For the monotherapy, treatment with 1-117 started at day 6 post tumor inoculation. For the combination, 1-117 treatment started either before (day 3), at the same time (day 6) or after (day 9) anti-PD 1 therapy. Anti-tumor efficacy was determined by assessing progression-free survival rate and tumor growth. (B) Progression-free survival. Fig. 2B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti- PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD1 therapy is indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups (taking all groups into account), p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : **** (C) Mean tumor growth. Fig. 2C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD 1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD1 therapy is indicated. Average tumor volume (mm3) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups (taking all groups into account) after a mixed effect model test, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (D) Individual tumor growth. Fig. 2D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD 1 therapy is indicated. The rate of complete response (CR) is indicated when applicable. (E) Mean tumor volume at day 20 (D20). Fig. 2E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti- PD1 , 1-117 or a combination of both anti-PD1 and 1-117 at day 20 (last day at which all mice were still alive in every group). Average tumor volume (mm3) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups (taking all groups into account), p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (F) Progression-free survival. Fig. 2F is a diagram showing the progression free survival rate in MC38 bearing mice treated with anti-PD1 or a combination of both anti-PD1 and 1-117. For the combination group, start of 1-117 treatment compared to anti-PD1 therapy is indicated. Log-rank (Mantel-Cox) test was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (G) Mean tumor growth. Fig. 2G is a diagram showing mean MC38 tumor volume changes in mice treated with anti-PD1 or a combination of both anti-PD1 and 1-117. For the combination groups, start of 1-117 treatment compared to anti-PD 1 therapy is indicated. Average tumor volume (mm3) and SD bars were plotted for each group. A mixed effect model test was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : **** (H) Mean tumor volume at day 20 (D20). Fig. 2H is a diagram showing individual MC38 tumor volume in mice treated with anti-PD1 or a combination of both anti-PD 1 and 1-117 at day 20 (last day at which all mice were still alive in every group). Average tumor volume (mm3) and SD bars were also plotted for each group. Mann-Whitney test was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****.
Figure 3: Influence of pharmacological inhibition of PAR2 by 1-117 on anti-tumor efficacy of anti-PD1 according to the dosing regimen. (A) Experimental design. Fig. 3A is a schematic diagram showing the design of the experiment performed to determine the effect of priming doses of 1-117 on the anti-tumor efficacy of immune checkpoint inhibitors. MC38 cells were subcutaneously injected into groups of 10 syngeneic C57BL/6 mice. Anti-PD1 antibody or isotype control were intraperitoneally injected at days 6, 9 and 12 post tumor inoculation. The PAR2 inhibitor 1-117 (at a 30mg/kg dose) or vehicle were given once a day by oral gavage. For the monotherapy, treatment with 1-117 started at day 2 post tumor inoculation and lasted for 5 days. For the combination treatment, 1-117 administrations either lasted for 21 days (days 3 to 24 post tumor inoculation) or 5 days (days 2 to 6 post tumor inoculation). Anti-tumor efficacy was determined by assessing progression-free survival rate and tumor growth. (B)Progression-free survival. Fig. 3B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1, 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups, start and end days of 1-117 treatment are indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups (taking all groups into account), p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (C) Mean tumor growth. Fig. 3C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD 1 and 1-117. For the combination groups, start and end days of 1-117 treatment are indicated. Average tumor volume (mm2) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups (taking all groups into account) after a mixed effect model test, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (D) Individual tumor growth. Fig. 3D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated when applicable. (E) Mean tumor volume at day 18 (D18). Fig. 3E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117 at day 18 (last day at which all mice were still alive in every group). For the combination groups start and end days of 1-117 treatment are indicated. Average tumor volume (mm2) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups (taking all groups into account), p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (F) Progression-free survival. Fig. 3F is a diagram showing the progression free survival rate in MC38 bearing mice treated with anti-PD1 or a combination of anti-PD1 and 1-117. For the combination group, start and end days of 1-117 treatment are indicated. Log-rank (Mantel-Cox) test was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (G) Mean tumor growth. Fig. 3G is a diagram showing mean MC38 tumor volume changes in mice treated with anti- PD1 or a combination of anti-PD1 and 1-117. For the combination group, start and end days of 1-117 treatment are indicated. Average tumor volume (mm2) and SD bars were plotted for each group. A mixed effect model test was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****.
Figure 4: Influence of priming doses of Compound 207 on anti-tumor efficacy of anti-PD 1. (A) Fig. 4A is a schematic diagram showing the design of the experiment performed to determine the effect of priming doses of Compound 207 on the anti-tumor efficacy of immune checkpoint inhibitors. MC38 cells were subcutaneously injected into groups of 12 syngeneic C57BL/6 mice. Anti-PD1 antibody or isotype control were intraperitoneally injected at days 6, 9 and 12 post tumor inoculation. The PAR2 inhibitor Compound 207 (207) or vehicle were given once a day by oral gavage from day 2 post tumor inoculation to day 6. For the monotherapy, Compound 207 was given at a 30mg/kg dose. For the combination treatment, Compound 207 was given at a 30mg/kg or 100mg/kg dose. Anti-tumor efficacy was determined by assessing progression-free survival rate and tumor growth. (B) Progression-free survival. Fig. 4B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207. For the combination groups, doses of Compound 207 used are indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (C) Mean tumor growth. Fig. 4C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207. For the combination groups, doses of Compound 207 used are indicated. Average tumor volume (mm2) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a mixed effect model test, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : **** (D) Individual tumor growth. Fig. 4D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD1 and Compound 207. For the combination groups, doses of Compound 207 used are indicated. The rate of complete response (CR) is indicated when applicable. (E) Mean tumor volume at day 25 (D25). Fig. 4E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti-PD1 , Compound 207 (207), or a combination of both anti-PD 1 and Compound 207 at day 25 (last day at which all mice were still alive in every group). For the combination groups, doses of Compound 207 used are indicated. Average tumor volume (mm2) and SD bars were also plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a one-way ANOVA. p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. Figure 5: Influence of priming doses of 1-117 on anti-tumor efficacy of anti-PD1 at later stage of tumor development. (A) Fig. 5A is a schematic diagram showing the design of the experiment performed to determine if the benefit of a combination between PAR2 inhibitors and immune-checkpoint inhibitors could also be observed at later stages of the tumor development. MC38 cells were subcutaneously injected into groups of 10 syngeneic C57BL/6 mice. Anti-PD 1 antibody or isotype control were intraperitoneally injected at days 9, 12 and 15 post tumor inoculation. The PAR2 inhibitor 1-117 (at a 30mg/kg dose) or vehicle were given once a day by oral gavage from day 5 post tumor inoculation to day 9. Anti-tumor efficacy was determined by assessing progression-free survival rate and tumor growth. (B) Progression-free survival. Fig. 5B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : **** (C) Mean tumor growth. Fig. 5C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD 1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. Average tumor volume (mm2) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a mixed effect model test . p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : **** (D) Individual tumor growth. Fig. 5D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117. For the combination groups start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated when applicable. (E) Mean tumor volume at day 15 (D15). Fig. 5E is a diagram showing individual MC38 tumor volume in mice treated with isotype control (Iso), anti-PD1 , 1-117 or a combination of both anti-PD1 and 1-117 at day 15 (last day at which all mice were still alive in every group). For the combination groups start and end days of 1-117 treatment are indicated. Average tumor volume (mm2) and SD bars were also plotted for each group. Brown-Forsythe ANOVA Test followed by a Dunnett's multiple comparison test were used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****.
Figure 6: Influence of the timing of priming doses of 1-117 on anti-tumor efficacy of anti-PD1 treatment. (A) Fig. 6A is a schematic diagram showing the design of the experiment performed to determine the effect of the timing of priming doses of 1-117 on the anti-tumor efficacy of immune checkpoint inhibitors. MC38 cells were subcutaneously injected into groups of 10 syngeneic C57BL/6 mice. Anti-PD1 antibody or isotype control were intraperitoneally injected at days 9, 12 and 15 post tumor inoculation. The PAR2 inhibitor 1-117 or vehicle were given once a day by oral gavage at a 30mg/kg dose at different timings. 1-117 was administered either from day 5 to day 9 post tumor inoculation, or day 3 to day 7 post tumor inoculation, or day 5 to day 7 post tumor inoculation, or on day 7 post tumor inoculation, or on days 7, 10 and 13 post tumor inoculation. Anti-tumor efficacy was determined by assessing progression-free survival rate and tumor growth. (B) Progression-free survival. Fig. 6B is a diagram showing the progression free survival rate in MC38 bearing mice treated with isotype control (Iso), anti-PD1 , or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated. Log-rank (Mantel-Cox) test with Bonferroni correction was used to compare the groups, p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : **** (C) Mean tumor growth. Fig. 6C is a diagram showing mean MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1, or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated. Average tumor volume (mm2) and SD bars were plotted for each group. Tukey's multiple comparisons test was used to compare the groups after a mixed effect model test . p < 0.05: *, p < 0.01 : **, p < 0.005: ***, p < 0.001 : ****. (D) Individual tumor growth. Fig. 6D is a set of diagrams showing MC38 tumor volume changes in mice treated with isotype control (Iso), anti-PD1 , or a combination of both anti-PD1 and 1-117. For the combination groups, the start and end days of 1-117 treatment are indicated. The rate of complete response (CR) is indicated.
Detailed description of the invention
In a first aspect, the present invention provides a PAR2 inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a second aspect, the invention provides an immune checkpoint inhibitor for use in the treatment of cancer, wherein the immune checkpoint inhibitor is administered in combination with a PAR2 inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a third aspect, the invention provides a combination of a PAR2 inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a fourth aspect, the invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PAR2 inhibitor and an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a fifth aspect, the invention relates to the use of a PAR2 inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with an immune checkpoint inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a sixth aspect, the invention relates to the use of an immune checkpoint inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with a PAR2 inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
In a seventh aspect, the invention relates to the use of a PAR2 inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor. The following detailed description, including the explanations as well as the exemplary and preferred features set out below, pertains to each aspect of the present invention. In particular, it relates specifically and individually to each one of the above-described first aspect, second aspect, third aspect, fourth aspect, fifth aspect, sixth aspect, and seventh aspect of the invention.
Typically, the PAR2 inhibitor can be provided in the form of a pharmaceutical composition comprising the PAR2 inhibitor and optionally one or more pharmaceutically acceptable excipients. Likewise, the immune checkpoint inhibitor can be provided in the form of a pharmaceutical composition comprising the immune checkpoint inhibitor and optionally one or more pharmaceutically acceptable excipients. Thus, for example, the present invention also provides a pharmaceutical composition comprising a PAR2 inhibitor (and optionally one or more pharmaceutically acceptable excipients), for use in the treatment of cancer, wherein the pharmaceutical composition comprising the PAR2 inhibitor is administered in combination with a pharmaceutical composition comprising an immune checkpoint inhibitor (and optionally one or more pharmaceutically acceptable excipients), wherein the administration of the pharmaceutical composition comprising the PAR2 inhibitor is started at least 1 day earlier than the administration of the pharmaceutical composition comprising the immune checkpoint inhibitor. Such different/separate pharmaceutical compositions, i.e. the (first) pharmaceutical composition comprising the PAR2 inhibitor and the (second) pharmaceutical composition comprising the immune checkpoint inhibitor, can also be provided in the form a kit that comprises the corresponding pharmaceutical compositions.
As explained above, in accordance with the administration/dosage regimen of the present invention, the administration of the PAR2 inhibitor is started at least 1 day earlier than (or, in other words, prior to) the administration of the immune checkpoint inhibitor. Accordingly, the PAR2 inhibitor is administered at least 1 day before the first administration/dose of the immune checkpoint inhibitor.
Preferably, the administration of the PAR2 inhibitor is started at least 2 days earlier than the administration of the immune checkpoint inhibitor. For example, the administration of the PAR2 inhibitor may be started from 2 to 30 days earlier than the administration of the immune checkpoint inhibitor, or from 2 to 21 days earlier than the administration of the immune checkpoint inhibitor, or 2 to 14 days earlier than the administration of the immune checkpoint inhibitor, or 2 to 7 days earlier than the administration of the immune checkpoint inhibitor. In particular, the administration of the PAR2 inhibitor may be started, e.g., 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days earlier than the administration of the immune checkpoint inhibitor. More preferably, the administration of the PAR2 inhibitor is started at least 3 days earlier than the administration of the immune checkpoint inhibitor. Thus, for example, the administration of the PAR2 inhibitor may be started 3 to 14 days (e.g., 3, 5, 7, 10 or 14 days), particularly 3 to 7 days (e.g., 3 or 5 days), earlier than the administration of the immune checkpoint inhibitor.
The PAR2 inhibitor is preferably administered at a regular dosing interval, e.g., daily (i.e., every day), every 2 days, weekly (i.e., every week), or biweekly (i.e., every 2 weeks). If the PAR2 inhibitor is a small molecule, it is preferred that it is administered daily or every 2 days. In the case of daily administration, the PAR2 inhibitor may be administered, e.g., once daily (QD), twice daily (BID), three times per day (TID), or four times per day (QID). More preferably, the PAR2 inhibitor is administered daily, even more preferably once daily. Accordingly, if the PAR2 inhibitor is a small molecule (e.g., any one of the compounds described in WO 2022/117882 or WO 2023/233033), it is particularly preferred that it is administered once daily. If the PAR2 inhibitor is an antibody (or an antigen-binding fragment thereof or an antibody construct), it is preferably administered weekly or biweekly, particularly once every 1 or 2 weeks, more preferably once every 2 weeks.
When the administration of the PAR2 inhibitor is started at a defined time interval (e.g., 5 days) prior to the administration of the immune checkpoint inhibitor, the PAR2 inhibitor may be continued to be administered (preferably at a regular dosing interval, as described above) until the first administration of the immune checkpoint inhibitor. Thus, for example, the PAR2 inhibitor may be administered daily (preferably once daily) up until the day when the first dose of the immune checkpoint inhibitor is administered. Once the administration of the immune checkpoint inhibitor is started, the administration of the PAR2 inhibitor may be discontinued (or, in other words, may be halted) or may be further continued. Alternatively, the administration of the PAR2 inhibitor may also be discontinued/halted shortly (e.g., 1 day) before the first administration of the immune checkpoint inhibitor. The present invention particularly relates to the sequential administration of the PAR2 inhibitor followed by the immune checkpoint inhibitor, whereby the administration of the PAR2 inhibitor is discontinued/halted when the administration of the immune checkpoint inhibitor is started.
In accordance with the above, the administration of the PAR2 inhibitor may be started, e.g., 3 to 5 days earlier than the administration of the immune checkpoint inhibitor, whereby the PAR2 inhibitor may be administered daily (preferably once daily) over a period of at least 3 days before the administration of the immune checkpoint inhibitor.
The immune checkpoint inhibitor is preferably administered at a regular dosing interval, e.g., every week (i.e., once every week), every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks.
The PAR2 inhibitor to be used in accordance with the present invention may be, in principle, any compound/substance that decreases, reduces, prevents, blocks, antagonizes or inhibits the activity, function or gene expression of protease-activated receptor-2 (PAR2). In particular, the PAR2 inhibitor may be a small molecule, a peptide, or an antibody (or an antigen-binding fragment thereof, or an antibody construct; e.g., a monoclonal antibody). The PAR2 inhibitor may be a PAR2 inhibitor that is known in the art, including, e.g., any one of the compounds disclosed in: Yau et al., Expert Opin Ther Pat, 2016, 26(4):471-83; Jiang et al., J Pharmacol Exp Ther, 2018, 364(2):246-57;
WO 2004/002418; WO 2005/030773; WO 2012/012843; WO 2012/026765; WO 2012/026766; WO 2012/101453;
WO 2015/048245; WO 2016/154075; WO 2017/194716; WO 2017/197463; WO 2018/043461 (or EP 3 508487);
WO 2018/057588; WO 2019/124567; WO 2019/163956 (or EP 3 760 631); WO 2019/199800; JP 2020/007262;
WO 2021/106864; WO 2022/117882; WO 2022/255408; or WO 2023/233033; whereby each of the aforementioned documents is incorporated herein by reference in its entirety. Accordingly, the PAR2 inhibitor may be, e.g., a compound disclosed in any one of the aforementioned documents (e.g., in the examples section of any one of the aforementioned patent documents), wherein said compound may be used in non-salt form or in the form of a pharmaceutically acceptable salt or solvate. The PAR2 inhibitor may also be an anti-PAR2 antibody, e.g., any one of the antibodies (or antigen-binding fragments thereof) that are disclosed in WO 2018/167322 or WO 2022/040345, each of which is incorporated herein by reference in its entirety.
Preferred examples of the PAR2 inhibitor to be used in accordance with the present invention include any one of the compounds described in WO 2022/117882 or WO 2023/233033, particularly any one of the PAR2 inhibitors described in the examples section of WO 2022/117882 or in the examples section of WO 2023/233033, either in non-salt form and/or non-solvated form or as a pharmaceutically acceptable salt or solvate of the respective compound.
Accordingly, it is preferred that the PAR2 inhibitor is selected from:
T-(4-chloro-3-fluorophenyl)-5'-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-2,3,5,6-tetrahydrospiro[pyran-4,3'- pyrrolo[3,2-b]pyridin]-2'(1'H)-one;
T-(4-chloro-3-fluorophenyl)-5'-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)spiro[cyclopentane-1,3'-pyrrolo[3,2- b]pyridin]-2'(1'H)-one;
4-(T-(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-2-one;
8-(1 (4-chloro-3-fl uoropheny I)- 1 ',2'-d i hydrospi ro[cyclopentane- 1 , 3'-py rrol o[3, 2-b] py ridi ne]-5'-carbony I)- 1 ,3,8- triazaspiro[4.5]decane-2, 4-dione; methyl 1-(T-(4-chloro-3-fluorophenyl)-T,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperidine-4-carboxylate;
1-(T-(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperidine-4-carboxylic acid; methyl 6-(4-(T-(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)- 3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(T-(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
4-(T-(3-chlorophenyl)- ,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-
2-one;
4-(T-(2-chlorophenyl)- ,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin- 2-one;
4-(3,3-dimethyl-1-(thiophen-3-yl)-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(3,4-difluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2- one; methyl 6-(4-(1-(3,4-difluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(1-(3,4-difluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid;
4-(1-(4-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one; methyl 6-(4-(1-(3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate; 6-(4-(1-(3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid;
4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin- 2-one;
4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-1-ethyl-3,3- dimethylpiperazin-2-one;
(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-5-yl)(3,3- dimethylmorpholino)methanone; tert-butyl 4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazine-1-carboxylate;
(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-5-yl)(2,2-dimethylpi perazin-1- yl)methanone;
(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-5-yl)(4-ethyl-2,2-dimethylpiperazin-1- yl)methanone;
1-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)ethan-1-one; ethyl 4-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-oxobutanoate;
4-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-oxobutanoic acid; ethyl 5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-5-oxopentanoate;
5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-5-oxopentanoic acid;
8-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-1-methyl-1 ,3,8- triazaspiro[4.5]decan-4-one;
2-(3-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- azabicyclo[3.1.0]hexan-6-yl)acetic acid; methyl 2-(3-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- azabicyclo[3.1.0]hexan-6-yl)acetate; methyl 2-((1 R,5S,6S)-3-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-
3-azabicyclo[3.1 ,0]hexan-6-yl)acetate;
2-((1 R,5S,6S)-3-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- azabicyclo[3.1.0]hexan-6-yl)acetic acid; ethyl 1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidine-4- carboxylate;
1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidine-4-carboxylic acid; methyl 2-(1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-4- yl)acetate; 2-(1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-4-yl)acetic acid;
2-(1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3-methoxypi peridin-
4-yl)acetic acid; methyl 2-(1 -(1 -(4-ch I oro-3-f I uoropheny I )-3, 3-d i methy 1-2,3-d i hy d ro- 1 H-py rrolo [3, 2-b] py ri d i ne-5-carbony I )-3- methoxypiperidin-4-yl)acetate; methyl 2-((3R,4S)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetate;
2-((3R,4S)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetic acid; ethyl 2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-methylpyrimidine-5-carboxylate;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-methylpyrimidine-5-carboxylic acid; ethyl 2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyrimidine-5-carboxylate;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-pyrimidine-5-carboxylic acid; ethyl 2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)thiazole-4-carboxylate;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)thiazole-4-carboxylic acid; methyl 6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
3-(1-(4-chloro-3-fluorophenyl)-N,3,3-trimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carboxamido)butanoic acid; methyl 3-(1-(4-chloro-3-fluorophenyl)-N,3,3-trimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamido)butanoate; methyl (R)-3-(1-(4-chloro-3-fluorophenyl)-N,3,3-trimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamido)butanoate;
(R)-3-(1-(4-chloro-3-fluorophenyl)-N,3,3-trimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carboxamido)butanoic acid;
N-(1-carbamoylcyclopropyl)-1-(4-chloro-3-fluorophenyl)-N,3,3-trimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamide; methyl 6-((2-(1-(4-chloro-3-fluorophenyl)-N,3,3-trimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamido)ethyl)(methyl)amino)-2,4-dimethylnicotinate;
6-((2-(1-(4-chloro-3-fluorophenyl)-N,3,3-trimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamido)ethyl)(methyl)amino)-2,4-dimethylnicotinic acid; 1-(4-chloro-3-fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamide;
1-(4-chloro-3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamide;
4-(1-(4-chloro-3-fluorophenyl)-3-ethyl-3-methyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-2-one;
N-(1-carbamoylcyclopropyl)-1-(4-chloro-3-fluorophenyl)-3-ethyl-3-methyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carboxamide;
4-( -(4-chloro-3-fluorophenyl)- ,2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-2-one;
6-(4-( -(4-chloro-3-fluorophenyl)- ,2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
4-(1'-(4-chloro-3-fluorophenyl)- j2'-dihydrospiro[cyclopropane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-2-one;
4-( -(4-chloro-3-fluorophenyl)- ,2',4,5-tetrahydro-2H-spiro[furan-3,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-2-one; methyl 6-(4-(T-(4-chloro-3-fluorophenyl)- ,2',4,5-tetrahydro-2H-spiro[furan-3,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-( -(4-chloro-3-fluorophenyl)- ,2',4,5-tetrahydro-2H-spiro[furan-3,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
4-(8-(4-chloro-3-fluorophenyl)-3a-methyl-3,3a,8,8a-tetrahydro-2H-furo[3',2':4,5]pyrrolo[3,2-b]pyridine-5-carbonyl)-
3.3-dimethylpiperazin-2-one; cis-4-(8-(4-chloro-3-fluorophenyl)-3a-methyl-3,3a,8,8a-tetrahydro-2H-furo[3',2':4,5]pyrrolo[3,2-b]pyridine-5- carbonyl)-3,3-dimethylpiperazin-2-one;
4-((3aR,8aR)-8-(4-chloro-3-fluorophenyl)-3a-methyl-3,3a,8,8a-tetrahydro-2H-furo[3',2':4,5]pyrrolo[3,2-b]pyridine-5- carbonyl)-3,3-dimethylpiperazin-2-one;
4-((3aS,8aS)-8-(4-chloro-3-fluorophenyl)-3a-methyl-3,3a,8,8a-tetrahydro-2H-furo[3',2':4,5]pyrrolo[3,2-b]pyridine-5- carbonyl)-3,3-dimethylpiperazin-2-one; methyl 2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; ethyl 5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-1 ,3,4-thiadiazole-2-carboxylate;
(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-5-yl)(2,2-dimethyl-4-(1 ,3,4-thiadiazol- 2-yl)piperazin-1-yl)methanone; ethyl 2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-methylthiazole-5-carboxylate;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-methylthiazole-5-carboxylic acid; ethyl 2-(2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-methylthiazol-5-yl)acetate;
2-(2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-methylthiazol-5-yl)acetic acid; methyl 2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-5-methylthiazole-4-carboxylate;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-5-methylthiazole-4-carboxylic acid;
1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-7,7-dimethyl-1 ,4- diazepan-5-one;
8-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-2,8- diazaspiro[4.5]decan-1-one;
8-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-2,8- diazaspiro[4.5]decan-3-one;
1-(1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-4- yl)imidazolidin-2-one; ethyl 2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylate;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-4-(trifluoromethyl)thiazole-5-carboxylic acid;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-N,N-dimethylthiazole-4-carboxamide;
(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-5-yl)(4-(4-(4-hydroxypiperidine-1- carbonyl)thiazol-2-yl)-2,2-dimethylpiperazin-1-yl)methanone;
(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-5-yl)(2,2-dimethyl-4-(4-(morpholine-4- carbonyl)thiazol-2-yl)piperazin-1-yl)methanone;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)thiazole-4-carboxamide; methyl 6-(4-(1-(3-fluoro-4-methylphenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(1-(3-fluoro-4-methylphenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(4-(4-chloro-3-fluorophenyl)-2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1 ,4]oxazepine-8-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate; methyl 6-(4-(4-(4-chloro-3-fluorophenyl)-2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1 ,4]oxazepine-8-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(4-(4-chloro-3-fluorophenyl)-2,2-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1 ,4]oxazepine-8-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(T-(4-chloro-3-fluorophenyl)-3J3-difluoro-TJ2'-dihydrospiro[cyclobutane-1 J3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-
3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(T-(4-chloro-3-fluorophenyl)-3-fluoro- ,2'-dihydrospiro[cyclobutane-1 J3'-pyrrolo[3,2-b]pyridin]-2-en-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-((3S,4S)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetate;
2-((3S,4S)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetic acid; methyl 2-((3R,4R)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetate;
2-((3R,4R)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetic acid; ethyl (2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)thiazole-4-carbonyl)glycinate;
(2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)thiazole-4-carbonyl)glycine; methyl 2-((3S,4R)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetate;
2-((3S,4R)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3- methoxypiperidin-4-yl)acetic acid; methyl 6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-5-yl)(2,2-dimethyl-4-(4-(4- methylpiperazine-1-carbonyl)thiazol-2-yl)piperazin-1-yl)methanone; methyl 6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-diethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-diethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)isonicotinate;
2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)isonicotinic acid; ethyl 3-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)isonicotinate;
3-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)isonicotinic acid; ethyl 6-((1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-3- yl)amino)nicotinate;
6-((1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-3- yl)amino)nicotinic acid; ethyl 6-((1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-3- yl)(methyl)amino)nicotinate;
6-((1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-3- yl)(methyl)amino)nicotinic acid hydrochloride; methyl 6-(4-(T-(3,4-difluorophenyl)- ,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-( -(3,4-difluorophenyl)- ,2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-4-yl)acetate;
2-(2-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-4-yl)acetic acid; ethyl 2-(5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-2-yl)acetate;
2-(5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-2-yl)acetic acid; methyl 2-(6-(4-(T-(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-
3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-( -(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid;
1 ‘-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2J3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)spiro[indoline-3,3‘- pyrrolidin]-2-one;
8-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-1-oxa-3,8- diazaspiro[4.5]decan-2-one; ethyl 6-(6-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-2,6- diazaspiro[3.3]heptan-2-yl)nicotinate;
6-(6-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-2,6- diazaspiro[3.3]heptan-2-yl)nicotinic acid; methyl 2-(1-( -(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)piperidin-4-yl)acetate;
2-(1-(T-(4-chloro-3-fluorophenyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)piperidin-4- yl)acetic acid;
4-( -(4-chloro-3-fluorophenyl)-TJ2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3- dimethylpiperazin-2-one; methyl 2-(6-(4-(T-(4-chloro-3-fluorophenyl)-3,3-difluoro-T,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-( -(4-chloro-3-fluorophenyl)-3,3-difluoro-T,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; ethyl 2-((1 R,5S)-8-(1 -(4-ch I oro-3-f I uoropheny I )-3, 3-d imethy I-2, 3-d I hy d ro- 1 H-py rrolo [3,2-b] py r id I ne-5-car bony l)-8- azabicyclo[3.2.1]octan-3-yl)acetate; 2-((1 R,5S)-8-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)acetic acid; methyl 6-(4-(6-(5-(4-(5-(methoxycarbonyl)-4,6-dimethylpyridin-2-yl)-2,2-dimethylpiperazine-1-carbonyl)-3,3- dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-1-yl)nicotinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate; methyl 6-(4-(1-(5-chloropyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(6-(5-(4-(5-carboxy-4,6-dimethylpyridin-2-yl)-2,2-dimethylpiperazine-1-carbonyl)-3,3-dimethyl-2,3-dihydro-1 H- pyrrolo[3,2-b]pyridin-1-yl)nicotinoyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(1-(5-chloropyridin-2-yl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-
1 -y I )-2, 4-d i methy In i coti n i c acid; methyl 6-(4-(3,3-dimethyl-1-(pyridin-2-yl)-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinate; ethyl 1 -(1 - (4-ch loro-3-fl uoropheny I )-3, 3-d I methy I-2, 3-d I hy d ro- 1 H -py rrolo [3, 2-b] py r id I ne-5-car bony I )-4- (py rid I n-2- yl)piperidine-3-carboxylate;
(cis)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-4-(pyridin-2- yl)piperidine-3-carboxylic acid;
(trans)-1-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-4-(pyridin-2- yl)piperidine-3-carboxylic acid; methyl 6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-3-methylpicolinate;
6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-3-methylpicolinic acid; methyl 5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2-methoxynicotinate;
5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2-methoxynicotinic acid; methyl 6-(4-((1 S,3R)-T-(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate; methyl 6-(4-((1 R,3R)-1 '-(4-chloro-3-fluorophenyl)-3-methoxy-1 2'-dihyd rospi ro [cyclopentane- 1 , 3'-py rrolo [3, 2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate; methyl 6-(4-((3R)-T-(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1 S,3R)- -(4-chloro-3-fluorophenyl)-3-methoxy-T,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-((1 R,3R)-1 '-(4-chloro-3-fluorophenyl)-3-methoxy-1 ',2'-d I hydrospi ro[cyclopentane- 1 , 3'-py rrol o[3, 2-b] py ridi ne]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-((3R)-T-(4-chloro-3-fluorophenyl)-3-methoxy-T,2'-dihydrospiro[cyclopentane-1J3'-pyrrolo[3J2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-((1 S,3S)-T-(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate; methyl 6-(4-((1 R,3S)-T-(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate; methyl 6-(4-((3S)-T-(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1 S,3S)-T-(4-chloro-3-fluorophenyl)-3-methoxy-T,2'-dihydrospiro[cyclopentane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-((1 RJ3S)-T-(4-chloro-3-fluorophenyl)-3-methoxy-TJ2'-dihydrospiro[cyclopentane-1 J3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-((3S)- -(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclopentane-1J3'-pyrrolo[3J2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-diethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-diethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)nicotinate; methyl 5-(4-(1-(3-fluoro-4-(4-(5-(methoxycarbonyl)pyridin-3-yl)-2,2-dimethylpiperazine-1-carbonyl)phenyl)-3,3- dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1-yl)nicotinate;
5-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)nicotinic acid;
5-(4-(4-(5-(4-(5-carboxypyridin-3-yl)-2,2-dimethylpiperazine-1-carbonyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2- b]pyridin-1-yl)-2-fluorobenzoyl)-3,3-dimethylpiperazin-1-yl)nicotinic acid; methyl 2-(6-(4-((1sJ3s)-T-(4-chloro-3-fluorophenyl)-3-methyl-1',2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-((1sJ3s)- -(4-chloro-3-fluorophenyl)-3-methyl-TJ2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-((1sJ3s)-T-(4-chloro-3-fluorophenyl)-3-methyl-1',2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-
5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1sJ3s)-1'-(4-chloro-3-fluorophenyl)-3-methyl-TJ2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-((1r,3r)- -(4-chloro-3-fluorophenyl)-3-methyl-TJ2'-dihydrospiro[cyclobutane-1J3'-pyrrolo[3J2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-((1 rJ3r)-1'-(4-chloro-3-fluorophenyl)-3-methyl-TJ2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-((1 r,3r)-1 (4-chloro-3-f I uoropheny l)-3-methy I- 1 ',2'-d i hydrospi ro[cyclobutane- 1 ,3'-py rrolo[3,2-b]py rid i ne] -
5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1 rJ3r)-1'-(4-chloro-3-fluorophenyl)-3-methyl- j2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(T-(4-chloro-3-fluorophenyl)-3-methyl-T,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate; 2-(6-(4-( -(4-chloro-3-fluorophenyl)-3-methyl-T,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-
3.3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-(T-(4-chloro-3-fluorophenyl)-3-methyl-T,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-( -(4-chloro-3-fluorophenyl)-3-methyl- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)propanoate;
2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)propanoic acid; methyl 6-(4-(1-(4-cyanocyclohexyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(1-(4-carbamoylcyclohexyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(1-(4,4-difluorocyclohexyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(1-(4,4-difluorocyclohexyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid;
4-(5-(4-(4,6-dimethylpyridin-2-yl)-2,2-dimethylpiperazine-1-carbonyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2- b]pyridin-1-yl)cyclohexane-1 -carbonitrile; methyl 2-(6-(4-(1-cyclopentyl-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-
1-yl)pyridin-3-yl)acetate;
2-(6-(4-(1-cyclopentyl-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1- y l)py ridin-3-y l)acetic acid; methyl 2-(6-(4-(1-(4-cyanocyclohexyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(1-(4-cyanocyclohexyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(3,4-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(3,4-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)-2-methylpropanoate;
2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)-2-methylpropanoic acid; methyl 2-(6-(4-(5-(4-chloro-3-fluorophenyl)-8,8-dimethyl-5,6,7J8-tetrahydro-1 ,5-naphthyridine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3-fluorophenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-1 ,5-naphthyridine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(4-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carbonyl)-
3.3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(4-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-(5-(3,4-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(3,4-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(5-cyclopentyl-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinate;
6-(4-(5-cyclopentyl-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid; methyl 6-(4-(5-(3-fluoro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(3-fluoro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(5-(4-chloro-3,5-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(4-chloro-3,5-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(5-(3-chloro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(3-chloro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(5-(3-chloro-4-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(3-chloro-4-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(5-(3-chloro-4-(trifluoromethyl)phenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(3-chloro-4-(trifluoromethyl)phenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6J7-tetrahydropyrazolo[1 ,5-a]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(3-(4-chloro-3-fluorobenzyl)-1-isobutyl-3-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-
3.3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(3-(4-chloro-3-fluorobenzyl)-1-isobutyl-3-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-((1sJ3s)-T-(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1s,3s)- -(4-chloro-3-fluorophenyl)-3-methoxy-T,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-((1 r,3r)-1 '-(4-chloro-3-fluorophenyl)-3-methoxy-1 2'-d I hydrospi ro[cyclobutane-1 , 3'-py rrol o[3, 2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1 r,3r)-T-(4-chloro-3-fluorophenyl)-3-methoxy-TJ2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(T-(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-( -(4-chloro-3-fluorophenyl)-3-methoxy- ,2'-dihydrospiro[cyclobutane-1,3'-pyrrolo[3,2-b]pyridine]-5'-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(5-(3-fluoro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(3-fluoro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(3-chloro-4-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(3-chloro-4-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(1-acetyl-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinate;
6-(4-(1-(1,3-dihydroisobenzofuran-5-yl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(5-(4-fluorophenethyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-fluorophenethyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3-dimethylpiperazin-
1 -yl)pyridin-3-yl)acetic acid; methyl 6-(4-(5-(4-fluorophenethyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
2-(6-(4-(5-(4-fluorophenethyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3-dimethylpiperazin- 1 -yl)pyridin-3-yl)acetic acid; methyl 6-(4-(T-(4-chloro-3-fluorophenyl)-3,3-dimethyl- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-( -(4-chloro-3-fluorophenyl)-3,3-dimethyl-T,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(7,7-dimethyl-5-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(7,7-dimethyl-5-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(3-chloro-4-(trifluoromethyl)phenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(3-chloro-4-(trifluoromethyl)phenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(3,4-dichlorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(3,4-dichlorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-(5'-(3,4-difluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5'-(3,4-difluorophenyl)-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-((1 r,3r)-1 '-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)-1 2'-d I hy d rospi ro[cyclobutane- 1 , 3'-py rrolo [3, 2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1 r,3r)-1 '-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)-1 2'-dihydrospi ro[cy clobutane- 1 , 3'-py rrolo [3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-((1sJ3s)-T-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)-TJ2'-dihydrospiro[cyclobutane-1J3'-pyrrolo[3J2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-((1s,3s)-r-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)-r,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(T-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-( -(4-chloro-3-fluorophenyl)-3-(methoxymethyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-(5'-(3,4-difluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5'-(3,4-difluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-
3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-(5'-(3,4-difluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5'-(3,4-difluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(3J3-dimethyl-5'-(3,4,5-trifluorophenyl)-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(3,3-dimethyl-5'-(3,4,5-trifluorophenyl)-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 2-(6-(4-((1sJ3s)-T-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)-TJ2'-dihydrospiro[cyclobutane-1 ,3'- pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-((1sJ3s)- -(4-chloro-3-fluorophenyl)-3-(methoxymethyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-((1 r,3r)-1 '-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)-1 ',2'-d I hydrospi ro[cyclobutane-1 ,3'- pyrrolo[3,2-b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-((1 r,3r)-T-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(T-(4-chloro-3-fluorophenyl)-3-(methoxymethyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2- b]pyridine]-5'-carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-( -(4-chloro-3-fluorophenyl)-3-(methoxymethyl)- ,2'-dihydrospiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-5'- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(4-chloro-3,5-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3,5-difluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-
3.3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5'-(3,4-difluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5'-(3,4-difluorophenyl)-3J3-dimethyl-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-
3.3-dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-(5'-(4-chloro-3-fluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5'-(4-chloro-3-fluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(5-(3,4-dichlorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(5-(3,4-dichlorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid; methyl 2-(6-(4-(5-(3-chloro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate 2-(6-(4-(5-(3-chloro-4-methylphenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(4-chloro-3-fluorophenyl)-8-methoxy-7,7-dimethyl-5,6,7,8-tetrahydro-1 ,5-naphthyridine-2- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3-fluorophenyl)-8-methoxy-7,7-dimethyl-5,6,7,8-tetrahydro-1 ,5-naphthyridine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(1-(4-chloro-3-fluorophenyl)-6-methoxy-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5- carbonyl)-3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(1-(4-chloro-3-fluorophenyl)-6-methoxy-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-3-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)- 3,3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-3-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid;
2-(6-(4-(1-(4-chloro-3-fluorophenyl)-6-hydroxy-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 8-(4-(5'-(4-chloro-3-fluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl)-3,3-dimethylpiperazin-1-yl)-8-oxooctanoate;
8-(4-(5'-(4-chloro-3-fluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl)-3,3-dimethylpiperazin-1-yl)-8-oxooctanoic acid;;
N-(37-(4-(5'-(4-chloro-3-fluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1,7'-pyrrolo[2,3-b]pyrazine]-2'- carbonyl )-3, 3-dimethy I pi perazi n-1 -y l)-3-methy I-4, 17, 30, 37-tetraoxo-7, 10, 13,20,23,26-hexaoxa-3, 16,29- triazaheptatriacontyl)-N-methylpalmitamide; methyl 4-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,6-dimethylnicotinate;
4-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,6-dimethylnicotinic acid; methyl 2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(1-(4-chloro-3-fluorophenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid;
1-(1-((5'-(4-chloro-3-fluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazin]-2'- yl)sulfonyl)piperidin-4-yl)imidazolidin-2-one; methyl 2-(6-(4-(4-(4-chloro-3-fluorophenyl)-2,2-dimethyl-3J4-dihydro-2H-pyrazino[2,3-b][1,4]oxazine-7-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(4-(4-chloro-3-fluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazine-7-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; tert-butyl 2-(4-(5-(2-methoxy-2-oxoethyl)pyridin-2-yl)-2,2-dimethylpiperazine-1-carbonyl)-7,7-dimethyl-2,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate; methyl 2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-carbonyl)-
3.3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid; methyl 6-(4-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; methyl 6-(4-(7,7-dimethyl-5-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(7,7-dimethyl-5-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine-2-carbonyl)-3,3-dimethylpiperazin-
1 -y I )-2, 4-d I methy In I coti n I c acid; methyl 6-(4-(1-(4-cyclopropylphenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinate;
6-(4-(1-(4-cyclopropylphenyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-
1 -y I )-2, 4-d I methy In I coti n I c acid; methyl 2-(6-(4-(5-(4-chloro-3-fluorophenyl)-3,7,7-trimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-carbonyl)-
3.3-dimethylpiperazin-1-yl)pyridin-3-yl)acetate;
2-(6-(4-(5-(4-chloro-3-fluorophenyl)-3,7,7-trimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)pyridin-3-yl)acetic acid;
4-(5'-(3,4-difluorophenyl)-3,3-dimethyl-5',6'-dihydrospiro[cyclobutane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-2-one;
4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1 ,3,3-trimethylpiperazin-2-one; methyl 2-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethyl-2- oxopiperazin-1 -yl)acetate;
2-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethyl-2-oxopiperazin-1- yl)acetic acid;
2-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethyl-2-oxopiperazin-1- yl)acetamide; 2-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethyl-2-oxopiperazin-1- yl)-N-methylacetamide;
2-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethyl-2-oxopiperazin-1- yl)-N,N-dimethylacetamide;
4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethyl-1-(2-morpholino-2- oxoethyl)piperazin-2-one;
(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-6-yl)(6-oxa-2-azaspiro[3.4]octan-2-yl)methanone;
(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-6-yl)(2-oxa-6-azaspiro[3.3]heptan-6- yl)methanone;
(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-6-yl)((1 R,3r,5S)-3-hydroxy-8- azabicyclo[3.2.1]octan-8-yl)methanone;
(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-6-yl)((1 R,3s,5S)-3-hydroxy-8- azabicyclo[3.2.1]octan-8-yl)methanone;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-2,8-diazaspiro[4.5]decan-1-one;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-2,8-diazaspiro[4.5]decan-3-one;
(3aS,6aS)-1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)hexahydropyrrolo[3,4- b]pyrrol-6(1 H)-one;
(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-6-yl)(2,2-dimethylpyrrolidin-1-yl)methanone;
4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)- 1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1 ,4-diazepan-2-one;
1-(1-(tertbutyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1 ,4-diazepan-5-one;
((1 R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)(1-(tertbutyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-6- yl)methanone;
4-(1-(tertbutyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1-methylpiperazin-2-one; methyl 1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperidine-4- carboxylate;
1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperidine-4- carboxylic acid;
1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperidine-4- carboxamide;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1 ,3,8-triazaspiro[4.5]decane-2,4- dione; methyl 6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinate;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
4-(3-(4-chloro-3-fluorophenyl)-1-(4-methoxybenzyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2- one;
4-(3-(4-chloro-3-fluorophenyl)-1-(3-methoxycyclobutyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-
2-one;
4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one; 4-(3-(4-chloro-3-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-2-one;
4-(3-(4-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2- one;
(3-(4-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1 H-pyrrolo[2,3-b]pyridin-6-yl)(1 ,4-oxazepan-4-yl)methanone;
(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(3-(4-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1 H-pyrrolo[2,3-b]pyridin-6- yl)methanone;
4-(3-(4-chloro-3-fluorophenyl)-1-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(4-chloro-3-fluorophenyl)-1-(cyclopropylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2- one;
4-(1-isobutyl-3-(pyrimidin-5-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(pyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-2-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2- one;
4-(3-(4-chloro-3-fluorophenyl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-2-one;
4-(1-(2-(1 H-1 ,2,4-triazol-1-yl)ethyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-2-one;
4-(3-(4-chloro-3-fluorophenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-2-one;
4-(3-(4-chloro-3-fluorophenyl)-1-(2-ethoxyethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(1-methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(3,6-dihydro-2H-pyran-4-yl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(tetrahydro-2H-pyran-4-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(1 ,2,3,6-tetrahydropyridin-4-yl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-cyclohexyl-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-phenyl-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethyl-piperazin-2-one;
4-[3-(3-chlorophenyl)-1-isobutyl-pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one;
4-[1-isobutyl-3-(p-tolyl)pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one;
4-[1-isobutyl-3-(o-tolyl)pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one;
4-[3-(2-chlorophenyl)-1-isobutyl-pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one;
4-[3-(4-chlorophenyl)-1-isobutyl-pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one;
4-[1-isobutyl-3-[4-(trifluoromethyl)phenyl]pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one;
4-[1-isobutyl-3-[4-fluorophenyl]pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one;
4-[1-isobutyl-3-[3-(trifluoromethoxy)phenyl]pyrrolo[2,3-b]pyridine-6-carbonyl]-3,3-dimethyl-piperazin-2-one; methyl 6-(4-(3-(tert-butyl)-1-(4-chloro-3-fluorophenyl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n ate;
6-(4-(3-(tert-butyl)-1-(4-chloro-3-fluorophenyl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid; 6-(4-(3-(tert-butyl)-1-(4-chloro-3-methoxyphenyl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethy Inicotinic acid;
4-(1-(2-(1 H-pyrazol-1-yl)ethyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-2-one;
4-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-1-methylpiperazin-2-one; methyl 6-(4-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinate;
6-(4-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
4-(3-isobutyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(3-chlorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one; methyl 1-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperidine-4- carboxylate;
1-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperidine-4-carboxylic acid;
8-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-1 ,3,8-triazaspiro[4.5]decane-2,4- dione;
4-(1-(4-chloro-3-fluorophenyl)-3-methyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(4-chloro-3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3- dimethylpiperazin-2-one;
4-(1-(2,4-dichlorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(2-chlorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
3-(tert-butyl)-1-(4-chloro-3-fluorophenyl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(4-chloro-3-fluorophenyl)-3-cyclopentyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(4-chloro-3-fluorophenyl)-3-cyclopropyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(4-chloro-3-fluorobenzyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-isobutyl-1-(4-(trifluoromethoxy)phenyl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(tert-butyl)-1-(4-chloro-3-fluorophenyl)-1 H-pyrazolo[3,4-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
1-(4-chloro-3-fluorophenyl)-3-isobutyl-6-methyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(piperidin-1-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-1 H-indazole-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(2,4-dichlorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-(4-chlorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one; methyl 6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrazolo[3,4-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-
1 -y I )-2, 4-d I methy In I coti n ate;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrazolo[3,4-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-
2,4-dimethy Inicotinic acid;
4-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)piperazin-2-one;
(3-(4-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1 H-pyrazolo[4,3-c]pyridin-6-yl)(1 ,4-oxazepan-4-yl)methanone; (8-oxa-3-azabicyclo[3.2.1]octan-3-yl)(3-(4-chloro-3-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1 H-pyrazolo[4,3-c]pyridin-6- yl)methanone;
4-(1-isobutyl-3-(1-methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-
2-one;
4-(3-isobutyl-1-(6-methoxypyridin-3-yl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-isobutyl-1-(4-methoxyphenyl)-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
8-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-pyrazolo[4,3-b]pyridine-5-carbonyl)-1-phenyl-1 ,3,8- triazaspiro[4.5]decan-4-one;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
4-(3-(4-chloro-3-fluorophenyl)-1-isopropyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isopropyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperazin-1-yl)-2,4- dimethylnicotinic acid;
6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidin-4-yl)amino)-2,4- dimethylnicotinic acid;
6-(6-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,6-diazabicyclo[3.2.0]heptan-
3-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(pyrazin-2-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-2-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid;
4-(1-isobutyl-3-(6-methoxypyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(6-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile;
4-(3-(3,4-dichlorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(3,5-difluorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(6-(dimethylamino)pyridin-3-yl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
5-(6-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)picolinonitrile;
4-(1-isobutyl-3-(4-methoxyphenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(2-(trifluoromethoxy)phenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(2-fluorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(3-fluorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(4-chloro-2-fluorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(4-(trifluoromethoxy)phenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
3-(6-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile; 4-(1-isobutyl-3-(m-tolyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
6-(4-(3-(4-chloro-3-fluorophenyl)-1 ,2-dimethyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
4-(3-(4-chloro-3-fluorophenyl)-1-(pyridin-4-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2- one;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(1-methylcyclobutyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidine-4-carboxamido)-2,4- dimethylnicotinic acid;
2-((1 R,5S,6s)-3-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3- azabicyclo[3.1.0]hexan-6-yl)acetic acid;
2-(1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidin-4-yl)acetic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(1-ethoxy-2-methylpropan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1 ,4-diazepan-1-yl)-2,4- dimethylnicotinic acid;
6-(7-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)- 2,4-dimethy Inicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-ethyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
(R)-6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3-methylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(2-(pyridin-2-yl)propan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-2-(methoxymethyl)piperazin-1- yl)-2,4-dimethylnicotinic acid;
6-(4-(1-(carboxymethyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(pyridin-3-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid;
(S)-6-(4-(3-(4-chloro-3-fluorophenyl)-1-(1-methoxypropan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)nicotinic acid;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)nicotinamide; 6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-
N, N-dimethylnicotinamide;
(S)-6-(4-(3-(4-chloro-3-fluorophenyl)-1-(1-methoxypropan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(3,4-difluorophenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(3-(3-fluoro-4-methylphenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(1-isobutyl-3-(3,4,5-trifluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid;
4-(3-(3,4-dimethoxyphenyl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-2-(methoxymethyl)piperazin-1- yl)-2,4-dimethylnicotinic acid;
6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidin-4-yl)(methyl)amino)- 2,4-dimethy Inicotinic acid;
6-((1 S,4S)-5-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(pyridin-4-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(pyridin-2-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid;
4-(3-(4-chloro-3-fluorophenyl)-1-(1-methoxy-2-methylpropan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-2-one;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(1-methoxy-2-methylpropan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
(R)-6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)pyrrolidin-3-yl)amino)-2,4- dimethylnicotinic acid;
(S)-6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)pyrrolidin-3-yl)amino)-2,4- dimethylnicotinic acid;
(R)-6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)pyrrolidin-3- yl)(methyl)amino)-2,4-dimethylnicotinic acid;
(S)-6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)pyrrolidin-3- yl)(methyl)amino)-2,4-dimethylnicotinic acid;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-2-(hydroxymethyl)piperazin-1- yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(pyrimidin-2-ylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; 6-(4-(3-(4-chloro-3-fluorophenyl)-1-((2,5-dimethyloxazol-4-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(cyclopropylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d i methy In i coti n i c acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-((6-methoxypyridin-2-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidine-4-carboxylic acid;
2-(1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidin-4-yl)acetamide;
2-(1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidin-4-yl)-N,N- dimethyl acetamide;
(R)-6-(4-(1-(sec-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-
2,4-dimethy Inicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(1 ,3-dimethoxypropan-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid; -(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-4,6-dimethyl- ,2',3',6'-tetrahydro-
[2,4'-bipyridine]-5-carboxylic acid;
6-(1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidin-4-yl)-2,4- dimethylnicotinic acid;
6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazine-1- carbony l)nicotinic acid;
6-(4-(1-isobutyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-
2,4-dimethy Inicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(cyclobutylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-
1 -y I )-2, 4-d i methy In i coti n i c acid;
(S)-6-(4-(1-(sec-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-
2,4-dimethy Inicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-(cyclobutylmethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-
1 -y I )-2, 4-d i methy In i coti n i c acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-5-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid;
6-(4-(5-(4-chloro-3-fluorophenyl)-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
2-(2-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)pyridin-4-yl)-2-methylpropanenitrile;
2-(2-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)pyridin-4-yl)-2-methylpropanamide; diethyl (6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-
1 -y I )py rid I n-3-y I )phosphon ate;
(S)-6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3-methylpiperazin-1-yl)-2,4- dimethylnicotinic acid; 6-(4-(3-(4-chloro-3-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-((3-methyloxetan-3-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
(S)-6-(4-(3-(4-chloro-3-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6- carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
(R)-6-(4-(3-(4-chloro-3-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(tert-butyl)-1-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-5-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperazin-1-yl)-2,4- dimethylnicotinic acid;
1-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperidin-4-yl)methyl)-1 H- pyrazole-4-carboxylic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-4-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-4-methyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(7-(4-chloro-3-fluorophenyl)-5-isobutyl-5H-pyrrolo[2,3-b]pyrazine-3-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(1-(tert-butyl)-3-(3,4-difluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4- dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-((6-methylpyridin-2-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-((3-methylpyridin-2-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
(6-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1- y l)py ridin-3-y l)phosphonic acid; ethyl hydrogen (6-(4-(1 - (tert-buty l)-3-(4-chloro-3-fl uoropheny l)-1 H-py rrolo[2, 3-b] py r id i ne-6-carbony I )-3, 3- dimethylpiperazin-1-yl)pyridin-3-yl)phosphonate;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3-methyl-1 ,3,8- triazaspiro[4.5]decane-2, 4-dione;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1 ,3-dimethyl-1 ,3,8- triazaspiro[4.5]decane-2, 4-dione;
6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3-methylpiperidin-4-yl)amino)-
2,4-dimethy Inicotinic acid;
6-((1-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3-methylpiperidin-4- yl)(methyl)amino)-2,4-dimethylnicotinic acid; 8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-6,6-dimethyl-1,3,8- triazaspiro[4.5]decane-2, 4-dione;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-6,6-difluoro-1 ,3,8- triazaspiro[4.5]decane-2, 4-dione;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1,8-diazaspiro[4.5]decan-2-one; methyl 2-(1-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-1 H-indole-6-carbonyl)piperidin-4-yl)acetate;
2-(1-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-1 H-indole-6-carbonyl)piperidin-4-yl)acetic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-isobutyl-2-(trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
2-(1-(3-acetyl-1-(4-chloro-3-fluorophenyl)-1 H-indole-5-carbonyl)piperidin-4-yl)acetic acid;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1-isopropyl-1 ,3,8- triazaspiro[4.5]decan-4-one;
5-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)piperazin-1-yl)pyridazin-3(2H)- one;
8-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-1-methyl-1 ,3,8- triazaspiro[4.5]decan-4-one;
4-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,6- dimethylbenzoic acid;
(S)-6-(4-(3-(4-chloro-3-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
(R)-6-(4-(3-(4-chloro-3-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-(4-(3-(4-chloro-3-fluorophenyl)-1-((5-methylpyridin-2-yl)methyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridin-6-yl)(1 ,1-dioxidothiomorpholino)methanone;
8-(4-(1-(tert-butyl)-3-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-1-yl)-8- oxooctanoic acid; ethyl 6-(4-(8-(tert-butyl)-6-(4-chlorophenyl)imidazo[1,5-a]pyrimidine-2-carbonyl)-3,3-dimethylpiperazin-1- yl)nicotinate;
6-(4-(8-(tert-butyl)-6-(4-chlorophenyl)imidazo[1,5-a]pyrimidine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)nicotinic acid; ethyl 6-(4-(3-(4-chlorophenyl)-1-isobutylimidazo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperazin-1-yl)nicotinate;
6-(4-(3-(4-chlorophenyl)-1-isobutylimidazo[1,5-a]pyridine-7-carbonyl)-3,3-dimethylpiperazin-1-yl)nicotinic acid;
6-(4-(1-(tert-butyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin- 1 -y I )-2, 4-d I methy In I coti n I c acid;
4-(3-(tert-butyl)-1-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)-3,3-dimethylpiperazin-2-one;
2-(1-(3-(tert-butyl)-1-(4-chloro-3-fluorophenyl)-1 H-pyrrolo[3,2-b]pyridine-5-carbonyl)piperidin-4-yl)acetic acid;
4-(3-(benzo[d][1,3]dioxol-5-yl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(benzofuran-2-yl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(3-(5-fluoro-1 H-indol-2-yl)-1-isobutyl-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one;
4-(1-isobutyl-3-(naphthalen-2-yl)-1 H-pyrrolo[2,3-b]pyridine-6-carbonyl)-3,3-dimethylpiperazin-2-one; 4-(1-(4-chloro-3-fluorophenyl)-3-isobutyl-1 H-indazole-5-carbonyl)-3,3-dimethylpiperazin-2-one; or a pharmaceutically acceptable salt or solvate of any one of the above-mentioned compounds. These compounds and their preparation have been described in WO 2023/233033 and WO 2022/117882, which are incorporated herein by reference in their entirety.
As explained above, the PAR2 inhibitor may also be an antibody. Corresponding preferred examples include, in particular, MEDI-0618 or PaB670129 (as described, e.g., in WO 2018/167322 which is incorporated herein by reference), or P24E1102 (as described, e.g., in WO 2022/040345 which is incorporated herein by reference).
Moreover, the PAR2 inhibitor may also be a peptide, particularly a pepducin, e.g., any one of the PAR2 pepducins disclosed in WO 2012/139137 (which is incorporated herein by reference). Corresponding preferred examples include any of PZ-235, OA-235i, OA-235c, or P2pal-18S (as described, e.g., in WO 2012/139137).
It is particularly preferred that the PAR2 inhibitor to be used in accordance with the present invention is any one of the following compounds:
A compound having the formula or the chemical name 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3- b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid, or a pharmaceutically acceptable salt or solvate thereof. This compound has been described in Example 207 of WO 2023/233033 and is also referred to herein as "Compound 207”.
A compound having the formula or the chemical name 6-[4-[7-tert-butyl-5-(4-chloro-3-fluoro-phenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3- dimethyl-piperazin-1-yl]-2,4-dimethyl-pyridine-3-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof. This compound has been described in Example 1.19 of WO 2018/057588 and is also referred to as compound "1-117”. A compound having the formula or the chemical name 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6- methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid, or a pharmaceutically acceptable salt or solvate thereof. This compound has been described in Example 10 of EP 3 508 487 A1.
A compound having the formula or the chemical name [7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1 H-imidazol-2-yl)methanol, or a pharmaceutically acceptable salt or solvate thereof. This compound has been described in Example 66 of WO 2017/194716. The PAR2 inhibitor may also be a stereoisomer of the aforementioned compound, e.g., (1 R)-[7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1 H-imidazol-2-yl)methanol or a pharmaceutically acceptable salt or solvate thereof, or (1 S)- [7-fl uoro-3- ( 1 -methy I cy cl opropy I) benzofu ran-4-y I] -( 1 H-i mi d azol-2- yl)methanol or a pharmaceutically acceptable salt or solvate thereof.
A compound having the formula or the chemical name 3-(4-(8-(tert-butyl)-6-(4-fluorophenyl)imidazo[1,2-b]pyridazine-2-carbonyl)-3,3- dimethylpiperazin-1-yl)-3-oxopropane-1 -sulfonic acid, or a pharmaceutically acceptable salt or solvate thereof. This compound has been described in Example 10 of WO 2019/124567.
A compound having the formula or the chemical name (2,2-dimethylpiperidin-1-yl)-[5-(cyclopentylmethyl)-7-propan-2-ylpyrazolo[1J5- a]pyrimidin-2-yl]methanone, or a pharmaceutically acceptable salt or solvate thereof. This compound has been described in Example 12 of WO 2022/255408.
A compound having the formula or the chemical name N-((3S,6S)-1-furan-2-carbonyl)-6-isobutyl-4,7-dioxo-8-(piperidin-4- y I methy l)octahydro-2H-py razi no[1 , 2-a] pyri midi n-3-yl)-3-methy I butaneamide, or a pharmaceutically acceptable salt or solvate thereof. This compound has been described in WO 2019/199800 (see, e.g., the synthesis disclosed on pages 35 to 37) and is also referred to as compound "0781”.
Thus, it is particularly preferred that the PAR2 inhibitor is any one of the following compounds:
6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-[4-[7-tert-butyl-5-(4-chloro-3-fluoro-phenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-2,4- dimethyl-pyridine-3-carboxylic acid;
2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1 ,5-a]pyrimidine-
2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid;
[7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1 H-imidazol-2-yl)methanol;
3-(4-(8-(tert-butyl)-6-(4-fluorophenyl)imidazo[1 ,2-b]pyridazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-3- oxopropane-1 -sulfonic acid;
(2, 2-dimethylpiperidin-1-yl)-[5-(cyclopentylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl] methanone;
N-((3S,6S)-1-furan-2-carbonyl)-6-isobutyl-4,7-dioxo-8-(piperidin-4-ylmethyl)octahydro-2H-pyrazino[1 ,2-a]pyrimidin- 3-yl)-3-methylbutaneamide; or a pharmaceutically acceptable salt or solvate thereof (i.e. , a pharmaceutically acceptable salt or solvate of any one of the aforementioned compounds).
Even more preferably, the PAR2 inhibitor to be used in accordance with the present invention is 6-(4-(5'-(4-chloro-3- fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)- 2,4-dimethylnicotinic acid or a pharmaceutically acceptable salt or solvate thereof, or 6-[4-[7-tert-butyl-5-(4-chloro-3- fluoro-phenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-2,4-dimethyl-pyridine-3-carboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
Yet even more preferably, the PAR2 inhibitor to be used in accordance with the present invention is a compound having the formula or the chemical name 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]- 2'-carbonyl)-3,3-dimethylpiperazin-1 -yl)-2,4-dimethylnicotinic acid, or a pharmaceutically acceptable salt or solvate thereof.
The immune checkpoint inhibitor to be used in accordance with the present invention may be, in principle, any immune checkpoint inhibitor known in the art. In particular, the immune checkpoint inhibitor may be an antibody (or an antigenbinding fragment thereof, or an antibody construct), typically a monoclonal antibody. Preferably, the immune checkpoint inhibitor is a monoclonal antibody (or an antigen-binding fragment thereof, or an antibody construct) directed against PD-1 , PD-L1 , CTLA-4, TIGIT, TIM3, VISTA, BTLA, CD47, LAG3, 0X40, or IGOS. Accordingly, it is preferred that the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti- CD47 antibody, an anti-LAG3 antibody, an anti-OX40 antibody, or an anti-ICOS antibody. Corresponding preferred examples include, but are not limited to, any one of the anti-PD-1 antibodies nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX- 4014, or APE02058, any one of the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301 , BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469 or bintrafusp alfa, any one of the anti-CTLA-4 antibodies ipilimumab or tremelimumab, any one of the anti-TIGIT antibodies tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, CCM902, ASP8374, SEA- TGT, BGB-A1217, IBI-939 or M6223, any one of the anti-TIM3 antibodies sabatolimab, cobolimab, lomvastomig, BGB-A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR-1702, Sym023, or TQB2618, any one of the anti-VISTA antibodies onvatilimab, HMBD-002, KVA12123, W0180, IGN-381 , PMC-309 or APX-201 , any one of the anti-BTLA antibodies tifcemalimab, icatolimab, ANB032 or HFB200603, any one of the anti-CD47 antibodies magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801 or TI-061 , any one of the anti-LAG3 antibodies relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701 , or IMP731 , any one of the anti-CX40 antibodies ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB- A445, YH-002, BMS 986178, INBRX-106, IBI 101 , or MCXR0916, and/or any one of the anti-ICOS antibodies alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, or MEDI-570. Thus, the immune checkpoint inhibitor may be, e.g., nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX-4014, APE02058, atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301 , BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, ipilimumab, tremelimumab, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, M6223, sabatolimab, cobolimab, lomvastomig, BGB-A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR- 1702, Sym023, TQB2618, onvatilimab, HMBD-002, KVA12123, W0180, IGN-381 , PMC-309, APX-201 , tifcemalimab, icatolimab, ANB032, HFB200603, magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801 , TI-061 , relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701 , IMP731 , ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX-106, IBI101 , MOXR0916, alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, or MEDI-570. In particular, the immune checkpoint inhibitor may be, for example, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti- CD47 antibody, or an anti-LAG3 antibody; as explained above, corresponding examples include nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP-514, JTX-4014, APE02058, atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301 , BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, ipilimumab, tremelimumab, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, CCM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, M6223, sabatolimab, cobolimab, lomvastomig, BGB-A425, INCAGN02390, LY3321367, LY3415244, Sym023, onvatilimab, HMBD-002, KVA12123, W0180, IGN-381 , PMC-309, APX-201 , tifcemalimab, icatolimab, ANB032, HFB200603, magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801 , TI-061 , relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701 , or IMP731. More preferably, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, particularly an anti-PD-1 antibody. Even more preferably, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, tislelizumab, toripalumab, penpulimab, cadonilimab, serplulimab, envafolimab, pucotenlimab, adebrelimab, camrelizumab, prolgolimab, retifanlimab, sintilimab, socazolimab, sugemalimab, zimberelimab, spartalizumab, and dostarlimab.
It will be understood that the present invention specifically and individually relates to each one of the aforementioned PAR2 inhibitors (e.g., Compound 207) in combination with each one of the aforementioned immune checkpoint inhibitors.
The cancer to be treated in accordance with the present invention may be, for example, a solid cancer or a hematological cancer. Preferably, the cancer is selected from colorectal cancer (e.g., colorectal carcinoma), colon cancer (e.g., colon adenocarcinoma), gastrointestinal cancer, gastric cancer (or stomach cancer; e.g., stomach adenocarcinoma), rectal cancer (e.g., rectum adenocarcinoma), anal cancer, liver cancer (e.g., hepatocellular carcinoma), breast cancer (e.g., triple-negative breast cancer, including in particular COX-2 expressing triple-negative breast cancer, or breast cancer having a BRCA1 and/or BRCA2 gene mutation), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer (e.g., cervical squamous cell carcinoma or endocervical adenocarcinoma), prostate cancer (e.g., prostate adenocarcinoma or hormone-refractory prostate cancer), ovarian cancer (e.g., ovarian carcinoma or ovarian serous cystadenocarcinoma), endometrial cancer (e.g., uterine corpus endometrial carcinoma), vaginal cancer, vulvar cancer, uterine cancer (e.g., uterine corpus cancer, uterine sarcoma, or uterine carcinosarcoma), testicular cancer, germ cell cancer (e.g., testicular germ cell cancer), esophageal cancer, laryngeal cancer, mouth cancer, hematological cancer, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia), lymphoma (e.g., Hodgkin lymphoma or non-Hodgkin lymphoma, such as, e.g., follicular lymphoma, diffuse large B-cell lymphoma, or lymphoid neoplasm diffuse large B-cell lymphoma), multiple myeloma, lung cancer (e.g., non-small cell lung cancer (including, e.g., lung adenocarcinoma or lung squamous cell carcinoma), small cell lung cancer, large cell carcinoma, lung carcinoid tumor, adenoid cystic carcinoma, pulmonary lymphoma, or pulmonary sarcoma), adrenal gland cancer (e.g., adrenocortical carcinoma), bile duct cancer (or biliary tract cancer; e.g., cholangio carcinoma), hepatobiliary cancer, genitourinary cancer, urothelial cancer (e.g., urothelial carcinoma), bladder cancer (e.g., bladder urothelial carcinoma), gallbladder cancer (e.g., gallbladder carcinoma), head and/or neck cancer (e.g., head and neck cancer, or head and neck squamous cell carcinoma), kidney cancer (e.g., kidney chromophobe, kidney renal cell carcinoma, kidney renal clear cell carcinoma, or kidney renal papillary cell carcinoma), mesothelioma, sarcoma, skin cancer, melanoma (e.g., skin cutaneous melanoma, or uveal melanoma), Merkel-cell cancer (e.g., Merkel-cell carcinoma), epidermoid cancer, thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, anaplastic thyroid cancer, or thyroid carcinoma), thymus cancer (or thymic cancer; e.g., thymoma), squamous cell cancer (or squamous cell carcinoma; including, e.g., oral squamous cell carcinoma/squamous-cell mouth carcinoma, squamous-cell skin cancer, squamous-cell lung carcinoma, squamous-cell thyroid carcinoma, squamous-cell esophageal carcinoma, or squamous-cell vaginal carcinoma), goblet cell cancer (e.g., goblet cell carcinoid), spleen cancer, bone cancer (e.g., osteosarcoma or osteogenic sarcoma), fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, neuroendocrine cancer (e.g., neuroendocrine carcinoma), neuroblastoma, and brain cancer (e.g., glioblastoma). The cancer to be treated may further be a carcinoma or a sarcoma. The cancer to be treated (including any one of the aforementioned specific types of cancer) may also be a relapsed or refractory cancer. Moreover, the cancer to be treated (including any one of the aforementioned specific types of cancer) may also be a metastatic cancer. The treatment can be used, e.g., as first-line, second-line or third-line therapy against cancer. When used as first-line therapy in resectable solid tumors, it can be administered in a neoadjuvant or adjuvant setting or both.
In particular, the cancer to be treated in accordance with the invention may be selected from colorectal cancer, colon cancer, gastric cancer, rectal cancer, liver cancer, breast cancer, pancreatic cancer, cervical cancer, prostate cancer, ovarian cancer, endometrial cancer, uterine sarcoma, germ cell cancer, esophageal cancer, leukemia, lung cancer, adrenal gland cancer, bile duct cancer, bladder cancer, head and neck cancer, kidney cancer, lymphoma, mesothelioma, sarcoma, melanoma, thyroid carcinoma, thymus cancer, and glioblastoma. The cancer to be treated (including any one of the aforementioned specific types of cancer) may also be a relapsed or refractory cancer. Moreover, the cancer to be treated (including any one of the aforementioned specific types of cancer) may also be a metastatic cancer. As explained above, the cancer to be treated in accordance with the present invention may also be a hematological cancer (e.g., a lymphoma or a leukemia). Thus, for example, the hematological cancer may be selected from: Hodgkin's lymphoma, including, e.g., nodular sclerosing subtype of Hodgkin's lymphoma, mixed-cellularity subtype of Hodgkin's lymphoma, lymphocyte-rich subtype of Hodgkin's lymphoma, or lymphocyte-depleted subtype of Hodgkin's lymphoma; non-Hodgkin's lymphoma, including, e.g., follicular non-Hodgkin's lymphoma, mantle cell lymphoma, or diffuse non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma or Burkitt's lymphoma); nodular lymphocyte predominant Hodgkin's lymphoma; peripheral/cutaneous T-cell lymphoma, including, e.g., mycosis fungoides, Sezary syndrome, T-zone lymphoma, lymphoepithelioid lymphoma (e.g., Lennert's lymphoma), or peripheral T-cell lymphoma; lymphosarcoma; a malignant immunoproliferative disorder, including, e.g., Waldenstrom's macroglobulinemia, alpha heavy chain disease, gamma heavy chain disease (e.g., Franklin's disease), or an immunoproliferative small intestinal disease (e.g., Mediterranean disease); multiple myeloma, including, e.g., Kahler's disease, or myelomatosis; plasma cell leukemia; lymphoid leukemia, including, e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy-cell leukemia (e.g., leukemic reticuloendotheliosis), or adult T-cell leukemia; myeloid leukemia, including, e.g., acute myeloid leukemia, chronic myeloid leukemia, subacute myeloid leukemia, myeloid sarcoma (e.g., chloroma, or granulocytic sarcoma), acute promyelocytic leukemia, or acute myelomonocytic leukemia; a myeloproliferative neoplastic disorder, including, e.g., polycythemia vera, essential thrombocythemia, or idiopathic myelofibrosis; monocytic leukemia; acute erythraemia or erythroleukemia, including, e.g., acute erythraemic myelosis, or Di Guglielmo's disease; chronic erythraemia, including, e.g., Heilmeyer-Schbner disease; acute megakaryoblastic leukemia; mast cell leukemia; acute panmyelosis; acute myelofibrosis; and Letterer-Siwe disease.
As explained above, the PAR2 inhibitor and the immune checkpoint inhibitor to be used in accordance with the present invention may each be formulated as a pharmaceutical composition (which may also be referred to as pharmaceutical formulation or medicament). Such pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as, e.g., carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.
The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in "Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22nd edition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include, e.g., coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include, e.g., solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. For example, a sterile aqueous solution may be used for parenteral administration, which may contain, e.g., suitable amounts of salts and/or glucose to make the solution isotonic with blood. Dosage forms for rectal and vaginal administration include, e.g., suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, e.g., by a metered inhaler. Dosage forms for topical administration include, e.g., creams, gels, ointments, salves, patches and transdermal delivery systems.
The PAR2 inhibitor and the immune checkpoint inhibitor (as well as corresponding pharmaceutical compositions) can, in principle, each be administered to a subject by any convenient route of administration. Preferably, the PAR2 inhibitor is administered orally (e.g., as a tablet, capsule, or as an ingestible solution), particularly by oral ingestion or swallowing. Oral administration is particularly preferred if the PAR2 inhibitor is a small molecule (such as, e.g., Compound 207). Conversely, if the PAR2 inhibitor is an antibody (or an antigen-binding fragment thereof or an antibody construct), it is preferably administered parenterally (e.g., intravenously or subcutaneously). The immune checkpoint inhibitor is preferably administered parenterally (e.g., intravenously), for example by injection or infusion, particularly by intravenous infusion.
The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.
As used herein, unless explicitly indicated otherwise or contradicted by context, the terms "a”, "an” and "the” are used interchangeably with "one or more” and "at least one”. Thus, for example, a composition comprising "a” PAR2 inhibitor can be interpreted as referring to a composition comprising "one or more” PAR2 inhibitors.
As used herein, the terms "optional”, "optionally” and "may” denote that the indicated feature may be present but can also be absent. Whenever the term "optional”, "optionally” or "may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, if a component of a composition is indicated to be "optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.
As used herein, the term "comprising” (or "comprise”, "comprises”, "contain”, "contains”, or "containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of "containing, inter alia”, i.e., "containing, among further optional elements, ...”. In addition thereto, this term also includes the narrower meanings of "consisting essentially of' and "consisting of”. For example, the term "A comprising B and C” has the meaning of "A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., "A containing B, C and D” would also be encompassed), but this term also includes the meaning of "A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).
It is to be understood that wherever numerical ranges are provided/disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, including the upper and lower endpoints of each numerical range, as well as each subrange encompassed by a numerical range disclosed herein. As used herein, the term "pharmaceutically acceptable” denotes that the corresponding substance is suitable/acceptable for human and/or veterinary pharmaceutical use.
A "pharmaceutically acceptable salt” of a compound (e.g., a PAR2 inhibitor) may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Further pharmaceutically acceptable salts are described in the literature, e.g., in Stahl PH & Wermuth CG (eds.), "Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002 (which is incorporated herein by reference) and in the literature cited therein. Preferred pharmaceutically acceptable salts of a PAR2 inhibitor (including, e.g., of any one of the specific/exemplary PAR2 inhibitors described herein) encompass, in particular, a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. The PAR2 inhibitor (including, e.g., any one of the specific/exemplary PAR2 inhibitors described herein) can also be used in non-salt form.
A pharmaceutically acceptable "solvate” of a compound (e.g., of a PAR2 inhibitor, either in salt or non-salt form) may be, e.g., a solvate of the respective compound with water (I ,e. , a hydrate) or a solvate of the compound with an organic solvent such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile.
The "subject” (or "patient”) to be treated in accordance with the present invention may be a human (e.g., a female human or a male human) or any other (non-human) animal, particularly a mammal. Examples of non-human mammals include, in particular, a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig. Most preferably, the subject/patient to be treated in accordance with the invention is a human.
As used herein, the term "treatment” (or "treating”) in relation to a disease/disorder (such as cancer) refers to the management and care of a patient for the purpose of combating the disease/disorder, such as to reverse, alleviate, inhibit or delay the disease/disorder, or one or more symptoms of such disease/disorder. It also refers to the administration of a compound or a composition for the purpose of preventing the onset of symptoms of the disease/disorder, alleviating such symptoms, or eliminating the disease/disorder. In particular, the treatment may be curative, ameliorating or palliative. The invention also specifically relates to non-prophylactic (or non-preventative) treatment.
As used herein, the term "small molecule” refers to an organic chemical compound having a molecular weight < 900 Dalton (Da), preferably < 500 Da. The molecular weight (in Da) corresponds to the mass of a compound and can be calculated from the molecular formula of the corresponding compound.
It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments.
In this specification, a number of documents including patent applications and scientific literature are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.
The reference in this specification to any prior publication (or information derived therefrom) is not and should not be taken as an acknowledgment or admission or any form of suggestion that the corresponding prior publication (or the information derived therefrom) forms part of the common general knowledge in the technical field to which the present specification relates.
The present invention particularly relates to the following items:
1. A protease-activated receptor-2 (PAR2) inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
2. An immune checkpoint inhibitor for use in the treatment of cancer, wherein the immune checkpoint inhibitor is administered in combination with a protease-activated receptor-2 (PAR2) inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor. 3. A combination of a protease-activated receptor-2 (PAR2) inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
4. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a protease-activated receptor-2 (PAR2) inhibitor and an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
5. Use of a protease-activated receptor-2 (PAR2) inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with an immune checkpoint inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
6. Use of an immune checkpoint inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with a protease-activated receptor-2 (PAR2) inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
7. Use of a protease-activated receptor-2 (PAR2) inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
8. The PAR2 inhibitor for use according to item 1 , the immune checkpoint inhibitor for use according to item 2, the combination for use according to item 3, the method according to item 4, or the use according to any one of items 5 to 7, wherein the administration of the PAR2 inhibitor is started at least 2 days earlier than the administration of the immune checkpoint inhibitor.
9. The PAR2 inhibitor for use according to item 1 , the immune checkpoint inhibitor for use according to item 2, the combination for use according to item 3, the method according to item 4, or the use according to any one of items 5 to 7, wherein the administration of the PAR2 inhibitor is started 2 to 14 days earlier than the administration of the immune checkpoint inhibitor.
10. The PAR2 inhibitor for use according to item 1 , the immune checkpoint inhibitor for use according to item 2, the combination for use according to item 3, the method according to item 4, or the use according to any one of items 5 to 7, wherein the administration of the PAR2 inhibitor is started 3 to 7 days earlier than the administration of the immune checkpoint inhibitor. The PAR2 inhibitor for use according to any one of items 1 or 8 to 10, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 10, the combination for use according to any one of items 3 or 8 to 10, the method according to any one of items 4 or 8 to 10, or the use according to any one of items 5 to 10, wherein the administration of the PAR2 inhibitor is discontinued when the administration of the immune checkpoint inhibitor is started. The PAR2 inhibitor for use according to any one of items 1 or 8 to 10, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 10, the combination for use according to any one of items 3 or 8 to 10, the method according to any one of items 4 or 8 to 10, or the use according to any one of items 5 to 10, wherein the administration of the PAR2 inhibitor is continued when the administration of the immune checkpoint inhibitor is started. The PAR2 inhibitor for use according to any one of items 1 or 8 to 12, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 12, the combination for use according to any one of items 3 or 8 to 12, the method according to any one of items 4 or 8 to 12, or the use according to any one of items 5 to
12, wherein the PAR2 inhibitor is a compound selected from: 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-[4-[7-tert-butyl-5-(4-chloro-3-fluoro-phenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-
2.4-dimethyl-pyridine-3-carboxylic acid;
2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1 ,5- a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid;
[7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1 H-imidazol-2-yl)methanol;
3-(4-(8-(tert-butyl)-6-(4-fluorophenyl)imidazo[1,2-b]pyridazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-3- oxopropane-1 -sulfonic acid;
(2,2-dimethylpiperidin-1-yl)-[5-(cyclopentylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]methanone; N-((3S,6S)-1-furan-2-carbonyl)-6-isobutyl-4,7-dioxo-8-(piperidin-4-ylmethyl)octahydro-2H-pyrazino[1,2- a]pyrimidin-3-yl)-3-methylbutaneamide; or a pharmaceutically acceptable salt or solvate thereof. The PAR2 inhibitor for use according to any one of items 1 or 8 to 13, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 13, the combination for use according to any one of items 3 or 8 to 13, the method according to any one of items 4 or 8 to 13, or the use according to any one of items 5 to
13, wherein the PAR2 inhibitor is 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1,7'- pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid or a pharmaceutically acceptable salt or solvate thereof. The PAR2 inhibitor for use according to any one of items 1 or 8 to 14, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 14, the combination for use according to any one of items 3 or 8 to 14, the method according to any one of items 4 or 8 to 14, or the use according to any one of items 5 to 14, wherein the PAR2 inhibitor is administered once daily.
16. The PAR2 inhibitor for use according to any one of items 1 or 8 to 15, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 15, the combination for use according to any one of items 3 or 8 to 15, the method according to any one of items 4 or 8 to 15, or the use according to any one of items 5 to
15, wherein the PAR2 inhibitor is administered once daily over a period of at least 3 days before the administration of the immune checkpoint inhibitor.
17. The PAR2 inhibitor for use according to any one of items 1 or 8 to 16, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 16, the combination for use according to any one of items 3 or 8 to 16, the method according to any one of items 4 or 8 to 16, or the use according to any one of items 5 to
16, wherein the PAR2 inhibitor is administered orally.
18. The PAR2 inhibitor for use according to any one of items 1 or 8 to 12, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 12, the combination for use according to any one of items 3 or 8 to 12, the method according to any one of items 4 or 8 to 12, or the use according to any one of items 5 to 12, wherein the PAR2 inhibitor is an antibody which is preferably selected from M EDI-0618, PaB670129 and P24E1102.
19. The PAR2 inhibitor for use according to any one of items 1 , 8 to 12 or 18, the immune checkpoint inhibitor for use according to any one of items 2, 8 to 12 or 18, the combination for use according to any one of items 3, 8 to 12 or 18, the method according to any one of items 4, 8 to 12 or 18, or the use according to any one of items 5 to 12 or 18, wherein the PAR2 inhibitor is administered weekly or biweekly.
20. The PAR2 inhibitor for use according to any one of items 1 , 8 to 12, 18 or 19, the immune checkpoint inhibitor for use according to any one of items 2, 8 to 12, 18 or 19, the combination for use according to any one of items 3, 8 to 12, 18 or 19, the method according to any one of items 4, 8 to 12, 18 or 19, or the use according to any one of items 5 to 12, 18 or 19, wherein the PAR2 inhibitor is administered parenterally.
21 . The PAR2 inhibitor for use according to any one of items 1 or 8 to 20, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 20, the combination for use according to any one of items 3 or 8 to 20, the method according to any one of items 4 or 8 to 20, or the use according to any one of items 5 to 20, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti- CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti-CD47 antibody, an anti-LAG3 antibody, an anti-OX40 antibody, or an anti-ICOS antibody.
22. The PAR2 inhibitor for use according to any one of items 1 or 8 to 21 , the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 21 , the combination for use according to any one of items 3 or 8 to 21 , the method according to any one of items 4 or 8 to 21 , or the use according to any one of items 5 to 21, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP- 514, JTX-4014, APE02058, atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, ipilimumab, tremelimumab, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, M6223, sabatolimab, cobolimab, lomvastomig, BGB- A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR-1702, Sym023, TQB2618, onvatilimab, HMBD-002, KVA12123, W0180, IGN-381, PMC-309, APX-201, tifcemalimab, icatolimab, ANB032, HFB200603, magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801, TI-061, relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701, IMP731, ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX- 106, IBI101, MOXR0916, alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, and MEDI-570.
23. The PAR2 inhibitor for use according to any one of items 1 or 8 to 21, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 21, the combination for use according to any one of items 3 or 8 to 21, the method according to any one of items 4 or 8 to 21, or the use according to any one of items 5 to 21, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.
24. The PAR2 inhibitor for use according to any one of items 1 or 8 to 23, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 23, the combination for use according to any one of items 3 or 8 to 23, the method according to any one of items 4 or 8 to 23, or the use according to any one of items 5 to
23, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, which is selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, tislelizumab, toripalumab, penpulimab, cadonilimab, serplulimab, envafolimab, pucotenlimab, adebrelimab, camrelizumab, prolgolimab, retifanlimab, sintilimab, socazolimab, sugemalimab, zimberelimab, spartalizumab, and dostarlimab.
25. The PAR2 inhibitor for use according to any one of items 1 or 8 to 24, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 24, the combination for use according to any one of items 3 or 8 to 24, the method according to any one of items 4 or 8 to 24, or the use according to any one of items 5 to
24, wherein the immune checkpoint inhibitor is administered every 2, 3, 4, 5 or 6 weeks.
26. The PAR2 inhibitor for use according to any one of items 1 or 8 to 25, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 25, the combination for use according to any one of items 3 or 8 to 25, the method according to any one of items 4 or 8 to 25, or the use according to any one of items 5 to
25, wherein the immune checkpoint inhibitor is administered parenterally.
27. The PAR2 inhibitor for use according to any one of items 1 or 8 to 26, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 26, the combination for use according to any one of items 3 or 8 to 26, the method according to any one of items 4 or 8 to 26, or the use according to any one of items 5 to
26, wherein the cancer is selected from colorectal cancer, colon cancer, gastrointestinal cancer, gastric cancer, rectal cancer, anal cancer, liver cancer, breast cancer, pancreatic cancer, cervical cancer, prostate cancer, ovarian cancer, endometrial cancer, vaginal cancer, vulvar cancer, uterine cancer, testicular cancer, germ cell cancer, esophageal cancer, laryngeal cancer, mouth cancer, hematological cancer, leukemia, lymphoma, multiple myeloma, lung cancer, adrenal gland cancer, bile duct cancer, hepatobiliary cancer, genitourinary cancer, urothelial cancer, bladder cancer, gallbladder cancer, head and/or neck cancer, kidney cancer, mesothelioma, sarcoma, skin cancer, melanoma, Merkel-cell cancer, epidermoid cancer, thyroid cancer, thymus cancer, squamous cell cancer, goblet cell cancer, spleen cancer, bone cancer, osteosarcoma, fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, neuroendocrine cancer, neuroblastoma, brain cancer, and glioblastoma.
28. The PAR2 inhibitor for use according to any one of items 1 or 8 to 27, the immune checkpoint inhibitor for use according to any one of items 2 or 8 to 27, the combination for use according to any one of items 3 or 8 to 27, the method according to any one of items 4 or 8 to 27, or the use according to any one of items 5 to
27, wherein the subject to be treated is a human.
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
EXAMPLES
Example 1 : Effect of PAR2 knock out on the anti-tumor efficacy of immune checkpoint inhibitors
To assess the impact of PAR2 inhibition on the efficacy of immune checkpoint inhibitors, the MC38 mouse model of colorectal cancer was utilized. 0.5x106 MC38 cells (ATCC), which do not express PAR2, were subcutaneously injected into groups of 10 syngeneic PAR2 knock out female C57BL/6 mice (PAR2-/-; Jackson Laboratory) or wild type litter mates (WT). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 6 days post tumor inoculation and 10Opig after 9 and 12 days. Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm2. A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
As shown in Figure 1, the absence of PAR2 did not have any effect on tumor growth on its own. However, the antitumor efficacy of anti-PD1 therapy was superior in PAR2 knock out mice compared to wild type mice. Indeed, an increased progression-free survival and decreased tumor growth was observed in PAR2-/- mice treated with anti- PD1 compared to all other groups. The rate of complete responses (CR) induced by anti-PD1 therapy was also higher in PAR2 knock out mice (80%) than in wild type (50%) mice.
These data demonstrate that the absence of PAR2 increases the anti-tumor efficacy of anti-PD1 therapy. Example 2: Effect of pharmacological PAR2 inhibition on the anti-tumor efficacy of immune checkpoint inhibitors according to timing of administration
To determine if pharmacological inhibition of PAR2 could have the same effect as gene deletion on the anti-tumor efficacy of immune checkpoint inhibitors, the same MC38 model was used (see Example 1 above). As an example, the compound 1-117, described in patent application WO 2018/057588, was used as it is a potent and selective PAR2 inhibitor with proven in vivo activity.
Compound 1-117
0.5x106 MC38 cells (ATCC) were subcutaneously injected into groups of 15 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 100 g of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected at days 6, 9, 12 and 15 post tumor inoculation. The PAR2 inhibitor 1-117 (in 10% Ethanol- 100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) was given once a day by oral gavage. 1-177 was administered at a 30mg/kg dose. For the monotherapy, treatment with 1-117 started at day 6 post tumor inoculation and lasted for 21 days. For the combination, in order to determine the influence of the timing of administration, 1-117 treatment lasted for 21 days and started either at day 3, 6 or 9 post tumor inoculation. Therefore, PAR2 inhibition started either 3 days before, at the same time or 3 days after anti-PD 1 therapy. Tumor growth was assessed with a caliper. Progression was noted when tumor volume became superior to 100mm3. A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
Surprisingly, as shown in Figure 2, the effect of pharmacological PAR2 inhibition recapitulated the results observed with PAR2 knock out mice only when 1-117 treatment started before the anti-PD1 treatment. Indeed, no improvement were observed when treatment with 1-117 started at the same time or after anti-PD 1 treatment compared to anti-PD1 alone. However, an increased progression-free survival rate and a decreased tumor growth were observed when PAR2 inhibition started 3 days before anti-PD1 injections compared to monotherapies. When compared head-to- head, the differences in progression-free survival and tumor volume observed between anti-PD 1 alone and the combination group where 1-117 treatment started earlier than anti-PD 1 treatment are statistically significant. The rate of complete response was also tripled in this group (40%) compared to anti-PD1 alone (13%). When the combination groups were compared, mice treated with a PAR2 inhibition starting before anti-PD1 had a statistically higher progression-free survival and lower tumor volume than mice for which PAR2 inhibition started at the same time or after anti-PD1 treatment.
These data demonstrate that pharmacological inhibition of PAR2 improves the anti-tumor efficacy of immune checkpoint inhibitors against cancer only when started earlier.
Example 3: Effect of priming doses of PAR2 inhibitors on the anti-tumor efficacy of immune checkpoint inhibitors
Since PAR2 inhibition only improved the anti-tumor efficacy when started earlier, it was hypothesized that the few administrations of 1-117 given before anti-PD 1 injections could be sufficient for this effect.
To test this hypothesis, the MC38 model was used. 0.5x106 MC38 cells (ATCC) were subcutaneously injected into groups of 10 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD 1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 6 days post tumor inoculation and 10Opig after 9 and 12 days. The PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage. 1-177 was administered at a 30mg/kg dose. For the monotherapy, treatment with 1-117 started at day 2 post tumor inoculation and lasted for 5 days. For the combination treatment, 1-117 administrations either lasted for 21 days (days 3 to 24 post tumor inoculation) or 5 days (days 2 to 6 post tumor inoculation). Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm2. A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
Surprisingly, as shown in Figure 3, both 5 days and 21 days administration of PAR2 inhibitor improved the anti-tumor efficacy of anti-PD-1 treatment in a similar way. Indeed, increased progression-free survival rate and a decreased tumor growth were observed in both combination groups compared to monotherapies. When compared head-to- head, the differences in progression-free survival and tumor growth observed between anti-PD1 alone and the combination of anti-PD1 and a 5 day treatment with 1-117 are statistically significant. Furthermore, tumors were rejected in 50% of animals when treated with anti-PD1 alone. In the combination groups, the rate of complete response increased to 90% and 80% when 1-117 was administered for 5 days and 21 days respectively.
These data show that priming doses of PAR2 inhibitors for 5 days increase anti-tumor efficacy of immune checkpoint inhibitors in a similar way than longer term administrations.
To determine if this observation could be extended to other PAR2 inhibitors we performed a similar experiment with the compound of Example 207 of the patent application WO 2023/233033 (referred to herein as "Compound 207”). This small molecule is structurally different from 1-117 but with similar pharmacokinetic properties and potency on PAR2 inhibition.
Compound 207
6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3- dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid
0.5x106 MC38 cells (ATCC) were subcutaneously injected into groups of 12 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 6 days post tumor inoculation and 10Opig after 9 and 12 days. The PAR2 inhibitor Compound 207 or vehicle (1 ,2% methylcellulose, 0, 1 % tween80) were given once a day by oral gavage. This treatment started at day 2 post tumor inoculation and lasted for 5 days (days 2 to 6 post tumor inoculation). For the monotherapy, Compound 207 was given at a 30mg/kg dose. For the combination treatment, Compound 207 was given at a 30mg/kg or 100mg/kg dose. Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm2. A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
As shown in Figure 4, priming doses of Compound 207 increased the anti-tumor efficacy of anti-PD1 in a similar way as 1-117. Indeed, as seen in the previous experiments, increased progression-free survival rate and a decreased tumor growth were observed in the combination group with the highest dose of Compound 207 (1 OOmg/kg) compared to monotherapies. Furthermore, tumors were rejected in 50% of animals when treated with anti-PD1 alone. In the combination groups, the rate of complete response increased in a dose dependent manner to 58% and 70% when Compound 207 was administered at 30mg/kg and 100mg/kg respectively.
These data show that priming doses of PAR2 inhibitors for 5 days are sufficient to increase anti-tumor efficacy of immune checkpoint inhibitors.
Example 4: Effect of priming doses of PAR2 inhibitors on the anti-tumor efficacy of immune checkpoint inhibitors at later stages of tumor development
Our data as described in Examples 1 to 3 clearly demonstrate that PAR2 inhibitors improve anti-tumor efficacy of immune checkpoint inhibitors when administration is started earlier. However, this dosing regimen forced us to start the treatment early in the tumor development (2 days post tumor inoculation). To determine if the benefit of a combination between PAR2 inhibitors and immune checkpoint inhibitors could also be observed at later stages of the tumor development, we performed a similar experiment where both treatments were delayed. 0.5x106 MC38 cells (ATCC) were subcutaneously injected into groups of 10 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 9 days post tumor inoculation and 10Opig after 12 and 15 days. The PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage. 1-177 was administered at a 30mg/kg dose from day 5 to day 9 post tumor inoculation. Tumor growth was assessed with a caliper. Progression was noted when tumor size became superior to 50mm2. A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
As shown in Figure 5, priming doses of 1-117 increased the anti-tumor efficacy of anti-PD 1 at later stages of tumor development. Indeed, similarly to previous experiments, increased progression-free survival rate and a decreased tumor growth were observed in the combination group compared to monotherapies when both treatments were delayed. Furthermore, tumors were rejected in 40% of animals when treated with anti-PD 1 alone. In the combination groups, the rate of complete response increased to 70%.
These data show that priming doses of PAR2 inhibitors increase anti-tumor efficacy of immune checkpoint inhibitors regardless of the tumor development stage.
Example 5: Influence of the timing of priming doses of PAR2 inhibitors on the anti-tumor efficacy of immune checkpoint inhibitors
Our data as described in Examples 1 to 4 clearly demonstrate that PAR2 inhibitors improve anti-tumor efficacy of immune checkpoint inhibitors when administration is started earlier. To better define the dosing regimen necessary to increase the superior efficacy of the combination therapy, we performed a similar experiment where 1-117 was administered at different timings.
0.5x106 MC38 cells (ATCC) were subcutaneously injected into groups of 10 syngeneic wild type female C57BL/6 mice (Jackson Laboratory). 200pig of anti-PD1 antibody (clone RMP1-14) or isotype control (Iso) were intraperitoneally injected 9 days post tumor inoculation and 10Opig after 12 and 15 days. The PAR2 inhibitor 1-117 or vehicle (10% Ethanol-100, 20% PEG 400, 5% HPMC 80-120 cp 2% in water, 40% HPpCD 30% in water, 25% water) were given once a day by oral gavage at a 30mg/kg dose. 1-117 was administered either from day 5 to day 9 post tumor inoculation, or from day 3 to day 7 post tumor inoculation, or from day 5 to day 7 post tumor inoculation, or on day 7 post tumor inoculation, or on days 7, 10 and 13 post tumor inoculation. Tumor growth was assessed with a caliper. Progression was noted when tumor size exceeded 50mm2. A complete response (CR) was considered when tumor volume decreased below the limit of detection and stayed that way during the rest of the study.
As shown in Figure 6, priming doses of 1-117 increased the anti-tumor efficacy of anti-PD1 treatment even when a 2-day washout period was allowed between the 2 treatments. Indeed, similarly to previous experiments, an increased progression-free survival rate and a decreased tumor growth were observed in the combination group compared to monotherapies when 1-117 was administered from day 5 to day 9 or from day 3 to day 7 post tumor inoculation. Furthermore, tumors were rejected in 50% of animals when treated with anti-PD 1 alone. In the combination groups, the rate of complete response increased to 70-80% with both regimens. A similar rate of complete response (70%) was also observed when 1-117 was administered for 3 days (from day 5 to day 7 post tumor inoculation) instead of 5 days.
These data show that priming doses of PAR2 inhibitors increase anti-tumor efficacy of immune checkpoint inhibitors if the administration of the PAR2 inhibitors is started earlier. Our data also demonstrate that a washout period can be allowed between the last priming dose of PAR2 inhibitors and the first administration of immune checkpoint inhibitors without affecting the superior efficacy of the combination therapy.

Claims

1. A protease-activated receptor-2 (PAR2) inhibitor for use in the treatment of cancer, wherein the PAR2 inhibitor is administered in combination with an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
2. An immune checkpoint inhibitor for use in the treatment of cancer, wherein the immune checkpoint inhibitor is administered in combination with a protease-activated receptor-2 (PAR2) inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
3. A combination of a protease-activated receptor-2 (PAR2) inhibitor and an immune checkpoint inhibitor for use in the treatment of cancer, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
4. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a protease-activated receptor-2 (PAR2) inhibitor and an immune checkpoint inhibitor, wherein the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
5. Use of a protease-activated receptor-2 (PAR2) inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with an immune checkpoint inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
6. Use of an immune checkpoint inhibitor for the manufacture of a medicament for the treatment of cancer, wherein the medicament is for administration in combination with a protease-activated receptor-2 (PAR2) inhibitor via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
7. Use of a protease-activated receptor-2 (PAR2) inhibitor and an immune checkpoint inhibitor for the manufacture of medicaments for the treatment of cancer, wherein the medicaments are for administration via a dosage regimen whereby the administration of the PAR2 inhibitor is started at least 1 day earlier than the administration of the immune checkpoint inhibitor.
8. The PAR2 inhibitor for use according to claim 1 , the immune checkpoint inhibitor for use according to claim 2, the combination for use according to claim 3, the method according to claim 4, or the use according to any one of claims 5 to 7, wherein the administration of the PAR2 inhibitor is started at least 2 days earlier than the administration of the immune checkpoint inhibitor.
9. The PAR2 inhibitor for use according to claim 1 , the immune checkpoint inhibitor for use according to claim 2, the combination for use according to claim 3, the method according to claim 4, or the use according to any one of claims 5 to 7, wherein the administration of the PAR2 inhibitor is started 3 to 7 days earlier than the administration of the immune checkpoint inhibitor.
10. The PAR2 inhibitor for use according to any one of claims 1 , 8 or 9, the immune checkpoint inhibitor for use according to any one of claims 2, 8 or 9, the combination for use according to any one of claims 3, 8 or 9, the method according to any one of claims 4, 8 or 9, or the use according to any one of claims 5 to 9, wherein the administration of the PAR2 inhibitor is discontinued when the administration of the immune checkpoint inhibitor is started.
11. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 10, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 10, the combination for use according to any one of claims 3 or 8 to 10, the method according to any one of claims 4 or 8 to 10, or the use according to any one of claims 5 to 10, wherein the PAR2 inhibitor is a compound selected from:
6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-
3.3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid;
6-[4-[7-tert-butyl-5-(4-chloro-3-fluoro-phenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazin-1-yl]-
2.4-dimethyl-pyridine-3-carboxylic acid;
2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1 ,5- a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid;
[7-fluoro-3-(1-methylcyclopropyl)benzofuran-4-yl]-(1 H-imidazol-2-yl)methanol;
3-(4-(8-(tert-butyl)-6-(4-fluorophenyl)imidazo[1 ,2-b]pyridazine-2-carbonyl)-3,3-dimethylpiperazin-1-yl)-3- oxopropane-1 -sulfonic acid;
(2,2-dimethylpiperidin-1-yl)-[5-(cyclopentylmethyl)-7-propan-2-ylpyrazolo[1 ,5-a]pyrimidin-2-yl]methanone; N-((3S,6S)-1-furan-2-carbonyl)-6-isobutyl-4,7-dioxo-8-(piperidin-4-ylmethyl)octahydro-2H-pyrazino[1 ,2- a]pyrimidin-3-yl)-3-methylbutaneamide; or a pharmaceutically acceptable salt or solvate thereof.
12. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 11 , the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 11 , the combination for use according to any one of claims 3 or 8 to 11 , the method according to any one of claims 4 or 8 to 11 , or the use according to any one of claims 5 to 11 , wherein the PAR2 inhibitor is 6-(4-(5'-(4-chloro-3-fluorophenyl)-5',6'-dihydrospiro[cyclopentane-1 ,7'- pyrrolo[2,3-b]pyrazine]-2'-carbonyl)-3,3-dimethylpiperazin-1-yl)-2,4-dimethylnicotinic acid or a pharmaceutically acceptable salt or solvate thereof.
13. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 11 , the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 11 , the combination for use according to any one of claims 3 or 8 to 11 , the method according to any one of claims 4 or 8 to 11 , or the use according to any one of claims 5 to 11, wherein the PAR2 inhibitor is 6-[4-[7-tert-butyl-5-(4-chloro-3-fluoro-phenyl)furo[3,2-b]pyridine-2- carbonyl]-3,3-dimethyl-piperazin-1-yl]-2,4-dimethyl-pyridine-3-carboxylic acid or a pharmaceutically acceptable salt or solvate thereof.
14. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 13, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 13, the combination for use according to any one of claims 3 or 8 to 13, the method according to any one of claims 4 or 8 to 13, or the use according to any one of claims 5 to 13, wherein the PAR2 inhibitor is administered once daily.
15. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 14, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 14, the combination for use according to any one of claims 3 or 8 to 14, the method according to any one of claims 4 or 8 to 14, or the use according to any one of claims 5 to 14, wherein the PAR2 inhibitor is administered once daily over a period of at least 3 days before the administration of the immune checkpoint inhibitor.
16. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 15, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 15, the combination for use according to any one of claims 3 or 8 to 15, the method according to any one of claims 4 or 8 to 15, or the use according to any one of claims 5 to 15, wherein the PAR2 inhibitor is administered orally.
17. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 10, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 10, the combination for use according to any one of claims 3 or 8 to 10, the method according to any one of claims 4 or 8 to 10, or the use according to any one of claims 5 to 10, wherein the PAR2 inhibitor is an antibody which is preferably selected from MEDI-0618, PaB670129 and P24E1102.
18. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 17, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 17, the combination for use according to any one of claims 3 or 8 to 17, the method according to any one of claims 4 or 8 to 17, or the use according to any one of claims 5 to 17, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti- CTLA-4 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-BTLA antibody, an anti-CD47 antibody, an anti-LAG3 antibody, an anti-OX40 antibody, or an anti-ICOS antibody.
19. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 18, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 18, the combination for use according to any one of claims 3 or 8 to 18, the method according to any one of claims 4 or 8 to 18, or the use according to any one of claims 5 to 18, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, spartalizumab, dostarlimab, camrelizumab, sintilimab, tislelizumab, toripalimab, zimberelimab, pidilizumab, penpulimab, cadonilimab, serplulimab, pucotenlimab, prolgolimab, retifanlimab, sintilimab, AMP-224, AMP- 514, JTX-4014, APE02058, atezolizumab, avelumab, durvalumab, envafolimab, adebrelimab, socazolimab, sugemalimab, CK-301, BMS-936559, MEDI4736, MPDL3280A, MDX-1105, MEDI6469, bintrafusp alfa, ipilimumab, tremelimumab, tiragolumab, vibostolimab, domvanalimab, etigilimab, BMS-986207, EOS-448, COM902, ASP8374, SEA-TGT, BGB-A1217, IBI-939, M6223, sabatolimab, cobolimab, lomvastomig, BGB- A425, BMS-986258, INCAGN02390, LY3321367, LY3415244, SHR-1702, Sym023, TQB2618, onvatilimab, HMBD-002, KVA12123, W0180, IGN-381 , PMC-309, APX-201 , tifcemalimab, icatolimab, ANB032, HFB200603, magrolimab, lemzoparlimab, ligufalimab, CC-90002, IMM0306, TG-1801 , TI-061 , relatlimab, ieramilimab, encelimab, tebotelimab, REGN3767, FS118, IMP701 , IMP731 , ivuxolimab, MEDI0562, MEDI6383, MEDI6469, INCAGN01949, ABBV-368, BAT6026, BGB-A445, YH-002, BMS 986178, INBRX- 106, IBI101 , MOXR0916, alomfilimab, feladilimab, izuralimab, vopratelimab, BMS-986226, and MEDI-570.
20. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 18, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 18, the combination for use according to any one of claims 3 or 8 to 18, the method according to any one of claims 4 or 8 to 18, or the use according to any one of claims 5 to 18, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.
21 . The PAR2 inhibitor for use according to any one of claims 1 or 8 to 20, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 20, the combination for use according to any one of claims 3 or 8 to 20, the method according to any one of claims 4 or 8 to 20, or the use according to any one of claims 5 to 20, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, which is selected from nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, tislelizumab, toripalumab, penpulimab, cadonilimab, serplulimab, envafolimab, pucotenlimab, adebrelimab, camrelizumab, prolgolimab, retifanlimab, sintilimab, socazolimab, sugemalimab, zimberelimab, spartalizumab, and dostarlimab.
22. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 21 , the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 21 , the combination for use according to any one of claims 3 or 8 to 21 , the method according to any one of claims 4 or 8 to 21 , or the use according to any one of claims 5 to 21 , wherein the immune checkpoint inhibitor is administered every 2, 3, 4, 5 or 6 weeks.
23. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 22, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 22, the combination for use according to any one of claims 3 or 8 to 22, the method according to any one of claims 4 or 8 to 22, or the use according to any one of claims 5 to 22, wherein the immune checkpoint inhibitor is administered parenterally.
24. The PAR2 inhibitor for use according to any one of claims 1 or 8 to 23, the immune checkpoint inhibitor for use according to any one of claims 2 or 8 to 23, the combination for use according to any one of claims 3 or 8 to 23, the method according to any one of claims 4 or 8 to 23, or the use according to any one of claims 5 to 23, wherein the cancer is selected from colorectal cancer, colon cancer, gastrointestinal cancer, gastric cancer, rectal cancer, anal cancer, liver cancer, breast cancer, pancreatic cancer, cervical cancer, prostate cancer, ovarian cancer, endometrial cancer, vaginal cancer, vulvar cancer, uterine cancer, testicular cancer, germ cell cancer, esophageal cancer, laryngeal cancer, mouth cancer, hematological cancer, leukemia, lymphoma, multiple myeloma, lung cancer, adrenal gland cancer, bile duct cancer, hepatobiliary cancer, genitourinary cancer, urothelial cancer, bladder cancer, gallbladder cancer, head and/or neck cancer, kidney cancer, mesothelioma, sarcoma, skin cancer, melanoma, Merkel-cell cancer, epidermoid cancer, thyroid cancer, thymus cancer, squamous cell cancer, goblet cell cancer, spleen cancer, bone cancer, osteosarcoma, fibrosarcoma, Ewing's sarcoma, Kaposi's sarcoma, neuroendocrine cancer, neuroblastoma, brain cancer, and glioblastoma.
PCT/EP2025/054098 2024-02-16 2025-02-14 Combinations of par2 inhibitors and immune checkpoint inhibitors for the treatment of cancer Pending WO2025172573A1 (en)

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