methods for administering sting agonists

专利摘要:
The present invention relates to methods of treating disease states, including cancer, in a human comprising comprising systemically administering a STING agonist or a pharmaceutically acceptable salt thereof, to said human being.
公开号:BR112020006761A2
申请号:R112020006761-0
申请日:2018-10-04
公开日:2020-10-06
发明作者:George Scott PESIRIDIS；Joshi M. Ramanjulu；Jean-Luc TRAN；Jingsong YANG
申请人:Glaxosmithkline Intellectual Property Development Limited；
IPC主号:

专利说明:

[001] [001] The present invention relates to methods of releasing STING agonists (Interferon Gene Stimulator). The invention also relates to the use of said compounds, combinations, compositions and drugs, in the treatment of diseases in which the modulation of STING (Interferon Gene Stimulator) is beneficial, for example, inflammation, allergic and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, skin warts, multiple sclerosis, human immunodeficiency virus (HIV) infection, AIDS, cancer, precancerous syndromes and as an immunogenic composition or adjuvants of vaccine.
[002] [002] Vertebrates are constantly threatened by the invasion of microorganisms and have developed immune defense mechanisms to eliminate infectious pathogens. In mammals, this immune system comprises two branches; innate immunity and adaptive immunity. The innate immune system is the first line of defense that is initiated by Pattern Recognition Receptors (PRRs) that detect pathogen ligands as well as associated harmful molecular patterns (Takeuchi O. et al., Cell, 2010: 140, 805 to 820 ). An increasing number of these receptors have been identified, including Toll type receptors (TLRs), type C lectin receptors, gene type receptors | inducible by retinoic acid (RIG-II) and NOD type receptors (NLRs) and double-stranded DNA sensors. The activation of PRRs leads to the overloading of genes involved in the inflammatory response including type 1 interferons, proinflammatory cytokines and chemokines that suppress pathogen replication and facilitate adaptive immunity.
[003] [003] The STING adapter protein (Interferon Gene Stimulator),
[004] [004] CDNs were first identified as secondary bacterial messengers responsible for controlling numerous responses in the prokaryotic cell. Bacterial CDNs, such as c-di-GMP, are symmetrical molecules characterized by two phosphodiester 3,5 bonds.
[006] [006] More recently, the response to cytosolic DNA has been elucidated and has been shown to involve the generation, by an enzyme called GMP-AMP cyclic synthase (cGAS, previously known as C6orf150 or MB21D1), of an identified innovative mammalian CDN signaling molecule like cGAMP, which activates the
[007] [007] Interferon was first described as a substance that can protect cells from viral infection (Isaacs & Lindemann, J. Virus Interference. Proc. R. Soc. Lon. Ser. B. Biol. Sci. 1957: 147, 258 to 267). In man, Type | are a family of related proteins encoded by genes on chromosome 9 and encoding at least 13 isoforms of interferon alpha (IFNa) and one isoform of interferon beta (IFNB). Recombinant IFNa was the first approved therapeutic biological and has become an important therapy in viral infections and cancer. In addition to direct antiviral activity in cells, interferons are known as potent modulators of the immune response, acting on cells of the immune system.
[008] [008] Administration of a small molecule compound that can stimulate the innate immune response, including activation of Type | and other cytokines, can become an important strategy for the treatment or prevention of human diseases including viral infections. This type of immunomodulatory strategy has the potential to identify compounds that may be useful not only in infectious diseases, but also in cancer (Zitvogel, L., et al., Nature Reviews Immunology, 2015 15 (7), p405 to 414), allergic diseases (Moisan J. et al. Am. J. Physiol. Lung Cell Mol. Physiol., 2006: 290, L987 to 995), other inflammatory conditions such as irritable bowel disease (Rakoff-Nahoum S., Cell., 2004, 23, 118 (2): 229 to 41) and as vaccine adjuvants (Persing et al. Trends Microbiol. 2002: 10 (10 Suppl), S32-7 and Dubensky et al., Terapeutic Advances in Vaccines, published in September 5, 2013).
[010] [010] In contrast, increased and prolonged production of type IFN | is associated with a variety of chronic infections, including Mycobacteria (Collins et al., CHM 2015; Wassermann et al., CHM 2015; Watson et al., CHM 2015), Franciscella (Storek et al., JI 2015; Jin et al ., JI 2011), Chlamydia (Prantner et al., JI 2010; Barker et al., Mbio 2013; Zhang et al., JI 2014), Plasmodium (Sharma et al., Immunity 2011) and HIV (Herzner et al. , Nat Immunol 2015; Nissen et al., Clin Exp Immunol 2014; Gao et al., Science 2013; Lahaye et al., Science 2013;) (revised in Stifter and Feng, JI 2014). Similarly, the excess production of type interferon | it is found among patients with complex forms of autoimmune disease. Genetic evidence in humans and support for studies in animal models support the hypothesis that STING inhibition results in interferon type | reduced, which causes autoimmune diseases (Crow Yy, et al., Nat. Genet. 2006; 38; 917 to 920, Stetson DB, et al., Cell 2008; 134; 587 to 598). Therefore, STING inhibitors provide treatment for patients with type interferon production | and chronic proinflammatory cytokine associated with complex autoimmune infections or disease. Allergic diseases are associated with a Th2-mediated immune response to allergens.
[011] [011] The type IFN | has been implicated in contributing to the innate immune detection of immunogenic tumors, leading to adaptive T cell responses via STING and IRF3 as demonstrated by Woo, S-Y et al. Immunity 41: 330 to 342 (2014), Diamond. M. et al. (2011). and Corrales.L. et al. CIl reports 11: 1018 to 1030 (2015).
[012] [012] Additionally, the small molecule of the mouse-specific STING agonist (DMXAA) has also been shown to induce tumor regression in multiple mouse tumor models and induced IFN-B Type-| l in normal wild-type mice and loss of normal wild-type ability to reject tumor growth and induction of Type-IFN-B | in the mouse with STING (”), this indicates that STING induces IFN-B type-1 is a central component-mediated tumor cell death and adaptive immunity responses to lead to tumor regression. Welsh. R. et al. (2012), Li.K. et al. (2017) and Vargas TR. et al. (2017).
[013] [013] Compounds that bind to STING and act as an agonist have been shown to induce type 1 interferons and other cytokines in incubation with human PBMCs. Compounds that induce human interferons can be useful in the treatment of various diseases, for example, inflammation, allergic and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, skin warts, multiple sclerosis, human immunodeficiency virus (HIV) infection, AIDS, cancer (including basal cell carcinoma and squamous cell carcinoma), precancerous syndromes (including actinic keratoses) and as an immunogenic composition or vaccine adjuvants.
[014] [014] Thus, there is a need for methods of administering these compounds for the effective treatment of these diseases. In particular, there remains a need for methods that take into account the increased production of cytokine in diseased tissue and for the safe and effective systemic administration of a STING agonist that does not require the use of a bleaching formulation.
[016] [016] In an embodiment of the present invention, methods of administering a STING agonist to a human in need thereof are provided, comprising administering said STING agonist systemically. In one embodiment, the STING agonist increases the concentration of at least one cytokine in the blood, plasma or serum of said human being to an effective concentration to stimulate T cells in said human being. In one aspect, the cytokine concentrations are not increased high enough to produce adverse immunological effects on said human being. In one embodiment, methods are provided comprising administering a STING agonist to a human in need thereof, wherein the STING agonist increases the concentration of at least one pro-inflammatory cytokine in the diseased tissue in said human being at least three times more than the concentration of said at least pro-inflammatory cytokine in the blood, plasma or serum of said human being.
[017] [017] FIG. 1: Compound 1 generates specific cytokines for STING in mice: Compound 1 induces IFNB and pro-inflammatory cytokines in WT, but not in a Knockout (KO) mouse with STING.
[018] [018] FIG. 2: Scheme representing the IV Administration of Compound 1 for kinetic study over time of the pharmacokinetics and pharmacodynamics of Compound 1 FIG. 2 (A): Outline of the kinetic study over time of the pk / pd (30 ug / Mouse - 1.5 mg / kg); FIG. 2 (B) Compound Dose Titration 1 measured 3.5 hours after Administration | V.
[019] [019] FIG. 3: Time profile of drug concentration in blood and tumor after a single bolus IV dose of 30 µg of Compound 1. Each point in time represents data collected from four repeated animals.
[020] [020] FIG. 4 (Fig. 4A, 4B, 4C and 4D): IV administration of Compound 1, kinetics over time of the cytokine response in BALB / c mice carrying a single CT-26 tumor (30 ug / Mouse - 1.5 mg / kg). Representative of PD responses in Administration IV in a single bolus of Compound-1 in PK / PD over time in tumor CT-26 in Mouse BALB / c FIG. 4 (A) Serum and Tumor IL-6; FIG. 4 (B) Serum and Tumor TNF-a; FIG. 4 (C) Serum and Tumor IFN-B; FIG. 4 (D) Serum and Tumor Ifn-y.
[021] [021] FIG. 5: Fig. 5 (A) Blood and tumor concentration of Compound 1 in 3.5 hours after IV bolus dose for BALB / c mice bearing CT26 tumor Fig. 5 (B) Compound 1 dose titration and IFNB detection blood and tumor.
[022] [022] FIG. 6: Correlation of pK / pD | V with Tumor Regression. FIG. 6 (A) IFNB ED5o Dose-Response Curves of the tumor at the dose of Compound 1 measured 3.5 hours after IV dose titration. FIG. 6 (B): ED50 curve of the Tumor volume area under the tumor regression curve responded to Administration IV treatment with Compound 1.
[023] [023] FIG. 7: Schematic of the outline of the tumor regression study in the dosing schedule for IV administration and tumor monitoring.
[024] [024] FIG. 8: Effect of IV administration of Compound 1 on different tumor models in mouse (A) CT-26: Colon; (B) EMT6: Breast; (C) H22: Liver; (D) Pan02: Pancreas; (E) RM1: Prostate; (F) B16F10: melanoma.
[025] [025] FIG. 9: IV administration of Compound 1 compromised tumor, drainage of lymph nodes and systemic immune cells. FIG. 9 (A) Increase in the dendritic cell in the tumor microenvironment and drainage of lymph nodes over time. FIG. 9 (B) Increased MHC-1 expression in lymph node drainage in NK, Be T cells.
[026] [026] FIG. 10: IV administration of Compound 1 in CD8 T cells induces tumor regression in the mouse model with CT-26 tumor. FIG. 10 (A) No effect of Body Weight after IV Compound Administration.
[027] [027] FIG. 10 (B) Loss of Compound 1 tumor regression efficacy in the CD8 T cell depleted tumor model).
[028] [028] FIG 11: Average volume of the group and individual mouse tumor - IV administration of Compound 1 in BALB / c mice carrying a single CT-26 tumor (n = 10 / group). The average tumor volume for mice in each group is shown along with individual tumor volume in mice with the orange number on each panel representing the number of complete tumor regressions.
[029] [029] Systemic activation of Pattern Recognition Receptors (PRR), including STING, throughout an organism can lead to the production of large amounts of pro-inflammatory cytokines resulting in an unacceptable side effect profile. These adverse side effects include, elevated body temperature, pain and nausea. Bacterial LPS, a TLRA agonist, is the main mediator of bacterial-induced septicemia, which is characterized in its early stages by a cytokine storm that often leads to death (Schulte, W .; Bernhagen, J .; Bucala, R ., Cytokines in Sepse: Potent Immunoregulators and Potential Therapeutic Targets - An Updated View. Mediators of Inflammation 2013, 2013, 16 pages). In addition to the systemic activation of TLR4 in sepsis, other conditions and therapeutic modalities that lead to the systemic cytokine storm are now recognized which, if not properly controlled, can lead to unacceptable side effects (Barrett, DM; Teachey, DT; Grupp, SA , Toxicity management for patients receiving novel T-cll engaging therapies. Current opinion in pediatrics 2014, 26 (1), 43 to 49). Although moderate systemic activation of proinflammatory cytokines is believed to be a beneficial mechanism used by the immune system to combat invading pathogens, the more potent activation, as noted above, can lead to unacceptable toxicity. The need to limit systemic activation of PRRs is well recognized in the vaccination field, which routinely uses a PRR agonist as an adjuvant to boost the immune response to the administered antigen (Wu, TYH, Strategies for designing synthetic immune agonists.! Immunology 2016 , 148 (4), 315 to 325.). Many of the intended uses of a PRR / STING agonist are best accomplished by local activation at the intended site of action leading to local activation of the immune response. For example, in cancer patients, local activation refers to the activation of STING in the tumor microenvironment. When STING activation occurs in a local environment or diseased tissue, the therapeutic benefit of a STING agonist can be improved and unnecessary systemic production of pro-inflammatory cytokines can be reduced. This ratio of location (for example, in a tumor microenvironment or diseased tissue) versus systemic cytokine production or concentration provides a means of quantifying the production of desired cytokines in the diseased tissue versus the production of cytokines in the blood, plasma or serum.
[030] [030] As used herein the term "therapeutic index (TI)" means the ratio of concentration of local cytokine in the targeted diseased tissue versus that of the non-diseased tissue. For example, in a disease, such as cancer, the target diseased tissue would include a tumor microenvironment. For agonists intended for the treatment of cancer, such as a solid tumor, the tumor tissue is considered to be the diseased tissue. For most purposes, the non-diseased tissue that will be used to build the TI is blood, serum or plasma. For the treatment of cancer, TI is defined as the ratio of cytokines in the tumor microenvironment versus that detected in blood and / or plasma and / or serum. TI can be applied to individual cytokines or various pro-inflammatory cytokines, as measured in the tumor microenvironment and blood and / or plasma and / or serum.
[031] [031] In some cases, a TI of 1 or less is considered unfavorable, as it indicates that the STING agonist stimulates cytokine production with equal effectiveness in the tumor and in the blood. In some cases, an IT of 3 or greater is considered favorable, an IT of 10 or more is considered more favorable, an IT of 30 or more is considered very favorable and an IT of 100 or more is considered extremely favorable. As is understood by one skilled in the art, the concentration of various proinflammatory cytokines can be measured in diseased tissue and blood and / or plasma and / or serum using various well-known techniques.
[032] [032] In some embodiments, the concentration of cytokine in the tumor is at least 100 times, at least 200 times, at least 300 times, at least 400 times, at least 500 times, at least 1000 times greater than the concentration of the cytokine in blood, serum and / or plasma after administration of the STING agonist.
[033] [033] As used here the term "tumor microenvironment" is the cellular environment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, lymphocytes, signaling molecules and the extracellular matrix. The tumor and the surrounding microenvironment are closely related and can interact constantly.
[034] [034] As used herein the term "diseased tissue" means any cell or tissue that exists in a disease state including, but not limited to, a tumor. As used herein, diseased tissue will also include the tissue affected by disease as well as the cellular environment of the diseased tissue including normal cells, molecules and blood vessels.
[035] [035] It is observed that serum and plasma are components of the blood. When referring to components for testing; "Blood", "serum" and "plasma" are used collectively and interchangeably here, as the corresponding analysis will produce identical results.
[036] [036] As used here in "pro-inflammatory cytokine" or "inflammatory cytokine" means any signaling molecule (a cytokine) that acts as immunomodulatory agents. Inflammatory cytokines include, but are not limited to, IFNB, IFNa, interleukin-1 (IL-1), I1L-12 and 11-18, IL-6, 11-10, tumor necrosis factor (TNF) (including TNF- a), gamma interferon (IFN-gamma) and granulocyte-macrophage colony stimulating factor, and play an important role in mediating the innate immune response. Inflammatory cytokines are involved in the suppression of inflammatory reactions and can be produced by a wide range of cells, including immune cells such as macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts and various stromal cells; a given cytokine can be produced by more than one cell type.
[037] [037] The targeted release of antitumor agents to improve the therapeutic index (TI) is a well-established principle in drug discovery. Typical methods used for drug targeting are fixing a portion of targeting to the active drug and formulating the drug in a nanoparticle (NP) delivery system (Arias, JL, Drug targeting strategies in cancer treatment: An overview. Mini. -Reviews in Medicinal Chemistry 2011, 11 (1), 1a 17 and Irvine, DJ; Hanson, MC; Rakhra, K .; Tokatlian, T., Synthetic Nanoparticles for Vaccines and Immunotherapy. Chemical Reviews 2015, 115 (19), 11.109 11,146). These same principles have been proposed for PRR agonists and NP formulations for drug release have been demonstrated in animal models for STING agonists (Hanson, MC; Crespo, MP; Abraham, W .; Moynihan, KD; Szeto, GL; Chen, SH; Melo, MB; Mueller, S .; Irvine, DJ, Nanoparticulate STING agonists are potent Iymph node-targeted vaccine adjuvants.Journal of Clinical Investigation 2015, 125 (6), 2532 to 2546). Intratumoral injection is a targeted delivery method that has achieved dramatic efficacy and improved Tls and has been demonstrated for both the TLR agonist and the STING agonist (Hammerich, L .; Bhardwaj, N .; Kohrt, HE; Brody, JD, In situ vaccination for the treatment of cancer. Immunotherapy 2016, 8 (3), 315 to 330 and Corrales, L .; Glickman, Laura H .; McWhirter, Sarah M .; Kanne, DavidB .; Sivick, KelseyE .; Katibah, George E .; Woo, S.-R .; Lemmens, E .; Banda, T .; Leong, Justin J .; Metchette, K .; Dubensky, Thomas W., Jr .; Gajewski, Thomas F., Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity.Cell Reports 2015, 11 (7), 1,018 to 1,030).
[038] [038] Unlike the targeted delivery examples noted above, this invention provides methods of systemically administering a STING agonist that does not require the addition of a targeting portion, the use of a NP formulation or direct intratumor (i.t.) injection. For a STING agonist to obtain T cell activation in the tumor microenvironment, the STING agonist must demonstrate adequate cell permeability and pharmacokinetics and improved distribution.
[039] [039] The endogenous mammalian ligand for STING is 2'3-cCGAMP, a cyclic dinucleotide that has two phosphodiester groups. Due to the 2'3-cCGAMP deficient membrane permeability, the compound has little to no activity in cell assays, even at very high concentrations. To overcome this limitation, membrane permeability enhancers are often added to allow the use of CDNs in cellular assays (Yildiz, S .; Albodundar, E .; Gungor, B .; Kahraman, T .; Bayyurt, B .; Gursel, |; Gursel, M., Enhanced immunostimuladory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG. European Journal of Immunology 2015, 45 (4), 1,170 to 1,179). A second limitation of the available STING agonist is the short serum half-life, which is believed to be the result of the rapid cleavage of the 2'5'-phosphdiester bond (Li, L .; Yin, Q .; Kuss, P .; Maliga , Z .; Millán, JL; Wu, H .; Mitchison, TJ, Hydrolysis of 2'3-cCGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat Chem Biol 2014, 10 (12), 1.043 to 1.048). Often, the phosphodiester cleavage rate can be decreased by replacing oxygen with sulfur in the phosphate dative double bond. Although the introduction of sulfur into both 2'3'-cCGAMP phosphates has been shown to improve serum stability and phosphodiesterase, the resulting CDNs were still only weakly active in a cell assay that monitors IFNB synthesis (IC50 - 30 uM) versus IC50 > 100 µM for 2'3-cCGAMP (Supplementary figure 13 by Li, L., et al. in Nat Chem Biol 2014).
[040] [040] Compatible with these limitations, there are very few reports of in vivo activity after systemic administration (i.v. or i.p) of STING agonist for CDN. Li, T., et al. were able to demonstrate some efficacy using 20 daily iv doses of 20 mg / kg of 2 ', 3-cCGAMP in the syngenic model of CT26 if 2', 3-cGAMP was dosed 4h after the injection of the tumor cells (Li, T .; Cheng, H .; Yuan, H .; Xu, Q .; Shu, C .; Zhang, Y .; Xu, P .; Tan, J .; Rui, Y .; Li, P .; Tan, X., Antitumor Activity of cGAMP via Stimulation of CGAS-CGAMP-STING-IRF3 Mediated Innate Immune Response. Scientific Reports 2016, 6, 19049). However, the same treatment was significantly less active when administered to animals with established tumors. In order to obtain robust antitumor activity, the researchers turned to direct injection of the STING agonist into the tumor (intratumor or i.t. injection, as noted above) (Corrales, et al. Supra).
[041] [041] DMXAA is an example of a STING agonist that potently inhibits tumor growth, leading to cures in mice, when administered once in the i.p. maximum tolerance of 500 ug / mouse (-99uMol / kg) in the syngenic model of CT26 with established tumors. When dosed in this way, DMXAA generates high levels of cytokine in the tumor and in the blood. Through careful optimization of various systemic dosing protocols, researchers were able to achieve good oral activity in mice, but only at doses that generated high levels of systemic cytokine and only in rodents that have very high levels of tolerance to pro-cytokines. inflammatory (Zhao, L .; Kestell, P .; Ching, LM; Baguley, BC, Oral activity and pharmacokinetics of 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) in mice. Cancer Chemother Pharmacol 2002, 49 (1) , 20 to 26). DMXAA has been extensively investigated as an anticancer agent in human clinical trials, but has failed to provide sufficient efficacy and has been discontinued. Although DMXAA does not induce high levels of systemic cytokines in humans, it was later found to be active as a STING agonist only in mice and no other species (Conlon, J .; Burdette, DL; Sharma, S .; Bhat, N. ; Thompson, M .; Jiang, Z .; Rathinam, VAK; Monks, B .; Jin, T .; Xiao, TS; Vogel, SN; Vance, RE; Fitzgerald, KA, Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-DimethyIxanthenone-4-Acetic Acid (The Journal of Immunology 2013, 190 (10), 5216 to 5225). Consequently, the activity that was observed in humans was not the result of STING's agonism, but of other effects of disruption of the vasculature (Baguley, BC; McKeage, MJ, ASA404: A tumor-vascular disrupting agent with broad potential for cancer therapy Future Oncology 2010, 6 (10), 1537 to 1543).
[042] [042] The present invention provides methods of systemically administering a STING agonist to a human in need of it where the STING agonist increases at least one cytokine in diseased tissue, but does not cause increases or pro-inflammatory cytokines in the blood of the said to be human at a level that causes adverse effects.
[043] [043] Thus, in one embodiment, the present invention provides methods of treating cancer in a human being comprising systemically administering a STING agonist to said human being, wherein the STING agonist induces a higher concentration of at least one cytokine in a tumor microenvironment of said human being compared to the concentration of said cytokine in the blood, serum and / or plasma of said human being.
[044] [044] In one aspect, the cytokine is selected from IL-6, TNFa, IFNB and IFNy. In one embodiment, the target index (TI) is 3 or more for a selected cytokine. In one embodiment, the TI is 10 or more for a selected cytokine. Thus, the TI for any given cytokine can be in the range of about 3 to about 10, about 3 to about 100, about 3 to about 1,000 to more than 1,000. As the TI represents a ratio of cytokine concentration in the diseased tissue versus blood or serum, the TI can be represented by any integer or fraction thereof, with a TI of more than about 3 considered favorable.
[045] [045] In one embodiment, the STING agonist increases the concentration of IL-6 at least three times more in the tumor microenvironment or diseased tissue in said human being compared to the concentration of IL-6 levels in the blood of said human being . In one embodiment, the STING agonist increases the concentration of TNFα at least three times more in the tumor microenvironment or diseased tissue in said human being compared to the concentration of TNFα levels in the blood or said human being. In one embodiment, the STING agonist increases the IFNB concentration at least three times more in the tumor microenvironment or diseased tissue in said human being compared to the concentration of IFNB levels in said human's blood. In one embodiment, the STING agonist increases the concentration of IFNy at least three times more in the tumor microenvironment or diseased tissue in said human being compared to the concentration of IFNy levels in the blood of said human being.
[046] [046] In yet another modality, the STING agonist has an IC 50 less than about 10 µM, in one aspect the STING agonist has an IC 50 less than about 1 µM; in one aspect the STING agonist has an IC 50 of less than about 0.1 µM.
[047] [047] In one embodiment, the STING agonist provides an AUC (0 to 24) in the range (850 to 1,060 ng.h / ml) when administered systemically to said human being.
[048] [048] In one embodiment, the STING agonist has a significantly higher Cmax concentration in a tumor microenvironment of said human being compared to blood, serum and / or plasma of said human being. In one embodiment, the STING agonist has a significantly higher Cmax concentration in a tumor microenvironment of said human being compared to blood, serum or plasma of said human being. The term "significantly higher" suitably refers to a 2-fold increase, suitably a 3-fold increase, suitably a 10-fold increase, suitably a 100-fold increase, suitably more than a 100-fold increase.
[049] [049] In one embodiment, the half-life of said STING agonist is significantly longer in a tumor microenvironment of said human being compared to the blood, serum and / or plasma of said human being. In one embodiment, the half-life of said STING agonist is significantly longer in a tumor microenvironment of said human being compared to the blood, serum or plasma of said human being. The term "significantly longer" suitably refers to a 2-fold increase, suitably a 3-fold increase, suitably a 10-fold increase, suitably a 100-fold increase, suitably more than a 100-fold increase.
[050] [050] As used herein, “Area Under the Curve” or “AUC” is used to describe the pharmacokinetic parameters and tumor volume. When used to describe pharmacokinetic drug concentration, AUC refers to the area under the curve on a graph of the concentration of a substance in the plasma over time. The AUC can be a measure of the integral of instantaneous concentrations over a period of time and has the units mass x time / volume, which can also be expressed as molar concentration x time such as nM x day. AUC is typically calculated using the trapezoidal method (e.g., linear, log-linear). The AUC is usually given for the zero to infinite time interval, and other time intervals are indicated (for example, AUC (t1, t2) where t1 and t2 are the start and end times for the interval). Thus, as used here “AUCo-24r” refers to an AUC over a 24 hour period, and “AUCo-12r" refers to an AUC over a 12 hour period. Similarly, the AUC can also be used to describe the volume of the tumor over time. When used to describe the volume of the tumor, the size of a tumor is plotted against time.
[051] [051] As used here, “weighted average AUC” is the AUC divided by the time interval over which the time AUC is calculated. For example, the weighted average AUC0-24n would represent AUC0-24n divided by 24 hours.
[052] [052] In one embodiment, the STING agonist provides an average Cmax with the range (1,900 to 3,800 ng / ml) of said STING agonist when administered to said human being.
[053] [053] As used herein, “maximum plasma concentration” or “Cmax” means the highest observed concentration of a substance (for example, a STING agonist) in mammalian plasma after administration of the substance to the mammal.
[054] [054] As used here, “confidence interval” or “Cl” is an interval in which an incorrect measurement or test corresponding to a given probability p where p refers to a 90% or 95% CI and is calculated around an arithmetic mean, a geometric mean, or a mean of least squares. As used here, a geometric mean is the mean of the values transformed into natural log retrotransformed by exponentiation, and the mean of least squares may or may not also be a geometric mean, but is derived from the analysis of variance model (ANOVA) using fixed effects .
[055] [055] As used here, the “coefficient of variation (CV)” is a measure of dispersion and is defined as the ratio of the standard deviation to the mean. It is reported as a percentage (%) by multiplying the above calculation by 100 (% of CV).
[056] [056] As used here, "Tmax" refers to the time observed to reach the maximum concentration of a substance in a mammal's plasma after administration of that substance to the mammal.
[057] [057] As used here, "blood" and / or "serum" and / or "plasma" "half-life" or "terminal half-life" refers to the time required for half the amount of a substance administered to a mammal to be metabolized or eliminated correspondingly from the mammal's blood, serum or plasma by normal biological processes.
[058] [058] In one embodiment, the STING agonist has a significantly higher Cmax concentration in the tumor microenvironment of said human being compared to blood, serum and / or plasma of said human being. In another embodiment, the half-life of said STING agonist is significantly longer in the tumor microenvironment of said human being compared to the blood, serum and / or plasma of said human being. In one aspect, the STING agonist is administered intravenously. As is understood in the art, several known methods are available to measure the concentration of drug in the tumor microenvironment and the blood, serum and / or plasma of a mammal. In addition, several statistical methods are well known for measuring statistically significant differences in pharmacokinetic parameters.
[059] [059] In one embodiment, the STING agonist is administered to humans via a selected intravenous, subcutaneous, transdermal, intramuscular and oral route. In one embodiment, the STING agonist is administered intravenously.
[060] [060] One embodiment of the invention relates to a STING agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in which the STING agonist is administered systemically.
[061] [061] One embodiment of the invention relates to the use of a STING agonist,
[062] [062] One embodiment of the invention relates to a pharmaceutical composition for systemic administration comprising a STING agonist, or a pharmaceutically acceptable salt thereof.
[063] [063] One embodiment of the invention relates to a pharmaceutical composition for systemic administration comprising a STING agonist, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
[064] [064] In one embodiment, the STING agonist is a compound according to Formula (I-N): -
[066] [066] In a modality, where when s of Formula | -N or Formula | is O, RC and Rº are each independently H or C1-Ca4 alkyl. In an embodiment, when s of Formula I-N or Formula | is 0, Rºº and Rº they are each independently ethyl.
[067] [067] In an embodiment, when r of Formula I-N or Formula | is 1, B, taken together with R8º and R & , forms -CH2CH = CHCH2-, -CH2CH2CH2CH> 2-, - CH2CH (OH) CH (OH) CH2- or -CH2CHaN (CH3) CH2CH> -.
[068] [068] In an embodiment, when r of Formula I-N or Formula | is 1, B, taken together with R8 * and R82, forms a -CH2CH = CHCH> -.
[069] [069] In a modality, Rº and Rº of Formula I-N or Formula | are each H. In one embodiment, R'º is H. In one embodiment, R * 4, R'º and R'7 are each independently C1-C3 alkyl.
[070] [070] In yet another modality, the STING agonist has the formula structure (I-N-B ')
[071] [071] In one embodiment, the STING agonist has the structure of the Formula (IN-b '), Re "q AT AT DO DO po É> KH N q Ô RO Formula (FNE) where B is -halo (C1-Cs alkyl), unsubstituted C1-Cs alkyl or -C2-Cs5 alkenyl unsubstituted; R * e and RM! are each independently H, halogen, hydroxyl, -O- P (O) ( OH) 2, -OP (O) (RIR! ') 2, (C1-C6s alkyl) optionally substituted or (C1- Ce alkyl) Optionally substituted oxy, where C1-Cs alkyl of said (C1-Cs alkyl) optionally substituted or (C1-Ce alkyl) 9Oxi- optionally substituted is optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, C1-Ca alkoxy, -N (Rº) (Rº), -COXR '), optionally substituted phenyl, and optionally substituted 5 to 6 membered heterocycloalkyl, and wherein said optionally substituted phenyl or 5 to 6 membered heterocycloalkyl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR "") 2e, amino, (C1-Cs alkyl) amino-, (C1-Ce alkyl) (C1-Cs alkyl) amino -, halo (C1-Cs alkyl), hydroxy- (C1-Ca4 alkyl) -, - (C1-Ca4 alkyl) -OP (O) (OH) 2, - (C1-Ca alkyl) -OP (OX (R 'R!) 2, halo (C1-Ca alkoxy) -, C1-C4a- alkoxy, hydroxy- (Ca-Ca alkoxy) -, - (Ca-Ca alkoxy) -OP (O) (OH) 2, - ( C2-Ca alkoxy -O- P (OX (RIR ") 2, - (C1-C6 alkyl) -NH; z, -C1-Ca- alkyl (C1-Ca alkoxy) and C1-Ca- (C1 alkoxy) -Here)-; Rº is selected from H, (C1-C4 alkyl), -CO (C1-C4 alkyl), -OCO (C1-Ca alkyl), - (C1-Ca alkyl) -NH> 2, - (C1-Ca alkyl) C1-Ca alkoxy or -COz (C1-C4 alkyl), each R 'is H or (C1-C4 alkyl); R * º is C1-Ca alkyl; Rº is C1-Ca alkyl; R '* is C1-C4 alkyl; and R * 7 is C1-Ca alkyl; each occurrence of R 'and R! are independently (C1-Ce alkyl) Oxi-; or a pharmaceutically acceptable salt thereof.
[072] [072] In a modality, in which R and Rºº of the Formula | -Nb 'are each independently H, optionally substituted (C1-Cs alkyl) or optionally substituted (C1-C6 alkyl), and said C1-C6s alkyl (said C1-Cs alkyl) optionally substituted, (optionally substituted C1-Ce6 alkyl) is optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, -N (Rº) (R5), C1-Ca alkoxy, phenyl, optionally substituted 5- to 6-membered heterocycloalkyl containing at least one nitrogen or oxygen as a ring member, and Rº and Rí are each independently H or C1-Ca alkyl.
[073] [073] In one embodiment, at least one of Rº or RO is independently H, (optionally substituted C1-Cs alkyl) or (optionally substituted C1-C6 alkyl), and said C1-C6s alkyl (said C1- alkyl) Optionally substituted Cs, (optionally substituted C1-C6 alkyl) is optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of -N (Rº) (R), tetrahydropyran, pyrrolidinyl, piperazinyl , piperidyl and morpholinyl, and Rº and Rí are each independently H or C1-Ca alkyl.
[074] [074] In one embodiment, the compound of Formula X AL is q HNA
[075] [075] In one aspect, the STING agonist of Formula (IN), (1) or (X) is not: (E) -1- (4- (S-carbamoyl-2- (1-ethyl-3- methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazole- 5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazole-5-carboxamide; (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3-di -hydro-1H-benzo [d] Jimidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5S-carboxamide; (Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino ) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide; or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
[076] [076] In one aspect, the STING agonist of Formula (IN), (1) or (X) is not: (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3- methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2- (1-ethyl- 3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | -5-carboxamide; (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3- hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-1) -2 - ((1-ethyl-3-methyl-1H-pyrazole- S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole | (Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3- hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1H-pyrazole- 5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole | or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
[077] [077] In one aspect, the STING agonist of Formula (IN), (1) or (X) is not: (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3- methyl-1 H-pyrazol-S5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazole- 5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole-5-carboxamide; (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3-di -hydro-1H-benzo [d] Jimidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo | (Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino ) -7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo | -5-carboxamide; or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
[078] [078] In one aspect, the STING agonist of Formula (IN), (1) or (X) is not: (E) -1- (4- (S-carbamoyl-2- (1-ethyl-3- methyl-1 H-pyrazol-S5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2- (1-ethyl -3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | -5-carboxamide; (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3- morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazol | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazole -5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole | (Z) -1 - ((E) -4 - ((Z) -S-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -7- (3- morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazole- 5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole |
[079] [079] In one aspect, the STING agonist of Formula (IN), (1) or (X) is not: 3 - (((Z) -6-carbamoyl-3 - ((E) -4 - (( Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole- 1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -2,3-dihydro-1H-benzo [ d] imidazo | -4-yl) oxy) propyl dihydrogen phosphate; (E) -3 - ((5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [ d] imidazol-1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-7- il) oxy) propyl dihydrogen phosphate; 3 - ((((Z) -6-carbamoyl-3 - ((E) -4 - ((Z) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl ) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl- 3- methyl-1H-pyrazol-5-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazol-4-yl) oxy) propyl dihydrogen phosphate; or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
[080] [080] In one aspect, the STING agonist of Formula (IN), (1) or (X) is not: (E) -4 - ((5-carbamoyl-1- (4- (5-carbamoyl- 2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2- (1-ethyl- 3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-7-yl) oxy) butanoic; (E) -7- (aminomethyl) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d ] imidazo | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] Jimidazol-5- carboxamide; and (E) -3- (5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole acid -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-7-yl) propanoic or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
[081] [081] In an embodiment of the present methods, the STING agonist is: (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-S5-carboxamido) -1H- benzo [d] imidazol-1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy ) -1H-benzo [d] imidazo | -5-carboxamide; (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] Jimidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5S-carboxamide; (Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino ) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide; (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-S5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazo -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | -5-carboxamide; (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1 H-pyrazol-S-carbonyl) imino) -7- (3 -hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H- pyrazol-S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo | (Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3- hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1H-pyrazole- S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazole | (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-S5-carboxamido) -1H-benzo [d] imidazol | -1-yl) but- 2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole-5-carboxamide; (E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-
[082] [082] The STING agonist of the present invention can be administered systemically to said human being by a route of administration selected from intravenous, subcutaneous, oral, intramuscular and transdermal.
[083] [083] In an embodiment of the present invention, methods of administering a STING agonist to a human in need thereof are provided, comprising administering said STING agonist systemically. In certain aspects, the STING agonist increases the cytokine levels in the blood of said human being to an effective concentration to stimulate T cells in said human being. In certain aspects, the STING agonist does not increase the levels of cytokine in the blood of said human being at a concentration high enough to cause adverse immunological reactions. In one embodiment, the adverse immune reaction is dose-limiting toxicity. In one embodiment, the human being has at least one disease selected from: inflammation, allergic and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, skin warts, multiple sclerosis, human immunodeficiency virus (HIV) infection, AIDS, cancer (including basal cell carcinoma and squamous cell carcinoma), precancerous syndromes (including actinic keratoses).
[084] [084] In one embodiment, the STING agonist is administered as an adjuvant vaccine.
[085] [085] The uses of a STING agonist to systemically administer to a human in need are also provided here where the STING agonist increases certain cytokines in diseased tissue to a concentration greater than said blood and / or cytokines plasma and / or serum of said human being. Compositions comprising at least one STING agonist are also provided for use in the treatment of inflammation, allergic and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), hepatitis B virus (HBV), influenza, skin warts, sclerosis multiple, infection by the human immunodeficiency virus (HIV), AIDS, cancer, precancerous syndromes in a human being characterized by the fact that the compositions are administered systemically to said human being and in which said STING agonist increases the concentration of at least one cytokine in the diseased tissue at least three times more than the concentration of at least one cytokine in the blood and / or serum and / or plasma. In one embodiment, the human being has cancer. In one embodiment, the diseased tissue is a tumor microenvironment. In one embodiment, the use of a STING agonist, or a pharmaceutical composition comprising said STING agonist, is provided for the treatment of cancer through systemic administration. In one aspect, the STING agonist increases the concentration of at least one cytokine in the tumor microenvironment or diseased tissue by at least three times as much as in blood and / or serum and / or plasma when administered systemically to a human. In one embodiment, the present invention provides for the use of a STING agonist in the manufacture of a medicament for systemic administration to a human in which the medicament increases the concentration of at least one cytokine in the diseased tissue compared to the concentration of at least a cytokine in the blood and / or serum and / or plasma.
[086] [086] Suitably, the invention relates to a method of treating cancer in a human being which comprises administering systemically an effective amount of a STING agonist to said human being, wherein the STING agonist induces a higher concentration of at least a cytokine in a tumor microenvironment of said human being compared to the concentration of said cytokine in the blood, serum and / or plasma of said human being. Suitably, the cytokine is selected from IL-6, TNFa, IFNB and IFNy. Suitably, the target index (TI) is 3 or more for the selected cytokine. Suitably, the target index (TI) is 10 or more for the selected cytokine.
[087] [087] Suitably, the invention relates to a method of treating cancer in a human being which comprises administering systemically an effective amount of a STING agonist to said human being, wherein the STING agonist induces a higher concentration of at least a cytokine in a tumor microenvironment of said human being compared to the concentration of said cytokine in the blood, serum, or plasma of said human being. Suitably, the cytokine is selected from IL-6, TNFa, IFNB and IFNy. Suitably, the target index (TI) is 3 or more for the selected cytokine. Suitably, the target index (TI) is 10 or more for the selected cytokine.
[088] [088] Suitably, the invention relates to a method of treating cancer in a human being which comprises administering systemically an effective amount of a STING agonist to said human being, wherein the STING agonist induces a significantly higher Cmax concentration high in the tumor microenvironment of said human being compared to blood, serum and / or plasma of said human being.
[089] [089] Suitably, the invention relates to a method of treating cancer in a human being which comprises administering systemically an effective amount of a STING agonist to said human being, wherein the STING agonist induces a significantly higher Cmax concentration high in the tumor microenvironment of said human being compared to blood, serum or plasma of said human being.
[090] [090] As used herein the term “agonist” refers to any compound, for example, a STING agonist, which upon contact with STING causes one or more of the following (1) to stimulate or activate the STING protein, ( 2) intensifies, increases or promotes, induces or prolongs an activity, function or presence of the STING and / or (3) intensifies, increases, promotes or induces the expression of the STING. Agonist activity can be measured in vitro by various assays known in the art such as, but not limited to, measurement of cell signaling, cell proliferation, immune cell activation markers, cytokine production. Agonist activity can also be measured in vivo by several assays that measure surrogate endpoints such as, but not limited to, measurement of T cell proliferation or cytokine production, in particular, interferon type |.
[091] [091] By the term "treat" or "treatment" and its grammatical variations, as used here, it is intended to mean at least the mitigation of a disease or disorder in a human being.
[092] [092] As used herein, the terms "cancer", "neoplasm" and "tumor" are used interchangeably and, in singular or plural form, refer to cells that have undergone a malignant transformation that make them pathological for the host organism. Primary cancer cells can be readily distinguished from non-cancer cells by well-established techniques, particularly histological examination. The definition of a cancer cell, as used herein, includes not only a primary cancer cell, but any cell derived from a predecessor of the cancer cell. This includes metastatic cancer cells and in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that normally manifests itself as a solid tumor, a "clinically detectable" tumor is one that is detectable based on the tumor mass, eg, by procedures such as computed tomography (CT) scanning, imaging by magnetic resonance imaging (MRI), X-rays, ultrasound or palpation on physical examination and / or that is detectable because of the expression of one or more specific cancer antigens in a sample obtainable from a patient.
[093] [093] As used herein the term "solid tumor" refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors can be benign or malignant. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors include, but are not limited to, sarcomas, carcinomas and lymphomas. Examples of solid tumor cancers include, but are not limited to, colon, breast, gastric, ovarian, lung, cervical, melanoma, kidney, prostate, lymphoma, neuroblastoma, pancreatic and bladder cancers.
[094] [094] Suitably, the methods of the invention are used in the treatment of solid tumors.
[095] [095] Carcinomas that may be amenable to therapy by a method disclosed herein include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), bladder carcinoma, including transitional cell carcinoma (a malignant neoplasm of the bladder), bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, carcinoma adrenocortical, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, renal cell carcinoma, medullary carcinoma, cell carcinoma ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonic carcinoma, tumo Wilms r, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma and nasopharyngeal carcinoma.
[096] [096] Sarcomas that may be amenable to therapy by a method disclosed herein include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosscocoma, lymphongiosscocoma, mesothelioma, lymph node Ewing's disease, leiomyosarcoma, rhabdomyosarcoma and other soft tissue sarcomas.
[097] [097] Other solid tumors that may be amenable to therapy by a method disclosed herein include, but are not limited to, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma,
[098] [098] Other cancers that can be treated according to the methods disclosed here include atypical meningioma (brain), islet cell carcinoma (pancreas), medullary carcinoma (thyroid), mesenchyma (intestine), hepatocellular carcinoma (liver) , hepatoblastoma (liver), clear cell carcinoma (kidney) and mediastinal neurofibroma.
[099] [099] Other exemplary cancers that may be amenable to treatment using a method disclosed herein include, but are not limited to, neuroectodermal and epithelial cancers. Examples of cancers of neuroectodermal origin include, but are not limited to, Ewing's sarcomas, spinal tumors, brain tumors, primitive supratentorial neuroectodermal tumors, tubulocystic carcinoma, mucinous and spindle cell carcinoma, kidney tumors, mediastinal tumors, neurogliomas and neuroblastomas sarcomas in adolescents and young adults. Examples of epithelial origin include, but are not limited to, small cell lung cancer, breast cancer, eye lens colon, colon, pancreas, kidney, liver, ovary and bronchial epithelium.
[0100] [0100] Tumors can be hematopoietic (or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which can be referred to as "liquid tumors". Specific examples of clinical conditions based on hematological tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma, Hodgkin's lymphoma; and the like.
[0101] [0101] Cancer can be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or which is diagnosed as a hematological cancer, including lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid leukemia (or myelocytic or myelogenous or myeloblastic) (undifferentiated or differentiated), acute promieloid leukemia (or promyelocytic or promyeloblastic or promyeloblastic), acute myelomonocytic leukemia (or acute myelomonoblastic, myelomonoblastic) (or monoblastic), erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia. These leukemias can be referred to together as acute myeloid leukemia (or myelocytic or myelogenic) (AML). Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis) and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which can be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB) and refractory anemia with excess blasts in transformation (RAEBT); as well as myelofibrosis (MFS) with or without agnogenic myeloid metaplasia.
[0102] [0102] Hematopoietic cancers also include lymphoid malignancies, which can affect lymph nodes, spleen, bone marrow, peripheral blood and / or extranodal sites. Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non-Hodgkin's lymphomas (B-NHLs). B-NHLs can be indolent (or low grade), intermediate grade (or aggressive) or high grade (very aggressive). Indolent B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and lymphoma of lymphoid tissue associated with the mucosa (MALT or extranodal marginal zone). Intermediate grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell lymphoma (or grade 3 or grade 3B), and primary mediastinal lymphoma ( PML). High-grade B-NHLs include Burkitt's lymphoma (BL), Burkitt-type lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-related) lymphomas and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte leukemia (LGL), acute lymphoid leukemia (or lymphocytic or lymphoblastic) and Castleman's disease. NHL may also include non-Hodgkin's T-cell lymphoma (T-NHLs), which include, but are not limited to otherwise unspecified T-cell non-Hodgkin's lymphoma (NOS), peripheral T-cell lymphoma (PTCL), lymphoma large cell anaplastic (ALCL), angioimmunoblastic lymphoid disorder (AILD), natural killer cell lymphoma (NK) / nasal T cells, gamma / delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides and Sezary syndrome.
[0103] [0103] Hematopoietic cancers also include Hodgkin's lymphoma (or disease) including classic Hodgkin's lymphoma, nodular sclerosing Hodgkin's lymphoma, mixed-cell Hodgkin's lymphoma, Hodgkin's lymphoma with predominant lymphocytes (LP), Hodgkin's lymphoma with nodular LP and Hodgkin's lymphoma with lymphocyte depletion. Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including latent MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL) , Waldenstróm macroglobulinemia, plasma cell leukemia and primary amyloidosis (LA). Hematopoietic cancers can also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues that include hematopoietic cells referred to herein as "hematopoietic cell tissues" include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with the mucosa (such as lymphoid tissues associated with the intestine), tonsils, patches and Peyer's appendix and lymphoid tissues associated with another mucosa, for example, bronchial linings.
[0104] [0104] Suitably, the methods of the invention are directed to the treatment of cancer. Suitably, the methods of the invention are directed to the treatment of a cancer selected from: non-small cell lung cancer (NSCLC), stable microsatellite colorectal cancer (MSS), gastroesophageal adenocarcinoma (GEC) and squamous cell carcinoma of the head and neck (SCCHN).
[0105] [0105] Appropriately the cancer is selected from: cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, intestine, endocrine system, thyroid gland, parathyroid gland, adrenal gland, urethra, prostate, penis, testicles, urethra, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; soft tissue sarcoma; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemagyoma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; CNS neoplasms; tumors of the spinal axis; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hanlartoma; inesothelioma; and Hodgkin's disease or a combination of one or more of the previous cancers.
[0106] [0106] Appropriately, cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, Wilms tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma , medulloblastoma, head and neck, kidney, liver, melanoma, ovary, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant bone cell tumor, thyroid, leukemia T-cell lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, tricholeukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute T-cell lymphoblastic leukemia, plasmacytoma, large-cell immunoblastic leukemia, myeloma myeloma , megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia , malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell lymphoblastic lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, cancer esophageal, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, mouth cancer, GIST (gastrointestinal stromal tumor) and testicular cancer.
[0107] [0107] Suitably, the methods of the invention are directed to the treatment of precancerous syndromes.
[0108] [0108] Suitably, the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammopathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, cutaneous nevi (pre-melanoma), intraepithelial prostatic neoplasia (intraductal) (PIN), ductal carcinoma in situ (DCIS), colon polyps and hepatitis or severe cirrhosis.
[0109] [0109] As used herein, "tumor antigens" are proteins that are produced by tumor cells that elicit an immune response, particularly immune responses mediated by T cells. The term "tumor antigen" as used herein includes tumor specific antigens and associated antigens tumor-specific antigens are exclusive to tumor cells and do not occur in other cells in the body. Tumor-associated antigens are not exclusive to a tumor cell and are instead expressed in a normal cell under conditions that do not induce a state of immune tolerance to the antigen. The expression of the antigen in the tumor can occur under conditions that allow the immune system to respond to the antigen. Tumor-associated antigens can be antigens that are expressed in normal cells during fetal development when the immune system is immature and unable to respond or may be antigens that are normally present at extremely high levels low in normal cells, but expressed at much higher levels in tumor cells.
[0111] [0111] Other tumor antigens include, but are not limited to TSP-180, MAGE-4, MAGE-5, MAGE-6, RAGE, NY-ESO, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA , TAG-72, CA 19 - 9, CA 72 - 4, CAM 17,1, NuMa, K-ras, beta-Catenin, CDKA4, Mum-1, p 15, p 16, 43 - 9F, 5T4, 791Tgp72, alpha-fetoprotein, beta-HCG, BCA225, BTAA, CA 125, CA 15 - 31CA 27,29BCAA, CA 195, CA 242, CA-50, CAMA43, CD681P1, CO-029, FGF-5, G250, Ga7331EpCAM, HTgp -175, M344, MA-SO0, MG7-Ag, MOV18, NB / 70K, NY-CO-1, RCAS1, SDCCAG16, TA-90WMac-2 binding protein / cyclophilin C-associated protein, TAAL6, TAG72, TLP , TPS, glioma-associated antigen, human chorionic B-gonadotrophin, alpha-fetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA 1X, human telomerase reverse transcriptase, RU1, RU2 (AS), carboxyl esterase intestinal, mut hsp70 - 2, M-CSF, prostase, prostate specific antigen (PSA), PAP, NY-ESO-1, LAGE-1a, p53, prostein, PSMA, Her2 / neu, survivin and telomerase, tumor antigen- 1 of prostate carcinoma (PCTA-1), ELF2M, neutrophil elastase, ephrinB2, CD19, CD20, CD22, ROR1, CD33 / IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIIl, GD-2, insulin growth factor ( IGF) -l, IGF-Il, IGF- receptor | and mesothelin.
[0112] [0112] It will be appreciated by one skilled in the art that the compounds of this invention may exist in other tautomeric forms including zwitterionic forms or isomeric forms. All tautomeric (including zwitterionic) and isomeric forms of the formulas and compounds described herein are intended to fall within the scope of the present invention.
[0113] [0113] It will also be appreciated by a person skilled in the art that the compounds of this invention may exist in tautomeric forms including, but not limited to Formula (A), Formula (B) and / or Formula (C) or zwitterionic forms including, but not limited to limited to Formula (D) or Formula (E).
[0114] [0114] The chemical names provided for the intermediate compounds and / or the compounds of this invention described herein can refer to any of the tautomeric representations of these compounds (in some cases, these alternative names are provided with the experiment). It should be understood that any reference to a named compound (an intermediate compound or a compound of the invention) or a structurally represented compound (an intermediate compound or a compound of the invention) is intended to cover all tautomeric forms including zwitterionic forms of these compounds and any mixture of them.
[0115] [0115] As used herein, the term "alkyl" represents a saturated straight or branched hydrocarbon group having the specified number of carbon atoms. The term "C1-C4 alkyl" refers to a straight or branched alkyl moiety containing 1 to 4 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , s-butyl, t-butyl, pentyl and hexyl.
[0116] [0116] When a substituent term such as "alkyl" is used in combination with another substituent term, for example, as in "hydroxy (C1- Ca alkyl)", the term substituent bond (eg, alkyl) is intended to cover a divalent portion, where the attachment point is through that bonding substituent. Examples of "hydroxy (C1-Ca alkyl)" groups include, but are not limited to, hydroxymethyl, hydroxyethyl and hydroxy-isopropyl.
[0117] [0117] As used herein, the term "halo (alkyl)" represents a saturated straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n + 1) halogen atoms. For example, the term "halo (C1-C4 alkyl)" represents a group having one or more halogen atoms, which can be the same or different, in one or more carbon atoms of an alkyl moiety containing from 1 to 4 atoms of carbon. Examples of "halo (C1-C4 alkyl)" groups include, but are not limited to -CF3 (trifluoromethyl), -CCI3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl and hexafluoroisopropyl.
[0118] [0118] "Alkenyl" "refers to the straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Examples include ethylene and propenyl.
[0119] [0119] "Alquinyl" refers to the straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethinyl and propynyl.
[0120] [0120] "Alkoxi-" or "(alkyl) oxy-" refers to an "alkyl-oxy-" group, containing an alkyl moiety, having the specified number of carbon atoms, linked via an oxygen-binding atom . For example, the term "C1-Ca- alkoxy" represents a saturated, straight or branched hydrocarbon moiety having at least 1 and up to 4 carbon atoms linked through an oxygen-binding atom. Exemplary “C1-C4- or alkoxy” (C1-Ca alkyl) oxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy and t-butoxy.
[0121] [0121] As used herein, the term 'halo (alkoxy) -' represents a saturated straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n + 1) halogen atoms, bonded through an oxygen-binding atom. For example, the term “halo (C1-C4 alkoxy) -" refers to a “haloalkyl-oxy-” group, containing a “halo (C1-C4 alkyl)” moiety bonded through an oxygen-binding atom. Exemplary “halo (C1-Ca alkoxy) -" groups include, but are not limited to -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), -OCH2CF3 (trifluoroethoxy) and -OCH (CF3) 2 (hexafluoroisopropoxy).
[0122] [0122] A carbocyclic moiety or group is a cyclic moiety or group in which the ring members are carbon atoms, which can be saturated, partially unsaturated (non-aromatic) or completely unsaturated (aromatic).
[0123] [0123] "Cycloalkyl" refers to a group of saturated non-aromatic hydrocarbon ring containing the specified number of carbon atoms in the ring. For example, the term "C3a-Cs cycloalkyl" refers to a cyclic group having three to six carbon atoms in the ring. Exemplary "C3-Cs cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0124] [0124] A heterocyclic moiety or group is a cyclic moiety or group having, as ring members, atoms of at least two different elements, whose moiety or cyclic group can be saturated, partially unsaturated (non-aromatic) or completely unsaturated (aromatic) .
[0125] [0125] "Heteroatom" "refers to a nitrogen, sulfur or oxygen atom, for example, a nitrogen atom or an oxygen atom.
[0126] [0126] "Heterocycloalkyl" refers to a non-aromatic monocyclic or bicyclic group containing 3 to 10 ring atoms and containing one or more (usually one or two) hetero atoms of the ring independently selected from oxygen, sulfur and nitrogen. of fixation of a heterocycloalkyl group can be by any suitable carbon or nitrogen atom.
[0127] [0127] Examples of "heterocycloalkyl" groups include, but are not limited to, aziridinyl, thi-iranyl, oxiranyl, azetidinyl, oxetanyl, tietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1,3-dioxolanyl, piperidinyl, piperininyl, piperazin tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1, 4-oxathianyl, 1,4-dithianyl, morpholinyl, thiomorpholinyl and hexahydro-1H-1,4-diazepinyl.
[0128] [0128] Examples of "4-membered heterocycloalkyl" groups include oxetanil, tietanyl and azetidinyl.
[0129] [0129] The term "5- to 6-membered heterocycloalkyl" represents a saturated monocyclic group containing 5 or 6 ring atoms, which includes one or two heteroatoms independently selected from oxygen, sulfur and nitrogen. Illustrative examples of 5- to 6-membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
[0130] [0130] "Heteroaryl" refers to an aromatic monocyclic or bicyclic group containing 5 to 10 atoms in the ring, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, in which at least a portion of the group is aromatic. For example, this term encompasses bicyclic heterocyclic aryl groups containing a phenyl ring fused to a heterocyclic moiety or a heteroaryl ring moiety fused to a carbocyclic moiety. The point of attachment of a heteroaryl group can be by any suitable carbon or nitrogen atom.
[0131] [0131] The term "5- to 6-membered heteroaryl" represents an aromatic monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 hetero atoms independently selected from nitrogen, oxygen and sulfur. The selected 5-membered heteroaryl groups contain a nitrogen, oxygen or sulfur ring heteroatom and, optionally,
[0132] [0132] The term "9 to 10 membered heteroaryl" refers to an aromatic bicyclic group containing 9 or 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of 9-membered heteroaryl (6,5-fused heteroaryl) groups include benzothienyl, benzofuranyl, indolyl, indolinyl (dihydroindolyl), isoindolyl, isoindolinyl, indazolyl, isobenzofuryl, 2,3-dihydrobenzofuryl, benzoxazolyl, benzoxazolyl, benzoisoxzolyl , benzoisothiazolyl, benzimidazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl and 1,3-benzodioxolyl.
[0133] [0133] Examples of 10 membered heteroaryl (6,6-fused heteroaryl) groups include quinolinyl (quinolyl), isoquinolyl, phthalazinyl, naphtridinyl (1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1, 8-naphthyridinyl),) - quinazolinyl, quinoxalinyl, 4H-quinolizinyl, 1,2,3,4-tetrahydroquinolinyl (tetrahydroquinolinyl), 1,2,3 4-tetrahydroisoquinolinyl (tetrahydroisoquinolinyl), cinnolinyl, pteridinyl and 2,3-dihydrobenzo [b] [1,4] dioxinyl.
[0134] [0134] The terms "halogen" and "halo" refer to a halogen radical, for example, a fluoro, chlorine, bromine or iodine substituent.
[0135] [0135] "Oxo0" represents a double bonded oxygen portion; for example, if attached directly to a carbon atom it forms a carbonyl moiety (C = O).
[0136] [0136] "Hydroxy" "or" hydroxyl "is intended to mean the radical -OH.
[0137] [0137] As used herein, the term "cyan" refers to a nitrile group, -C = N.
[0138] [0138] As used herein, the term "optionally substituted" indicates that a group (such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl or heteroaryl group) or ring or portion may be unsubstituted, or the group, ring or portion can be replaced by one or more substituents as defined in the substituent definitions (A, R3, etc.,) provided herein. In the case where groups can be selected from several alternative groups, the selected groups can be the same or different.
[0139] [0139] The term “independently” means that where more than one substituent is selected from several possible substituents, these substituents can be the same or different.
[0140] [0140] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and dosage forms that are, within the scope of medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation or other problem or complication, proportional to a reasonable risk / benefit ratio.
[0141] [0141] As used herein, the terms "compound (s) of the invention" or "compound (s) of this invention" mean a compound of Formula (IN) or Formula (1), as defined herein, in any form, ie, any tautomeric form, any isomeric form, any salt or non-salt form (eg, as an acid or free base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (eg, including non-solid forms (eg, liquid or semi-solid forms) and solid forms (eg, amorphous or crystalline forms, specific polymorphic forms, solvated forms, including hydrated forms (eg, mono-, di- and hemi-hydrated)) and mixtures of various shapes.
[0142] [0142] Consequently, compounds of Formula (I-N) or (1), as defined herein, in any form of salt or non-salt and any physical form thereof, and mixtures of various forms are included in the present invention. Although included in the present invention, it will be understood that compounds of Formula (IN) or (|), as defined herein, in any form of salt or non-salt, and in any physical form thereof, may have varying levels of activity, different bioavailability and different handling properties for formulation purposes.
[0143] [0143] A therapeutically "effective amount" is intended to mean the amount of a compound that, when administered to a patient in need of such treatment, is sufficient to treat or prevent effectively, as defined herein. Thus, eg, a therapeutically effective amount of a compound of Formula (IN) or (|), or a pharmaceutically acceptable salt thereof, is an amount of an inventive agent which, when administered to a human in need thereof, is enough to modulate STING activity such that a disease condition that is mediated by that activity is reduced, relieved or avoided. The amount of a given compound that will correspond to that amount will vary depending on factors such as the particular compound (eg, the potency (PIC50o), efficacy (ECso) and the biological half-life of the particular compound), disease condition and its severity, the identity (eg, age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by a person skilled in the art. Likewise, the duration of treatment and the period of time of administration (time between dosages and dosing time, eg, before / during / after meals) of the compound will vary according to the identity of the mammal in need of treatment (eg, weight), the particular compound and its properties (eg, pharmacokinetic properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by a person skilled in the art. technical.
[0144] [0144] The compounds of the invention can be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal or inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs, whether inhaled through the mouth or nasal passages. Topical administration includes application to the skin. The compounds of the present invention, as well as the methods of making and using these compounds are disclosed and described in PCT / IB2017 / 051945 (filed on April 5, 2017) which is incorporated here in its entirety.
[0145] [0145] The invention also provides a pharmaceutical composition comprising from 0.5 to 1,000 mg of a compound selected from any of the Formulas: (IN), (1), (INB), (IN-B ') and (X) , or pharmaceutically acceptable salt thereof, and from 0.5 to 1,000 mg of a pharmaceutically acceptable excipient.
[0146] [0146] The following examples illustrate several non-limiting aspects of this invention.
[0147] [0147] Methyl 4-Chloro-3-methoxy-S-nitrobenzoate (1000 mg, 4.07 mmol) was stirred in NH4OH (10 mL, 77 mmol) at RT for 24 h. The reaction temperature was then raised to 50 ° C for 2 h. An additional 2 mL (- 3.7 eq) of NHaOH was added to the vessel. After an additional 2 h of stirring at 50 ° C (4 h total), the reaction was cooled to RT. The solid was filtered and rinsed with cold water. The solid was dried under high vacuum and lyophilized to provide 4-chloro-3-methoxy-5-nitrobenzamide (710 mg, 2.99 mmol, 73% yield) as a beige solid. 1H NMR (400 MHz, DMSO-ds) 5 ppm 8.31 (br. S., 1 H), 8.06 (d, J = 1.77 Hz, 1 H), 7.88 (d, J = 1.77 Hz, 1 H), 7.81 (br. S., 1 H), 4.02 (s, 3 H). LCMS (LCMS Method D): Rt = 0.71 min, [M + HJ * = 230.9.
[0148] [0148] 4-Chloro-3-methoxy-S-nitrobenzamide (1 g, 4.34 mmol) was suspended in dry DCM (15 mL) and stirred at room temperature. To the reaction, BBr3 (17.4 mL, IM in DCM) was added to the drops. A suspension formed quickly and was stirred overnight at room temperature under nitrogen. The reaction was poured into ice water (300 ml) and stirred vigorously for 30 min. The resulting suspension was filtered and the solids dried to provide the title compound (610 mg, 2.82 mmol, 65% yield). * H NMR (400 MHz, DMSO-d6s) 5 ppm 11.53 (br. S., 1 H), 8.17 (br., 1 H), 7.92 (s, 1 H), 7.72 (s, 1 H), 7.66 (br. S., 1 H). LC-MS (LCMS Method D) Rt = 0.60 min, [M + H] * = 217.
[0149] [0149] The mixture of ethyl 3-methyl-1H-pyrazol-5-carboxylate (22 g, 143 mmol), (5-chloropent-1-in-1-iDtrimethylsilane (24.94 g, 143 mmol), K2CO3 ( 39.4 g, 285 mmol), and DMF (4 mL) was stirred at 60 ° C overnight under a nitrogen gas atmosphere. The mixture was then dissolved in DCM and washed with water. The organic phase was dried over anhydrous Na2SOa , filtered, concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 10: 1) to provide 3-methyl-1- (5- (trimethylsily) pent-4-in-1- il) ethyl -1H-pyrazol-S-carboxylate
[0151] [0151] The mixture of 1-ethyl-3-methyl-1 H-pyrazol-5-carboxylic acid (20 g, 130 mmol), (bromomethyl) benzene (22.2 g, 130 mmol), K2CO; 3 (26 , 9 g, 195 mmol) and DMF (200 mL) was stirred at 60 ° C overnight. The mixture was then dissolved in DCM, washed with water, dried over Na2SO. anhydrous, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 10: 1) to provide benzyl 1-ethyl-3-methyl-pyrazole-S-carboxylate (31.4 g, 129 mmol, 99% yield) as a colorless oil. LCMS (LCMS Method A): Rt = 2.09 min, [M + H] * = 245.
[0152] [0152] The mixture of benzyl 1-ethyl-3-methyl-1H-pyrazol-5-carboxylate (31.6 9, 129 mmol), 1-iodopyrrolidine-2,5-dione (34.9 g, 155 mmol ) and DMF (400 mL) was stirred at 90 ºC for 2 days. The mixture was then allowed to cool to room temperature, dissolved in DCM, and washed with a saturated aqueous solution of sodium thiosulfate. The organic layer was dried over Na2SO. anhydrous, filtered, concentrated under reduced pressure and purified by column chromatography (petroleum ether / EtOAc = 10: 1) to provide benzyl 1-ethyl-4-iodo-3-methyl-1 H-pyrazol-S-carboxylate ( 42.6 9, 115 mmol, 89% yield). LCMS (LCMS Method A): Rt = 2.31 min, [M + HJ * = 371. Step 5: 4- (5- (5- (Ethoxycarbonyl) -3-methyl-1 H-pyrazol-1-yl) pent-1-in-1-i1) -1-ethyl-3-methyl-1 H- benzyl pyrazol-5-carboxylate o of BnO: == Bno í »NT Me À DO '= Sh Me and N To, Ne LE PA (PPh3) 2Cla, Cul VN TEA, 60º A Me / 7 Me
[0153] [0153] The mixture of ethyl 3-methyl-1- (pent-4-in-1-yl) -1 H-pyrazol-5-carboxylate (10.0 g, 45.4 mmol), 1-ethyl- Benzyl 4-sludge-3-methyl-1 H-pyrazol-S5-carboxylate (16.8 g, 454 mmol), copper iodide (ll (0864 g, 4.54 mmol) bis (triphenylphosphine) palladium ( II) (0.319 g, 0.454 mmol) and EtaN (200 mL) was stirred at 60 ° C overnight under a nitrogen gas atmosphere. The mixture was then dissolved in DCM and washed with water. The organic phase was dried over anhydrous Na2SOa , filtered, concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether / EtOAc = 5: 1) to provide 4- (5- (5- (ethoxycarbonyl) -3-methyl-1H-pyrazole- Benzyl 1-yl) pent-1-in-1-i1) -1-ethyl-3-methyl-1 H-pyrazol-S-carboxylate (9.5 g, 20.5 mmol, 45.3% yield ) as a yellow solid LCMS (LCMS Method B): Rt = 2.66 min, [M + H] * = 463.
[0154] [0154] The mixture of 4- (5- (5- (ethoxycarbonyl) -3-methyl-1H-pyrazol-1-yl) pent-1-in-1- iI) -1-ethyl-3-methyl-1 Benzyl H-pyrazol-S-carboxylate (19.0 g, 41.10 mmol), 10% Pd / C (0.22 g, 2.05 mmol) and THF (500 mL) was stirred at room temperature under an atmosphere of hydrogen gas (4 atm) for 2 days. The reaction mixture was then filtered and concentrated under reduced pressure. The residue obtained was recrystallized from EtOAc / petroleum ether (1: 5, v / v) to provide 4- (5- (5- (ethoxycarbonyl) -3-methyl-pyrazol-1-yl) pentyl) - 1-ethyl-3-methyl-pyrazol-5-carboxylic (10.5 g, 27.90 mmol, 67.9% yield). 1H NMR (400 MHz, CDCI3) to NMR (400 MHz, CDCI, v / v) to provide —4- (5- (5- (ethoxycarbonyl) -3-methyl-pyrazol-1-yl) pentyl) - 1-ethyl-3-methyl-pyrazol-5-carboxylic (10.5 g, 27.90 mmol, 67.9% yield). * H NMR (400 MHz, CDCl3) δ ppm 6.63 (s, 1 H), 4.57 - 4.48 (m, 4 H), 4.38 - 4.32 (m, 2 H), 2.74 - 2.62 (m, 2 H), 2.32 (s, 3 H), 2.23 (s, 3 H), 1.91 - 1.86 (m, 2 H), 1, 59 - 1.54 (m, 2H), 1.45 - 1.37 (m, 8 H). LCMS (LCMS Method A): Rt = 1.59 min, [M + H] * = 377.
[0155] [0155] To a 4- (5- (5- (ethoxycarbonyl) -3-methyl-1 H-pyrazol-1-yl) pentyl) -1-ethyl-3-methyl-1 H-pyrazol-5 acid suspension -carboxylic (9.0 g, 23.9 mmol) in MeOH (120 mL) and water (120 mL) stirred at room temperature was added aq. of 2M NaOH (60 mL, 119.5 mmol). The reaction mixture was stirred at room temperature for 30 min. The mixture was then acidified to pH 4 with the addition of a 6M HCI solution on which a solid precipitated from the reaction mixture. The solid was collected by filtration and dried under reduced pressure to provide 4- (5- (5-carboxy-3-methyl-1 H-pyrazol-1-yl) pentyl) -1-ethyl-3-methyl-1 H -pyrazole-5-carboxylic (6.5 g, 18.7 mmol, 78.1% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 6.57 (s, 1 H), 4.40 - 4.34 (m, 4 H), 2.53 (t, J = 7.6 Hz , 2H), 2.16 (s, 3 H), 2.09 (s, 3 H), 1.74 - 1.67 (m, 2 H), 1.44 - 1.37 (m, 2H) , 1.27 - 1.16 (m, 5 H). LCMS (LCMS Method A): Rt = 1.40 min, [M + H] * = 349.
[0156] [0156] 1H-imidazole! (13.4 g, 197 mmol) in DCM (100 mL) 3-bromopropan-1-ol (13.7 gg 99 mmol) was added slowly followed by tert-butylchlorodimethylsilane (17.8 g, 118 mmol) in DCM ( 20 ml). After 3 hnaRT, the reaction was concentrated to -100 ml and poured into EtOAc (800 ml), washed with aq. 5% (2 x 200 mL) and brine. The organic layer was dried over MgSOa, filtered and concentrated to provide the title compound (10.0 g, 39.5 mmol, 40% yield). * H NMR (400 MHz, chloroform-d) 5 ppm 3.78 (t, J = 5.70 Hz, 2H), 3.56 (t, J = 6.46 Hz, 2 H), 2.07 (t, J = 5.83 Hz, 2 H), 0.94 (s, 9 H), 0.11 (s, 6 H).
[0157] [0157] To 2,2,3,3-tetrafluorobutane-1,4-diol (10.0 g, 61.7 mmol) in pyridine (150 mL) at 0 ° C, 4-methylbenzene-1-sulfonyl chloride was added (29.4 g, 154 mmol) for 5 min, and then the reaction was heated to 55 ° C. After 1 day, the reaction was cooled quickly with ice water, and the resulting solid was collected by filtration, dissolved in DCM (200 ml) and washed with aq. 5% (100 mL x 3). The organic layer was dried over Na2SO. and concentrated to provide the title compound (27.3 g, 58.0 mmol, 94% yield) as a white solid. LCMS (LCMS Method A): Rt = 1.750 min, [M + H] * = 470.9 Step 2: 1,4-Diazido-2,2,3,3-tetrafluorobutane F F SAX FF
[0158] [0158] Bis (4-methylbenzenesulfonate) of 2,2,3,3-tetrafluorobutane-1,4-diyl (10.0 g, 21.3 mmol) and sodium azide (5.53 g, 85.0 mmol) in DMF (40 mL) were stirred at 110 ° C overnight. The reaction was quenched with NaClIO (aq.) And extracted with DCM (5 mL x 3). The combined organic layers were washed with water (10 ml), dried over Na2SO: u and concentrated to provide the title compound (3.5 g, 16.5 mmol, 78% yield). LCMS (LCMS Method A): Rt = 1.520 min, [M + H] '= 213.1 Step 3: 2,2,3,3-Tetrafluorobutane-1,4-diamine NATAN FF
[0159] [0159] To a solution of 1,4-diazide-2,2,3,3-tetrafluorobutane (36.0 g, 170 mmol) in MeOH (350 mL) was added 10% Pd on carbon (18.1 g , 17.0 mmol). The reaction mixture was stirred at 40 ºC under hydrogen (4 atm) for 16 h. The mixture was filtered through a pad of Celite, washed with MeOH and the filtrate was concentrated in vacuo to provide the title compound (22.0 g, 124 mmol, 73% yield). * H NMR (400 MHz, chloroform-d) 5 ppm 3.12 - 3.37 (m, 4 H), 1.43 (br. S., 4 H).
[0160] [0160] To a 1L round bottom flask was added 1-ethyl-3-methyl-1H-pyrazole-S-carboxylic acid (25 g, 162 mmol) and DCM (500 ml). To this heterogeneous solution was added DMF (0.1 ml, 1.291 mmol) followed by the slow addition of oxalyl chloride (15.61 ml, 178 mmol). During the addition, bubbling was noted. After stirring for 1 h at room temperature, the volatiles were removed in vacuo and the crude was coevaporated twice with dichloromethane (100 ml each). 100% yield was considered and the crude (1-ethyl-3-methyl-1H-pyrazol-S-carbonyl chloride (28.0 g, 162 mmol, 100% yield)) was used directly as in the next reaction.
[0161] [0161] KSCN was added to a dry 1L round bottom flask
[0162] [0162] The mixture of 4-fluoro-3-nitrobenzamide (10.0 g, 54.3 mmol), (E) -tert-butyl (10, aminobut-2-en-1-yl) carbamate (10, 62 g, 57.0 mmol) and K2CO3 (15.01 g, 109 mmol) in DMSO (200 mL) was stirred at RT overnight. The reaction was poured into water (2000 mL) and stirred for 30 min. The resulting solid was collected by filtration to provide the title compound (18.3 g, 52.2 mmol, 96% yield). LCMS (LCMS Method A): Rt = 1.38 min, [2M + H] * = 700.5 Step 2: (4 - (((2-Amino-4-carbamoylphenyl) amino) but-2-en-1- il) (E) - tert-butyl carbamate oe HN
[0163] [0163] Ao (4 - ((4-carbamoyl-2-nitrophenyl) amino) but-2-en-1-yl) (E) - tert-butyl carbamate (18.3 g, 52.2 mmol) in DMF (300 ml) was added stannous chloride dihydrate (58.9 g, 261 mmol). After stirring at RT overnight, the reaction was added to NaHCO; aq. sat. (2000 mL), dropwise, and extracted with EtOAc (5 x 500 mL). The combined organic layers were washed with brine (200 ml), dried over Na2SO4: filtered and concentrated to provide the title compound (16.59, 51.5 mmol, 99% yield) as a yellow oil. LCMS (LCMS Method A): Rt = 1.275 min, [M - BOC + H] * = 221.1 Step 3: (4- (2-Amino-5-carbamoyl-1H-benzo [d] imidazol-1-yl (E) -tert-butyl but-2-en-1-yl) carbamate Ho DA.
[0164] [0164] The mixture of (E) -tert-butyl (4 - ((2-amino-4-carbamoylphenyl) amino) but-2-en-1-yl) carbamate (16.5 g, 51.5 mmol ) and cyanogen bromide (8.18 g, 77 mmol) in THF (200 mL) was heated to reflux overnight. The reaction was cooled to room temperature, diluted with NaHCO; aq. sat. (500 ml), and extracted with EtOAc (5 x 300 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel, eluting with 50: 1 to 20: 1 DCM in MeOH (+ 3% NHaOH) to provide the title compound (13.7 g, 39.7 mmol, 77% yield ) as an almost white solid. LCMS (LCMS Method A): Rt = 1,150 min, [M + H] * = 346.1 Step 4: (4- (5-Carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5- carboxamido) -1H-benzo [d] imidazole | -1-yl) but-2-en-1-yl) (E) -tert-butyl carbamate N P. "soc
[0165] [0165] To 1-ethyl-3-methyl-1H-pyrazol-5-carboxylic acid (9.17 g, 59.5 mmol) in DCM (500 mL) at 0 ° C EDC (20.53 g, 107 mmol) and HOBT (18.22 g, 119 mmol). After 15 min) a mixture of (4- (2-amino-5-carbamoyl-1H-benzo [d] imidazol | -1-yl) but-2-en-1-yl) carbamate of (E) -tert -butyl (13.7 g, 39.7 mmol) in DMF (50 mL) was added, followed by TEA (27.6 mL, 198 mmol). The reaction was heated to RT, stirred overnight and concentrated. The residue was diluted with water (500 ml) and extracted with ethyl acetate (3 x 300 ml), and the combined organic phases were washed with brine, dried over NazSO:, filtered and concentrated. The residue was purified on silica gel, eluting with DCM: MeOH 50: 1 to 20: 1 to provide the crude product, which was rinsed with DCM (300 mL) and collected by filtration to provide the title compound (14.0) g, 29.1 mmol, 73% yield) as an off-white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 12.84 (s, 1 H), 8.00 - 7.97 (m, 2 H), 7.80 - 7.78 (m, 1 H ), 7.49 (d, J = 8.4 Hz, 1 H), 7.34 (s, 1 H), 6.95 (t, J = 5.5 Hz, 1 H), 6.66 ( s, 1 H), 5.73 - 5.65 (m, 2 H), 4.83 (d, J = 4.3 Hz, 2 H), 4.62 (q, J = 7.0 Hz, 2 H), 3.52 (s, 2 H), 2.18 (s, 3 H), 1.38 - 1.33 (m, 12H); LCMS (LCMS Method A): Rt = 1.409 min, [M + H] * = 482.0 Step 5: (E) -1- (4-aminobut-2-en-1-i1) -2- ( 1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole | -5-carboxamide DÁ! " N f HN
[0166] [0166] To a suspension of (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2 -en-1-yl) carbamate = from - (E) -tert-butyl (3.00 g, 6.23 mmol) in dioxane (60 mL) 4N HCI in dioxane (15.6 mL, 62.3 mmol), followed by MeOH (15 mL) to dissolve any remaining solid. After 30 min at RT, the reaction mixture becomes cloudy and was allowed to stir for approximately 3 days. The resulting solid was collected by filtration and washed with DCM to provide the title compound (2.0 g, 4.8 mmol, 77% yield) as a white solid. ! H NMR (400 MHz, DMSO-ds) at ppm 7.97 - 8.09 (br. S., 1 H), 7.82 (d, J = 8.11 Hz, 1 H), 7, 50 (d, J = 8.11 Hz, 1 H), 7.38 (br. S, 1 H), 6.70 (s, 1 H), 5.97 - 6.08 (m, 1 H ), 5.68 - 5.80 (m, 1 H), 4.91 (d, J = 4.31 Hz, 2 H), 4.60 (q, J = 6.67 Hz, 2 H), 3.42 (br. S., 2 H), 2.18 (s, 3 H), 1.36 (t, J = 6.97 Hz, 3 H); LCMS (LCMS Method D): Rt = 0.53 min, [M + H] * = 382.2 Intermediate 7 Acid - 1- (5- (5- (ethoxycarbonyl) -1-ethyl-3-methyl-1H- pyrazol-4-yl) pentyl) -3-methyl-1H-pyrazol-5-carboxylic oo - or AO Ho R BrBr Bno KR “WU emo N [AN> [AN ——— | AN KHCO; 3 PPhz3, DIAD Me Me Me
[0167] [0167] The mixture of 3-methyl-1H-pyrazol-5-carboxylic acid (50 mg, 0.396 mmol) and KHCO; s (47.6 mg, 0.477 / 6 mmol) in DMSO (2 mL) was stirred for 30 minutes. min, and (bromomethyl) benzene (0.045 mL, 0.377 mmol) was added. The mixture was stirred for 4 h at RT, diluted with EtOAc (20 ml), washed with water and brine, and dried over Na2SO4s. The mixture was filtered and concentrated, and the residue was purified by column chromatography (Combiflash, 50% EtOAc O in hexane) to provide the title compound (66 mg, 0.305 mmol, 77% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 13.19 (br. S., 1 H) 7.34 - 7.48 (m, 5 H) 6.52 (s, 1 H) 5, 29 (s, 2 H) 2.27 (s, 3 H). LCMS (LCMS Method D): Rt = 0.86 min, [M + HJ] * = 216.9.
[0168] [0168] The mixture of DIAD (25.9 mL, 133 mmol) and triphenylphosphine (34.9 g, 133 mmol) in tetrahydrofuran (THF) (600 mL) was stirred for 30 min at 0 ºC, and 4-in-1-01 (11.36 mL, 122 mmol) was then added. The mixture was stirred for 30 min, and benzyl 3-methyl-1H-pyrazol-S-carboxylate (24 g, 111 mmol) was added. It was allowed to warm to RT and stirred overnight. The reaction was diluted with EtOAc (1,000 ml), washed with NaHCO; saturated and brine, dried over Na2SO4, filtered and concentrated. The oily residue was treated with 10% EtOAc in hexane (500 ml), and a white precipitate formed. The precipitate was filtered off and washed with 10% EtOAc in hexane. The combined filtrates were concentrated, and the residue was purified by column chromatography (Combiflash, 15% EtOAc O in hexane) to provide the title compound (27.5 g, 97 mmol, 88% yield) as a white solid . * H NMR (400 MHz, D-CHLOROPHORM) δ ppm 7.34 - 7.47 (m, 5 H) 6.68 (s, 1 H) 5.33 (s, 2 H) 4.63 (t , J = 7.03 Hz, 2 H) 2.30 (s, 3 H) 2.19 - 2.26 (m, 2 H) 2.09 (quin, J = 7.09 Hz, 2 H) 1 , 97 (br. S., 1 H); LCMS (LCMS Method D): Rt = 1.21 min, [M + H] * = 283.0.
[0169] [0169] Oxalyl chloride (5.68 ml, 64.9 mmol) was added to a suspension of 1-ethyl-3-methyl-1H-pyrazol-5-carboxylic acid (5 g, 32.4 mmol) in DCM (40 ml) at RT under N2 and two drops of DMF were added. The mixture was stirred for 2 hours at RT, concentrated and dried in vacuo. Ethanol (50 ml, 856 mmol) was added, and the mixture was stirred for 1 hour at RT. The reaction was concentrated and dried in vacuo to provide a light yellow oil which was taken up in EtOAc (100 ml), washed with NaHCO; saturated and brine, dried over Na2SO4, filtered, concentrated and the resulting residue was dried in vacuo to provide the title compound (5.5 g, 30.2 mmol, 93% yield) as a light yellow oil. 1 H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 6.63 (s, 1 H) 4.56 (q, J = 7.11 Hz, 2H) 4.35 (q, J = 7.11 Hz , 2H) 2.30 (s, 3 H) 1.44 (t, J = 7.28 Hz, 3 H) 1.39 (t, J = 7.28 Hz, 3 H). LCMS (LCMS Method E): Rt = 0.81 min, [M + H] * = 183.1.
[0170] [0170] The mixture of ethyl 1-ethyl-3-methyl-1H-pyrazol-S-carboxylate (5.5 g, 30.2 mmol) and NIS (8.15 g, 36.2 mmol) in DMF ( 100 mL) was heated to 90 ºC and stirred for 3 days under Nz. The reaction was cooled to RT, diluted with EtOAc (200 mL), washed with Na2S20O; 3 saturated, 5% LiCl and brine, dried over Na2SOa2, filtered, concentrated, and the resulting residue was purified by column chromatography (Combiflash, 0 to 7% EtOAc in hexane) to provide the title compound (9.1 g, 29.5 mmol, 98% yield) as a colorless oil. * H NMR (400 MHz, D-CHLOROPHORM) 5 ppm 4.57 (q, J = 7.03 Hz, 2 H) 4.43 (q, J = 7.03 Hz, 2 H) 2.32 ( s, 3 H) 1.45-1.50 (m, 3 H) 1.39 - 1.45 (m, 3 H). LCMS (LCMS Method D): Rt = 1.12 min, [M + H] * = 308.9.
[0171] [0171] A flask that was previously purged with nitrogen was loaded with Cs2CO; (23.08 g, 70.8 mmol), 1.10-phenanthroline (1.915 g, 10.63 mmol), copper (1) chloride (0.175 g, 1.771 mmol), 3-methyl-1- (pent- Benzyl 4-in-1-yl) -1H-pyrazol-S-carboxylate (10 g, 35.4 mmol), ethyl 1-ethyl-4-iodo-3-methyl-1H-pyrazol-5-carboxylate ( 13.10 g, 42.5 mmol), Pd [P (o-tolyl) 3] 2 (0.760 g, 1.063 mmol) and degassed toluene (100 mL). The mixture was degassed for 15 min, heated to 100 ºC and stirred overnight (18 h) under N2. The reaction was cooled to RT and diluted with EtOAc. The inorganic solids were filtered off and washed with EtOAc. The combined organics were concentrated and the residue was purified by silica gel chromatography (25% EtOAc / Hexanes O) to provide the title compound (11.38 g, 24.60 mmol, 69.5% yield) like a colorless oil. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 ppm 7.34 - 7.47 (m, 5 H) 6.68 (s, 1 H) 5.31 (s, 2 H) 4.67 (t J = 7.03 Hz, 2 H) 4.51 (q, J = 7.19 Hz, 2 H) 4.39 (q, J = 7.03 Hz, 2H) 2.51 (t, J = 7 , 28 Hz, 2 H) 2.31 (s, 3 H) 2.29 (s, 3 H) 2.17 (t, J = 7.15 Hz, 2H) 1.40 (t, J = 7, 03 Hz, 6 H). LCMS (LCMS Method D): Rt = 1.43 min, [M + H] * = 463.3.
[0172] [0172] To a flask loaded with 4- (5- (5 - ((benzyloxy) carbonyl) -3-methyl-1H-pyrazol-1-yl) pent-1-in-1-i1) -1-ethyl- Ethyl 3-methyl-1 H-pyrazol-5-carboxylate (11.3 g, 24.43 mmol) and Pd / C (2.60 g, 2.443 mmol) were added ethanol (200 mL). The flask was purged with N>, then hydrogen (via balloon) and the mixture was stirred under an atmosphere of H2 overnight (18 h). The catalyst was filtered off and the filtrate was concentrated in vacuo to provide the title compound (8.89 g, 23.62 mmol, 97% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 13.14 (br. S., 1 H) 6.57 (s, 1 H) 4.33 - 4.43 (m, 4 H) 4, 28 (m, J = 7.09 Hz, 2 H) 2.51 - 2.56 (m, 2 H) 2.16 (s, 3 H) 2.10 (s, 3 H) 1.72 (m , J = 7.34 Hz, 2H) 1.41 (m, J = 7.58 Hz, 2H) 1.25 - 1.31 (m, 6 H) 1.16 - 1.24 (m, 2H) . LCMS (LCMS Method D): Rt
[0173] [0173] A microwave tube containing (E) -1- (4-aminobut-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazole-S5- hydrochloride carboxamido) -1H-benzo [d] imidazole-5-carboxamide (517 mg, 1.24 mmol, in DMSO (10 mL) was treated with TEA (0.28 mL, mmol), followed by K2CO3 (274 mg, 1 , 98 mmol) and 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-chloro-S-nitrobenzamide (385 mg, 0.990 mmol). The reaction was heated to 75 ° C. After 7 h, The mixture was concentrated, and the residue was purified on silica gel, eluting with 10 to 90% EtOAc to remove impurities, followed by 0 to 10% MeOH in DCM to provide the title compound (200 mg, 0.273 mmol, 28% yield) as an orange solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 8.16 (d, J = 1.52 Hz, 1 H), 7.94 - 8.08 (m, 3 H ), 7.74 (d, J = 8.11 Hz, 2H), 7.50 (s, 1 H), 7.31 - 7.43 (m, 3 H), 6.62 (s, 1 H ), 5.74 - 5.81 (m, 2 H), 4.80 (br. S., 2 H), 4.59 (d, J = 6.84 Hz, 2 H), 4.13 ( br., 2 H), 4.01 (t, J = 6.08 Hz, 2 H), 3.63 (t, J = 5.96 Hz, 2 H), 2.16 (s, 3 H), 1.76 - 1.88 (m, 2 H), 1.33 (t J = 7.10 Hz, 3 H), 0.74 - 0.82 (m, 9 H), -0.06 (s, 6 H ); LCMS (LCMS Method D): Rt = 1.23 min, [M + H] * = 734.6 Step 2: (E) -1- (4 - ((2-Amino-6- (3 - ((tert -butyldimethylsilyl) oxy) propoxy) -4-carbamoylphenyl) amino) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d ] imidazole-5-carboxamide o DPÁLIOO *) N | TBDNSO NO
[0174] [0174] (E) -1- (4 - ((2- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoyl-6-nitrophenyl) amino) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (1 g, 1.363 mmol) was suspended in MeOH (20 mL) and ammonium hydroxide (4.62 mL, 34.1 mmol) was added and stirred for 5 min at RT. Sodium hydrosulfite (1.675 9, 8.18 mmol) in water (5 mL) was then added. After 60 min, EtOAc (300 ml) was added and the mixture was extracted with water (50 ml x 3). The organic phase was separated, dried with Na2S0O3, and concentrated in vacuo to provide the title compound (710 mg, 1.009 mmol, 74.0% yield) as a light yellow solid that was used without further purification. * H NMR (400 MHz, DMSO-ds) 5 ppm 12.80 (br. S, 1 H), 8.00 (s, 1 H), 7.97 (br. S., 1H), 7 , 75 (dd, J = 8.49, 1.14 Hz, 1 H), 7.63 (br. S., 1 H), 7.28 - 7.41 (m, 2 H), 7.00 (br. s., 1 H), 6.84 (d, J = 1.52 Hz, 1 H), 6.74 (d, J = 1.52 Hz, 1 H), 6.65 (s, 1 H), 5.79 - 5.96 (m, 1H), 5.64 - 5.78 (m, 1 H), 4.81 (d, J = 4.82 Hz, 2 H), 4, 68 (br. S., 2 H), 4.61 (d, J = 7.10 Hz, 2 H), 3.92 (t, J = 5.83 Hz, 2 H), 3.84 (br . s., 1 H), 3.63 (t, J = 6.08 Hz, 2 H), 3.57 (br. s., 2H), 2.17 (s, 3 H), 1.70 - 1.82 (m, 2 H), 1.34 (t, J = 7.10 Hz, 3 H), 0.68 - 0.83 (m, 9 H), -0.06 (s, 6 H); LCMS (LCMS Method J): Rt = 1.05 min, [M + H] * = 704.3 Step 3: (E) -2-Amino-7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-S-carboxamido) -1H-benzo [d] imidazo | -1-yl) but-2- en- 1-yl) -1H-benzo [d] imidazole-5-carboxamide YA Ã
[0175] [0175] JA a solution of (E) -1- (4 - ((2-amino-6- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4-carbamoylphenyl) amino) but-2-en- 1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide (120 mg, 0.170 mmol) in MeOH (5 ml) was cyanogen bromide (36 mg, 0.34 mmol) was added at RT. After 2 h, the reaction was concentrated, and EtOAc was added (10 ml). After stirring for 30 min, the solid was isolated by filtration, and washed with EtOAc to provide the title compound (120 mg, 0.165 mmol, 97% yield) as a light brown solid, which was used without further purification. 1H NMR (400 MHz, MeOH-da) 5 ppm 8.00 (d, J = 1.27 Hz, 1 H), 7.81 (dd, J = 8.36, 1.77 Hz, 1 H) , 7.49 (d, J = 1.27 Hz, 1 H), 7.39 - 7.45 (m, 1 H), 7.36 (d, J = 1.27 Hz, 1 H), 6 , 61 (s, 1 H), 5.82 - 5.99 (m, 2 H), 4.96 - 5.01 (m, 2 H), 4.56 - 4.65 (m, 2 H) , 4.12 (t, J = 6.21 Hz, 2H), 3.62 - 3.75 (m, 2 H), 2.18 - 2.29 (m, 3 H), 1.79 (t , J = 6.21 Hz, 2 H), 1.24 - 1.54 (m, 5H), 0.84 - 0.98 (m, 9 H), -0.01 - 0.11 (m, 6 H); LCMS (LCMS Method D): Rt = 0.97 min, [M + H] * = 729.5 Step 4: (E) -7- (3 - ((tert-Butyldimethylsilyl) oxy) propoxy) -1- ( 4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] Jimidazol-1-yl) but-2-en-1-i1) - 2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] Jimidazol-5-carboxamide
[0176] [0176] To a solution of 1-ethyl-3-methyl-1H-pyrazole-S-carboxylic acid (33 mg, 0.21 mmol) in DMF (3 mL) was added HATU (75 mg, 0.20 mmol) and HOBt (12.6 mg, 0.082 mmol). After stirring at RT for 10 min, triethylamine (0.09 mL, 0.66 mmol) was added, followed by (E) -2-amino-7- (3 - (((tert-butyldimethylsilyl) oxy) propoxy) - 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2-en-1 -i1) -1 H-benzo [d] imidazo | -5- carboxamide (120 mg, 0.165 mmol) and the reaction was continued at RT. After 3 days, a solid was precipitated out of the reaction by adding the drops of water. The solid was isolated by filtration and washed with water. The solid was then purified on silica gel (12 g HP Gold column), eluting with 20% MeOH O in DCM. The desired fractions were combined and concentrated to provide the title compound (29 mg, 0.034 mmol, 20% yield) as an off-white solid. * H NMR (400 MHz, THF-da) to pom 12.53 (br. S., 2 H), 8.00 (d, J = 1.01 Hz, 1 H), 7.61 (d, J = 1.01 Hz, 1 H), 7.53 (dd, J = 8.36, 1.52 Hz, 1 H), 7.36 (d, J = 6.84 Hz, 2 H), 7 , 29 (d, J = 1.01 Hz, 1 H), 7.12 (d, J = 8.36 Hz, 1 H), 6.83 (br., 2 H), 6.66 ( d, J = 2.28 Hz, 2 H), 6.06 (dt, J = 15.46, 5.58 Hz, 1 H), 5.87 (dt, J = 15.46, 5.83 Hz , 1 H), 5.09 (d, J = 5.32 Hz, 2 H), 4.89 (d, J = 5.58 Hz, 2 H), 4.59 - 4.72 (m, 4 H), 3.97 (t, J = 6.21 Hz, 2 H), 3.69 (t, J = 5.96 Hz, 2 H), 2.20 (s, 6 H), 1.73 - 1.78 (m, 2 H), 1.40 (td, J = 7.03, 1.14 Hz, 6 H), 0.82 - 0.94 (m, 9 H), -0.03 - 0.09 (m, 6 H); LCMS (LCMS Method D): Rt = 1.21 min, [M / 2 + H] * = 433.6 Step 5: (E) -1- (4- (5-Carbamoyl-2- (1-ethyl- 3-methyl-1H-pyrazol-5-carboxamido) -
[0177] [0177] To a solution of (E) -7- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H- pyrazol-5-carboxamido) -1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido ) -1H-benzo [d] imidazole-5-carboxamide (25 mg, 0.029 mmol) and 1M TBAF in THF (0.058 mL, 0.058 mmol) in THF (2 mL) in RT was added acetic acid (3.3 µL, 0.058 mmol). After 12 h, the reaction was concentrated, triturated with diethyl ether and EtOAc, and further purified on silica gel (12 g Gold column) eluting with 25% methanol O in DCM. The desired fractions were concentrated to provide the title compound (7 ma, 9 µMol, 32% yield) as an off-white solid. * H NMR (400 MHz, THF-ds) 5 ppm 12.51 (br. S., 2 H), 8.01 (d, J = 1.01 Hz, 2 H), 7.55 - 7, 65 (m, 3 H), 7.33 (d J = 1.01 Hz, 2 H), 7.14 - 7.20 (m, 2 H), 6.00 - 6.15 (m, 2 H ), 5.82 - 5.96 (m, 2 H), 5.05 - 5.13 (m, 4 H), 4.04 (t, J = 6.59 Hz, 4 H), 3.78 - 3.90 (m, 5 H), 2.19 (d, J = 2.03 Hz, 6 H), 1.87 - 2.00 (m, 2 H), 1.36 - 1.44 ( m, 6 H); LCMS (LCMS Method D): Rt = 0.79 min, [IM + HJ * = 751.4.
[0178] [0178] The compound prepared by the above process can exist in a tautomeric or isomeric form, eg, as (E) -1 - ((E) - <4 - ((E) -S-carbamoyl-2 - ((1- ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2- ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide oo Dico "N Ne) N 1 Homo (
[0179] [0179] To a suspension of 4-chloro-3-methoxy-5-nitrobenzamide (1.50 g, 6.50 mmol) in EtOH (25 mL) was added (4-aminobut-2-en-1-yl) (E) -tert-butyl carbamate (1.454 g, 7.81 mmol) and DIEA (3.4 mL, 20 mmol). The reaction was stirred at 120 ° C in a sealed tube overnight and allowed to cool to RT. The resulting orange solid was collected by filtration and washed with EtOH to provide the title compound (2.10 g, 5.52 mmol, 85% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 8.19 (d, J = 1.77 Hz, 1 H) 8.03 (br. S., 1 H) 7.76 (t, J = 6.08 Hz, 1 H) 7.55 (d, J = 1.52 Hz, 1 H) 7.34 (br. S, 1 H) 6.95 (t, J = 5.45 Hz, 1 H) 5.53 (br., 2 H) 4.09 (br., 2 H) 3.88 (s, 3 H) 3.48 (br., 2 H) 1.35 (s, 9 H); LCMS (LCMS Method D): Rt = 0.89 min, [Mt-Bu + H] * = 325.1 Step 2: (E) -4 - ((4-aminobut-2-en-1-yl hydrochloride ) amino) -3-methoxy-5-nitrobenzamide ON À no
[0180] [0180] To a suspension of tert-butyl (E) - (4 - ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) but-2-en-1-yl) carbamate (20 g, 47 , 3 mmol) in methanol (50 mL) 4M HCl in dioxane (100 mL, 400 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h, then the resulting solid was isolated by filtration, washed with Et2O 3 times (100 ml x 3), and dried under a high vacuum column to provide the title compound (13.90 g, 43.9 mmol, 93% yield). * H NMR (400 MHz, DMSO-d6s) 5 pom 8.22 (d, J = 2.03 Hz, 1 H), 7.76 - 8.16 (br. M., 5 H), 7, 60 (d, J = 2.03 Hz, 1 H), 7.37 (br. S., 1 H), 5.87 (dt, JU = 15.52, 5.80 Hz, 1 H), 5 , 62 (dt, J = 15.65, 6.37 Hz, 1 H), 4.18 (d, J = 5.32 Hz, 2 H), 3.90 (s, 3 H), 3.40 (t, J = 5.70 Hz, 2 H); LCMS (LCMS Method K): Rt = 0.41 min, [M + H] * = 281.1 Step 3: (E) -3- (3 - ((tert-Butyldimethylsilyl) oxy) propoxy) -4- ( (4 - ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) but-2-en-1-yl) amino) -5-nitrobenzamide
[0181] [0181] To a suspension of (E) -4 - ((4-aminobut-2-en-1-yl) amino) - 3-methoxy-S-nitrobenzamide hydrochloride (9.77 g, 30.9 mmol) in 1-Butanol (90 ml), sodium bicarbonate (5.18 g, 61.7 mmol) and DIEA (22.45 ml, 129 mmol) were added. The mixture was stirred at RT for 10 min, then 3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) - 4-chloro-S-nitrobenzamide (10 g, 25.7 mmol) was added and the reaction mixture it was stirred at 120 ° C overnight. The solution was allowed to cool to RT and the resulting dark orange solid was isolated by filtration and washed with EtoH (15 ml). The crude material was then stirred in water (100 ml) for 10 min, filtered and washed again with water (100 ml), EtOAc (50 ml) and EtOH (20 ml). The material was dried in a vacuum oven to provide the title compound (10 g, 14.54 mmol, 56.5% yield). * H NMR (400 MHz, DMSO-d6s) 5 pom 8.16 (t, J = 1.77 Hz, 2 H), 8.04 (br. S., 2H), 7.72 (d, J = 5.83 Hz, 2 H), 7.53 (s, 2 H), 7.35 (br. S., 2 H), 5.53 - 5.68 (m, 2 H), 3.99 - 4.16 (m, 6 H), 3.74 (t, J = 6.08 Hz, 2 H), 3.43 (br. S., 3 H), 1.92 (t, J = 6 .08 Hz, 2 H), 0.74 - 0.88 (m, 9 H), 0.00 (s, 6 H); LCMS (LCMS Method K): Rt = 1.32 min, [M + H] * = 633.4 Step 4: (E) -3-Amino-4 - ((4 - ((2-amino-4-carbamoyl -6-methoxyphenyl) amino) but-2- en-1-yl)> amino) -5- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) benzamide
[0182] [0182] To a solution of (E) -3- (3 - ((tert-butyldimethylsilyl) oxy) propoxy) -4 - ((4 - ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) but -2-en-1-yl) amino) -S-nitrobenzamide (5 à, 7.90 mmol) in methanol (120 mL) at 0 ° C, sodium hydrosulfite (16.19 g, 79 mmol) in water was added (50 mL) and ammonium hydroxide (25.6 mL, 198 mmol). The reaction mixture was allowed to warm to RT. After 10 min at RT, the mixture was extracted with EtOAc (100 x 3), dried over Na2SO. and concentrated in vacuo. The crude material was purified by chromatography on silica gel (Isco column) eluting with hexane: (EtOH: EtOAc 3: 1) with 2% NHXOH additive (gradient 100%) to provide the title compound (2, 1 g, 3.34 mmol, 42.2% yield). * H NMR (400 MHz, DMSO-ds) 5 ppm 7.63 (br. S., 2 H), 6.99 (d, J = 5.58 Hz, 2 H), 6.72 - 6, 91 (m, 6 H), 5.62 - 5.73 (m, 2 H), 4.66 (d, J = 8.36 Hz, 4 H), 4.00 (t, J = 5.96 Hz, 2H), 3.69 - 3.84 (m, 4 H), 3.40 - 3.49 (m, 2 H), 3.35 (s, 3 H), 1.90 (t, J = 6.08 Hz, 2 H), 0.79 - 0.91 (m, 9 H), -0.03 - 0.07 (m, 6 H); LCMS (LCMS Method K): Rt = 0.46 min, [M + H]) * = 573.3 Step 5: (E) -1- (4- (5-Carbamoyl-2- (1-ethyl-3 -methyl-1 H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazol | -1-yl) but-2-en-1-i1) -2- (1- ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | -5-carboxamide
[0184] [0184] The compound prepared by the above process can exist in a tautomeric or isomeric form, eg, as (E) -1 - ((E) -4 - ((E) -S5-carbamoyl-2 - ((1-ethyl -3-methyl-1H-pyrazol-S-carbonyl) imino) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazo | -1- iN) but-2-en -1-11) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-S5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] Jimidazole | -5-carboxamide (Ara
[0185] [0185] Step 1: À (E) 1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-1- il) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7- (3-hydroxy-propoxy) -1H-benzo [d] imidazole-5-carboxamide (17 mg, 0.023 mmol) in THF (3 mL) was added triethylamine (9.5 µL, 0.068 mmol). After 10 min at RT, methanesulfonyl chloride (2.1 µL, 0.027 mmol) was added. After 2 h, LCMS indicated the presence of (E) -3 - ((5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazole- methanesulfonate- 5-carboxamido) -1H-benzo [d] imidazo | -1- yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) - 1H-benzo [d] imidazole | -7- iNoxy) propyl, and the reaction mixture was used directly in the next reaction LCMS (LCMS Method D): Rt = 0.80 min, [M + H] * = 751, 6010.
[0186] [0186] Step 2: To a solution of (E) -3 - ((5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazole-) methanesulfonate- 5-carboxamido) -1H-benzo [d] imidazole-1-iN) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-S5-carboxamido) -1H -benzo [d] imidazo! -7- iNoxy) propyl (18 mg, 0.022 mmol) in THF (5 mL) was added morpholine (9.5 µL, 0.11 mmol) and K2CO; 3 (9.0 mg, 0.065 mmol) After 5 h at RT, the reaction was heated to 45 ° C for 2 h and then concentrated.The residue was purified on silica gel eluting with 20% MeOH in DCM to provide the title compound (7 mg , 9 µMol, 39% yield) * H NMR (400 MHz, MeOH-ds) 5 ppm 7.99 (d, J = 1.27 Hz, 1 H), 7.73 (dd, J = 8 , 36, 1.52 Hz, 1 H), 7.59 (d, J = 1.27 Hz, 1 H), 7.36 (d, J = 8.62 Hz, 1 H), 7.28 ( d, J = 1.27 Hz, 1 H), 6.64 (s, 1 H), 6.57 (s, 1 H), 5.92 - 6.05 (m, 1 H), 5.73 - 5.88 (m, 1 H), 4.51 - 4.71 (m, 4 H), 4.00 (t, J = 6.21 Hz, 2 H), 3.56 - 3.67 ( m, 8 H), 2.27 - 246 (m, 6 H), 2.22 (d, J = 10.39 Hz, 6 H), 1.83 (dt, J = 14.19, 6, 84 Hz, 2H), 1.26 - 1.44 (m, 6 H); LCMS (LCMS Method D): Rt = 0.73 min, [M / 2 + H] * = 410.9876
[0187] [0187] The compound prepared by the above process can exist in a tautomeric or isomeric form, eg, as (E) -1 - ((E) - <4 - ((E) -S-carbamoyl-2 - ((1- ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide oo ÁGAS) N OND 2 * O (or (Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) ) imino) -2,3-dihydro-1H-benzo [d] Jimidazol | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H- pyrazol-S-carbonyl) imino) -7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo! - 5-carboxamide yo
[0188] [0188] (E) -4 - ((4-aminobut-2-en-1-yl) amino) -3-methoxy-5-nitrobenzamide hydrochloride (1.79, 5.37 mmol), 4-chloro- 3- (3-morpholinopropoxy) -5-nitrobenzamide (1.655 g, 4.81 mmol) i-PrOH (15 ml) and DIPEA (2.94 ml, 16.85 mmol) were divided into two 24 ml vials, then the bottles were capped and heated to 120 ºC for 42 h. The solid was isolated by filtration, rinsed with i-PrOH (2 x 3 mL) to provide (E) -4 - ((4 - ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) but-2-en-1-yl) amino) -3-methoxy-S-nitrobenzamide (1.95 g, 2.79 mmol, 51.9% yield)
[0189] [0189] À (E) -4 - ((4 - ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) but- 2-en-1-yl) amino) -3-methoxy -5-nitrobenzamide (4.6 g, 6.65 mmol) in MeOH (83.0 mL) at RT was added sodium hydrosulfite (19.08 g, 93.0 mmol) in water (70 mL). After 15 min, solid sodium bicarbonate (24 grams) was added. After min, the reaction was filtered, and the solid was rinsed with MeOH (4 x 20 ml). The combined filtrates were concentrated on Celite and purified by dry loading on silica gel (80 g Gold column), eluting with 2 to 40% (MeOH: NHaOH aq. 10: 1) in DCM to provide the title compound ( 1.81 g, 3.26 mmol, 49% yield) as a dark yellow film. * H NMR (400 MHz, DMSO-ds) 5 ppm 7.64 (br. S., 2 H), 6.99 (br., 2 H), 6.85 (dd, J = 5, 07, 1.77 Hz, 2 H), 6.78 (dd, J = 4.31.1.77 Hz, 2 H), 5.63 - 5.72 (m, 2 H), 4.66 ( d, J = 8.11 Hz, 4 H), 3.96 (t, J = 6.21 Hz, 2 H), 3.74 (s, 3 H), 3.51 - 3.60 (m, 6 H), 3.17 (br. S, 4 H), 2.43 (t, J = 7.10 Hz, 2 H), 2.35 (br. 4 h), 1.87 (t, J = 6.72 Hz, 2 H); LCMS (LCMS Method K): Rt = 0.37 min, [M + H] * = 528.4 Step 3: (E) -1- (4- (5-carbamoyl-2- (1-ethyl) hydrochloride tris -3-methyl-1H-pyrazol-5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazol | -1-yl) but-2-en-1-i1) -2- (1 -ethyl- 3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole-5-carboxamide
[0190] [0190] JA (E) -3-amino-4 - (((4 - ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy) phenyl) amino) -but-2-en-1-yl) amino) -5-methoxybenzamide - (368 mo, 0.697 mmol) in DMF (6.97 mL) at 0 ° C 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate in dioxane ( 2.0 mL, 0.80 mmol). After -10 min, another portion of 0.4M 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate in dioxane (0.5 mL, 0.20 mmol) was added, followed by -15 min later by a final portion (0.5 mL, 0.20 mmol). After 35 min of total reaction time, EDC (334 mg, 1.74 mmol) was added followed by triethylamine (0.486 ml, 3.49 mmol). The mixture was allowed to warm to RT and stirred overnight (-14 hours). The reaction was cooled quickly with water: saturated aqueous NHaCI solution 3: 1 (40 mL) and extracted with chloroform: ethanol 3: 1 (2x 40 mL). The combined organic phases were washed with water (20 ml), dried over MgSO: u and concentrated. The resulting residue was purified on silica gel (Gold column 40 g), eluting with (MeOH: NH4OH aq. 10: 1) 2a 40% in DCM to provide the pure material as the free base. This product was partially dissolved in MeOH and treated with 4M HCl in dioxane (0.35 ml, 1.40 mmol), then concentrated. The residue was taken up in MeCN-water and lyophilized to provide the title compound (403.6 mg, 0.421 mmol, 60% yield) as an off-white solid. * H NMR (400 MHz, methanol-da) 5 7.70 (dd, J = 2.66, 1.14 Hz, 2H), 7.42 (d, J = 1.27 Hz, 2 H), 6.72 (d, J = 3.04 Hz, 2 H), 5.79 - 6.12 (m, 2 H), 5.19 (dd, J = 11.03, 5.45 Hz, 4 H ), 4.61 - 4.81 (m, 4 H), 4.00 - 4.25 (m, 4 H), 3.79 - 3.96 (m, H), 3.45 (d, J = 12.42 Hz, 2 H), 3.28 - 3.36 (m, 2 H), 3.14 (td, J = 12.23, 3.68 Hz, 2
[0191] [0191] (3 - (((Z) -6-Carbamoyl-3 - (((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazole- S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-yl) -
[0192] [0192] The suspension of (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H- benzo [d] imidazo | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [ d] imidazole-5-carboxamide (1.00 g, 1.28 mmol) and 0.45 M 2H-tetrazole in acetonitrile (14.2 mL, 6.40 mmol) in DMF (5 mL) was concentrated on a rotary evaporator to remove acetonitrile. The resulting heterogeneous mixture in DMF was cooled to 0 ° C then a solution of di-tert-butyl diisopropylphosphoramidite (1.617 ml, 5.12 mmol) in 5 ml of DMF was added. Soon after the addition, the solution becomes homogeneous, but again it becomes heterogeneous as the reaction is stirred at RT for an additional 2 hours. The temperature was lowered to 0 ° C and H202 (30% by weight in water, 2.62 ml, 25.6 mmol) was added. After stirring for 20 min, an additional 10 eq. of H2O »2 was added and the reaction stirred until homogeneous (30 min). A 2 ml portion of NaHCO; 3 aqueous and Na2S2O03 (0.4AM in NaHCO; 3.2M in NazS203) was added to 200 ml of water. When the reaction mixture was poured into this solution, a precipitate was formed. The precipitate was then collected on a filter, dissolved in 200 ml of THF, dried with MgSO: and concentrated to provide the title compound as an off-white solid (1.1 g, 1.13 mmol, 88% yield). * H NMR (400 MHz, DMSOdes) 5 ppm 12.8 (s, 2 H), 10.2 (s, 1 H), 7.98 (m, 2 H), 7.65 (d, J = 2.5 Hz, 2 H), 7.34 (m, 4 H), 6.51 (d, J = 2.5 Hz, 2 H), 5.83 (m, 2 H), 4, 91 (m, 4 H), 4.52 (m, 4 H), 4.09 (m, 2 H), 3.93 (m, 2 H), 3.74 (s, 3 H), 3, 60 (m, 2 H), 2.11 (s, 6 H), 1.90 (m, 2 H), 1.76 (m, 2 H), 1.4 - 1.3 (m, 18 H , 1.27 (m, 6 H); LCMS (LCMS Method 1): Rt = 1.09 min, [M + HJ *
[0193] [0193] 3 - (((Z) -6-carbamoyl-3 - ((E) -4 - ((Z) -S-carbamoyl-2- ((1-ethyl-3-methyl-1-di-hydrogen-phosphate) H-pyrazol-S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazol | -1-yl) but-2-en-1-i1) -2- ( (1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazol-4-yl) oxy) propylates the RP O "rod Aq 2 7
[0194] [0194] Ao (3 - (((Z) -6-carbamoyl-3 - ((E) -4 - ((Z) -S-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazole) -5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) - 2 - ((1- ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazo | -4- iN) oxy) -propyl) di-tert-butyl phosphate (18 mg, 0.018 mmol) suspended in dioxane (1 mL) at RT 4N HCl in dioxane (0.028 mL, 0.11 mmol) was added. Some precipitate formed immediately. The reaction was stirred for 2 h and 4N HCI in additional dioxane (0.028 ml, 0.11 mmol) was added. After 2 h, the reaction was placed in the freezer, and after 16 h, the reaction was diluted with diethyl ether. The mixture was adjusted to pH 2-3 with concentrated ammonium hydroxide. The precipitate was collected by filtration and washed with ether to provide the title compound (15 mg, 0.017 mmol, 92% yield) as a white solid. * H NMR (600 MHz, DMSO-ds) 5 ppm 12.85 (br s, 1 H), 8.02 (br, d, J = 6.6 Hz, 2 H), 7.65 (d, J = 5.7 Hz, 2 H), 7.35 - 7.41 (m, 2 H), 7.34 (br. D, J = 10.6 Hz, 2 H), 6.51 (d, J = 12.8 Hz, 2H), 5.74 - 5.89 (m, 2 H), 4.92 (br. Dd, J = 12.0, 4.9 Hz, 4 H), 4.50 (quin, J = 7.0 Hz, 4 H), 4.10 (br. t, J = 6.1 Hz, 2 H), 3.91 - 3.94 (m, 2 H), 3.75 (s, 3 H), 2.10 (d, J = 3.1 Hz, 6 H), 1.84 - 1.93 (m, 2 H), 1.22 - 1.28 (m, 6 H ); LCMS (LCMS Method |): Rt = 0.68 min, [M
[0195] [0195] The compound prepared by the above process can exist in a tautomeric or isomeric form, eg, as (E) -3 - ((5-carbamoyl-1- (4- (S5-carbamoyl-2- ( 1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazol | -1-yl) but-2-en-1-i1) -2- (1 -ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-7-yl) oxy) propyl 9 o, É HN N FU
[0196] [0196] (E) -3- (5-Carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-B-carboxamido) -1H-benzo acid [d ] imidazol | -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-7- il) propanoic
[0197] [0197] To 3-bromo-4-fluoro-5-nitrobenzamide (1g, 3.65 mmol) in DMF (12.17 ml) were added tetra-n-butylammonium chloride (1.035 g, 3.65 mmol), Pd (OAc) (0.084 g, 0.365 mmol). After flushing with nitrogen for 10 min, 3,3-diethoxyprop-1-ene (1.739 ml, 10.95 mmol) and tributylamine (1.766 ml, 7.380 mmol) were added. The 20 ml microwave vessel was sealed and heated to 125 ºC for 6 h. The reaction products were divided between EtOAc (50 ml) and a mixture of saturated NHaCI / brine (50 ml). The aqueous layer was extracted twice with EtOAc (20 ml). The combined EtOAc layer was dried over magnesium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (Isco Combiflash Lumen, 12 g column, gradient 45 to 100% EtOAc / hexanes) to provide 3- (5-carbamoyl-2-fluoro-3-nitrophenyl) | ethyl oropanoate (360 mg, 1.267 mmol, 34.7% yield). LCMS (m / z): 285.1 [M + HJ *. Step 2: (E) -3- (5-Carbamoyl-2 - ((4 - (((4-carbamoyl-2-nitrophenyl) amino) but-2-en-1-yl)> amino) -3-nitrophenyl) ethyl propanoate oo
[0198] [0198] Ao 2C (E) -4 - ((4-aminobut-2-en-1-yl) amino) -3-nitrobenzamide (for example, prepared as Intermediate 6) (0.317 g, 0.960 mmol) in DMF (3 mL), triethylamine (0.402 mL, 2.88 mmol) and a solution of
[0199] [0199] (E) -3- (5-Carbamoyl-2 - ((4 - (((4-carbamoyl-2-nitrophenyl) amino) but-2-en-1-yl)> amino) -3-nitrophenyl) ethyl propanoate (330 mg, 0.841 mmol) was suspended in MeOH (9.33 mL) and 28% ammonium hydroxide solution (2.18 mL, 16.04 mmol) was added and stirred for 5 min. Sodium hydrosulfite (788 mg, 3.85 mmol) in water (2.33 mL) was added and stirred for 10 min. Due to incomplete reduction, more sodium hydrosulfite (788 mg, 3.85 mmol) in water (2.33 mL), then MeOH (3 mL) was added. The color of the suspension changed from orange to light yellow and the mixture was stirred at room temperature for an additional 60 min. To the mixture, EtOAc (50 ml) and water (50 ml) were added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated to provide the crude product as a yellow solid. The crude material was purified by chromatography on silica gel (Isco CombiFlash Rf, 24 g column, gradient 30 to 100% EtOAc: EtOH 3: 1 / hexanes). The pure fractions were collected and concentrated in vacuo to provide the title compound (79 mg, 0.174 mmol, 27% yield) as a white solid. LCMS (m / z): 455.2 [M + HJ *.
[0200] [0200] To a solution of (E) -3- (3-amino-2 - ((4 - ((2-amino-4-carbamoylphenyl) amino) but-2-en-1-yl) amino) -5 -carbamoylphenyl) ethyl oropanoate (79 mg, 0.174 mmol) in DMF (1738 uL) at 0 ° C was added in 2 portions 1-ethyl-3-methyl-1H-pyrazol-5-carbonyl isothiocyanate (for example, as prepared in Intermediate 11) (869 µL, 0.348 mmol, 0.4M in dioxane). The reaction was stirred for 1 h before EDC (100 mg, 0.521 mmol) and TEA (121 µl, 0.869 mmol) were added. The reaction was stirred at 50 ° C for 18 h. When cooled, the reaction was poured into a 10% NHaCI solution. The resulting precipitate was collected on a filter and washed with water to provide the title compound (85 mg, 0.109 mmol, 63% yield). LCMS (m / z): 777.5 [M + HJ *.
[0201] [0201] To a suspension of (E) -3- (5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H- benzo [d] Jimidazol | -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole- 7-yl) Ethyl dropanoate (80 mg, 0.103 mmol) in THF (1716 µL) and water (1716 µL) LiOH (49.3 mg, 2.060 mmol) was added at 25 ° C. The mixture becomes homogeneous and was stirred for 60 min. THF was evaporated to provide a slurry. The suspension was acidified with HCl 5N and filtered. The cake was rinsed 3X with water and dried in a vacuum oven for 2 h to provide the title compound (56 mg, 0.075 mmol, 72.6% yield) as a light brown solid. * H NMR (400 MHz, DMSO-d6s) 5 ppm 12.05 - 13.83 (br. S., 1 H), 7.94 - 8.00 (m, 2 H), 7.88 (s , 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.59 (s, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7 , 35 (d, J = 7.4 Hz, 1 H), 6.55 (s, 1 H), 6.51 (s, 1 H), 5.95 - 6.04 (m, 1 H), 5.51 - 5.60 (m, 1 H), 5.02 (br., 2 H), 4.84 (br., 2 H), 4.46 - 4.59 (m, 4 H), 3.90 - 4.35 (m, 4 H), 3.10 (t, J = 7.0 Hz, 2 H), 2.64 (t, J = 7.5 Hz, 2H), 2.11 (s, 6 H), 1.26 (t, J = 6.21 Hz, 6 H). LCOMS (m / z): 749.4 [M + HJ *.
[0202] [0202] (E) -4 - ((5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo acid) [ d] imidazole | -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-7- il) oxy) butanoic Nn = & PQ [o NE SN XY N
[0203] [0203] Example 8 can be prepared according to a combination of methods 14 and 16 as described in PCT / IB2017 / 051945 (filed April 5, 2017, incorporated in its entirety) with modifications known to a person skilled in the art .
[0204] [0204] Triphenylphosphine (2.059 g, 7.85 mmol), tert-butyl 4- (3-hydroxypropyl) piperazine-1-carboxylate (1.692 g, 6.93 mmol) and (E) -diazene-1,2- diisopropyl dicarboxylate (1.587 g, 7.85 mmol) was mixed in THF (20 mL) at 0 ° C, and then 4-chloro-3-hydroxy-S-nitrobenzamide (1 g, 4.62 mmol) was added . The reaction solution was kept at RT for 16 h, then the brown reaction solution was divided between NaHCO; (aq.) sat. and EtOAc. The organic layer was rinsed with brine, dried over MgSO2, concentrated and purified on silica gel (20% to 80% EtOAc / EtoH
[0205] [0205] 2Cl] (E) -1- (4-aminobut-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy hydride -1H-benzo [d] imidazole-5-carboxamide (242 mg, 0.499 mmol) was dissolved in n-butanol (10 mL) at RT, and then DIPEA (0.476 mL, 2.72 mmol) was added, followed by 4 - tert-Butyl (3- (5-carbamoyl-2-chloro-3-nitrophenoxy) propyl) piperazine-1-carboxylate (201 mg, 0.454 mmol). The reaction mixture was maintained at 120 ºC for 16 h. The reaction mixture was cooled to RT and the red solid was collected by filtration (296 mg, 73% yield). 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.14 (d, J = 1.77 Hz, 1 H), 8.00 (br. S., 2 H), 7.84 (t, J = 6.46 Hz, 1 H), 7.66 (s, 1 H), 7.44 (s, 1 H), 7.380 - 7.41 (m, 3 H), 6.59 (s, 1 H ), 5.61 - 5.87 (m, 2 H), 4.89 (d, J = 5.58 Hz, 2 H), 4.58 (q, J = 7.35 Hz, 2 H), 4.14 (br. S., 2 H), 3.89 (t, J = 6.34 Hz, 2 H), 3.84 (s, 3 H), 3.25 (br. S., 4 H), 2.27 (t, J = 6.72 Hz, 2 H), 2.21 (br. S., 4 H), 2.16 (s, 3 H), 1.75 (d, J = 6.08 Hz, 2 H), 1.39 (s, 9 H) 1.23 - 1.35 (m, 3 H). LCMS (LCMS Method K): Rt =
[0206] [0206] Sodium hydrosulfite (371 mg, 1.81 mmol) was dissolved in H2O (2 mL) at RT, and then a solution of (E) -4- (3- (5-carbamoyl-2 - ((4 - (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazol | -1-yl) but-2-en-1 - yl)> amino) -3-nitrophenoxy) propyl) tert-butyl piperazine-1-carboxylate (296 mg, 0.362 mmol) and ammonium hydroxide (0.486 mL, 3.62 mmol) in 5 mL of MeOH was added. The reaction mixture was kept at room temperature for 2 h, then the reaction mixture was filtered and the filtrate was partially concentrated to remove MeOH. The resulting yellow aqueous mixture was then extracted with EtOAc 3 times, the organic extracts were combined and concentrated to provide the title compound as a yellow solid (114 mg, 40% yield). * H NMR (400 MHz, METANOL-d4) 5 ppm 7.60 (d, J = 1.27 Hz, 1 H), 7.31 (d, J = 1.27 Hz, 1 H), 6, 81 (d, J = 1.77 Hz, 1 H), 6.67 (s, 1 H), 6.59 (d, J = 1.77 Hz, 1 H), 5.74 - 5.84 ( m, 1 H), 5.53 - 5.65 (m, 1 H), 4.12 (q, J = 7.18 Hz, 2 H), 3.84 - 3.91 (m, 3 H) , 3.61 - 3.71 (m, 4 H), 3.38 (br. S., 4 H), 2.31 -2.36 (m, 6 H), 2.26 (s, 3 H ), 2.03 (s, 2H), 1.68 - 1.78 (m, 2H), 1.47 (s, 9 H), 1.42 (t, J = 7.10 Hz, 3 H) . LCMS (LCMS Method K): Rt = 0.65 min, [M + H] + = 788.5.
[0207] [0207] (E) -4- (3- (3-Amino-5-carbamoyl-2 - ((4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido Tert-butyl) -7-methoxy-1H-benzo [d] imidazol-1-yl) but-2-en-1-iN)> amino) phenoxy) propyl) piperazine-1-carboxylate (114 ma, 0.145 mmol ) was dissolved in DMF (10 ml) at 0 ° C, and then 1-ethyl-3-methyl-1H-pyrazole-S-carbonyl isothiocyanate (0.362 ml, 0.145 mmol) was added. The reaction mixture was maintained at 0 ºC for 15 min, then TEA (0.050 ml, 0.362 mmol) and EDC (33.3 mg, 0.174 mmol) were added to the reaction mixture. The reaction mixture was maintained at RT for 16 h. The reaction mixture was then added to a sat. NaHCO3; (aq.) Stirring solution. The resulting white precipitate was collected by filtration to provide the title compound (103 mg, 75% yield). LCMS (LCMS Method K): Rt = 0.82 min, [M + H] * = 950.5.
[0208] [0208] Step 5: (E) -4- (3 - ((5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-S5-carboxamido)) -7-methoxy-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H -benzo [d] imidazol-7-yl) oxy) propyl) piperazine-1-tert-butyl carboxylate (103 mg, 0.109 mmol) was dissolved in MeOH (2 mL) and DCM (2 mL), and then HCI ( AN in 1,4-dioxane) (0.271 ml, 1.085 mmol) was added. The reaction mixture was maintained at RT for 16 h. DMSO (2 mL) was then added to the reaction mixture, and this mixture was filtered and the filtrate was concentrated and purified by HPLC (XSELECT CSH C18 column, 150 mm x 30 mm, id 5 um packaging diameter, 30 to 85 % 10 mM ammonium bicarbonate in water with acetonitrile). The light fractions after HPLC were combined and partially concentrated to provide the title compound as a white precipitate (25 mg, 27% yield). 1H NMR (400 MHz, METANOL-ds) 5 ppm 7.57 (d, J = 16.48 Hz, 2H), 7.14 - 7.30 (m, 2 H), 6.50 - 6.70 (m, 2 H), 5.81 (d, J = 3.04 Hz, 2 H), 4.99 (br. s., 4 Hd) 4.50 - 4.69 (m, 4 H) 3 , 86 (t, J = 5.70 Hz, 2 H) 3.69 (s, 3 H) 2.81 (t, J = 4.69 Hz, 4 H) 2.32 - 2.36 (m, 6 H) 2.20 (d, J = 12.93 Hz, 6 H), 1.70 (br. S., 2 H), 1.25 - 1.45 (m, 6 H). LCMS (LCMS Method K): Rt = 0.67 min, [M + H] * = 849.8.
[0209] [0209] Example 38 can be prepared according to method 20 with modifications known to a person skilled in the art. The last step of the preparation is provided: (E) -1- (4 - ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy) phenyl) amino) but-2- en-1-i1) -7 -ethoxy-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazo | -5-carboxamide (46 mg, 0.065 mmol) was dissolved in DMF (655 µL) at 0 ° C, and then 1-ethyl-3-methyl-1H-pyrazol-S-carbonyl isothiocyanate (196 µl, 0.079 mmol) was added. The reaction solution was kept at O ºC for 15 min., Then EDC (15.06 mg, 0.079 mmol) and TEA (22.81 µl, 0.464 mmol) were added and the reaction solution was maintained at RT. After 16 h, the reaction was concentrated and the yellow residue was purified by HPLC (XSELECT CSH C18 column, 150 mm x 30 mm, id of packaging diameter, 15 to 55% 10 MM ammonium bicarbonate in water with acetonitrile ). The desired fractions were combined and concentrated to provide the title compound as a white solid (19.2 mg, 34% yield). * H NMR (400 MHz, METANOL-ds) 5 ppm 7.62 (d, J = 1.27 Hz, 1 H), 7.58 (d, J = 1.27 Hz, 1 H), 7, 24 (d, J = 1.27 Hz, 1 H), 7.20 (d, J = 1.27 Hz, 1 H), 6.64 (s, 1 H), 6.62 (s, 1 H ), 5.78 (d, J = 3.30 Hz, 2 H), 5.01 (d, J = 2.79 Hz, 4 H), 4.63 (q, J = 7.10 Hz, 4H ), 3.86 - 4.08 (m, 6 H), 3.69 - 3.81 (m, 2 H), 3.37 (br. S., 2H), 3.16 - 3.23 ( m, 2 H), 2.97 - 3.13 (m, 2H), 2.23 (s, 6 H), 1.96 - 2.04 (m, 2 H), 1.39 (t, J = 7.10 Hz, 6 H), 1.15 (t, J = 6.97 Hz, 3 H). LCMS (LCMS Method K): Rt = 0.76 min, [M + HJ + = 864.5.
[0210] [0210] To a solution of (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) hydrochloride -1H-benzo [d] imidazo | -1-yl) but-2-en-1- 11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H -benzo [d] imidazole-5-carboxamide (150 mg, 0.184 mmol) in DMF (2 mL) TEA (0.20 mL, 1.435 mmol) was added. The solution was cooled to 0 ºC. Methanesulfonyl chloride (42.0 mg, 0.367 mmol) was added at this temperature. The reaction mixture was stirred at this temperature for 1 h, then another 1 eq. of methanesulfonyl chloride (21.0 mg, 0.183 mmol) was added, and the reaction was continued at 0 ° C for 1 h. K2CO; 3 (127 mg, 0.918 mmol) was then added to the reaction mixture followed by 1 ml of dimethyl amine (2M in THF, 2.0 mmol). The reaction mixture was stirred at 80 ºC in a sealed tube for 2 hours, then allowed to cool to room temperature, and the crude material was purified by mass HPLC. HPLC analysis was performed on an XSELECT SCH C18 column. Solvent condition: A = 10 mM ammonium bicarbonate in H2O adjusted to pH 10 with Ammonia, B = MeCN B%: 15 to 55. Desired MW peaks collected. The solvent was removed and the residue was dissolved in 1 ml of MeOH. 4N HCI in dioxane (1 ml) was added. The solution was stirred at room temperature for 10 min. The solvent was removed and the solid washed with ethyl ether (5 ml x 2) to provide the title compound (76 mg, 0.082 mmol, 44.7% yield). * H NMR (DMSO-d6, 600MHz): 5 (ppm) 12.89 (br s, 2 H), 10.18 - 10.41 (m, 1 H), 7.96 - 8.04 (m , 2 H), 7.66 (d, J = 10.0 Hz, 2 H), 7.35 - 7.41 (m, 2 H), 7.28 - 7.35 (m, 2 H), 6.53 (d, J = 2.8 Hz, 2 H), 5.82 (dt, J = 15.5, 5.3 Hz, 1 H), 5.71 (dt, J = 15.4, 5.6 Hz, 1 H), 4.85 - 4.98 (m, 4 H), 4.52 (quin, J = 6.5 Hz, 4 H), 3.96 - 4.04 (m, 2 H), 3.70 (s, 3 H), 3.00 - 3.09 (m, 2 H), 2.66 (d, J = 4.8 Hz, 6 H), 2.11 (d , J = 4.4 Hz, 6 H), 1.85 - 2.03 (m, 2 H), 1.20 - 1.32 (m, 6 H); LCMS Method K: Rt = 0.67 min, [M + H] * = 808.5 Example 13 STING agonist formulations:
[0211] [0211] The STING agonist was prepared in a PEG / saline formulation or a DMSO / PEG / Water formulation for tumor regression IV and PK / PD experiments disclosed here.
[0212] [0212] The DMSO / PEG / Water formulation was prepared using the following methods: 1) STING agonist dissolved first with DMSO and then vortexed to ensure that the compound is in solution, 2) PEG added to the DMSO compound in step 1, then vortexed; 3) Saline or water added depending on the water depending on the formulation to make one of the three formulations.
[0213] [0213] The PEG / saline formulation was prepared as follows: 1) The STING agonist was dissolved in 100% PEG 400 or PEG-300 and then sonicated in a heated water bath for 30 minutes to ensure that the compound was completely in solution, 2) Saline solution added and continued sonicated in a heated water bath to ensure that the compound is uniform and mixed and remains in the solution to make one of the two formulations.
[0214] [0214] Compound 1 was evaluated in a knockout mouse model for genetic STING (KO) using a wild type (WT) animal as a control for off-target activity. STING KO and WT (Jackson Laboratories) animals were dosed with compound 1 at 2.5 mg / kg in PEG vehicle / saline (40% PEG-400 in normal saline) and then sacrificed after 3.5 h. Serum cytokines were analyzed using the PBLº and eBioscienceº Elisa and MSDºO mouse multiplex assay kits.
[0215] [0215] Compound 1 induced cytokine response only in WT mice with complete loss of IFN-B and induction of other cytokines in STING mice ”showing that compound 1 induces a specific cytokine response for STING. Compound 1 induced pro-inflammatory cytokines such as IL-6 and TNFa as well as a specific T cell response demonstrated by the increase in IFN-γ in WT but not in the STING KO mouse (Fig. 1).
[0216] [0216] Compound 1 causes significant inhibition of tumor growth in BALB / c mice containing CT-26 tumors after intravenous injection. The mice were grouped n = 10 per dose (100 µg, 30 µg or 10 µg of Compound 1) with a dosing regimen on days 0, 3 and 7. The tumors were measured twice a week and the mice were sacrificed when the tumor volume reached> 2000 mm or day 43, whichever comes first. Compound 1 induced a significant dose-dependent inhibition of CT-26 tumor growth at all doses tested for treatment groups compared to vehicle control (100 µg p <0.0001; 30 µg p <0.0001 ; 10 µg p = 0.0016). Treatment with 100 µg of compound 1 resulted in 9 complete tumor regressions. Treatment with ug resulted in 5 complete tumor regressions and substantial delay in tumor growth in the other 5 animals. There were no complete regressions with 10 ug of treatment, however, there was a significant delay in tumor growth vs. vehicle control (Figure 11).
[0217] [0217] The tumor volume from the regression studies above was used to generate the data analysis of the ED50 curves, using the area of tumor volume under the curve (AUC) for the duration of the surviving animal of all 10 mice per group and, in then, using the four parameters of the Graphpad software to generate the ED50 dose as illustrated in FIG. 6B.
[0218] [0218] Compound 1 is enriched in tumors after intravenous (IV) administration and generates significantly high levels of tumor cytokines compared to serum cytokines. Here, the key feature found by Compound 1 is that it generates high tumor cytokines that correlate with tumor efficacy while minimizing systemic cytokines typically associated with systemic cytokine release toxicities.
[0219] [0219] Seven-week-old female BALB / c mice (Charles River) were inoculated with TC-26 (ATCC: CRL-2638), the cells on the right rear flank. When the average tumor volume was -100 mm , Mice were randomized based on tumor volume in the study with randomization set to O-day. For pharmacokinetic / pharmacodynamic studies (pk / pd), animals received an IV bolus of injection of Compound 1 and were sacrificed on time and at the specified dose. Tumors and blood were collected for each cohort (N = 4) representing a single point in time (0.05, 0.25, 0.5, 1, 3, 6, 24, 48 and 72 hours after the dose) and a dose of 30 µg (see Figure 2). A cytokine panel was measured from blood and tumor tissue homogenate using MSDº-10 plex and PBLº-IFNB and eBioscienceº-IFNa ELISA assays (IL-1b, I1L-2, IL-6, IL-8, IL -10, I1L12, IFN-a, IFN-B, IFN-y and TNF-0) in the lysates and tumor sera of each animal for each cohort in the PK / PD experiment. The drug concentration of Compound 1 in the blood and tumor lysate of these PK / PD studies was analyzed by LC-MS / MS.
[0220] [0220] Compound 1 was rapidly distributed in the tumor with a long terminal half-life of about 25 hours in the tumor. The ratio of tumor AUC to blood was about 1. The blood and tumor concentration time profile is shown in (see FIG. 3).
[0221] [0221] Cytokine response over time (select cytokines IL-6, TNF-a, IFN-B and IFN-y described here) increased in both serum and tumors and peaked in approximately 3.5 hours in serum and tumor homogenates after IV administration of Compound 1 (see FIG. 4). A key aspect of the systemic activity of compound 1 is that there was a significantly higher level of cytokines observed in tumors compared to serum with the tumor / serum ratio equivalent to 135, 1607, 4000 and 2200 times for | L-6, TNF- a, IFN-y and IFN-E, respectively. Compound 1 demonstrates a key feature of a systemically delivered STING agonist that generates tumor cytokines, minimizing the release of systemic cytokines typically associated with systemic toxicity. Compound 1 achieved these characteristics in terms of tumor selectivity after IV administration with good PK / PD correlation.
[0222] [0222] Compound 1 blood and tumor concentrations and cytokine responses were measured in BALB / c mice with a single CT-26 tumor following the bolus IV dose escalation from 0.001 to 100 µg per mouse. Blood and tumors were collected at the peak cytokine response time of 3.5 hours after the dose and analyzed for the cytokine response and concentration of the drug. Average concentrations of Compound 1 in the blood and tumor are reported in Table 1. Despite the high variability in the measured tumor drug concentrations, there is an approximately 10-fold higher level of Compound 1 in tumors compared to blood after IV injection (see FIG. 5).
[0223] [0223] Table 1. Blood and tumor concentrations in mice bearing CT26 tumor following IV bolus dose escalation (n = 4, IV bolus dose composite (ug) | SD Concentration SD concentration and leaving So [will use 0.3 0.63 0.65 <LLQ N / A Fo Ee wo NS; no sample, <LLQ; below the limit of quantification, NA; not applicable
[0224] [0224] IFN-B concentrations increased in tumors with increasing dose of Compound 1 (FIG. 5 (B)). Similar to the high tumor-to-blood ratio of cytokines seen in the time-course study, the IFN-B response was significantly higher in tumors, compared to serum with an increasing amount of Compound 1. The dose-response of cytokines appears saturated for the highest IV doses studied (30 to 100 ug - 1.2 to 4 mg / kg) and is about 450 times higher in tumors, compared to serum (3.4 ug / g tumor versus 7 , 9 ngmL). The IV dose that generates a 50% maximum IFN-B (EDso) response was determined to be 11 pug / mouse or about 0.55 mg / kg (Figure 6A - PK / PD correlation with tumor regression) and correlate with EDso of dose titration efficacy of 17 µg / mouse determined from the tumor volume area under the curve (Fig. 6B). In general, the analysis of tumor cytokine and compound levels in the blood demonstrates an excellent correlation between EDso determined from efficacy IV and IFN-B extracted from the tumor.
[0225] [0225] Compound 1 demonstrated inhibition of tumor growth in different murine tumors (Figure 8) after IV administration. Each murine tumor model was progressed in a similar method by subcutaneous inoculation of specified tumor cells (CT-26 (colon), EMT-6 (breast), H22 (liver), Pan02 (pancreas), RM1 (prostate), B1I6BL6 and B16F10 (melanoma). Tumors were grown to 100 mm , followed by randomization and three repeated doses | V of 30 ug or 10 ug (depending on the murine tumor model) on days 1, 4 and 8. Body weight and Tumor volumes were measured for 30 days after the first IV dose or when the tumors reached 2,000 mm (Fig. 7).
[0226] [0226] As shown in Fig. 8, Compound 1 demonstrated inhibition of tumor growth in various tumor models by IV release with varying degrees of tumor volume efficacy.
[0227] [0227] Activation of STING with CD8 T cells induced by Compound 1 which led to long-term induced immunity. Compound 1 involved CD8 T cells in the CT-26 tumor regression study. A CD-8 neutralizing antibody was administered with Compound 1 in a CT-26 tumor model.
[0228] [0228] Female BALB / c mice aged six to eight weeks (Envigo) were inoculated subcutaneously with CT-26 cells on the right rear flank. When the average tumor volume was -100 mm , mice were randomized based on tumor volume in study groups with 10 mice per group. Compound 1 was dosed in groups of 30 µg and 10 µg / mouse. In a separate group, the mice were treated with an antibody that depletes CD8 to deplete CD8 T cells or an IgG control followed by three repeated doses of 30 ug of Compound 1.
[0229] [0229] On day 0, the mice were administered 300 µg of intraperitoneal (IP) dose of anti-CD8 antibodies in 100 µl saline vehicle. T-cell depletion doses were administered on days 1, 4 and 8, while Compound 1 was injected intravenously into the 40% PEG-400 formulation in saline.
[0230] [0230] There was a significant inhibition of tumor growth with a dose of 30 µg of Compound 1 compared to the control vehicle, as illustrated in (Fig. 10). Depletion of CD8 T cells prior to IV administration of 30 µg of Compound 1 of 30 µg / mouse abolished inhibition of tumor growth.
[0231] [0231] In the absence of CD8 T cells, the immune system has lost the function that mediates tumor growth inhibition, as indicated by diamond-shaped dots (Fig. 10) when compared to the intact system at shaped data points. of squares in control cohorts. In addition, Compound 1 lost its effectiveness in the absence of CD8-T cells, as indicated by the circle-shaped data points (including the CD-8 neutralizing antibody), compared to the intact system with Compound 1 treatment. in the inverted triangle graph. These results indicate that the compound 1 involved induces a tumor specific CD8 + T cell response. Thus, Compound 1 appears to induce adaptive immunity.
[0232] [0232] The effect of Compound 1 on tumor lymph nodes and draining immune cells in the TC-26 tumor model was tested using the dosing scheme used in tumor regression studies. Briefly, 200 to 250 mm of syngeneic tumors TC-26 were 7 weeks old, female BALB / c mice followed by IV injection of a dose of 30 pug / mouse, with Compound 1 or vehicle (40% PEG / saline). Eight mice treated with Compound 1 and the vehicle-treated mice were sacrificed 24 hours after the first IV dose (Day 1). A similar repeated dose cohort was generated on day 5, approximately 24 hours after a second dose. At both times, the tumoral and draining inguinal lymph nodes (dLN) were collected and analyzed by flow cytometry as an experimental scheme in FIG. 9
[0233] [0233] There was an increase in dendritic cells present in the tumor microenvironment and drainage of the lymph node after intravenous administration of Compound 1 (see FIG. 9). There was an increase in MHC-1 expression in NK, B and T cells in draining lymph nodes. These findings further support that Compound 1 activates STING in immune cells to inhibit tumor growth and induce long-term immunity by improving the presentation of antigens and the education of T cells.
[0234] [0234] An injectable form for administration of the present invention is produced by stirring 1.7% by weight of Compound 1 in 10% by volume of propylene glycol in water.
[0235] [0235] Although the preferred embodiments of the invention are illustrated by the above, it should be understood that the invention is not limited to the precise instructions disclosed herein and that the right to all modifications included in the scope of the following claims is reserved.

权利要求:
Claims (49)
[1]
1. Method of treating cancer in a human being, CHARACTERIZED by the fact that it comprises administering systemically an effective amount of a STING agonist to said human being, in which the STING agonist induces a higher concentration of at least one cytokine in one tumor microenvironment of said human being compared to the concentration of said cytokine in the blood, serum and / or plasma of said human being.
[2]
2. Method, according to claim 1, CHARACTERIZED by the fact that the cytokine is selected from IL-6, TNFa, IFNB and IFNy.
[3]
3. Method, according to claim 1 or claim 2, CHARACTERIZED by the fact that the target index (TI) is 3 or higher for said cytokine.
[4]
4. Method according to any one of claims 1 to 3, CHARACTERIZED by the fact that TI is 10 or greater for said cytokine.
[5]
5. Method according to any one of claims 1 to 4, CHARACTERIZED by the fact that the STING agonist increases the concentration of IL-6 by at least three times more in the tumor microenvironment in said human compared to the concentration of levels of IL-6 in the blood, serum and / or plasma of said human being.
[6]
6. Method according to any one of claims 1 to 4, CHARACTERIZED by the fact that the STING agonist increases the concentration of TNFa by at least three times more in the tumor microenvironment in said human compared to the concentration of TNFa levels in the blood, serum and / or plasma of said human being.
[7]
7. Method according to any one of claims 1 to 4, CHARACTERIZED by the fact that the STING agonist increases the concentration of IFNB at least three times more in the tumor microenvironment in said human compared to the concentration of levels of IFNB in the blood, serum and / or plasma of said human being.
[8]
8. Method according to any one of claims 1 to 4, CHARACTERIZED by the fact that the STING agonist increases the concentration of IFNy at least three times more in the tumor microenvironment in said human compared to the concentration of levels of IFNy in the blood, serum and / or plasma of said human being.
[9]
9. Methods according to any one of claims 1 to 8, CHARACTERIZED by the fact that the STING agonist has an IC 50 less than about 10 µM.
[10]
10. Methods according to any of claims 1 to 8, CHARACTERIZED by the fact that the STING agonist has an IC 50 less than about 1 UM.
[11]
11. Methods according to any one of claims 1 to 8, CHARACTERIZED by the fact that the STING agonist has an IC 50 less than about 0.1 UM.
[12]
12. Methods according to any one of claims 1 to 8, CHARACTERIZED by the fact that the STING agonist provides an AUC (0-24) of about 850 to 1,060 ng.h / ml when administered systemically to said human being .
[13]
13. Method according to any one of claims 1 to 8, CHARACTERIZED by the fact that the STING agonist provides an average Cmax of about 1,900 to 3,800 ng / ml of said STING agonist when administered to said human being.
[14]
14. Method according to any one of claims 1 to 8, CHARACTERIZED by the fact that the STING agonist has a significantly higher Cmax concentration in the tumor microenvironment of said human being compared to the blood, serum and / or plasma of the said to be human.
[15]
15. Method according to any one of claims 1 to 14, CHARACTERIZED by the fact that the half-life of said STING agonist is significantly longer in the tumor microenvironment of said human being compared to blood, serum and / or plasma of said human being.
[16]
16. Method according to any one of claims 1 to 15, CHARACTERIZED by the fact that the STING agonist is administered intravenously.
[17]
17. Method according to any one of claims 1 to 16, CHARACTERIZED by the fact that the STING agonist is a compound according to Formula (I-N): Rº N Re The SN of É> N AA | X Rai R & O Rs
RE peace RB2 | Cc2 REL D St À | Z À ms Rê O R7 Rº (I-N) where: géboul; rébdoul; seboul; where q + r + s = 10u2;
when q is O, Rº 'and RM are each independently H, halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR "!), -N (RºNR)), -CO2R, -N (RÍCOR, - N (R9) SO2 (C1-Ca alkyl) -N (Rº) (R), -N (R9) CO (C1-Ca alkyl) -N (Rº) (R), (C1-Cs6 alkyl) optionally substituted, ( C1-Ce6 alkyl) Optionally substituted oxide, (optionally substituted C1- alkyl) and (optionally substituted C1i-Cs alkyl) (C1-C6 alkyl) amino,
wherein the (optionally substituted C1-Cs alkyl) said (C1-Cs alkyl), (optionally C1-Ce alkyl) Oxy-optionally substituted, (optionally C1-Cs alkyl)> amino- and (C1-Cs alkyl) ( optionally substituted amino-C1-Ca) alkyl is optionally substituted by 1 to 4 substituents, each independently selected from the hydroxy group, -OP (O) (OH) 2, -OP (O) (RIR! ') 2, alkoxy C1-Ca-, -N (Rº) (R), -COR '), -CON (Rº) R), optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl, where said optionally substituted phenyl, 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -O- P (O) (OH) 2, -OP (O) (RIR!) 2, amino, (C1-Cs alkyl) amino-, (C1-Cs alkyl) (C1-Cs alkyl) amino-, - (C1-C6 alkyl) -NH> 2, halo (C1-Cs alkyl), hydroxy- (C1-Ca4 alkyl) -, - (C1-C4 alkyl) -O- P (O) (OH) 2, - (C1-C4 alkyl) -OP (O) (RIR! ") 2, halo (C1-C4 alkoxy) -, C1-Ca- alkoxy, hydroxy- (C2-Ca alkoxy) ) -, - (C2-Ca alkoxy) -OP (O) (OH) 2, - (C2-Ca alkoxy) -OP (O) (RIR!) 2, - C1-Ca- alkyl (C1-C4 alkoxy) and C1-Ca alkoxy (C1-Ca alkoxy) -;
when r is O, RE and R8 are each independently H, optionally substituted C1-C6 alkyl, halo (C1-Cs alkyl), optionally substituted C2-Cs alkenyl, — optionally substituted C2-Cs alkynyl, optionally substituted C3-Ce cycloalkyl, 4 to 6 heterocycloalkyl optionally substituted members, optionally substituted phenyl, optionally substituted 5 to 6 membered heteroaria or optionally substituted 9 to 10 membered heteroaryl,
wherein said optionally substituted C1-Cs alkyl, optionally substituted C2-Cs alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-Cs cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted, heteroary from 5 to 6 optionally substituted members or 9 to 10 optionally substituted heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, nitro, -Rº, -OH, -OP (O) (OH) 2, -O- P (OXRIR ") 2, -ORº, -NH2, -NRºRº, -NRºR9, -NORºR9, -OCOR" º, -CO2H, -CO2Rº, -SORº, -SO2Rº, - CONH> 2, -CONRºRº, -SO2NH2, -SO2NRºR $ , -OCONH2, -OCONRºR $, -NRICOR "º, - NRISORº, -NRICO2Rº and -NRÍSO2Rº;
when s is O, Rº is H, halogen, or C1-Ca alkyl and Rº is optionally substituted C1-Ca alkyl, wherein said optionally substituted C1-C4a alkyl group is optionally substituted by a substituent selected from -ORº, - NRºRº, -CO2Rº, -CONRºRº , -SO2NRºRº and -OCONRºR $;
when q is 1, Rºº and Rºº are each independently -CH> 2, -NRº- or - O- and A, taken together with Rº! and Rº , form a linking group, where A is halo (C1-C12 alkyl) -, optionally substituted C1-C12- alkyl, optionally substituted C2-C12- alkenyl, optionally substituted C2-C12- alkynyl, C1- alkyl Ce- C1-Cs-alkyl- optionally substituted, C1-Ce-NRºalkyl C1-Ce- alkyl optionally - substituted, C1- Ce alkyl (cycloalkyl “Ca-Cs)” —C1-Ce- alkyl optionally - substituted, Ci-Ces alkyl -C1-Cs- phenylalkyl optionally substituted, C1 alkyl: -Ce- (4 to 6 membered heterocycloalkyl) optionally substituted C1-Ce- alkyl or C1-Ce- alkyl (5 to 6 membered heteroaryl) -C1- Cs- alkyl optionally replaced,
wherein the alkyl portion of said optionally substituted C1-C12- alkyl, optionally substituted C2-C12- alkenyl, optionally substituted C2-C12- alkynyl, optionally substituted C1-Ces-Oalkyl-C1-C6- alkyl, C1-Ce-NR-alkyl optionally substituted C1-C6-alkyl, optionally substituted C1-Cs- (C1-cycloalkyl) alkyl, optionally substituted C1-Cs-phenyl-C1-C6- alkyl, optionally substituted C-Ces- (4-heterocycloalkyl) optionally substituted C1-Ce- alkyl or optionally substituted C1-Ce- alkyl (5- to 6-membered heteroaryl) -C1- Ce- optionally substituted alkyl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, halo (C1-C4 alkyl), -OH, -O- P (O) (OH) 2, -OP (O) (RIRu) 2, -ORº, -NH2, -NRºR9%, -OCORº, -CO2H, - CO2Rº, -SORº, - SO2Rº, -CONH2, -CONRºRº, -SO2NH2, -SO2NRºRi, -OCONH2, -OCONRºRº, - NRºCORº, -NRºSORº, -NRICO2Rº and -NRÍSO2Rº, and the heterocyclic chain, 4 to 6 members os or 5- to 6-membered heteroaryl of said C1-Ce- (C3-Ce cycloalkyl) optionally substituted C1-Ce- alkyl, —C1-Cs-phenylalkyl C1i-Cs- “optionally substituted, C1-Ce- (4- to 6-membered heterocycloalkyl) optionally substituted C1-Ce- alkyl or optionally substituted C1-Ce- alkyl (5 to 6-membered heteroaryl) -C1-Csalkyl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -O- P (OXRIR! ") 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca4 alkyl, halo (C1-C4 alkyl), halo (C1-Ca4 alkoxy) -, C1-Ca4- alkoxy, hydroxy- (C1-Ca alkoxy) -, - (C1-Ca4 alkoxy) -OP (O) (OH) 2, - (C1-Ca alkoxy) -OP (O) (RR!) 2 and C1-Ca- alkoxy (C1-C4 alkoxy) -;
when r is 1, R8 & º and R8 are each independently -CH2 and B taken together with R8 ' and R8 ', form a linking group, where B is a bond or B is halo (C1-C10 alkyl) -, optionally substituted C1-C10- alkyl, optionally substituted C2-C10- alkenyl, C2-C10- alkynyl substituted, optionally substituted C1-Ce-O-C1-Cs alkyl, optionally substituted C1-Cs-NRº C1-Ce- alkyl, optionally substituted C3-Cs cycloalkyl, optionally substituted phenyl, 4- to 6-membered heterocycloalkyl, optionally substituted heteroaryl 5- to 6-membered optionally substituted, optionally substituted C1-Ca- (C3-Cs-cycloalkyl) alkyl, optionally substituted C1-Ca-phenyl-C1-C4- alkyl, optionally substituted C-Ca- (4 to heterocycloalkyl) 6 members) optionally substituted C1-C4-alkyl or optionally substituted C1-Ca- (5- to 6-membered heteroaryl) -C1-C4-alkyl,
wherein the alkyl portion of said optionally substituted C1-C10-alkyl, optionally substituted C2-C10- alkenyl, optionally substituted C2-C10-alkynyl, optionally substituted C1-Ce-O-C6-alkyl-alkyl, C1-Ce-NR-alkyl optionally substituted C1-C6 alkyl, C1-Ca- alkyl (C3-Ce cycloalkyl) optionally substituted C1-C4 alkyl, optionally substituted C1-Ca-phenylalkylC1-Ca4-alkyl, 4-heteroalkyl alkyl 6-membered) optionally substituted C1-Ca- alkyl or C1-Ca- alkyl (5- to 6-membered heteroaryl-C1-C4 alkyl) - optionally substituted is optionally substituted by 1 or 2 substituents, each independently selected from halogen, halo (C1-C4 alkyl), -OH, -O- P (O) (OH) 2, -OP (O) (RIR!) 2a, -ORº, -NH2, -NRºRº, -OCORº, -CO2H, - CO2Rº, -SORº, - SO2Rº, -CONH2, -CONRºRº, -SO2NH2, -SO2NRºRi, -OCONH2, -OCONRºR $ º, - NRºCORº, -NR $ SORº, -NRÍCO2Rº and -NR $ SO2Rº, and the cycle3- Cs, phenyl, heterocycloalkyl of 4 to 6 memb or 5- to 6-membered heteroaryl of said optionally substituted C3-C6s cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5 to 6-membered heteroaryl, C1-Ca- (C3-Cs cycloalkyl) alkyl optionally substituted C1-C4 alkyl, optionally substituted C1-Ca-phenylalkyl C1-C4-alkyl, 4- to 6-membered heterocycloalkyl) optionally substituted C1-C4-alkyl or C1-Ca- (heteroaryl) alkyl 5 to 6 members) -C1-C4 alkyl- optionally substituted is optionally substituted by 1 to 4 substituents, each independently selected from halogen,
hydroxy, -OP (O) (OH) 2, -OP (O) (RIR! ') a, amino, (C1-Ca alkyl) amino-, (C1- Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-C4 alkyl), halo (C1-Ca4 alkoxy) -, C1-C4- alkoxy, hydroxy- (C2-Ca alkoxy) -, - (C2-Ca alkoxy) OP (O) ( OH) 2, - (C2-Ca alkoxy) -O- P (O) (RIR!) 2 and C1-Ca- (C1-C4 alkoxy) -;
when s is 1, Rºº and Rº are each independently -CH2 and C, taken together with Rº * and Rº , form a linking group, where C is halo (C1-C12 alkyl) -, optionally substituted C1-C12- alkyl, C2- alkenyl Optionally substituted C1-2, optionally substituted C2-C12-alkynyl, optionally substituted C1-Ce6-Oalkyl-C1-Ce- alkyl, optionally substituted C1-Ce-NRº C1-Ce- alkyl, C1-Ce- alkyl (C3-Ce cycloalkyl) optionally substituted C1-C6 alkyl, optionally substituted C1-Cse-phenylalkyl C1-C- alkyl (4- to 6-membered heterocycloalkyl) optionally substituted C1-Cs-alkyl or C1-Ce- (heteroaryl) alkyl to 6 members) -C1-C6 alkyl- optionally substituted,
wherein the alkyl portion of said optionally substituted C1-C12- alkyl, optionally substituted C2-C12- alkenyl, optionally substituted C2-C12- alkynyl, optionally substituted C1-Ces-Oalkyl C1-Ce6- alkyl, C1-Ce-NRºalkyl C1-C6- optionally substituted, C1-Ce- alkyl (C3-Cs cycloalkyl) optionally substituted C1-C6- alkyl, optionally substituted C1-Cs-phenylalkyl C1-C6- alkyl, C1-Ces- alkyl (4 to 6 heterocycloalkyl members) optionally substituted C1-Ce- alkyl or C1-Ce- (5- to 6-membered heteroaryl) alkyl-optionally substituted C1-Calkyl is optionally substituted by 1 or 2 substituents, each independently selected from halogen, halo ( alkyl C1-C4), -OH, -O- P (O) (OH) 2, -OP (O) (RIR!) 2, -ORº, -NH2, -NRºRº, -OCORº, -CO2H, -CO2Rº, -SORº, - SO2Rº, -CONH2, -CONRºRº, -SO2NH2, -SO2NRºRi, -OCONH2, -OCONRºRº, - NRºCORº, -NRºSORº, -NRICO2Rº and -NRÍSO2Rº, and the C3-heterocyclyl alkylate; 6 mem 5 to 6-membered heteroaryl of said C1-Ce- alkyl (C3-Ce cycloalkyl) C1-Ce- alkyl
optionally - substituted, C 1 -Cs-phenylalkyl C 1 -C 6 alkyl- "optionally substituted, C 1 -C 6 alkyl- (4 to 6 membered heterocycloalkyl) C 1 -C 6 alkyl- optionally substituted or C 1 -C 6- alkyl (5 to 6 heteroaryl) members) -C1-Calkyl- optionally substituted is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -O- P (OX (RIR! ") 2, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-C4 alkyl), halo (C1-Ca alkoxy) -, C1-Ca- alkoxy, hydroxy- (Ca-Ca alkoxy) -, - (C2-Ca alkoxy) -OP (O) (OH) 2, - (Ca-Ca alkoxy) -OP (O) (RIR!) 2 and C1-Ca- alkoxy (C1- Ca alkoxy) -;
R3 and Rº are each independently -CON (Rº) (R ”), or one of R $ and R $ is -CON (Rº) (R), and the other of R and Rº is H, COOH or -CO2 (Rº);
Rº and R $ are each independently selected from H, halogen, halo (C1-Cs alkyl), halo (C1-Cs6 alkoxy) -, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR!) 2, -NH>, - NRºRº, -NRºR $, -CORº, -CO2Rº, -N (R9) CORº, -N (RI) SO2Rº, -N (R9) SO> (C1-C2 alkyl) - N (RP (R)), -N (R9) CO (C1-C2 alkyl) -N (RP) (R '), (optionally substituted C1-C6 alkyl), (optionally substituted C1-C6s alkyl) , (optionally substituted C1-Cs alkyl) and (optionally substituted C1-Ces alkyl) (C1-Ca alkyl)> amino,
wherein the (optionally substituted C1-Cs alkyl) said (C1-Cs alkyl), (optionally C1-Ce alkyl) Oxy-optionally substituted, (optionally C1-Cs alkyl)> amino- and (C1-Cs alkyl) ( optionally substituted C1-Ca) alkyl is optionally substituted by 1 to 4 substituents, each independently selected from -OH, -OP (O) (OH) 2, -OP (O) (RIR!) 2, -ORº , -NH2, -NRºRº, -NRºR $, - CO2H, -CO2Rº, -OCORº, -CO2H, -CO2RºY, -SORº, -SO2Rº, -CONH2, -CONRºR $ º, - SO2NH2, -SO2NRºRº, -OCONH> 2 , -OCONRºR $ 9, -NRÍCORº, -NRIÍSORº, -NRICO2Rº, - NR9SO> 2Rº, optionally substituted phenyl, optionally substituted 5- to 6-membered heterocycloalkyl and optionally substituted 5- to 6-membered heteroaryl, in which the said optionally substituted phenyl 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -O- P (O) (OH) 2, -OP (O) ( RIR! ') 2, amino, (C1 alkyl) -Ca) amino-, (C1-Ca alkyl) (C1- Ca alkyl) amino-, C1-Ca4 alkyl, halo (C1-C4 alkyl), hydroxy- (C1-Ca4 alkyl) -, - (C1-Ca alkyl ) - OP (O) (OH) 2, - (C1-Ca alkyl) -OP (O) (RR!) 2, halo (C1-Ca alkoxy) -, C1-Ca- alkoxy, hydroxy- (C2- alkoxy) Ca) -, - (C2-Ca alkoxy) -OP (O) (OH) 2, - (C2-Ca alkoxy) -OP (O) (RIR !!) 2, C1-Ca4- alkoxy (C1-Ca alkoxy) ) -, -CORº, -CON (RI) (R ') and -CO2R $ *;
R * º is optionally substituted C1-C4a alkyl, wherein said optionally substituted C1-Ca alkyl is optionally substituted by a substituent selected from -ORº, -NRºR $, -CO2Rº, -CONRºRº, -SO2NRºRº and -OCONR-ºR $ º;
R'6 is H, halogen or C1-Ca alkyl;
R'º and R'7 are each independently H, cyclopropyl or C1-Ca alkyl;
Rº is H, -Rº, -CORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºR $ º, - SO2NH> 2 or -SO2NRºR $ i;
each Rº is independently C1-Ca alkyl, halo (C1-C4 alkyl), - (C1- Ca4 alkyl) -OH, - (C1-C4 alkyl) -OP (O) (OH) 2, - (C1-C4 alkyl ) -OP (O) (RIR! ') 2, - (C1-Ca alkyl) - O- (C1-C4 alkyl), (C1-Ca alkyl) -N (Rº) (R), (C1-C4 alkyl ) -O-CO (C1-C4 alkyl) or (C1-C4 alkyl) -CO-O- (C1-C4 alkyl);
each Rº is independently C1-Ca alkyl, halo (C1-C4 alkyl), - (C1- Ca alkyl) -OH, - (C1-Ca alkyl) -OP (O) (OH) 2, - (C1-Ca4 alkyl ) -OP (O) (R'R !!) 2, - (C1-Ca alkyl) - O- (C1-Ca alkyl), (C1-Ca alkyl) -N (RºNR '), (C1-Ca alkyl) ) -O-CO (C1-Ca4 alkyl), (C1-Ca4 alkyl) -CO-O- (C1-C4 alkyl), optionally substituted C3-C6s cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5 to 6-membered heteroaryl, optionally substituted 9 to 10-membered heteroaryl, optionally substituted C-Ca-cycloalkyl C3-Ce alkyl, optionally substituted C1-Ca alkyl-phenyl, alkyl-
optionally substituted 4 to 6 membered C1-C4a heterocycloalkyl, optionally substituted 5 to 6 membered C1-C4 alkylheteroaryl or optionally substituted 9 to 10 membered C1-Ca4 alkylheteroaryl,
wherein the C3-Ce cycloalkyl moiety, phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl optionally substituted from said substituted C3-Cs cycloalkyl, optionally substituted phenyl, 4 to 6 heterocycloalkyl optionally substituted members, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 9 to 10-membered heteroaryl, optionally substituted C1-Ca-cycloalkyl C3-C4 alkyl, optionally substituted C1-C4 alkylphenyl, C1- C4-alkyl heteroaryl Optionally substituted 4 to 6 members, optionally substituted 5 to 6 membered C1-C4-alkyl heteroaryl or optionally substituted 9 to 10 membered C1-C4 alkyl heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -O- P (O) (R'R! ') 2, amino, - (C1-Ca alkyl) NH;>, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, -C1-Ca4 alkyl, hal o (C1-C4 alkyl), halo (C1-Ca alkoxy) -, C1-Ca- alkoxy, hydroxy- (C2-Ca alkoxy) -, - (Ca-C4 alkoxy) -OP (O) (OH) 2, - (C2-Ca alkoxy) -OP (O) (RIR!) 2, C1-Ca- (C1-C4 alkoxy) -, -CORI, -CON (Rº) (R) and -CO2Rº;
each Rº is independently H or C1-Ca alkyl;
each Rº is independently H, C1-C4 alkyl, -CO (C1-Ca4 alkyl), - OCO (C1-C4 alkyl), -COz (C1-C4 alkyl), - (C1-Ca alkyl) NH>, - ( C1-Ca alkyl) C1-Ca alkoxy, -CO- (optionally substituted 5-6 membered heterocycloalkyl), - CO (optionally substituted 5-6 membered heterocycloalkyl), - CO (5-membered heteroaryl) optionally substituted 6-membered), -CO (C1-C4 alkyl) - (optionally substituted 5-6 membered heteroaryl),
wherein the optionally substituted 5- to 6-membered heterocycloalkyl or optionally substituted 5- to 6-membered heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, - OP (O) (RIR! ') A, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-C4 alkyl), halo (C1-C4 alkoxy) -, C1-C4- alkoxy, hydroxy- (Ca-Ca alkoxy) -, - (Ca-Ca alkoxy) OP (O) (OH) 2, - (C2-Ca alkoxy) -O - P (O) (RIR!) 2, C1-Ca- (C1-Ca alkoxy) -, -CORI, -CON (RI) (R /) and -CO2R; each R 'is independently H or C1-Ca alkyl; Rº and R "are each independently H or C1-Ca alkyl or Rº and Rº, taken together with the atom or atoms through which they are connected, form a 5- to 6-membered ring; and each occurrence of R ' and R1 are independently (C1-Ce alkyl) oxide, or a pharmaceutically acceptable salt thereof.
[18]
18. Method according to any one of claims 1 to 17, CHARACTERIZED by the fact that the STING agonist or a pharmaceutically acceptable salt thereof, has the structure of Formula (|) Ro 14
WN R Red XY No É> N | | X Ro Re O RE Re! dae É do A N 1 É sl RA DN No É> N |
X RE or R7 Re (1) where:
géboul;
réboul;
seboul;
where q + r + s = 10u2;
when q is O, Rº 'and RM are each independently H, halogen, hydroxy, -N (RºN (R), -CO2R, -N (R) COR, -N (R9) SOz (C1-Ca alkyl) -N (RºI (R), - N (Rº) CO (C1-Ca alkyl) -N (Rº) (R5), (C1-C6 alkyl) optionally substituted, (C1-Ces alkyl) ÓXi- - optionally - substituted, (C1-Ce alkyl) amino - optionally substituted and optionally substituted (C1-Ce alkyl) (C1-Ca alkyl) amino-,
wherein the (optionally substituted C1-Cs alkyl) said (C1-Cs alkyl), optionally substituted (C1-Ce alkyl) oxide, (optionally C1-Ce alkyl)> optionally substituted amino and (C1-Cs alkyl) ( optionally substituted C1-Ca) alkyl is optionally substituted by 1 to 4 substituents, each independently selected from the hydroxy group, C1-Ca-, -N (Rº) (R5), -COXR '), -CON ( RI (R '), optionally substituted phenyl, optionally substituted 5 to 6 membered heterocycloalkyl and optionally substituted 5 to 6 membered heteroaryl, wherein said optionally substituted phenyl, 5 to 6 membered heterocycloalkyl or 5 to 6 membered heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, amino, (C1-Ce alkyl) amino-, (C1-Ce alkyl) (C1-Ces alkyl) amino-, halo (C1-Cs alkyl) ), hydroxy- (C1-Ca alkyl) -, halo (C1-C4 alkoxy) -, C1-Ca- alkoxy, hydroxy- (Ca-Ca alkoxy) - and C1-Ca- (C1-C4 alkoxy) -
when r is O, RE and R8 are each independently H, optionally substituted C1-C6 alkyl, halo (C1-Cs alkyl), optionally substituted C2-Cs alkenyl, — optionally substituted C2-Cs alkynyl, optionally substituted C3-Ce cycloalkyl, 4 to 6 heterocycloalkyl optionally substituted members, optionally substituted phenyl, optionally substituted 5 to 6 membered heteroaria or optionally substituted 9 to 10 membered heteroaryl,
wherein said optionally substituted C1-Cs alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-Cs cycloalkyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted, 5 to 6 heteroaryl optionally substituted members or 9 to 10 optionally substituted heteroaryl members is optionally substituted by 1 to 4 substituents, each independently selected from halogen, nitro, -Rº, -OH, -ORº, -NH2, -NRºRº, - NRºRº, - OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºR $ º, -SO2NH;>, - SO2NRºR $, -OCONH> 2, -OCONRºR $ º, -NRICORº, -NRISORº, -NRÍCO2Rº e -NRISO2Rº;
when s is O, Rº is H, halogen, or C1-Ca alkyl and Rº is optionally substituted C1-Ca alkyl, wherein said optionally substituted C1-C4a alkyl group is optionally substituted by a substituent selected from -ORº, - NRºRº, -CO2Rº, -CONRºRº , -SO2NRºRº and -OCONRºR $;
when q is 1, Rº and Rºº are each independently -CH> 2, -NRº- or - O- and A, taken together with Rº! and Rº , form a linking group, where A is halo (C1-C12 alkyl) -, optionally substituted C1-C12- alkyl, optionally substituted C2-C12- alkenyl, optionally substituted C2-C12- alkynyl, C1- alkyl Ce- C1-Cs- alkyl optionally substituted, C1-Ce-NRºalkyl C1-Ce- alkyl optionally - substituted, C1- Ce alkyl (cycloalkyl - “Ca-Ces) alkyl —C1-Ce- optionally - substituted, C1- alkyl Ces-phenylalkyl C1-Cs- optionally substituted, C1 alkyl: -Ce- (4 to 6 membered heterocycloalkyl) optionally substituted C1-Ce- alkyl or C1-Ce- alkyl (5 to 6 membered heteroaryl) -C1- Csalkyl - optionally replaced,
wherein the alkyl portion of said optionally substituted C1-C12- alkyl, optionally substituted C2-C12- alkenyl, optionally substituted C2-C12- alkynyl, optionally substituted C1-Ces-Oalkyl-C1-C6- alkyl, C1-Ce-NR-alkyl optionally substituted C1-C6-alkyl, optionally substituted C1-Cs- (C1-cycloalkyl) alkyl, optionally substituted C1-Cs-phenyl-C1-C6- alkyl, optionally substituted C-Ces- (4-heterocycloalkyl) optionally substituted C1-Ce- alkyl or optionally substituted C1-Ce- alkyl (5- to 6-membered heteroaryl) -C1- Ce- optionally substituted alkyl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, halo (C1-C4 alkyl), -OH, - ORº, -NH2, -NRºR $, -OCORº, -CO> 2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, - SO2NH2, -SO2NRºRº, -OCONH2, -OCONRºR $ º, -NRICORº, -NRISORº, -NRÍCO2Rº and - NRISO> 2Rº, and the C3-Cs cycloalkyl portion, phenyl, 4 to 6 membered heterocycloalkyl or 5 to 6 m heteroaryl members of said C1-Ce- alkyl (C3-Ce cycloalkyl) optionally substituted C1-Ce- alkyl, —C1-Cs-phenylalkyl C1i-Cs- “optionally substituted, C1-Ce- alkyl (4- to 6-membered heterocycloalkyl ) optionally substituted C1-Ce- alkyl or C1-Ce- (5- to 6-membered heteroaryl) alkyl-optionally substituted C1-Calkyl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, amino , (C1- Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-C4 alkyl), halo (C1-C4 alkoxy) -, C1- alkoxy Ca-, hydroxy- (C2-Ca4 alkoxy) - and C1-Ca- alkoxy (C1-Ca alkoxy) -
when r is 1, RE and R8 are each independently -CH2 and B taken together with R8 ' and R8 ', form a linking group, where B is a bond or B is halo (C1-C10 alkyl) -, optionally substituted C1-C10- alkyl, optionally substituted C2-C10- alkenyl, C2-C10- alkynyl substituted, optionally substituted C1-Ce-O-C1-Cs alkyl, optionally substituted C1-Cs-NRº C1-Ce- alkyl, optionally substituted C3-Cs cycloalkyl, optionally substituted phenyl, 4- to 6-membered heterocycloalkyl, optionally substituted heteroaryl 5- to 6-membered optionally substituted, optionally substituted C1-Ca- (C3-Cs cycloalkyl) alkyl, optionally substituted C1-Ca-phenylalkyl C1-C4- alkyl, optionally substituted C1-Ca- alkyl (4 to heterocycloalkyl 6 members) optionally substituted C1-C4-alkyl or optionally substituted C1-Ca- (5- to 6-membered heteroaryl) -C1-C4-alkyl,
wherein the alkyl portion of said optionally substituted C1-C10-alkyl, optionally substituted C2-C10-alkenyl, optionally substituted C2-C10-alkynyl, optionally substituted C1-Ce-O-C6-alkyl-alkyl, C1-Ce-NRº alkyl optionally substituted C1-C6-alkyl, optionally substituted C1-Ca- (C3-Ces cycloalkyl) alkyl, optionally substituted C1-Ca-phenylalkyl C1-Ca4- alkyl, optionally substituted C1-Ca- alkyl (4-heterocycloalkyl optionally substituted C1-Ca- alkyl or C1-Ca- alkyl (5- to 6-membered C1- Ca4 alkyl heteroaryl) - optionally substituted is optionally substituted by 1 or 2 substituents, each independently selected from halogen, halo (C1-C4 alkyl), -OH, - ORº, -NH2, -NRºRº, -OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºR $, - SO2NH2, -SO2NRºR $ º, -OCONH2, -OCONRºRº, -NRCORº, -NRISORº, -NRÍCO2Rº and - NRºSO> 2Rº, and the C3-Cs cycloalkyl portion, phenyl, 4 to 6 membered heterocycloalkyl or 5 to 6 heteroaryl members of said optionally substituted C3-Cs cycloalkyl, optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted C1-Ca- (C3-Cs-cycloalkyl) C1-C4- alkyl , optionally substituted C1-Ca-phenylalkyl-C4-alkyl, C1-Ca- alkyl (4- to 6-membered heterocycloalkyl) optionally substituted C1-C4- alkyl or C1-Ca- alkyl (5- to 6-membered heteroaryl) -alkyl Optionally substituted C1-C4- is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino- , C1- alkyl
Ca, halo (C1-C4 alkyl), halo (C1-Ca alkoxy) -, C1-Ca4- alkoxy, hydroxy- (C2-Ca alkoxy) - and C1-Ca- (C1-C4 alkoxy) - alkoxy;
when s is 1, Rºº and Rº are each independently -CH2 and C, taken together with Rº * and Rº , form a linking group, where C is halo (C1-C12 alkyl) -, optionally substituted C1-C1i2- alkyl, C2- alkenyl C1-optionally substituted, C2-C12- optionally substituted alkynyl, C1-Ce6-O1 alkyl C1-Ce- optionally substituted, C1-Ce-NRº C1-C6- alkyl optionally substituted, C1-Ce- alkyl (C3-Ce cycloalkyl) optionally substituted C1-Cs-alkyl, optionally substituted C1-Cs-phenylalkyl C1-Cs-alkyl, 4- to 6-membered heterocycloalkyl) optionally substituted C1-Cs-alkyl or C1-Ce- (heteroaryl-alkyl) to 6 members) -C1-C6 alkyl- optionally substituted,
wherein the alkyl portion of said optionally substituted C1-C12- alkyl, optionally substituted C2-C12- alkenyl, optionally substituted C2-C12-alkynyl, optionally substituted C1-C6-O-C6-alkylalkyl, optionally substituted C1-Cs-alkyl -NRº C1-Ce- alkyl, C1-Ce- alkyl (C3a-Cs cycloalkyl) optionally substituted C1-C6- alkyl, optionally substituted C1-Cs-phenylalkyl C1-Ce6- alkyl, C-Cs- alkyl (4 to 6 heterocycloalkyl) members) optionally substituted C1-Ce- alkyl or C1-Ces- (5- to 6-membered heteroaryl) alkyl-optionally substituted C1-Calkyl is optionally substituted by 1 or 2 substituents, each independently selected from halogen, halo ( alkyl C1-C4), -OH, - ORº, -NH2, -NRºR $, -OCORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºRº, - SO2NH2, -SO2NRºRº, -OCONH> 2 , -OCONRºRº, -NRICORº, -NRISORº, -NRÍCO2Rº and - NRºSO> 2Rº, and the C3-Cs cycloalkyl portion, phenyl, 4 to 6 membered heterocycloalkyl or 5 to 6 m heteroaryl members of said C1-Ce- alkyl (C3-Cs cycloalkyl) optionally substituted C1-Ce- alkyl, C1-Cs-phenylalkyl C1-Cs- optionally substituted, C1 alkyl: -Ce- (4 to 6 membered heterocycloalkyl) C1-Ce- alkyl
optionally substituted or C1-Ce- alkyl (5- to 6-membered heteroaryl) -C1-6 alkyl- optionally substituted is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, amino, (C1- Ca alkyl) ) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, halo (C1-C4 alkyl), halo (C1-C4 alkoxy) -, C1-Ca- alkoxy, hydroxy- ( (Ca-Ca alkoxy) - and C1-Ca- (C1-C4 alkoxy) alkoxy -
R3 and Rº are each independently -CON (Rº) (R ”), or one of R $ and R $ is -CON (Rº) (R), and the other of R and Rº is H or -CO2 (Rº);
Rº and R $ are each independently selected from H, halogen, halo (C1-Cs alkyl), halo (C1-C6 alkoxy) -, hydroxy, -NH2, -NRºRº, -NRºR9, -NRºR9, -CORº, -CO2Rº, -N (R9) CORº, -N (Rº) SO2Rº, -N (R9) SOz (C1-C2 alkyl) -N (R ") (Rº), -N (Re) CO (C1- C2 alkyl) -N (RP) (R '), (optionally substituted C1-Cs alkyl), optionally substituted (C1-Ces alkyl) oxide, optionally substituted (C1-Cs alkyl) amino (C1-Ce alkyl) (C1-Ca alkyl) optionally substituted amino-,
wherein the (optionally substituted C1-Cs alkyl) said (C1-Cs alkyl), optionally substituted (C1-Ce6 alkyl), optionally substituted (C1-Ce alkyl)> amino-optionally and (C1-Cs alkyl) ( optionally substituted C1-Ca) alkyl is optionally substituted by 1 to 4 substituents, each independently selected from the group -OH, -ORº, -NH2, -NRºRº, -NRºR9 $, -CO2H, -CO2Rº, -OCORº, - CO2H, -CO2R, -SORº, -SO2Rº, -CONH2, -CONRºRº, -SO2NH2, -SO2NRºR $, - OCONH2, -OCONRºRi, -NRºCORº, -NRISORº, -NRͺCO2Rº% -NRÍSO2R optionally substituted 6-membered and optionally substituted 5- to 6-membered heteroaryl, wherein said optionally substituted phenyl, 5- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected halogen, hydroxy, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca alkyl, ha lo (C1-Ca4 alkyl), hydroxy- (alkyl
C1-C4) -, halo (C1-C4 alkoxy) -, C1-Ca- alkoxy, hydroxy- (C2-Ca alkoxy) -, C1-Ca- (C1-C4 alkoxy) alkoxy -, -CORI, -CON ( R) (R ') and -CO2Rº;
R * º * is optionally substituted C1-C4 alkyl, wherein said optionally substituted C1-Ca alkyl is optionally substituted by a substituent selected from -ORº, -NRºR $, -CO2Rº, -CONRºRº, -SO2NRºRº and -OCONR-ºR $;
R'6 is H, halogen or C1-Ca alkyl;
R '* and R'7 are each independently H, cyclopropyl or C1-Ca alkyl;
Rº is H, -Rº, -CORº, -CO2H, -CO2Rº, -SORº, -SO2Rº, -CONH2, -CONRºR $, - SO2NH2 or -SO2NRºR $;
each Rº is independently C1-Ca alkyl, halo (C1-Ca alkyl), - (C1-Ca alkyl) -OH, - (C1-Ca alkyl) -O- (C1-Ca alkyl), (C1-Ca alkyl) -N (Rº) (R5), (C1-Ca alkyl) -O-CO (C1-C4 alkyl) or (C1-Ca alkyl) -CO-O- (C1-C4 alkyl);
each Rº is independently C1-Ca alkyl, halo (C1-C4 alkyl), - (C1- C4 alkyl) -OH, - (C1-Ca alkyl) -O- (C1-Ca alkyl), (C1-Ca alkyl) -N (Rº) (R5), (C1-Ca4 alkyl) -O- CO (C1-Cs alkyl), (C1-C4 alkyl) -CO-O- (C1-Ca alkyl), optionally substituted C3a-Cs cycloalkyl , optionally substituted phenyl, optionally substituted 4- to 6-membered heterocycloalkyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 9 to 10-membered heteroaryl, optionally substituted C1-Ca-alkyl-C3-Cs alkyl, C1-Ca-alkyl phenyl optionally substituted, optionally substituted 4- to 6-membered C 1-4 alkylheterocycloalkyl, optionally substituted 5 to 6-membered C 1-4 alkylheteroaryl or optionally substituted 9 to 10-membered C 1-4 alkylheteroaryl,
wherein the C3-Ce cycloalkyl moiety, phenyl, 4 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or 9 to 10 membered heteroaryl optionally substituted from said substituted C3-Cs cycloalkyl, optionally substituted phenyl, 4 to 6 heterocycloalkyl optionally substituted members, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 9 to 10-membered heteroaryl, optionally substituted C 1 -C-cycloalkyl alkyl, optionally substituted C 1 -C 4 alkyl-phenyl, C 1-4 alkyl-heterocycloalkyl Optionally substituted 4 to 6 members, optionally substituted 5 to 6 membered C1-C4-alkyl heteroaryl or optionally substituted 9 to 10 membered C1-C4 alkyl heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, amino, (C1- Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1-Ca4 alkyl, halo (C1-C4 alkyl), halo (C1-C4 alkoxy) -, C1-C4- alkoxy , hydroxy- (C2-Ca alkoxy) -, C1-Ca- (alkoxy C1-Ca) alkoxy -, -COR $, -CON (RI) (R) and -CO2R $;
each Rº is independently H or C1-Ca alkyl;
each Rº is independently H, C1-Ca alkyl, -CO (C1-C4 alkyl), - OCOf (C1-C4 alkyl), -CO2 (C1-C4 alkyl), -CO- (5- to 6-membered heterocycloalkyl optionally substituted ), -CO (C1-Ca alkyl) - (optionally substituted 5 to 6 membered heterocycloalkyl), -CO (optionally substituted 5 to 6 membered heteroaryl), -CO (C1-C4 alkyl) - (5 to 6 membered heteroaryl) optionally replaced members),
wherein the optionally substituted 5- to 6-membered heterocycloalkyl or optionally substituted 5- to 6-membered heteroaryl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, amino, (C1-Ca alkyl) amino-, (C1-Ca alkyl) (C1-Ca alkyl) amino-, C1- Ca alkyl, halo (C1-C4 alkyl), halo (C1-C4 alkoxy) -, C1-Ca- alkoxy, hydroxy- (C2-C4 alkoxy ) -, C1-Ca alkoxy (C1-Ca alkoxy) -, -CORI, -CON (RI) (R ') and -CO2 R $;
each R 'is independently H or C1-Ca alkyl;
Rº and R "are each independently H or C1-Ca alkyl or Rº and Rº, taken together with the atom or atoms through which they are connected, form a 5- to 6-membered ring;
or a pharmaceutically acceptable salt thereof.
[19]
19. Method, according to claim 17 or 18, CHARACTERIZED by the fact that when s is O, Rºº and Rº are each independently H or C1-Ca alkyl.
[20]
20. Method, according to claim 17 or 18, CHARACTERIZED by the fact that when s is 0, Rº * and Rº they are each independently ethyl.
[21]
21. Method according to any one of claims 17 to 20, CHARACTERIZED by the fact that r is 1, and B is taken together with R8º and R8 & to form: -CHCH = CHCH2-, -CH2CH2CH2CH2-, -CH2CH (OH) CH (OH) CH2- or - CH2CH2aN (CH3) CH2CH> -.
[22]
22. Method according to any one of claims 17 to 21, CHARACTERIZED by the fact that r is 1, and B is taken together with R8 ' and R8 , forms a -CH2CH = CHCH> 2-.
[23]
23. Method, according to any one of claims 17 to 22, CHARACTERIZED by the fact that Rº and Rô are each H.
[24]
24. Method according to any of claims 17 to 23, CHARACTERIZED by the fact that R'º is H.
[25]
25. Method according to any one of claims 17 to 24, CHARACTERIZED by the fact that R'4, R'5, and R'7 are each independently C1-C3 alkyl.
[26]
26. Method according to any one of claims 1 to 17, CHARACTERIZED by the fact that the STING agonist has the structure of Formula (I-N-B ')
RA Rº 4 by ÚD Y Ré
RO RS Re Tr Re: O o A RÉ o RU RÉ (EN-B ') where R3 and Rº are each independently -CON (Rº) (R ”), or one of R $ and R $ is - CON (Rº) (R), and the other from R and Rº is H, COOH or -CO2 (Rº); Rº is C1-Ca alkyl; RE and RE are each independently -CH2-; B is -halo (C1-Cs alkyl),-unsubstituted C1-Cs alkyl or -C2-C5 alkenyl unsubstituted; Rº and RM! are each independently H, halogen, hydroxyl, -O- P (O) (OH) 2, -OP (O) (RIR!) 2, (optionally substituted C1-Cs alkyl) or (C1- Cs6 alkyl) Optionally substituted oxide, in which C1-Cs alkyl of said (C1-Cs alkyl) optionally substituted or (C1-Ce6 alkyl) Optionally substituted oxide is optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of in hydroxyl, -OP (O) (OH) 2, -OP (OX (RIR!) 2, C1-Ca alkoxy, -N (RºNR)), -CO (RI), optionally substituted phenyl, and 5 to heterocycloalkyl 6 members optionally replaced;
wherein said optionally substituted phenyl or 5- to 6-membered heterocycloalkyl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (O) (RIR! !) 2, amino, (C1-Cs alkyl) amino-, (C1-Cs alkyl) (C1-Cs alkyl) amino-, halo (C1-Cs alkyl), hydroxy- (C1-Ca alkyl) -, - ( alkyl C1-C4) -OP (O) (OH) 2, - (C1-Ca alkyl) -OP (O) (RIR!) 2, halo (C1-C4 alkoxy) -, C1-Ca- alkoxy, hydroxy- (Ca-Ca alkoxy) -, - (C2-Ca alkoxy) -OP (O) (OH) 2, - (C2-C4 alkoxy) -OP (O) (R'R! ") 2, - (C1 alkyl) -Cs) -NH>, -C1-Ca alkyl (C1-C4 alkoxy) and C1-Ca alkoxy (C1-C4 alkoxy) -; each Rº is independently H or C1-Ca alkyl; Rº is selected from H, (C1-C4 alkyl), -CO (C1-C4 alkyl), -OCO (C1- Ca alkyl), - (C1-Ca alkyl) -NH>, - (C1-C4 alkyl) C1-Ca alkoxy or -COz (C1-C4 alkyl), each occurrence of R is H or (C1-C4 alkyl); Rº and Rº are H; R * º is C1-Ca alkyl; Rº * is H or C1-Ca alkyl; Rº is C1 alkyl -Ca; R '* is H or C1-Ca alkyl; R'º is H or C1-Ca alkyl; R'7 is H or C1-Ca4 alkyl; and each occurrence of R 'and R! are independently (C1-C6 alkyl) Oxy-; or a pharmaceutically acceptable salt thereof.
[27]
27. Method, according to claim 26, CHARACTERIZED by the fact that the STING agonist has the structure of Formula (I-N-b '),
Re ia K SAX Í Vaza Ro [e] É> H N 4 o Õ RO Formula (I-N-b ')
on what
B is -halo (C1-Cs alkyl),-unsubstituted C1-Cs alkyl or -C2-C5 alkenyl unsubstituted;
Rº and RM! are each independently H, halogen, hydroxyl, -O- P (O) (OH) 2, -OP (O) (RIR! ") 2, (optionally substituted C1-Cs alkyl) or (C1- C alkyl) ) Optionally replaced oxide,
wherein the optionally substituted C1-Cs alkyl (C1-Cs alkyl) or optionally substituted C1-C6 alkyl is optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, alkoxy C1-Ca, -N (Rº) (Rº), -CO2 (R), optionally substituted phenyl, and optionally substituted 5 to 6 membered heterocycloalkyl, and wherein said optionally substituted phenyl or 5 to 6 membered heterocycloalkyl is optionally substituted by 1 to 4 substituents, each independently selected from halogen, hydroxy, -OP (O) (OH) 2, -OP (OX (RIR!) o, amino, (C1-Cs alkyl) amino-, (alkyl C1-Ce) (C1-Cs alkyl) amino-, halo (C1-Cs alkyl), hydroxy- (C1-Ca alkyl) -, - (C1-C4 alkyl) -OP (O) (OH) 2, - ( alkyl C1-Ca) -OP (OX (R'R!) 2, halo (C1-Ca alkoxy) -, C1-C4a- alkoxy, hydroxy- (C2a-Ca alkoxy) -, - (Ca-Ca alkoxy) - OP (O) (OH) 2, - (C2-Ca alkoxy) -O- P (OXRIR!) 2, - (C1-Cs alkyl) -NH>,
-C1-Ca alkyl (C1-C4 alkoxy) and C1-Ca alkoxy (C1-Ca alkoxy) -; Rº is selected from H, (C1-C4 alkyl), -CO (C1-C4 alkyl), -OCO (C1- Ca alkyl), - (C1-Ca alkyl) -NH>, - (C1-C4 alkyl) alkoxy C1-C4 or -COz (C1-C4 alkyl), each R 'is H or (C1-C4 alkyl); R * º is C1-Ca alkyl; Rº is C1-Ca alkyl; R '* is C1-C4 alkyl; and R * 7 is C1-Ca alkyl; each occurrence of R 'and R! are independently (C1-C6 alkyl) oxide; or a pharmaceutically acceptable salt thereof.
[28]
28. Method, according to claim 26 or claim 27, CHARACTERIZED by the fact that Rº and RA! are each independently H, (optionally substituted C1-Cs alkyl) or (optionally substituted C1-C6 alkyl), and the optionally substituted C1-Cs alkyl (C1-C6 alkyl), (C1-Ce alkyl) ) Optionally substituted oxxi- is optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of hydroxyl, -N (Rº) (Rº), C1-Ca alkoxy, phenyl, 5- to 6-membered heterocycloalkyl optionally containing at least one nitrogen or oxygen as a ring member, and R and R are each independently H or C1-Ca alkyl.
[29]
29. Method, according to claim 26 or claim 27, CHARACTERIZED by the fact that at least one of R * and Rº! is optionally substituted H, (C1-C6 alkyl) or optionally substituted (C1-C6 alkyl) oxide, and the optionally substituted C1-Cs alkyl (C1-Cs alkyl) optionally substituted (C1-Ces alkyl) is optionally substituted by 1 to 4 substituents, each independently selected from the group consisting of -N (Rº) (R), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl, and Rº and Rí are each independently H or C1-Ca alkyl.
[30]
30. Method according to any one of claims 1 to 29, CHARACTERIZED by the fact that the STING agonist is selected from:
(E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-1-yl) but-2 -en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazole-5-carboxamide;
(E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide;
(Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino ) -7- (3-hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide;
(E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7- (3-hydroxypropoxy) -1H-benzo [d] imidazole -1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | - 5-carboxamide;
(E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1 H-pyrazol-S-carbonyl) imino) -7- (3 -hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazole -S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo |
(Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3- hydroxypropoxy) -2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H-pyrazole- S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo |
(E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-S5-carboxamido) -1H-benzo [d] imidazol | -1-yl) but- 2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazole-5-carboxamide;
(E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-S-carbonyl) imino) - 2,3- dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-
carbonyl) imino) -7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazole-5-carboxamide;
(Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) - 2,3-di -hydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -7- (3-morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo |
(E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-S5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | - 5-carboxamide;
(E) -1 - ((E) -4 - ((E) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl) imino) -7- (3 -morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H- pyrazol-S-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo |
(Z) -1 - ((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl) imino) -7- (3 -morpholinopropoxy) -2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -2 - ((1-ethyl-3-methyl-1H- pyrazol-5-carbonyl) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo |
3 - ((((Z) -6-carbamoyl-3 - ((E) -4 - ((Z) -5-carbamoyl-2 - ((1-ethyl-3-methyl-1H-pyrazol-5-carbonyl)) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazol-1-yl) but-2-en-1-11) -2 - ((1-ethyl-3-methyl- 1H-pyrazol-S-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazo | -4-yl) oxy) propyl dihydrogen phosphate;
(E) -3 - ((5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [ d] imidazo | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazo | -7 -il) Oxy) propyl dihydrogen phosphate;
3 - ((((Z) -6-carbamoyl-3 - ((E) -4 - ((Z) -5-carbamoyl-2 - (((1-ethyl-3-methyl-1 H-pyrazol-5-carbonyl ) imino) -7-methoxy-2,3-dihydro-1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2 - ((1-ethyl- 3- methyl-1H-pyrazol-S-carbonyl) imino) -2,3-dihydro-1H-benzo [d] imidazo | -4-yl) oxy) propyl dihydrogen phosphate; (E) -4 - ((5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo acid [d] imidazol-1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-7-yl) oxide ) butanoic; (E) -7- (aminomethyl) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d ] imidazol-1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5-carboxamide; (E) -3- (5-carbamoyl-1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole- 1-yl) but-2-en-1-i1) -2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -1H-benzo [d] imidazol-7-yl) propanoic; (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7- (3- (piperazin-1-yl) propoxy) - 1H-benzo [d] imidazo | -1-yl) but-2-en-1-11) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -7-methoxy-1H- benzo [d] imidazole-5-carboxamide; (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7- (3-morpholinopropoxy) -1H-benzo [d] imidazo | -1-yl) but-2-en-1-i1) -7-ethoxy-2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d] imidazole-5 -carboxamide; and (E) -1- (4- (5-carbamoyl-2- (1-ethyl-3-methyl-1 H-pyrazol-5-carboxamido) -7-methoxy-1H-benzo [d] imidazole | -1 -yl) but-2-en-1-i1) -7- (3- (dimethylamino) propoxy) -2- (1-ethyl-3-methyl-1H-pyrazol-5-carboxamido) -1H-benzo [d ] imidazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.
[31]
31. Method according to any one of claims 1 to 30, CHARACTERIZED by the fact that the STING agonist is administered to said human being through a selected administration route of intravenous, subcutaneous, oral and transdermal.
[32]
32. Method according to any one of claims 1 to 31, CHARACTERIZED by the fact that the STING agonist is administered to said human being intravenously.
[33]
33. Method according to any one of claims 1 to 32, CHARACTERIZED by the fact that said cancer is a solid tumor.
[34]
34. Method of administering a STING agonist to a human being in need of it, CHARACTERIZED by the fact that it comprises administering said STING agonist systemically.
[35]
35. Method, according to claim 34, CHARACTERIZED by the fact that the STING agonist increases the concentration of at least one cytokine in the blood of said human being to an effective concentration to stimulate T cells in said human being.
[36]
36. Method according to claim 34 or 35, characterized by the fact that the STING agonist does not increase the levels of cytokine in the blood of said human being at a high concentration sufficient to cause dose limiting toxicity.
[37]
37. Method according to any one of claims 34 to 36, CHARACTERIZED by the fact that the human being has at least one disease selected from: inflammation, allergic and autoimmune diseases, infectious diseases, hepatitis C virus (HCV), virus hepatitis B (HBV), influenza, warts on the skin, multiple sclerosis, human immunodeficiency virus (HIV) infection, AIDS, cancer, precancerous syndromes.
[38]
38. Method according to any one of claims 34 to 37, CHARACTERIZED by the fact that the STING agonist increases the concentration of at least one pro-inflammatory cytokine in diseased tissue in said human being at least three times higher than the concentration of said at least pro-inflammatory cytokine in the blood, plasma or serum of said human being.
[39]
39. Method according to any one of claims 34 to 38, CHARACTERIZED by the fact that the STING agonist is administered as a vaccine adjuvant.
[40]
40. Method according to any of claims 34 to 39, CHARACTERIZED by the fact that the STING agonist is administered systemically.
[41]
41. Method according to any one of claims 34 to 40, CHARACTERIZED by the fact that the STING agonist is administered intravenously, subcutaneously, orally or transdermally.
[42]
42. STING agonist or a pharmaceutically acceptable salt thereof, CHARACTERIZED by the fact that it is for use in the treatment of cancer in which the STING agonist is administered systemically.
[43]
43. Use of a STING agonist or a pharmaceutically acceptable salt thereof, CHARACTERIZED by the fact that it is for the manufacture of a drug for the treatment of cancer in which the STING agonist is administered systemically.
[44]
44, Composition - pharmaceutical “for systemic administration, CHARACTERIZED by the fact that it comprises a STING agonist or a pharmaceutically acceptable salt thereof.
[45]
45. Pharmaceutical composition according to claim 44, CHARACTERIZED by the fact that it is for use in the treatment of cancer.
[46]
46. Method according to any one of claims 1 to 33, CHARACTERIZED by the fact that said cancer is selected from: non-small cell lung cancer (NSCLC), microsatellite stable corrective cancer (MSS), gastroesophageal adenocarcinoma ( GEC), squamous cell carcinoma of the head and neck (SCCHN).
[47]
47. Method according to any one of claims 1 to 33 or 38, CHARACTERIZED by the fact that the concentration of at least one cytokine, not in the tumor microenvironment, is measured in the blood.
[48]
48. The method of any one of claims 1 to 33 or 38,
CHARACTERIZED by the fact that the concentration of at least one cytokine, not in the tumor microenvironment, is measured in the serum.
[49]
49. Method according to any one of claims 1 to 33 or 38, CHARACTERIZED by the fact that the concentration of at least one cytokine, not in the tumor microenvironment, is measured in the plasma.

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法律状态:
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