3H-pyrazolo[4,3-f]quinoline compounds as STING antagonists

Abstract

3H-pyrazolo[4,3-f]quinoline compounds that inhibit interferon gene-stimulating factor (STING); compositions comprising the same compounds; and their use for the treatment of STING-related diseases, such as STING-related inflammatory diseases, autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 454,438, filed on 24 March 2023, which is incorporated herein by reference in its entirety.

[0002] (Technical field) This disclosure relates to 3H-pyrazolo[4,3-f]quinoline compounds that are interferon gene-stimulating factor (STING) inhibitors, and their use for treating or suppressing STING-related diseases, such as inflammatory diseases, as well as responses to injuries such as cardiac trauma, trauma, and brain injury. [Background technology]

[0003] This section presents aspects that may aid in a deeper understanding of this disclosure. Therefore, these statements should be interpreted in this context and not as an admission or denial of prior art.

[0004] Activation of innate immunity is crucial for initiating a rapid response to adverse events (e.g., pathogenic infection or cytotoxicity). Recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern recognition receptors enables downstream activation, inducing the expression of inflammatory cytokines (e.g., type 1 interferon, nuclear factor kappa-beta (NF-κβ), and other cytokines such as interleukin 1 and 6). These cytokines play a vital role in T cell priming and activation. As a signaling motif indicating cytotoxicity or invasion by a DNA-containing pathogen, cytoplasmic double-stranded DNA is recognized by the DNA sensor cyclic GMP-AMP synthase (cGAS)3, which catalyzes the formation of a phosphodiester bond between adenosine triphosphate (ATP) and guanosine triphosphate (GTP), thereby initiating the production of 2'-3' cyclic GMP-AMP (cGAMP). The binding of cGAMP to the universal cyclic dinucleotide sensor protein IFN gene stimulator (STING) leads to the recruitment of Tank-binding kinase I (TBK1), which, via phosphorylation, activates the transcription factor interferon regulator 3 (IRF3). Following IRF3 activation and translocation to the nucleus, IRF3 acts as a transcription activator that strongly induces type 1 interferons, and is crucial for initiating a proper immune response to pathogen invasion, as illustrated in Figure 1.

[0005] The cGAS-STING pathway plays a crucial role in protecting higher organisms from pathogen or cancer invasion by promoting the production of cytokines and interferons. While cGAS-STING activation has beneficial aspects, abnormal activity and dysfunction of this pathway have been shown to lead to chronic upregulation of cytokine expression and play a significant role in the progression of chronic autoimmune diseases. Structural activation of STING by gain-of-function (GOF) mutations plays a significant role in the progression of wasting diseases (e.g., infant-onset STING-associated vasculitis (SAVI)) characterized by prominent vascular lesions and symptoms such as pneumonia. Activated STING is believed to play a crucial role in the exacerbation of various conditions (e.g., traumatic brain injury, diabetic nephropathy, and colitis).

[0006] On the other hand, cytoplasmic nucleic acid clearance dysfunction plays a major role in the onset and progression of other autoimmune diseases (e.g., Ecardi-Goutier syndrome (AGS)), such as loss of function of the TREX1 exonuclease, which leads to DNA accumulation and chronic cGAS-STING activation. With increasing evidence suggesting the involvement of the cGAS-STING pathway in various inflammatory diseases, STING has gained significant attention as an attractive target for improving associated symptoms of these autoimmune diseases (European Journal Medicinal Chemistry, 2019, 182, 111591; Frontiers in Immunology, 2022, 13, 5232). STING antagonists may play a significant role in addressing various inflammatory diseases. STING agonists may be used as immunotherapies.

[0007] To date, only a few small molecule STING inhibitors have been identified, and these are primarily based on cell-based quantification methods for downstream cytokines (e.g., interferon-β) in the cGAS-STING pathway. This, like the previous discoveries of STING antagonists (e.g., C-176, H-151, and AstinC), was obtained via either reporter cell bioassays or basic strategies (e.g., quantification of cytokine mRNA expression via quantitative polymerase chain reaction (qPCR) analysis) (see Figure 2) (Nature 2018, 559, 269-273; Cell Rep 2018, 25, 3405-3421; Proc Natl Acad Sci USA 2021; 118, 24; ACS Med Chem Lett 2019; 10: 92-97).

[0008] Therefore, there is a need to develop compounds that strongly bind to and inhibit STING. The object of this disclosure is to provide such compounds. This object, as well as other objects and advantages, and features of the invention will be apparent from this specification. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] European Journal Medicinal Chemistry, 2019, 182, 111591 [Non-Patent Document 2] Frontiers in Immunology, 2022, 13, 5232 [Non-Patent Document 3] Nature 2018, 559, 269-273 [Non-Patent Document 4] Cell Rep 2018, 25, 3405-3421 [Non-Patent Document 5] Proc Natl Acad Sci USA 2021; 118, 24 [Non-Patent Document 6] ACS Med Chem Lett 2019; 10: 92-97 [Overview of the Initiative]

[0010] A method for treating or suppressing diseases associated with the hyperactivity of interferon gene stimulating factor (STING), wherein the therapeutically effective dose is given by formula (I): [ka] [In the formula, R1 is selected from H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolineamide, pyrimidine carboxamide, imidazole carboxamide, pyrazole carboxamide, and any of the aforementioned derivatives; R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R3 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, and alkynyl; and Each X is independently O, S, SO, SO2, CRR', CNRR', COR', NR', and X n Selected from, where n is 0 to 2; each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, where R2 is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle. A method is provided which involves administering to a patient a compound represented by, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

[0011] Examples of diseases associated with excessive STING activity include, but are not limited to, inflammatory diseases, autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis. In some embodiments, the disease is an inflammatory disease.

[0012] Equation (IA); [ka] [In the formula, R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R4 is selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolinamide, and any of the aforementioned derivatives; and R4 may be appropriately substituted with OH, OR2, halogen, CF3, CN, NRR', CONRR', SO2R2, SO2NRR', NCOR2, or NSO2R2, wherein each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, wherein R2 is as defined above; or R and R', together with the bonded atom, form a 4- to 6-membered ring or heterocycle; R5 is selected from alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolinamide, and any of the aforementioned derivatives; and R5 may be appropriately substituted with OH, OR2, halogen, CF3, CN, NRR', CONRR', SO2R2, SO2NRR', NCOR2, or NSO2R2, wherein R2, R, and R' are as defined above; however, R5 is not a phenyl group appropriately substituted with a substituent selected from H, methyl, CF3, CH2-CH2-OH, CH2-CH2-Cl, COOH, or OMe, COOMe, and amino; R4 and R5 may be the same or different; and Each X is independently O, S, SO, SO2, CRR', CNRR', COR', NR', and X n Selected from, where n is 0 to 2; each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, where R2 is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle. A compound represented by, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, is provided.

[0013] In some embodiments, the compound represented by formula (IA) is [ka] [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0014] In some embodiments, the compound represented by formula (IA) is [Chemical formula] [wherein R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; each R4 and R5 is independently selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, and the amide is selected from sulfonamide, benzamide, nicotinamide, picolinamide, and derivatives of any of the foregoing, and the alkyl may be optionally substituted with OH, OR2, halogen, CF3, CN, NRR’, CONRR’, SO2R2, SO2NRR’, NCOR2, or NSO2R2, and the R2, R, and R’ are as defined above; each R8 and R9 is independently selected from H, methyl, alkyl, and heteroalkyl; each R 10 , R 11 , R 12 , and R 13 is independently selected from H, methyl, alkyl, and heteroalkyl; or R 10 and R 12 together with the atoms to which they are attached form a 4- to 6-membered ring or heterocycle; or R 11 and R 13 together with the atoms to which they are attached form a 4- to 6-membered ring or heterocycle; Z is selected from O, S, SO, SO2, CRR’, CNRR’, COR’, and NR’, and each R and R’ are as defined above; Y is selected from COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, and C6H5R2, and the R2 is as defined above] or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0015] Formula (IB): [ka] [In the formula, R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R3 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, and alkynyl; Each X is independently O, S, SO, SO2, CRR', CNRR', COR', NR', and X n Selected from, where n is 0 to 2; each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, where R2 is as defined above; or R and R', together with the bonded atom, form a 4- to 6-membered ring or heterocycle; Y is either N or CR2, where R2 is as defined above; n is either 0 or 1; Q is selected from NR'', CR2R2, N(COR2), N(SO2)R2, N(C=O)NR2, N(C=NH)R2, and N(C=O)OR2, except that if Q is NR'', R'' is not H, methyl, isopropyl, CH2CH2OH, COCH3, or SO2-methyl; and if Q is CR2R2, R2 is not H or dimethylamine. A compound represented by, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, is provided.

[0016] In some embodiments, the compound represented by formula (IB) is [ka] [ka] [ka] Alternatively, pharmaceutically acceptable salts, hydrates, tautomers, or optical isomers thereof are provided.

[0017] In some embodiments, the compound represented by formula (I) has the structure: [ka] It is also represented by a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0018] A pharmaceutical composition is provided comprising a compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0019] A pharmaceutical composition is provided comprising a compound represented by formula (IA) or formula (IB), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer of either of the foregoing, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0020] A method for treating or suppressing a disease associated with the hyperactivity of interferon gene stimulating factor (STING) is further provided, comprising administering to a patient a therapeutically effective amount of a compound represented by formula (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

[0021] A method for treating or suppressing a disease associated with the hyperactivity of interferon gene stimulating factor (STING) is further provided, comprising administering to a patient a therapeutically effective amount of a compound represented by formula (IB), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

[0022] Examples of diseases associated with excessive STING activity include, but are not limited to, inflammatory diseases, autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis. In some embodiments, the disease is an inflammatory disease. [Brief explanation of the drawing]

[0023] The above and other purposes, features, and advantages of this disclosure will become clear when read in conjunction with the drawings.

[0024] [Figure 1] Figure 1 shows the cyclic GMP-AMP synthase-interferon gene stimulating factor (cGAS-STING) activation pathway. [Figure 2] Figure 2 shows the structures of small molecules (e.g., H-151, C-178, Astin-C, SN-011, and C-18) that have been reported to act as STING antagonists. [Figure 3] Figure 3 shows probe substitution with STING binders. A) The structure of the Fc-di-GMP probe is illustrated. B) A schematic diagram shows the use of the developed FP assay for another purpose, specifically for screening promising low-molecular-weight STING binders that competitively replace Fc-di-GMP. [Figure 4A] Figure 4A shows the synthesis of quinoline compounds using a Doebner-Povarov type multicomponent reaction and the structure of compound HSD1077. [Figure 4B]Figure 4B shows a plot illustrating the anisotropy of compound HSD1077 with respect to concentration, representing dose-dependent competitive probe substitution. The probe and STING concentrations used were 50 nM and 10 μM, respectively. [Figure 5A] Figure 5A shows the ring A-modified analog, whose STING binding was tested via the STING-FP assay. [Figure 5B] Figure 5B shows the proportion of probes bound to STING after incubation with the listed drug compounds (Fbound). The fluorescent dye -c-di-GMP was used at a concentration of 50 nM, and STING at a concentration of 10 μM. All compounds (e.g., ADU-S100, DIABZI-3, compound HSD1077) were used at a concentration of 20 μM. [Figure 6A] Figure 6A shows an analog modified with cyclohexyl ring B, whose STING binding was tested via the STING-FP assay. [Figure 6B] Figure 6B shows the proportion of probes bound to STING after incubation with drug compounds (e.g., ADU-S100, DIABZI-3, and compound HSD1077) (Fbound). [Figure 7A] Figure 7A shows ring-C modified analogs whose STING binding was tested via the STING-FP assay. [Figure 7B] Figure 7B shows the fbound percentage of probes bound to STING after incubation with drug compounds (e.g., ADU-S100, DIABZI-3, and compound HSD1077). The fluorescent dye-c-di-GMP was used at a concentration of 50 nM, and STING at a concentration of 10 μM. Compounds ADU-S100, DIABZI-3, and HSD1077 were used at a concentration of 20 μM. [Figure 8A]Figure 8A shows that when RAW interferon-stimulated gene (ISG) Blue was treated with compound HSD1077 for 24 hours, no significant change in interferon expression concentration was observed. When pre-treated with compound HSD1077 and then cGAMP induction was performed, type 1 interferon expression decreased in a dose-dependent manner. [Figure 8B] Figure 8B shows the results of pre-treating raw ISG cells with either compound HSD1077 or compound H-151 (as a positive control) for 6 hours, followed by stimulation with 100 μM cGAMP for 3 hours to induce interferon-β. mRNA concentrations were quantified by RT-PCR. Gene expression was normalized with β-actin. The experiment was performed with two biological replicates. Error bars indicate the mean error of the two independent experiments. [Figure 9] Figure 9 shows that compound HSD1077 reduces STING and IRF3 phosphorylation in raw ISG cells. Raw ISG cells were treated with 5 μM compound HSD1077 or 1 μM compound H151 for 4 hours, followed by treatment with 100 μM cGAMP for 3 hours. Control cells were treated with dimethyl sulfoxide (DMSO) and sterile water. p-STING and p-IRF3 concentrations were analyzed by Western blotting. The experiment was performed in two biological replicas. [Figure 10A] Figure 10A shows that when THP-1 dual monocytes and human cells were pre-treated with the compound HSD1077 for 2 hours and then stimulated with 2'-3'cGAMP for 24 hours to induce interferon, interferon expression decreased in a dose-dependent manner. [Figure 10B] Figure 10B shows that when human THP-1 dual (KI STING N154S) cells with a gain-of-function point mutation were treated with the compound HSD1077, the interferon expression level decreased after 24 hours of incubation. [Figure 11]Figure 11 shows that when THP-1 Dual (KI STING N154S) cells with a gain-of-function point mutation were treated with the compound, the interferon expression level decreased after 24 hours of incubation. [Modes for carrying out the invention]

[0025] To further understand the principles of this disclosure, embodiments shown in the drawings will be referred to and described here using specific terminology. However, it will be understood that this is not intended to limit the scope of the claims.

[0026] The term "STING" (also known as MITA, MPYS, ERIS, and TMEM173) refers to an adapter protein functionally activated by interferon-stimulating or IFN-stimulating factors, cyclic dinucleotides, which result in the production of interferons and inflammatory cytokines (e.g., TNF, IL-1, IL-6, IFNγ, type 1 interferon (IFN), and nuclear factor kappa-beta (NF-κβ)).

[0027] This disclosure is based, at least in part, on the discovery that the 3H-pyrazolo[4,3-f]quinoline moiety is a privileged moiety that binds to the hinge region of kinases (Int'. Pat. Appl. No. WO2018183586A1, US Pat. Pub. No. 20200308173A1, US Pat. No. 11040973); substitution of the 3H-pyrazolo[4,3-f]quinoline moiety results in compounds that inhibit kinases with growth-inhibiting properties. In numerous therapeutic applications, 3H-pyrazolo[4,3-f]quinoline compounds may have low cytotoxicity to mammalian cells while exhibiting high efficacy against receptors that modulate disease states.

[0028] From the above perspective, this disclosure provides a compound comprising a 3H-pyrazolo[4,3-f]quinoline moiety that binds to STING, inhibits the function of STING, and is tolerable by numerous mammalian cell lines at concentrations of 0.5 μM or higher.

[0029] A method for treating or suppressing diseases associated with the hyperactivity of interferon gene stimulating factor (STING), wherein the therapeutically effective dose is given by formula (I): [ka] [In the formula, R1 is selected from H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolineamide, pyrimidine carboxamide, imidazole carboxamide, pyrazole carboxamide, and any of the aforementioned derivatives; R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R3 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, and alkynyl; and Each X is independently O, S, SO, SO2, CRR', CNRR', COR', NR', and X n Selected from, where n is 0 to 2; each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, where R2 is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle. A method is provided which involves administering to a patient a compound represented by, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

[0030] In some embodiments, the compound represented by formula (I) is represented by formula (IA): [ka] [In the formula, R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R4 is selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolinamide, and any of the aforementioned derivatives; and R4 may be appropriately substituted with OH, OR2, halogen, CF3, CN, NRR', CONRR', SO2R2, SO2NRR', NCOR2, or NSO2R2, wherein each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, wherein R2 is as defined above; or R and R', together with the bonded atom, form a 4- to 6-membered ring or heterocycle; R5 is selected from alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolinamide, and any of the aforementioned derivatives, and R5 may be appropriately substituted with OH, OR2, halogen, CF3, CN, NRR', CONRR', SO2R2, SO2NRR', NCOR2, or NSO2R2, where R2, R, and R' are as defined above; however, R5 is not a phenyl group appropriately substituted with a substituent selected from H, methyl, CF3, CH2-CH2-OH, CH2-CH2-Cl, COOH, or OMe, COOMe, and amino; R4 and R5 may be the same or different; and Each X is independently O, S, SO, SO2, CRR', CNRR', COR', NR', and X n Selected from, where n is 0 to 2; each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, where R2 is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle. It is represented by the compound indicated by , or by its pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer.

[0031] In some embodiments, the compound represented by formula (IA) is [ka] [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0032] In some embodiments, the compound represented by formula (IA) is [ka] [In the formula, R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; Each R4 and R5 is independently selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolineamide, and any of the aforementioned derivatives, and the alkyl may be appropriately substituted with OH, OR2, halogen, CF3, CN, NRR', CONRR', SO2R2, SO2NRR', NCOR2, or NSO2R2, and each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, wherein R2 is as defined above; or R and R', together with the bonded atom, form a 4- to 6-membered ring or heterocycle; Each of R8 and R9 is independently selected from H, methyl, alkyl, and heteroalkyl; Each R 10 , R 11 , R 12 , and R 13 The elements are independently selected from H, methyl, alkyl, and heteroalkyl; or R 10 and R 12 Together with the bonded atoms, they form a 4-6 membered ring or heterocycle; or R 11 and R 13 Together with the atoms it is bonded to, it forms a 4-6 membered ring or heterocycle; Z is selected from O, S, SO, SO2, CRR', CNRR', COR', and NR', where each R and R' is as defined above; Y is selected from COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, and C6H5R2, where R2 is as defined above. or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0033] In some embodiments, formula (IA) is: R2 is H; R4 is either H or alkyl; Each X independently corresponds to O, S, SO, SO2, CRR', CNRR', COR', NR', and X n Selected from, where n is 0 to 2; each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, where R2 is as defined above; or R and R', together with the bonded atoms, form a 4-6 membered ring or heterocycle; and R5 is selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolinamide, and any of the aforementioned derivatives; and R5 may be appropriately substituted with OH, OR2, halogen, CF3, CN, NRR', CONRR', SO2R2, SO2NRR', NCOR2, or NSO2R2, wherein R2, R, and R' are as defined above; however, R5 is not a phenyl group appropriately substituted with a substituent selected from H, methyl, CF3, CH2-CH2-OH, CH2-CH2-Cl, COOH, or OMe, COOMe, and amino. This includes compounds, or their pharmaceutically acceptable salts, hydrates, tautomers, or optical isomers.

[0034] In some embodiments, compounds represented by formula (IA) [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0035] In some embodiments, the compound represented by formula (I) is represented by formula (IB): [ka] [In the formula, R2 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R3 is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, and alkynyl; Each X is independently O, S, SO, SO2, CRR', CNRR', COR', NR', and X n Selected from, where n is 0 to 2; each R and R' is independently selected from H, halogen, CF3, CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR2R2, COR2, SO2R2, (C=O)NR2, (C=NH)R2, (C=O)OR2, C6H5R2, morpholine, and piperazine, where R2 is as defined above; or R and R', together with the bonded atom, form a 4- to 6-membered ring or heterocycle; Y is either N or CR2, where R2 is as defined above; n is either 0 or 1; Q is selected from NR'', CR2R2, N(COR2), N(SO2)R2, N(C=O)NR2, N(C=NH)R2, and N(C=O)OR2, except that if Q is NR'', R'' is not H, methyl, isopropyl, CH2CH2OH, COCH3, or SO2-methyl; and if Q is CR2R2, R2 is not H or dimethylamine. It is represented by the compound indicated by , or by a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0036] In some embodiments, the compound represented by formula (IB) is [ka] [ka] [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0037] In some embodiments, the compound represented by formula (I) is [ka] or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0038] A method is provided for treating or suppressing a disease associated with the hyperactivity of interferon gene stimulating factor (STING), comprising administering to a patient a therapeutically effective amount of a compound represented by formula (IA), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

[0039] A method is provided for treating or suppressing a disease associated with the hyperactivity of interferon gene stimulating factor (STING), comprising administering to a patient a therapeutically effective amount of a compound represented by formula (IB), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

[0040] The term "substituted" refers to a functional group in which one or more hydrogen atoms are replaced by one or more non-hydrogen atoms. The terms "functional group" or "substituent" refer to a group that is substituted for or can be substituted for in a molecule. Examples of substituents or functional groups include, but are not limited to, halos (e.g., F, Cl, Br, and I); groups containing oxygen atoms, e.g., hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, and carboxyl groups (including carboxylic acids, carboxylates, and carboxylate esters); groups containing sulfur atoms, e.g., thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; groups containing nitrogen atoms, e.g., amines, azides, hydroxylamines, cyanos, nitro groups, N-oxides, hydrazides, and enamines; and various other groups containing other heteroatoms.

[0041] Examples of substituents that can bond to the substituted carbon atom (or other atom such as nitrogen) include, but are not limited to, F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, (CH2) 0-2 P(O)OR2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2) 0-2 N(R)C(O)R, (CH2) 0-2N(R)C(O)OR, (CH2) 0-2 Examples include N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, where R may be a hydrogen or carbon-based part, and the carbon-based part itself may be further substituted; for example, R may be hydrogen, alkyl The group may be a R, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, and any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or R may be independently monosubstituted or polysubstituted; or the heterocycle may be monosubstituted or independently polysubstituted if two R groups bonded to one nitrogen atom or two adjacent nitrogen atoms can form a heterocyclyl with the bonded one or two nitrogen atoms.

[0042] The term "alkyl" refers to a group of 1 to approximately 20 carbon atoms (C1-C1). 20 ), 1 to 12 carbon atoms (C1-C 12) refers to substituted and unsubstituted, linear and branched, alkyl and cycloalkyl groups having 1 to 8 carbon atoms (C1-C8), or in some embodiments, 1 to 6 carbon atoms (C1-C6). Examples of linear alkyl groups include linear alkyl groups having 1 to 8 carbon atoms (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups). Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as branched forms of other alkyl groups. Typical substituted alkyl groups may be substituted once or more with any group listed herein (e.g., amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups).

[0043] The term "heteroalkyl" refers to a stable linear or branched chain, or a combination thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be oxidized as appropriate, and the nitrogen heteroatom may be quaternized as appropriate. The heteroatoms O, N, P, S, B, As, and Si may be located at any position within the heteroalkyl group, or at a position where the alkyl group is bonded to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Two or three or fewer heteroatoms may be consecutive (e.g., -CH2-NH-OCH3 and -CH2-O-Si(CH3)3). The heteroalkyl portion may contain at least one heteroatom (e.g., O, N, S, Si, or P).

[0044] The term "alkenyl" refers to a group of 2 to 20 carbon atoms (C2-C2). 20 ), 2-12 carbon atoms (C2-C 12 This refers to substituted and unsubstituted, linear and branched, divalent alkenyl and cycloalkenyl groups having 2 to 8 carbon atoms (C2-C8), or in some embodiments, 2 to 4 carbon atoms (C2-C4), and at least one carbon-carbon double bond. Examples of linear alkenyl groups include linear alkenyl groups having 2 to 8 carbon atoms, such as -CH=CH- and -CH=CHCH2-. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)-.

[0045] The term "alkynyl" refers to an unsaturated monovalent carbon chain containing at least one triple bond, and may be a branched chain as appropriate. In various embodiments containing alkynyls, exemplary examples include lower alkynyls such as C2-C6 and C2-C4 alkynyls.

[0046] The term "hydroxypropyl" refers to an alkyl group that is substituted with at least one hydroxyl (-OH) group.

[0047] The term "cycloalkyl" refers to substituted and unsubstituted cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, a cycloalkyl group may have 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 4, 5, 6, or 7. In some embodiments, a cycloalkyl group may have 3 to 6 carbon atoms (C3-C6). Cycloalkyl groups further include polycyclic cycloalkyl groups (e.g., norbornyl, adamantyl, boronyl, camphenyl, isocamphenyl, and calenyl groups, but not limited to) and fused rings (e.g., dekalinyl, but not limited to).

[0048] The term “acyl” refers to a group containing a carbonyl moiety, which is bonded via a carbonyl carbon atom. The carbonyl carbon atom may also be bonded to other carbon atoms and may constitute part of a substituted or unsubstituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, etc. In the special case where the carbonyl carbon atom is bonded to hydrogen, the group is a “formyl” group and is an acyl group in the sense defined herein. An acyl group may contain additional carbon atoms bonded to a carbonyl group of 0 to about 12 to 40, 6 to 10, 1 to 5, or 2 to 5. The acryloyl group is an example of an acyl group. An acyl group may also contain heteroatoms in the sense defined herein. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group in the sense defined herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. An example is the trifluoroacetyl group.

[0049] The term "aryl" refers to substituted and unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms on the ring. Therefore, aryl groups include, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, the aryl group has about 6 to about 14 carbon atoms (C6-C) in the ring portion of the group. 14 ) or 6-10 carbon atoms (C6-C 10) contains. The aryl group may be unsubstituted or substituted as defined herein. Typical substituted aryl groups may be monosubstituted or double-substituted, and include, but are not limited to, phenyl groups substituted with 2, 3, 4, 5, or 6 substituents or naphthyl groups substituted with 2 to 8 substituents, which may be substituted with carbon or non-carbon groups (e.g., groups listed herein).

[0050] The term “heteroaryl” refers to an aromatic ring containing at least one heteroatom (e.g., N, S, O, or Se). The heteroaryls of this disclosure may be any heteroaryl group. Heteroaryls include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, benzothiazolinyl, benzimidazolinyl groups, or any combination thereof.

[0051] The term "halo" is used to describe compounds containing one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine. The term "haloalkyl" group includes monohaloalkyl groups, polyhaloalkyl groups (where all halogen atoms may be the same or different), and perhaloalkyl groups (where all hydrogen atoms are substituted with halogen atoms, such as fluoro). Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and -CF(CH3)2.

[0052] The term "heterocycloalkyl" refers to a non-aromatic heterocycle in which one or more ring-forming atoms are heteroatoms (e.g., O, N, or S atoms). Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., 2, 3, or 4-fused rings) systems as well as spirocycles. Examples of heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, and imidazolidinyl. Furthermore, moieties having one or more aromatic rings fused with a non-aromatic heterocycle (i.e., sharing a common bond) (e.g., phthaliumidyl, naphthaliumidyl, and benzo derivatives of heterocycles) are included in the definition of heterocycloalkyl groups. Heterocycloalkyl groups having one or more condensed aromatic rings may be bonded via either aromatic or non-aromatic moieties. Furthermore, the definition of a heterocycloalkyl group includes a portion in which one or more ring-forming atoms are substituted with one or two oxo or sulfide groups. In some embodiments, heterocycloalkyl groups have 1 to about 20 carbon atoms, and in further embodiments, about 3 to about 20 carbon atoms. In some embodiments, heterocycloalkyl groups contain 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, heterocycloalkyl groups have 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 triple bonds.

[0053] It should be understood that any of the alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkylene, and heterocyclic groups may be substituted as appropriate with independently selected groups, such as alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, carboxylic acids and their derivatives (including esters, amides, and nitrites), hydroxy, alkoxy, acyloxy, amino, alkylamino and dialkylamino, acylamino, thio, and combinations thereof.

[0054] The terms “may be substituted as appropriate” and “optional substituent” indicate that the group in question is either unsubstituted or substituted with one or more specific substituents. If the group in question is substituted with two or more substituents, the substituents may be identical or different. The terms “independently,” “independently are,” and “selected independently of” indicate that the groups in question may be identical or different. Certain terms may appear multiple times in a structure, in which case each term shall be defined independently of the others.

[0055] The term "amine" refers to primary, secondary, and tertiary amines having the formula N(group)3 (wherein each group is independently H or not H, e.g., alkyl, aryl, etc.). Amines include, but are not limited to, R-NH2, e.g., alkylamines, arylamines, alkylarylamines; R2NH (wherein each R is independently selected), e.g., dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and R3N (wherein each R is independently selected), e.g., trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine" also includes the ammonium ion.

[0056] The term "amino group" refers to -NH2, -NHR, -NR2, and -NR3. + The structure of (wherein each R is selected independently), and -NR3 +This refers to the substituents in the structure that are protonated, except for those that cannot be protonated. Therefore, any compound substituted with an amino group can be considered an amine. The "amino group" can be a primary, secondary, tertiary, or quaternary amino group. The "alkylamino" group includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0057] As used herein, the term “compound” includes all stereoisomers, geometric isomers, and tautomers of the structure depicted. “Optical isomer” may exist as multiple stereoisomers if it contains one or more chiral centers or for other reasons. In various embodiments, without being limited to any particular stereochemical conditions, the compound, as well as compositions, methods, uses, and pharmaceuticals containing it, may be optically pure or any variety of stereoisomeric mixtures (including racemates and other enantiomeric mixtures, other diastereomeric mixtures, etc.). Such a mixture of stereoisomers may contain a single stereochemical configuration at one or more chiral centers while containing a mixture of stereochemical configurations at one or more other chiral centers.

[0058] Similarly, the compounds described herein may contain geometric isomeric centers (e.g., cis, trans, E, and Z double bonds). In various embodiments, the compounds may be pure or a mixture of any variety of geometric isomers, without being limited to any specific geometric isomer conditions. Such a mixture of geometric isomers may contain a single configuration in one or more double bonds while containing a geometric isomer mixture in one or more other double bonds.

[0059] This compound can be synthesized by a Doebner-type three-component reaction using an amine, ketone, and aldehyde. These STING antagonists can be used to treat diseases resulting from hyperactive STING. Examples of STING-related diseases include, but are not limited to, inflammatory diseases, autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis.

[0060] In some embodiments, a pharmaceutical composition is provided comprising a compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0061] In some embodiments, a pharmaceutical composition is provided comprising a compound represented by formula (IA) or (IB), or any of the aforementioned pharmaceutically acceptable salts, hydrates, tautomers, or optical isomers, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0062] Diseases associated with STING hyperactivity include, but are not limited to, STING-derived inflammatory diseases, STING-derived autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis. In some embodiments, the disease is an inflammatory disease.

[0063] In some embodiments, compounds represented by formula (I), (IA), or (IB), or their pharmaceutically acceptable salts, hydrates, tautomers, or optical isomers may be administered by an appropriate route of administration, such as orally, parenterally, topically, intratumorally, peritumorally, or intranasally.

[0064] (With respect to a disease or symptom,) the terms “treat,” “treating,” “treated,” or “treatment” mean means to obtain a beneficial or intended outcome, preferably a clinical outcome, including, but not limited to, one of the following: improvement of a disease-related condition, cure of a disease, reduction of disease severity, delay of disease progression, relief of one or more disease-related symptoms, improvement of the quality of life of a person suffering from a disease, extension of survival, and / or prophylactic or preventative treatment.

[0065] The term "pharmaceutical composition" refers to a composition containing one or more therapeutically effective amounts of a compound for treating a patient's STING-related disease. The composition may also contain other components and / or ingredients (including, but not limited to, other therapeutically active compounds and / or one or more pharmaceutically acceptable carriers, diluents, excipients, etc.). The carriers, excipients, or diluents may vary depending on the specific route of administration (see, for example, Remington's The Science and Practice of Pharmacy, 23rd ed. (2020)).

[0066] The term "therapeutic effect" refers to a beneficial local or systemic effect in animals, particularly mammals, and especially humans, caused by the administration of a compound.

[0067] The term "therapeutic dose" refers to the amount of a compound that is effective in treating a disease or disorder (e.g., STING-related inflammatory diseases, STING-related autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis) in a reasonable benefit / risk ratio. The therapeutic dose of such a compound varies depending on the patient and disease or disorder being treated, the patient's weight and age, the severity of the disease or disorder, the method of administration, etc., and can be readily determined by those skilled in the art.

[0068] The compound may be administered in unit dosage forms and / or compositions containing one or more pharmaceutically acceptable carriers, adjuvants, diluents, excipients, and / or vehicles, and combinations thereof. As used herein, the term “administration” and its derivatives generally refer to any method of administering the compound to a patient, including, but not limited to, routes of administration such as oral, intravenous, intratumoral, intramuscular, subcutaneous, transdermal, and topical.

[0069] For oral administration, compounds can be readily formulated by combining the active compound with pharmaceutically acceptable carriers, excipients, or diluents known in the art. Such carriers, excipients, or diluents allow the compound to be formulated as tablets, pills, powders, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, solutions, etc., for oral administration by the target patient.

[0070] The effective dosage of a compound can be determined by comparing its in vitro activity with its in vivo activity in animal models. Methods for estimating effective dosages for human subjects from mice and other animals are known in the field. In practice, the dosage of a compound can vary considerably depending on the subject's symptoms, age, the type of disease the subject has or may have, the specific compound used, the stage of the disease, the route of administration of the compound, and the possibility of concomitant use with other drugs in combination or in combination therapy with other treatments. The amount of composition required for use in treatment (e.g., therapeutically effective dose or dosage) varies not only with the specific application but also with the salt selected (if applicable) and the subject's characteristics (e.g., age, symptoms, sex, body surface area and / or weight, drug tolerance), and ultimately depends on the discretion of the attending physician, healthcare professional, or other relevant parties.

[0071] Compositions containing this compound can be formulated in unit dose forms, with each dose containing approximately 5 to 1,000 mg (1 g) of the active ingredient, and more generally, approximately 100 mg to 500 mg.

[0072] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of the active ingredient. Those skilled in the art will understand that this includes compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.

[0073] In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. Those skilled in the art will understand that this includes compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient.

[0074] In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of active ingredient. Those skilled in the art will understand that this includes compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

[0075] Active compounds may be effective at a wide range of doses and are generally administered at pharmaceutically effective doses. However, it should be understood that the actual amount of compound administered is usually determined by the physician, depending on relevant circumstances including the treatment conditions, the chosen route of administration, the actual compound being administered, the patient's age, weight, response, and the severity of the patient's symptoms.

[0076] In some embodiments, the compound may be administered in amounts ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compound may be administered in amounts ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. Examples include approximately 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, or 100 mg / kg. In some embodiments, such administration may be once daily or twice daily (BID).

[0077] The compounds of this disclosure may also be used in combination with other compounds or known agents used as STING inhibitors. Examples of known agents that may be used to treat inflammatory diseases include, but are not limited to, DMXAA, FAA, H-151, C-170, C-171, CMA, GSK690693, α-mangostine, carbonyl cyanide-3-chlorophenylhydrazone (CCCP), C-178, SA-2, SN-01, and badimesan.

[0078] A pharmaceutically acceptable combination for treating or suppressing STING-related disease in patients in need is provided, comprising (i) a compound represented by formula (I), (IA), or (IB), or any of the aforementioned pharmaceutically acceptable salts, hydrates, tautomers, or optical isomers; (ii) an additional therapeutic agent; and (iii) optionally at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0079] The term "pharmaceutical combination" refers to a pharmaceutical therapy obtained by mixing or combining two or more active ingredients. Regarding combinations, a compound represented by formula (I), (IA), or (IB), or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and at least one additional therapeutic agent, may be administered to a patient simultaneously or sequentially, in a single composition or two separate compositions, via the same or different routes of administration, to achieve the desired effect. The therapeutic agents may be administered in amounts that provide the desired therapeutic effect. The effective dose range for each therapeutic agent is well known in the art, and the therapeutic agents are administered within such established ranges to patients in need.

[0080] A compound containing a 3H-pyrazolo[4,3-f]quinoline moiety is provided, which binds to STING, inhibits STING function, and is tolerable in numerous mammalian cell lines at concentrations of 0.5 μM or higher. Such a compound, i.e., a STING activator or antagonist with a low cytotoxicity profile in numerous mammalian cell lines, may have more applicability to a wider range of indications than conventional compounds similarly containing a 3H-pyrazolo[4,3-f]quinoline moiety. While such a compound is not expected to be low in cytotoxicity in all cell lines, it is generally expected to exhibit low cytotoxicity in cell lines (e.g., raw macrophages, THP-1, and HEK-293 cell lines) (24-hour incubation) at least 1 μM. Alternatively, such a compound is expected to be tolerable for at least one week when chronically administered to animal models at concentrations sufficient to provide a systemic concentration (at least 50%) that binds to disease-controlling receptors.

[0081] Identification of compound HSD1077 as a STING binder Various compounds synthesized via Doebner-Povarov type multicomponent reactions were screened for STING inhibitors using a STING-based fluorescence polarization assay described in Karanja CW et al., RSC Chemical Biology, 2021, 2, 206-214 (with particular reference to the teachings therein, incorporated herein). Compound HSD1077 was able to compete with 50 nM of the fluorescent dye -c-di-GMP for STING binding, reaching a 50% inhibitory concentration (IC). 50 The concentration was 10.65 μM (see Figure 4). Compound HSD1077 is permeable into cells and can suppress the expression of type 1 interferon in both mouse RAW macrophages and human THP-1 monocytes.

[0082] SAR evaluation of compound HSD1077 analog The quinoline compound HSD1077 was identified as a novel scaffold capable of binding to STING and resulting in competitive substitution of a fluorescent cyclic dinucleotide ligand; therefore, prominent motifs within compound HSD1077 were identified as potentially playing a significant role in STING binding. The binding efficiency of the compound to STING was expressed in the form of the percentage of Fc-di-GMP binding, with a low percentage of binding probes (fluorescent dye-c-di-GMP) suggesting a strong STING binding agent (see Figure 5). The importance of the 3H-pyrazolo[4,3-f]quinoline moiety containing ring A to STING binding was determined, and compounds that function as isostears of the hit compound with significant changes around ring A were generated (Figure 5(A)). As a preliminary screen, 20 μM of the compound and 50 nM of the probe were incubated with 10 μM STING for 5 minutes, and then fluorescence anisotropy was evaluated. As a positive control, incubation was also performed with the potent STING-binding agonist ADU-S100 and DiABZI compound 3 (hereinafter referred to as DIABZI-3), resulting in the expected strong probe substitution from STING.

[0083] The pyrazollo moiety of ring A was observed to be crucial for the STING bond. Deletion of the pyrazollo moiety in compound HSD1077, as shown in analogue 1, resulted in the loss of the STING bond. Direct substitution of the pyrazollo moiety with dimethoxy or dioxolo moieties (compounds 2 and 3, see Figure 5) also resulted in a significant reduction in the STING bond compared to compound HSD1077. Fluorine substitution at position 5 of the 3H-pyrazolo[4,3-f]quinoline moiety (compound 4, Figure 5) was acceptable and resulted in a slight reduction in the STING bond compared to compound HSD1077. Changes to the pyrazollo moiety in compound HSD1077 to pyrrolo (compound 5, Figure 5) or imidazo (compound 6, Figure 5) also resulted in a significant reduction in the STING bond, highlighting the essential role of the pyrazollo moiety in effective STING bonding. Interestingly, another pyrazolo-containing compound, 1H-pyrazolo[4,3-h]quinoline (compound 7, Figure 5), was inferior as a STING binder compared to compound HSD1077, a 3H-pyrazolo[4,3-f]quinoline-containing compound. The 3-methyl-3H-pyrazolo[4,3-f]quinoline compound (compound 8, Figure 5) did not bind to STING as well as compound HSD1077, suggesting that the different functional group orientations of compound HSD1077 are important for STING binding.

[0084] Compound HSD1077 contains a saturated six-membered ring (labeled as ring B in Figure 6A), and the essentiality of this portion was determined. Substitution of the cyclohexyl ring with an ethyl or cyclopropyl group resulted in a decrease in the STING bond in the case of compounds 9 and 10 (Figure 6A). As seen in compounds 11 and 12 (Figure 6A), other ring systems (cyclopentyl ring or cycloheptyl ring) restored the STING bond, with compound 11, which has a cyclopentyl ring, having a slightly lower ability to bind to STING compared to compound HSD1077. As seen in compounds 13 and 14 (Figure 6A), the incorporation of heteroatoms (e.g., O and S) into the saturated heterocyclyl ring reduced the STING bond. Regarding substituents on the cyclohexyl ring, the incorporation of nonpolar substituents (e.g., the methyl group in compound 15 (Figure 6A)) did not affect the STING bond. However, polar substituents (e.g., nitrile, amine, or alcohol moieties) (e.g., compounds 16, 17, and 18 (Figure 6A)) were not very acceptable with respect to the STING bond.

[0085] Modification of the pyrazole ring C was investigated, and the pyrazole ring was substituted with other heterocycles (Figure 7A). The deletion of the pyrazole ring in compound 19 (Figure 7A) resulted in a significant decrease in STING binding, so the presence of the pyrazole ring was initially considered critical to STING binding. C-1 alkylation of the pyrazole ring was confirmed to reduce the compound's ability to bind to STING, as observed in compounds 20, 21, and 22 (Figure 7A) in the form of methyl, t-butyl, and trifluoromethyl substituents. Nitrogen transfer within the pyrazole ring also negatively affects STING binding, as shown in compounds 23 and 24 (Figure 7A). Substitution from pyrazole to triazole also resulted in a similar decrease in STING binding, as shown in compound 25 (Figure 7A). Substitution of the pyrazole moiety with nitrogen-containing aryl moieties (e.g., pyridine and pyrimidine groups), as in the case of compounds 26 and 27 (Figure 7A), also negatively affects STING binding. Interestingly, as seen in analog compound 28 (Figure 7A), methylation of the pyrazole ring was confirmed to generally preserve the STING bond, suggesting that further modification of the 1-position of the pyrazole moiety may be permissible.

[0086] The compound HSD1077 reduces type 1 interferon expression in mouse RAW macrophages. Compound HSD1077 was identified as a STING binder capable of competitively substituting cyclic dinucleotides, and it was determined whether treatment with compound HSD1077 modulates the cGAS-STING pathway through STING binding in cells. To understand the potential regulatory effects of compound HSD1077 on the cGAS-STING pathway, we quantified type I interferon expression after HSD1077 treatment in-cellulo via the commercially available mouse macrophage cell line RAW ISG Blue, which expresses secreted embryonic alkaline phosphatase (SEAP) under the control of the inducible promoter interferon-stimulating gene 54 (ISG54). Following stimulation of pathways that activate type I interferon production (e.g., cGAS-STING), SEAP was expressed and detected by the chromogenic detection substrate Quaniblue. (登録商標) This can be quantified using [specific method / tool]. Treatment of raw ISG-blue cells with compound HSD1077 did not induce type 1 interferon production, suggesting that compound HSD1077 does not function as an agonist in the cGAS-STING pathway (Figure 8A). Furthermore, pretreatment with compound HSD1077 (≤1 μM) before activating STING with the innate ligand cGAMP resulted in a dose-dependent decrease in type 1 interferon expression, suggesting that compound HSD1077 modulates cGAS-STING as a STING antagonist. Surprisingly, even at a low concentration of only 20 nM, a significant decrease in interferon expression occurred (Figure 8). As a second analysis, mouse interferon-β mRNA concentration was again quantified by quantitative PCR (qPCR) after cGAMP stimulation of raw macrophages with and without pretreatment with the compound HSD1077. Treatment with compound HSD1077 similarly showed a dose-dependent decrease in mouse interferon-β concentration compared to DMSO-treated cell samples stimulated with cGAMP, supporting the findings obtained through the Quantiblue assay (Figure 8B).

[0087] Treatment with the compound HSD1077 results in a decrease in the phosphorylation of interferon regulator 3 (IRF3) in RAW macrophages. Considering that IRF3 phosphorylation is a key feature of the STING-TBK1-IRF3 pathway, we also investigated and compared the phosphorylation of STING and IRF3 in raw ISG cell samples treated with and untreated with compound HSD1077. Our results showed that pretreatment with 5 μM compound HSD1077 for 4 hours before cGAMP stimulation reduced the concentrations of phosphorylated STING and phosphorylated IRF3 compared to DMSO+cGAMP-treated samples, supporting previous studies that inhibiting the STING pathway is one of the mechanisms of action that suppresses type I interferon (Figure 9).

[0088] The compound HSD1077 reduces type 1 interferon expression in human THP-1 monocytes. Mouse STING (mSTING) and human STING (hSTING) are isoforms with only 61% amino acid sequence agreement in their ligand-binding domains (Acta Pharm. Sin. B, 2020, 10, 2272-2298). Therefore, these essential differences may lead to differences between mSTING and hSTING in terms of drug binding and interaction with STING. This was demonstrated in the case of an mSTING agonist where the lack of bulk in the G230 region allowed the DMXAA molecule to move freely from the hSTING binding site, preventing the induction of an agonist effect in hSTING. The compound HSD1077 was investigated to determine whether it similarly inhibits type 1 interferon expression after cGAMP stimulation in human THP-1 monocytes. By using a THP-1 dual cell line (Invivogen) possessing the luciferase gene under the control of an ISG54-inducible promoter, relative quantification of type 1 interferon expression was possible by detecting luciferase after induction of the cGAS-STING pathway. As a result, pretreatment of THP-1 monocytes with the compound before cGAMP stimulation resulted in a dose-dependent decrease in type 1 interferon expression, similar to the results obtained with pretreatment of mouse RAW macrophages (see Figure 10A). This indicates that the compound HSD1077 can reduce type 1 interferon in both mouse and human cell lines and can target both mSTING and hSTING.

[0089] In autoimmune diseases characterized by chronic inflammation (e.g., SAVI), possible contributing factors include the expression of structurally active STING variants such as N154S or V155M STING isoforms. This leads to chronic upregulation of type 1 interferon expression without the need for ligand activation, resulting in undesirable inflammatory symptoms. Therefore, it was investigated whether the compound HSD1077 could reduce type 1 interferon expression in cell models constitutively expressing active STING isoforms. THP-1 dual cells constitutively expressing active STING (N154S) isoforms via knock-in were treated with compound HSD1077, and the expression of the corresponding luciferase was detected. Furthermore, THP-1 dual monocytes expressing the knock-in STING (N154S) phenotype were treated with compound HSD1077 for 24 hours, and the expressed Lucia luciferase was detected using the luminescent reagent QuantiLuc. (登録商標) Quantitative analysis using [method / tool ​​name] revealed a mild suppression, with a 42% reduction in luminescence intensity compared to the DMSO control (Figure 10B). This suggests that compound HSD1077 can indeed regulate type 1 interferon expression via STING inhibition through prolonged treatment. [Examples]

[0090] The following embodiments are for illustrative purposes only. The embodiments are not intended to limit in any way the scope of the inventions described in the claims. Assay: hSTING expression and affinity purification A cloning plasmid containing the hSTING gene (PET28a, SUMO) was used in *Escherichia coli* Rosetta (登録商標)Cells were transformed into 2(pLysS) cells. Kanamycin (50 μg / mL) and chloramphenicol (32 μg / mL) were used as selectors. Single colonies were selected and cultured in 10 mL of LB medium (containing the selectors) and incubated overnight at 37°C. The culture medium was then inoculated into 1 L of Terrific broth supplemented with kanamycin and chloramphenicol, and cultured at 37°C until the logarithmic growth phase (OD600 = 0.6) was reached. Protein expression was observed using isopropyl-β- D -HSTING was induced by adding thiogalactopyranoside to a final concentration of 1 mM. The culture medium was incubated at 25°C for 18 hours. The obtained cells were centrifuged at 5000 rpm for 30 minutes to precipitate. The resulting cell precipitate was then resuspended in 25 mL of cell lysis buffer (50 mM Na3PO4, 300 mM NaCl, 20 mM imidazole, 5 mM 2-mercaptoethanol, 10% glycerol, and a 1x cOmplete protein inhibitor cocktail). The cells were sonicated and lysed, and the lysate was centrifuged at 22000 rpm for 25 minutes, followed by collection of the supernatant. The supernatant containing hSTING was purified by passing it through a HisTrap-HP column, and pure hSTING was eluted with an elution buffer containing 50 mM Na3PO4 (pH=7.4), 300 mM NaCl, 300 mM imidazole, 5 mM 2-mercaptoethanol, and 10% glycerol. The purified hSTING was dialyzed for 24 hours in a dialysis buffer containing 50 mM Na3PO4 (pH=7.4), 300 mM NaCl, 5 mM β-mercaptoethanol, and 10% glycerol to remove imidazole, and the absorbance was measured at λ=280 nm (ε=47955M). -1 cm -1 Quantified by ).

[0091] STING-based fluorescence polarization assay 50 nM 2'-Fluo-AHC-c-diGMP (Biolog) was incubated with 10 μM hSTING and 20 μM screening compound / dimethyl sulfoxide (DMSO) in 1x phosphate-buffered saline at room temperature for 5 minutes. The fluorescence polarization (λ) was then applied.ex / em The fluorescence (485 / 528 nm) was quantified using a Biotek Cytation5 multimode reader, and anisotropy was calculated using a Gen5 microplate reader and imaging software. Anisotropy was normalized by setting the measurement at 0 μM hSTING to zero. The experiment was performed three times using a 384 Greiner-Bio 384 fluorescence analysis plate (flat bottom). Anisotropy was expressed by the following formula: [ka] (In the formula, r refers to the anisotropy value at hSTING with a concentration of 10 μM after compound addition, r free ∫ refers to the anisotropy value of the unbound fluorescent dye, and Q refers to the ratio of fluorescence intensities of the bound and free fluorescent dyes. The binding ratio was converted to Fc-di-GMP using ∫(∫). The change in anisotropy with increasing concentration of compound HSD1077 was plotted, and a four-parameter dose-response model was applied using GraphPad Prism (San Diego, CA, USA). The reported IC50 was used to determine the reported IC50. 50 The value was calculated.

[0092] Cell viability of RAW ISG Blue reporter cells after treatment with compound HSD1077 RAW ISG Blue macrophage reporter cells (Invivogen) were cultured in DMEM (containing 10% heat-inactivated fetal bovine serum and 1x penicillin / streptomycin) at 37°C and 5% CO2. 2x10 3 Cells were seeded in a 96-well plate and incubated for 24 hours to allow adhesion. The cells were then treated with increasing concentrations of compound HSD1077 for 24 hours. Following this, CellTiter-Blue cell viability assay reagent (Promega) was added, as recommended by the manufacturer, and incubated for 3 hours. Fluorescence (λ) was measured in each well. ex / em The wavelengths (560 / 590 nm) were quantified using a Biotek Cytation5 multimode reader. The experiment was performed in three biological duplicates, and the data were reported as the mean and standard deviation of the three data points. Readings from DMSO-treated cell samples were normalized to 100%.

[0093] Detection of IRF activation in RAW ISG Blue reporter cells Raw ISG Blue macrophage reporter cells (Invivogen) were cultured in DMEM (containing 10% heat-inactivated fetal bovine serum and 1x penicillin / streptomycin) at 37°C and 5% CO2. 5 Cells were seeded in a 96-well plate and incubated for 24 hours to allow adhesion. Subsequently, the cells were pre-treated with a drug compound for 2 hours, followed by the addition of 100 μM 2'-3'cGAMP to induce the cGAS-STING pathway, and incubated for another 24 hours. The medium from each well was then collected, and IRF activation was estimated using a SEAP colorimetric assay with QUANTI-blue reagent (Invivogen) in a clear 96-well flat-bottom plate, according to the manufacturer's protocol. 20 μL of medium from each well was then mixed with 180 μL of QUANTI-blue reagent. (登録商標) The solution was incubated at 37°C for 6 hours. The absorbance (630 nm) of each well was quantified using a Biotek Cytation 5 multimode reader. The experiment was performed in three biological duplicates, and the data were reported as the mean and standard deviation of the three data points.

[0094] Detection of IRF activation in THP-1 dual reporter cells THP-1 dual or THP-1 (STING N154S) dual reporter cells (Invivogen) were cultured in RPMI medium (containing 10% heat-inactivated fetal bovine serum and 1x penicillin / streptomycin) at 37°C and 5% CO2. 1x10 5 Cells were seeded in a 96-well plate and incubated for 24 hours. Subsequently, the cells were pre-treated with a drug compound for 1 hour, followed by treatment with 100 μM 2'-3'cGAMP to induce the cGAS-STING pathway, and incubated for another 24 hours. The cell suspensions from each well were then collected and quent into QUANTI-Luc (登録商標)IRF activation was relatively quantified using a Lucia luciferase-based luminescence assay with reagent (Invivogen). 10 μL of cell suspension obtained from each well was mixed with 50 μL of QUANTI-Luc. (登録商標) The solution was then added. Endpoint luminescence measurements were then performed using a Biotek Cytation5 multimode reader with a start time of 4 seconds and a reading time of 0.1 seconds. The experiment was performed in three biological duplicates, and the data were reported as the mean and standard deviation of the three data points.

[0095] Evaluation of interferon-β mRNA concentration in RAW cells via qPCR Raw ISG Blue macrophages were cultured in DMEM (containing 10% heat-inactivated fetal bovine serum). 1 x 10 6 Cells were seeded in 6-well plates and incubated for 24 hours to allow adhesion. After 24 hours, cells were pre-treated with compound HSD1077 or compound H-151 for 6 hours, followed by further treatment with 100 μM 2'-3'cGAMP for 3 hours. Cells were then harvested, and RNA extraction was performed using TRIzol reagent (Thermo-Fisher). Using 1 μg of RNA extracted from each sample, cDNA synthesis was performed using random hexamers, dNTPs, and Superscript II reverse transcriptase (Thermo Fisher). For qPCR analysis, 2x Quanti-tect SYBR Green master mix (Qiagen) was used, as recommended by the manufacturer. Forward and reverse primers were used for the relative quantification of interferon-β and β-actin, as reported in Wiser C, Science Reports, 2020, 10, 1-11 and Wang M, ACS Chemical Biology, 2021, 16, 1663-1670 (with the relevant teachings being incorporated herein by special reference).

[0096] Evaluation of phosphorylated interferon regulator 3 (pIRF3) concentration in RAW cells via Western blotting. 0.5~1X106 Raw ISG cells were seeded in 6-well plates. After 24 hours, cells were treated with compound HSD1077 or H151 for 4 hours, followed by treatment with 100 μM 2',3'-cGAMP for 3 hours. Cells were then collected in RIPA cell lysis buffer (50 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 0.1% sodium dodecyl sulfate (SDS), 0.5% sodium deoxycholate) with a protease inhibitor cocktail (Roche) and 1 mM phenylmethylsulfonyl fluoride. After sonication, cells were centrifuged at 14000xg for 15 minutes, and the supernatant was collected. Protein quantification was performed using the Pierce Rapid Gold BCA protein assay kit (Thermo-Fisher). Next, 10% SDS polyacrylamide gel electrophoresis was performed, and the proteins were then transferred to a polyvinylidene difluoride (PVDF) membrane. The membranes were probed overnight at 2–8°C with pSTING (CST #50907), STING (CST #13647), pTBK1 (CST #5483), TBK1 (CST #3013), pIRF3 (CST #E7J8G), IRF3 (CST #4302), and β-actin (CST #8457) antibodies. After overnight incubation, the membranes were further incubated at 37°C for 2 hours with the corresponding horseradish peroxidase (HRP) conjugate secondary antibody. SuperSignal West Pico PLUS chemiluminescent substrates were used for signal detection on the Azure300 imaging system.

[0097] The solvents and reagents were obtained from commercial sources and used without further purification. 1 H and 13 13C NMR spectra were obtained in methanol-d4 or DMSO-d6 using a Bruker AV500 (500 MHz) or AV800 (800 MHz) spectrometer with tetramethylsilane as an internal standard. 1¹H NMR data were reported as chemical shifts (δ ppm) (multiplicity, coupling constant (Hz), integral value). Chemical shifts were shown in parts per million (δ ppm) in downfield order. Multiplicity was reported as s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, m=multiplet, or a combination thereof. Electron spray ionization (ESI) and TOF mass spectrometry were used to record high-resolution mass spectra (HRMS). All synthetic compounds were analyzed. 1 H, 13 It was characterized using C and HRMS.

[0098] The quinoline compound was prepared using a procedure well known in the art (Dayal et al., European Journal of Medicinal Chemistry, 2019, 180, 449-456; the instructions relating thereto are incorporated herein by special reference).

[0099] General procedure In a screw-top glass vial, the corresponding amine (1 mmol) and aldehyde (1 mmol) were refluxed in anhydrous ethanol (5 mL) for 2 hours. The reaction mixture was then cooled to room temperature, followed by the addition of the corresponding ketone (2.5 mmol) and a catalytic amount of concentrated hydrochloric acid. The reaction was further refluxed for 6–12 hours. Immediately after the completion of the reaction, the reaction mixture was concentrated and purified using silica gel column chromatography (hexane:ethyl acetate = 50:50–0:100) or ethyl acetate / methanol (99:01–80:20).

[0100] Example 1 7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine (compound HSD1077) [ka] This compound was prepared using procedures well-known in the art (Dayal et al., Future Medicinal Chemistry 2018, 10, 823-835, the teachings of which are hereby expressly incorporated by reference in their entirety).

[0101] Example 2 6-(1H-Pyrazol-4-yl)-7,8,9,10-tetrahydrophenanthridine (Compound 1)

Chem.

[0102] Example 3 2,3-Dimethoxy-6-(1H-pyrazol-4-yl)-7,8,9,10-tetrahydrophenanthridine (Compound 2)

Chem.

[0103] Example 4 7-(1H-ピラゾール-4-イル)-8,9,10,11-テトラヒドロ-[1,3]ジオキソロ[4,5-a]フェナントリジン (Compound 3)

change

[0104] Example 5 7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,2-a]phenanthridine (compound 4) [ka] Yellow solid (147 mg, 51%). 1 H NMR (500MHz, DMSO-d6)δ 12.38(s, 1H), 8.37(s, 2H), 8.13 - 7.93(m, 2H), 7.72 - 7.54(m, 1H), 7.15(s, 1H), 3.39(t, J=6.4 Hz, 2H), 2.97(t, J=6.2 Hz, 2H), 2.02 - 1.93(m, 2H), 1.82 - 1.76(m, 2H); 13 C NMR (200MHz, DMSO-d6)δ 150.92, 144.49, 140.42, 135.86, 134.05, 133.38, 131.51, 128.59, 126.0 8, 122.16, 119.80, 115.93, 114.52, 106.42, 31.00, 28.12, 21.98, 21.78. HRMS(ESI)m / z calculated value C 18 H 17 N4[M+H] + 289.1453, measured value 289.1451.

[0105] Example 6 7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-amine (compound 5) [ka] Light brown solid (80 mg, 27%). 1H NMR (800MHz, DMSO-d6) δ 8.59 - 8.47 (m, 3H), 8.27 (d, J=9.2 Hz, 1H), 8.07 (d, J=9.3 Hz, 1H), 3.78 - 3.59 (m, 2H), 3.03 - 2.90 (m, 2H), 1.99 - 1.87(m, 2H), 1.83 - 1.75(m, 2H); 13 C NMR(200MHz, DMSO-d6)δ 152.88, 145.51, 142.11, 140.01, 136.34, 134.55, 132.16, 129.47, 119.54, 116.19, 112.73, 31.20, 27.90, 21.68, 21.45. HRMS(ESI)m / z Calculation Value C 17 H 16 N5[M+H] + 290.1405, measured value 290.1405.

[0106] Example 7 5-(1H-ピラゾール-4-イル)-6,7,8,9-テトラヒドロ-3H-ピラゾロ[4,3-c]フェナントリジン (Compound 6)

change

[0107] Example 8 [[ID=⑤]] 3-Methyl-7-(1H-pyrazol-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine (Compound 7)

Chem.

[0108] Example 9 9-Cyclopropyl-7-(1H-pyrazol-4-yl)-3H-pyrazolo[4,ʒ-f]quinoline (Compound 8)

Chem.

[0109] Example 10 9-Ethyl-7-(1H-pyrazol-4-yl)-3H-pyrazolo[4,3-f]quinoline (Compound 9)

Chemical Structure

[0111] Example 12 7-(1H-pyrazole-4-yl)-3,8,9,10,11,12-hexahydrocyclohepta[c]pyrazolo[4,3-f]quinoline (compound 11) [ka] Brown solid (39 mg, 15%). 1H NMR (methanol-d4) δ7.96(s, 1H), 7.56(s, 2H), 7.19(d, J=4,35 Hz, 1H) 6.86(d, J=4.4Hz, 1H), 4.04(d, J=4.0 Hz, 1H), 3.03(d, J=4.3 Hz, 1H), 2.85(d, J=1.6 Hz, 1H), 2.23(t, J=8.3 Hz, 1H), 1.72-1.74(m, 2H), 1.60 - 1.65(m,2H), 1.36 - 1.38(m, 1H), 1.10(d, J=5.0 Hz, 1H); 13 ¹³C NMR (125 MHz, methanol-d4): δ 149.73, 143.70, 142.13, 139.91, 138.49, 136.15, 129.62, 129.17, 128.90, 121.64, 121.00, 116.55, 114.16, 49.06, 29.85, 28.66, 22.64, 22.48. HRMS(ESI)m / z calculated value C 18 H 17 N5[M+H] + 304.1562, measured value 304.1563.

[0112] Example 13 7-(1H-pyrazole-4-yl)-3,8,10,11-tetrahydropyrano[3,4-c]pyrazolo[4,3-f]quinoline (compound 12) [ka] White solid (75 mg, 26%). 1 H NMR (500MHz, methanol-d4): δ 8.55(s, 1H), 8.07(s, 2H), 7.84-7.91(m, 2H), 4.99(s, 2H), 4.22(t, J=4.4Hz, 2H) 3.41(brs, 2H); 13 ¹³C NMR (125 MHz, methanol-d4): δ 149.87, 146.49, 145.79, 143.68, 139.77, 136.12, 132.18, 128.68, 128.06, 127.39, 120.99, 119.91, 76.08, 66.82, 64.04, 54.83, 31.66, 29.03, 29.00, 28.61. HRMS(ESI)m / z calculated value C 16 H 13 N5O [M+H] + 292.1198, measured value 292.1200.

[0113] Example 14 7-(1H-pyrazole-4-yl)-3,8,10,11-tetrahydropyrazolo[4,3-f]thiopyrano[3,4-c]quinoline (compound 13) [ka] Light brown solid (120 mg, 38%). 1 H NMR (500MHz, DMSO-d6): δ 8.56(s, 1H), 8.22(brs, 1H), 8.11(brs, 1H), 7.81 - 7.87(m, 2H), 4.11(s, 2H), 3.59(brs, 2H), 3.13(t, J=6.0 Hz, 2H); 13 C NMR (125MHz, DMSO-d6): 148.93, 144.06, 141.91, 138.64, 136.30, 129.61, 126.76, 121.38, 121.01, 116.25, 114.86, 31.44, 29.04, 25.66. HRMS(ESI)m / z calculated value C 16 H 13 N5S [M+H]w + 308.0969, measured value 308.0974

[0114] Example 15 9-methyl-7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine (compound 14) [ka] Yellow solid (118 mg, 39%). 1H NMR (500MHz, DMSO-d6): δ 8.49(s, 1H), 8,17(brs, 1H), 8.05(brs, 1H), 7.81(s, 2H), 3.21-3.27(m, 1H), 3.00(dd, J =8.3Hz, 3.7Hz, 1H), 2.63-2.68(m, 1H), 2.09(brs, 1H), 1.82(brs, 1H), 1.55(hept, J=6.0 Hz, 1H), 1.11(d, J=6.5 Hz, 3H); 13 C NMR (125MHz, DMSO-d6): δ149.72, 143.71, 141.80, 140.03, 138.49, 136.14, 129.56, 128.63, 121.63, 120.82, 116.58, 114.19, 36.89, 30.43, 29.79, 28.58, 22.08. HRMS(ESI) m / z calculated value C 18 H 17 N5[M+H] + 304.1562, measured value 304.1560.

[0115] Example 16 7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrrolo[3,4-a]phenanthridine-9-carbonitrile (compound 15) [ka] Light brown solid (116 mg, 37%). 1 H NMR (500MHz, methanol-d4): δ 8.51(s,1H), 8.22(brs, 1H), 8.05(brs, 1H), 7.82-7.88(m, 2H), 5.73(s, 1H), 4.92(s, 2H), 3.94(quin, J=6.1 Hz, 2H), 2.16(s, 2H); 13 ¹³C NMR (125 MHz, methanol-d4): δ 169.01, 147.93, 147.59, 144.13, 140.04, 138.53, 135.87, 129.43, 126.22, 120.82, 120.56, 116.36, 115.02, 55.36, 47.28, 29.71, 21.46. HRMS(ESI) m / z calculated value C 18 H 14 N6[M+H] + 315.1358, measured value 315.1358.

[0116] Example 17 2-(7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-yl)isoindoline-1,3-dione (compound 16) [ka] Off-white solid (191 mg, 44%). 1 H NMR (800MHz, DMSO-d6)δ 8.78 - 8.66 (m, 1H), 8.43 - 8.21 (m, 3H), 8.16 (s, 1H), 7.96 - 7.77 (m, 4H), 4.65 - 4.50 (m, 1H), 3.78 - 3.65(m, 2H), 3.60(s, 1H), 3.24(dd, J=16.3, 5.1 Hz, 1H), 2.86 - 2.66(m, 1H), 2.43 - 2.26(m, 1H); 13 C NMR (200MHz, DMSO-d6)δ 168.37, 145.76, 138.71, 136.17, 134.70, 132.15, 128.66, 123.46, 123.34, 121.47, 118.25, 115.45, 46.51, 31.19, 30.76, 25.36. HRMS(ESI)m / z calculated value C 25 H 19 N6O2[M+H] + 435.1569, measured value 435.1565.

[0117] Example 18 7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-imidazo[4,5-a]phenanthridine (compound 17) [ka] Synthesized from compound 16. In a 20 mL reaction vial, compound 16 (150 mg, 0.34 mmol) was dissolved in methanol (4 mL), followed by the addition of hydrazine monohydrate (0.5 mmol). The reaction was refluxed for 5 hours. After the reaction was complete, the reaction was concentrated and dried, and purified by silica gel chromatography to obtain the desired deprotected compound. Off-white solid (79 mg, 75%). 1 H NMR (800MHz, DMSO-d6)δ 8.67 - 8.51(m, 3H), 8.22(s, 2H), 7.93(s, 2H), 3.57(s, 1H), 3.52 - 3.40(m, 2H), 3.36 - 3.29(m, 1H), 3.23 - 3.11(m, 1H), 2.49 - 2.40(m, 1H), 2.12 - 2.01(m, 1H); 13 C NMR (200MHz, DMSO-d6)δ 147.96, 146.45, 143.58, 141.84, 140.30, 138.61, 136.00, 131.28, 125.57, 120.64, 118.77, 115.85, 46.27, 32.26, 28.23, 25.82. HRMS(ESI)m / z calculated value C 17 H 17 N6[M+H] + 305.1514, measured value 305.1512.

[0118] Example 19 7-(1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-9-ol (compound 18) [ka] Off-white solid (100 mg, 26%). 1H NMR (500MHz, DMSO-d6) δ 8.54 (s, 1H), 8.12 (bs, 2H), 7.88 - 7.68 (m, 2H), 4.92 (d, J=3.3 Hz, 1H), 4.06 (td, J=7.2, 3.6 Hz, 1H), 3.47 - 3.26 (m, 2H), 3.19 (td, J=15.5, 14.4, 3.7 Hz, 1H), 2.91 (dd, J=16.5, 7.1 Hz, 1H), 2.14 (q, J=6.5 Hz, 1H), 1.93 (dq, J=12.7, 6.7, 5.9 Hz, 1H); 13 C NMR (125MHz, DMSO) δ 149.91, 143.78, 141.67, 138.53, 136.18, 129.47, 127.02, 121.51, 120.60, 116.53, 114.35, 64.71, 37.54, 30.26, 27.71. HRMS(ESI)m / z Calculation Value C 17 H 16 N5O [M+H] + 306.1354, measured value 306.1356.

[0119] Example 20 7-(1H-ピラゾール-3-イル)-8,9,10,11-テトラヒドロ-3H-ピラゾロ[4,3-a]フェナントリジン (Compound 19)

change

[0120] Example 21 7-(1-methyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine (compound 20) [ka] Off-white solid (64 mg, 21%). 1 H NMR (800MHz, DMSO-d6)δ 8.53(s, 1H), 8.44(d, J=5.3 Hz, 1H), 8.12(d, J=5.4 Hz, 1H), 8.03(t, J=7.3 Hz, 1H), 7.96(t, J=7.2 Hz, 1H), 3.98(s, 3H), 3.25 - 3.08(m, 2H), 2.94 - 2.83(m, 2H), 1.99 - 1.89(m, 2H), 1.83 - 1.75(m, 2H); 13 C NMR (200MHz, DMSO-d6)δ 148.71, 145.80, 140.35, 138.14, 137.32, 135.56, 133.22, 129.96, 123. 44, 121.49, 117.17, 116.65, 115.23, 39.25, 30.37, 28.12, 21.82, 21.74. HRMS(ESI)m / z calculated value C 18 H 18 N5[M+H] + 304.1562, measured value 304.1565.

[0121] Example 22 (4-methylpiperazine-1-yl)(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)methanone (compound 21) [ka] Method C: Off-white solid (510 mg, 4 mmol, 30%). 1 H NMR (500MHz, (CD3)2SO)δ 8.57(s, 1H), 7.86(d, J=9.0 Hz, 1H), 7.82(s, 1H), 7.61(d, J=7.9 Hz, 2H), 7.47(d, J=8.0 Hz, 2H), 3.53(s, 4H), 3.34(t, J=6.8 Hz, 2H), 2.79(t, J=6.3 Hz, 2H), 2.39 - 2.32(m, 4H), 2.22(s, 3H), 2.07 - 1.98(m, 2H), 1.77(m, 2H); 13 C NMR(126MHz, (CD3)2SO)δ 169.4, 156.1, 143.8, 142.5, 142.4, 135.8, 129.6, 129.5, 129.2, 128.1, 127.0, 122.1, 121.0, 116.3, 114.5, 55.0, 46.0, 29.7, 28.8, 22.6, 22.5. HRMS(ESI)m / z calculated value C 26 H 28 N5O [M+H] + 426.2289, measured value 426.2290.

[0122] Example 23 1-(4-(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzoyl)piperazine-1-yl)ethane-1-one (compound 22) [ka] Method C: Off-white solid (13.8 mg, 0.5 mmol, 5.7%). 1H NMR (500MHz, (CD3)2SO) δ 8.56 (s, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.81 (d, J=9.8 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.54 - 7.49 (m, 2H), 3.57 - 3.50 (m, 6H), 3.34 (q, J=9.8, 7.4 Hz, 4H), 2.79 (t, J=6.1 Hz, 2H), 2.05 - 1.97 (m, 5H), 1.79 - 1.73 (m, 2H); 13 C NMR(126MHz, (CD3)2SO)δ 169.7, 169.1, 156.1, 143.8, 142.6, 142.6, 135.5, 129.6, 129.6, 129.3, 127.2 , 122.1, 118.0, 116.5, 116.4, 114.5, 46.1, 41.4, 29.6, 28.8, 22.6, 22.5, 21.6. HRMS(ESI)m / z Calculation Value C 27 H 28 N5O2[M+H] + 454.2237, measured value 454.2241.

[0123] Example 24 4-(3,8,9,10,11,12-ヘキサヒドロシクロヘプタ[c]ピラゾロ[4,3-f ]キノリン-7-イル)フェニル)(4-メチルピペラジン-1-イル)メタノン(Compound 23)

change

[0124] Example 25 (4-Methylpiperazine-1-yl)(4-(3,8,9,10-tetrahydrocyclopenta[c]pyrazolo[4,3-f]quinoline-7-yl)phenyl)methanone (Compound 24) [ka] Method C: Off-white solid (71 mg, 31%). 1 H NMR(800MHz, (CD3)2SO)δ 8.51 - 8.44(m, 1H), 7.96(d, J=7.8 Hz, 2H), 7.94 - 7.84(m, 2H), 7.53(d, J=7.9 Hz, 2H), 3.65(s, 2H), 3.48(t, J=7.6 Hz, 4H), 3.28(t, J=7.5 Hz, 2H), 2.54(s, 1H), 2.41(s, 4H), 2.28(d, J=7.4 Hz, 2H), 2.26(d, J=8.8 Hz, 3H); 13 C NMR(201MHz, (CD3)2SO)δ 169.2, 151.2, 149.7, 145.0, 141.5, 136.1, 135.9, 135.0, 129.2, 128.9, 127.6 , 127.3, 119.4, 116.5, 115.0, 54.8, 47.5, 45.8, 41.9, 40.9, 33.5, 33.0, 24.9. HRMS(ESI)m / z calculated value C 25 H 26 N5O [M+H] +412.2132, measured value 412.2133.

[0125] Example 26 (4-Methylpiperazine-1-yl)(4-(3,8,10,11-tetrahydropyrano[3,4-c]pyrazolo[4,3-f]quinoline-7-yl)phenyl)methanone (Compound 25) [ka] Method C: Off-white solid (5 mg, 0.5 mmol, 4.7%). 1 H NMR (800MHz, (CD3)2SO)δ 8.60(s, 1H), 7.92(d, J=9.0 Hz, 1H), 7.86(d, J=9.3 Hz, 1H), 7.69 - 7.62(m, 2H), 7.53 - 7.48(m, 2H), 4.81(s, 2H), 4.16(t, J=5.9 Hz, 2H), 3.65(s, 2H), 3.40(t, J=6.1 Hz, 4H), 2.47 - 2.28(m, 4H), 2.24(s, 3H); 13 C NMR(201MHz, (CD3)2SO)δ 169.1, 152.9, 144.3, 140.8, 139.4, 138.8, 136.1, 135.7, 129.4, 129.2, 127.4 , 127.2, 121.4, 116.0, 115.1, 66.8, 64.3, 54.8, 47.3, 45.8, 41.8, 40.5, 28.6. HRMS(ESI)m / z calculated value C 25 H 26 N5O2[M+H] + 428.2081, measured value 428.2080.

[0126] Example 27 (4-(5-fluoro-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)(4-methylpiperazine-1-yl)methanone (compound 26) [ka] Method C: Off-white solid (37 mg, 0.38 mmol, 22%). 1 H NMR (800MHz, (CD3)2SO)δ 8.55(s, 1H), 7.71(d, J=10.0 Hz, 1H), 7.64(d, J=7.6 Hz, 2H), 7.50(d, J=7.0 Hz, 2H), 3.65(s, 2H), 3.30(s, 2H), 2.79(d, J=6.7 Hz, 2H), 2.34(d, J=68.6 Hz, 4H), 2.20(d, J=6.3 Hz, 3H), 1.99(q, J=6.6, 6.1 Hz, 2H), 1.74(q, J=6.2 Hz, 2H); 13 C NMR (201MHz, (CD3)2SO)δ 169.2, 157.8( 1 J=250 Hz), 156.1, 143.0, 141.9, 136.4, 135.8, 134.3, 130.7, 130.7, 129.5, 127.0 , 122.7, 112.9, 98.4, 55.1, 54.6, 47.5, 46.0, 41.8, 29.6, 28.8, 22.3, 22.2. HRMS(ESI)m / z calculated value C 26 H 27 FN5O [M+H] + 444.2194, measured value 444.2196.

[0127] Example 28 (2-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)(4-methylpiperazine-1-yl)methanone (Compound 27) [ka] Method C: Yellow solid (18 mg, 0.25 mmol, 8%). 1H NMR(500MHz, (CD3)2SO)δ 8.57(s, 1H), 7.86(d, J=9.0 Hz, 1H), 7.81(s, 1H), 7.47(t, J=5.1 Hz, 3H), 3.68(s, 2H), 2.81(t, J=6.4 Hz, 2H), 2.42 - 2.27(m, 5H), 2.22(d, J=7.7 Hz, 4H), 2.01(m, 2H), 1.82 - 1.71(m, 2H); 13 C NMR (126MHz, (CD3)2SO)δ 164.4, 161.1, 158.7(d, 1 J= 247 Hz), 154.8, 144.6(d, 3 J= 7.56 Hz), 143.8, 142.7, 142.4, 129.6, 129.2, 128.8, 126.1, 123.9(d, 2 J= 17.6 Hz), 122.3, 121.8, 116.7(d, 2 J= 21 Hz), 116.2, 55.2, 46.1, 456.0, 29.7, 28.7, 22.5, 22.5. HRMS(ESI)m / z calculated value C 26 H 27 FN5O [M+H] + 444.2194, measured value 444.2194.

[0128] Example 29 (3-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)(4-methylpiperazine-1-yl)methanone (Compound 28) [ka] Method C: Off-white solid (56 mg, 0.5 mmol, 25.3%). 1H NMR (500MHz, (CD3)2SO)δ 8.58(s, 1H), 7.88(d, J=9.1 Hz, 1H), 7.82(s, 1H), 7.52(t, J=7.6 Hz, 1H), 7.38 - 7.29(m, 2H), 3.56(s, 4H), 3.41 - 3.30(m, 2H), 3.27 - 3.11(m, 2H), 2.65(t, J=6.2 Hz, 2H), 2.46(s, 2H), 2.28(s, 3H), 2.00(p, J=6.5 Hz, 2H), 1.80(tq, J=9.2, 6.2, 4.4 Hz, 2H); 13 C NMR (126MHz, (CD3)2SO)δ 167.9, 160.4(d, 1 J= 245.7 Hz), 158.4, 151.6, 143.9, 142.4, 138.9, 138.3(d, 3 J= 7.56 Hz), 136.3, 132.1, 130.1, 130.0, 129.4, 123.4, 122.4, 116.4, 114.6(d, 2 J= 23 Hz), 54.6, 54.5, 45.6, 29.5, 27.4, 22.6, 22.2. HRMS(ESI)m / z calculated value C 26 H 27 FN5O [M+H] + 444.2194, measured value 444.2193.

[0129] Example 30 (2-Methoxy-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)(4-methylpiperazine-1-yl)methanone (Compound 29) [ka] Method C: Off-white solid (56 mg, 24%). 1H NMR (800MHz, (CD3)2SO)δ 8.57(s, 1H), 7.87 - 7.82(m, 1H), 7.82 - 7.74(m, 1H), 7.28(dd, J=7.4, 2.4 Hz, 1H), 7.12(s, 1H), 7.05(d, J=7.4 Hz, 1H), 3.74(d, J=2.5 Hz, 3H), 3.65(s, 2H), 3.38(d, J=18.1 Hz, 1H), 3.30(d, J=24.0 Hz, 2H), 2.67(dd, J=16.0, 7.9 Hz, 1H), 2.52 - 2.44(m, 2H), 2.43 - 2.27(m, 4H), 2.22(d, J=2.3 Hz, 3H), 2.04 - 1.92(m, 2H), 1.81(dd, J=14.1, 7.0 Hz, 1H), 1.75 - 1.68(m, 1H); 13 C NMR(201MHz, (CD3)2SO)δ 169.1, 156.8, 154.8, 143.5, 141.4, 138.6, 137.5, 136.2, 131.5, 130.5, 130.4, 129.4, 121.9, 119.2, 116.5, 114.0, 110.2, 55.9, 46.0, 29.3, 27.0, 22.6, 22.1. HRMS(ESI)m / z calculated value C 27 H 29 FN5O2[M+H] + 456.2394, measured value 456.2397.

[0130] Example 31 (2-Methoxy-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)(4-methylpiperazine-1-yl)methanone (compound 30) [ka] Method C: Off-white solid (77 mg, 0.75 mmol, 22.6%). 1H NMR (800MHz, (CD3)2SO)δ 8.61 - 8.53(m, 1H), 7.87(dd, J=9.0, 4.2 Hz, 1H), 7.84(s, 1H), 7.26(dd, J=7.6, 4.2 Hz, 1H), 7.22(d, J=4.1 Hz, 1H), 7.15 (dd, J=7.9, 3.8 Hz, 1H), 3.84 (d, J=4.4 Hz, 3H), 3.72 - 3.64 (m, 1H), 3.61 (d, J=16.7 Hz, 1H), 3.33 - 3.28 (m, 2H), 3.25 - 3.17(m, 2H), 2.80(q, J=6.1, 5.6 Hz, 2H), 2.34(m, 3H), 2.26 - 2.22(m, 1H), 2.21(d, J=4.3 Hz, 3H), 2.01(m, 2H), 1.76(m, J=6.1 Hz, 2H); 13 C NMR(201MHz, (CD3)2SO)δ 166.7, 156.3, 155.0, 143.5, 143.4, 142.4, 138.7, 136.3, 129.5, 129.3, 127.7, 125.5, 122. 0, 121.8, 116.5, 114.5, 112.6, 56.1, 55.1, 54.7, 46.6, 46.0, 41.3, 29.6, 28.7, 22.5, 22.4. HRMS(ESI)m / z calculated value C 27 H 30 N5O2[M+H] + 456.2394, measured value 456.2394.

[0131] Example 32 (4-Methylpiperazine-1-yl)(5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)thiophen-2-yl)methanone (Compound 31) [ka] Method C: Off-white solid (17 mg, 0.5 mmol, 7.9%). 1H NMR (800MHz, (CD3)2SO) δ 8.56 (s, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.57 (d, J=3.9 Hz, 1H), 7.40 (d, J=3.8 Hz, 1H), 3.68 (t, J=5.2 Hz, 4H), 3.34 (s, 2H), 3.11 (t, J=6.2 Hz, 2H), 2.39 (t, J=5.2 Hz, 4H), 2.23 (s, 3H), 2.05 - 2.00 (m, 2H), 1.89 - 1.85 (m, 2H); 13 C NMR(201MHz, (CD3)2SO)δ 162.8, 148.3, 147.8, 143.3, 143.2, 138.8, 138.4, 136.4, 129.7, 129.2, 128.9, 127.5, 122.0, 116.2, 115.0, 55.0, 45.9, 29.9, 28.9, 22.4, 22.2. HRMS(ESI)m / z Calculation Value C 24 H 26 N5OS [M+H] + 432.1852, measured value 432.1853.

[0132] Example 33 1-(4-(4-(8,9,10,11-テトラヒドロ-3H-ピラゾロ[4,3-a]フェナ(Compound 32)

change

[0133] Example 34 N-(1-(methylsulfonyl)piperidine-4-yl)-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzamide (compound 33) [ka] 1 H NMR (500MHz, DMSO): δ 8.58(s, 1H), 7.85(q, J=9.1 Hz, 2H), 7.68 - 7.61(m, 2H), 7.55 - 7.45(m, 2H), 3.64(d, J=100.5 Hz, 4H), 3.36(s, 2H), 3.19(s, 4H), 2.91(s, 3H), 2.80(t, J=6.1 Hz, 2H), 2.06 - 1.97(m, 2H), 1.77(q, J=5.7 Hz, 2H); 13 C NMR (126MHz, DMSO) δ 169.5, 156.1, 143.6, 142.6, 138.8, 136.5, 135.3, 129.7, 129.4, 127.2, 122.0, 116.4, 114.6, 45.9, 34.6, 28.9, 22.6, 22.5. HRMS(ESI), m / z calculated value C 26 H 27 N5O3S [M+H] + 490.1913, measured value 490.1917.

[0134] Example 35 Morpholino(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)methanone (compound 34) [ka] 1 H NMR (500MHz, DMSO) δ 8.57(s, 1H), 7.85(q, J=9.1 Hz, 2H), 7.66 - 7.58(m, 2H), 7.53 - 7.46(m, 2H), 3.63(s, 8H), 3.39 - 3.33(m, 2H), 2.79(t, J=6.1 Hz, 2H), 2.05 - 1.96(m, 2H), 1.76(q, J=5.4 Hz, 2H); 13 C NMR (126MHz, DMSO): δ 169.4, 156.2, 143.7, 142.6, 142.5, 138.7, 136.4, 135.4, 129.6, 129.4, 127.2, 122.0, 116.5, 114.6, 66.6, 31.2, 29.7, 28.9, 22.6, 22.5. HRMS(ESI), m / z calculated value C 25 H 24 N4O2[M+H] + 413.1978, measured value 413.1988.

[0135] Example 36 (4-Hydroxy-4-methylpiperidine-1-yl)(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)methanone (Compound 35) [ka] 1H NMR (500MHz, DMSO) δ 8.57 (s, 1H), 7.85 (q, J=9.1 Hz, 2H), 7.68 - 7.54 (m, 2H), 7.47 (d, J=8.0 Hz, 2H), 4.44 (s, 1H), 3.36 (s, 4H), 3.24 (s, 2H), 2.80 (t, J=6.1 Hz, 2H), 2.01 (d, J=6.5 Hz, 2H), 1.76 (d, J=6.3 Hz, 2H), 1.46 (s, 4H), 1.16 (s, 3H); 13 C NMR (126MHz, DMSO) δ 169.1, 142.6, 142.1, 136.3, 129.5, 126.8, 114.6, 40.5, 40.4, 40.3, 30.3, 28.9, 22.6, 22.5. HRMS (ESI), m / z calculation value C 27 H 28 N4O2[M+H] + 441.2291 The measured value is 441.2294.

[0136] Example 37 (1,1-ジオキシドチオモルホリノ)(4-(8,9,10,11-テトラヒドロ-3H -ピラゾロ[4,3-a]フェナントリジン-7-イル)フェニル)メタノン (Compound 36)

change

[0137] Example 38 ((2S,6R)-2,6-dimethylmorpholino)(4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)methanone (compound 37) [ka] 1 H NMR (500MHz, DMSO)δ 8.57(s, 1H), 7.85(q, J=9.1 Hz, 2H), 7.66 - 7.57(m, 2H), 7.52 - 7.44(m, 2H), 3.57(dd, J=12.7, 6.3 Hz, 3H), 3.36(d, J=6.4 Hz, 2H), 3.30(s, 2H), 2.80(t, J=6.1 Hz, 4H), 2.05 - 1.95(m, 2H), 1.76(q, J=5.6 Hz, 2H), 1.08(d, J=59.6 Hz, 6H); 13 C NMR (126MHz, DMSO)δ 169.1, 156.2, 143.7, 142.6, 142.4, 138.7, 136.4, 135.5, 129.6, 129.4, 127.3, 122.0, 116.5, 114.6, 71.7, 29.7, 28.9, 22.6, 22.5, 18.9. HRMS(ESI), m / z calculated value C 27 H 28 N4O2[M+H] + 441.2290, measured value 441.22922.

[0138] Example 39 (4-(3,8,9,10,11,12-hexahydrocyclohepta[c]pyrazolo[4,3-f]quinoline-7-yl)phenyl)(4-(methylsulfonyl)piperazine-1-yl)methanone (compound 38) [ka] 1 H NMR (500MHz, DMSO) δ 8.64 (s, 1H), 7.89 - 7.77 (m, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 3.74 (s, 2H), 3.56 (s, 4H), 3.20 (s, 4H), 3.05 - 2.98 (m, 2H), 2.91 (s, 3H), 1.93 - 1.83 (m, 4H), 1.69 - 1.61 (m, 2H); 13 C NMR(126MHz, DMSO)δ 169.5, 155.2, 148.9, 144.5, 143.1, 139.0, 135.6, 135.5, 135.0, 129.7, 127.3, 121.4, 116.2, 115.0, 45.9, 34.6, 31.5, 31.1, 27.4, 25.0. HRMS (ESI), m / z calculation value C 27 H 29 N5O3S [M+H] + 504.2069, measured value 504.2070.

[0139] Example 40 N-(2-スルファモイルエチル)-4-(8,9,10,11-テトラヒドロ-3H -ピラゾロ[4,3-a]フェナントリジン-7-イル)ベンズアミド(Compound 39)

change

[0140] Example 41 N-(2-(N-メチルスルファモイル)エチル)-4-(8,9,10,11-テトラヒドロ-3H-ピラゾロ[4,3-a]フェナントリジン-7-イル)ベンズアミド (Compound 40)

change

[0141] Example 42 N-methyl-N-(2-sulfamoylethyl)-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzamide (compound 41) [ka] 1 H NMR(500MHz, DMSO)δ 8.57(s, 1H), 7.85(d, J=4.9 Hz, 2H), 7.62(d, J=7.9 Hz, 2H), 7.51(d, J=7.7 Hz, 2H), 6.94(d, J=27.1 Hz, 2H), 3.75(d, J=89.0 Hz, 2H), 3.36(d, J=7.2 Hz, 4H), 3.01(s, 3H), 2.78(t, J=6.1 Hz, 2H), 2.00(tt, J=8.6, 4.6 Hz, 2H), 1.78 - 1.72(m, 2H); 13 C NMR (126MHz, DMSO)δ 170.7, 156.2, 143.6, 142.6, 142.4, 138.7, 136.4, 136.0, 129.7, 129.5, 127.1, 126.7, 122.0, 116.5, 114.5, 51.8, 43.1, 38.2, 28.9, 22.6, 22.5. HRMS(ESI), m / z calculated value C 24 H 25 N5O3S [M+H] + 464.1756, measured value 464.1761.

[0142] Example 43 7-(1-ethyl-3-isopropyl-1H-pyrazole-4-yl)-8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine (compound 42) [ka] 1H NMR (500MHz, MeOD) δ 8.60 (s, 1H), 7.85 (t, J=7.6 Hz, 2H), 7.73 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.43 (d, J=6.7 Hz, 2H), 3.00 (h, J=6.9 Hz, 1H), 2.77 (t, J=6.2 Hz, 2H), 2.09 (td, J=7.3, 4.6 Hz, 2H), 1.95 - 1.83 (m, 2H), 1.50 (t, J=7.2 Hz, 3H), 1.16 (d, J=7.0 Hz, 7H); 13 C NMR (126MHz, MeOD) δ 156.3, 143.2, 135.9, 131.3, 129.4, 128.4, 117.8, 116.2, 113.7, 46.2, 29.6, 28.2, 26.7, 22.2, 22.0, 21.3, 14.9. HRMS (ESI), m / z calculation value C 22 H 25 N5[M+H] + 360.2188, measured value 360.2189.

[0143] Example 44 7-(1-イソプロピル-3-メチル-1H-ピラゾール-4-イル)-8,9,10 ,11-Torotron-3H-ピラゾロ[4,3-a]フェナンTorotron (compound 43)

change

[0144] Example 45 (3-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)(4-(methylsulfonyl)piperazine-1-yl)methanone (compound 44) [ka] 1 H NMR (500MHz, DMSO) δ 8.59(s, 1H), 7.88(d, J=9.1 Hz, 1H), 7.83(d, J=9.0 Hz, 1H), 7.55(t, J=7.5 Hz, 1H), 7.46 - 7.35(m, 2H), 3.74(s, 1H), 3.52(s, 1H), 3.36(t, J=6.6 Hz, 2H), 3.30(s, 4H), 2.91(s, 3H), 2.64(s, 2H), 2.09 - 1.91(m, 2H), 1.79(s, 2H); 13 C NMR (126MHz, DMSO) δ 168.0, δ 159.35 (d, J=246.0 Hz), 151.7, 143.7, 142.5, 138.8, 138.0, 136.5, 132.2, 130.2, 130.1, 129. 5, 123.6, 122.4, 116.4, 115.0, 114.8, 45.8, 34.6, 29.5, 27.4, 22.6, 22.1. HRMS(ESI), m / z calculated value C 26 H 26 FN5O3S [M+H] + 508.1819, measured value 508.1817.

[0145] Example 46 3-Fluoro-N-(2-sulfamoylethyl)-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)benzamide (compound 45) [ka] 1 H NMR (500MHz, DMSO) δ 8.81(t, J=5.7 Hz, 1H), 8.59(s, 1H), 7.88(d, J=9.0 Hz, 1H), 7.84 - 7.74(m, 3H), 7.58(t, J=7.6 Hz, 1H), 6.96(s, 2H), 3.68(dt, J=8.4, 5.8 Hz, 2H), 3.30 - 3.26(m, 2H), 2.64 - 2.57(m, 2H), 1.98(p, J=6.1 Hz, 2H), 1.81 - 1.74(m, 2H), 1.25 - 1.18(m, 2H); 13 C NMR (126MHz, DMSO) δ 165.3, δ 159.46 (d, J=244.7 Hz), 151.6, 142.5, 136.6, 136.6, 136.5, 132.0, 132.0, 131.8, 131.6, 130.1, 129.5, 123.8, 122.4, 116.4, 114.9, 114.7, 54.1, 53.9, 40.4, 35.3, 29.5, 27.4, 22.5, 22.1. HRMS(ESI), m / z calculated value C 23 H 22 FN5O3S [M+H] + 468.1506, measured value 468.1505.

[0146] Example 47 (2-Fluoro-4-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)phenyl)(4-(methylsulfonyl)piperazine-1-yl)methanone (Compound 46) [ka] 1H NMR (500MHz, DMSO) δ 8.57 (s, 1H), 8.00 - 7.75 (m, 2H), 7.62 - 7.41 (m, 3H), 3.79 (t, J=5.0 Hz, 2H), 3.43 (t, J=5.0 Hz, 2H), 3.23 (t, J=5.2 Hz, 2H), 3.14 (t, J=5.0 Hz, 2H), 2.92 (s, 3H), 2.81 (t, J=6.1 Hz, 2H), 2.07 (s, 2H), 2.01 (qd, J=7.4, 4.4 Hz, 2H), 1.76 (h, J=5.5 Hz, 2H). HRMS (ESI), m / z calculation value C 26 H 26 FN5O3S [M+H] + 508.1819, measured value 508.1818.

[0147] Example 48 2-フルオロ-N-(2-スルファモイルエチル)-4-(8,9,10,11-テトラヒドロ-3H-ピラゾロ[4,3-a]フェナントリジン-7-イル)ベンズアミド (Compound 47)

change

[0148] Example 49 4-(4-(8,9,10,11-テトラヒドロ-3H-ピラゾロ[4,3-a]フェナントリジン-7-イル)ベンゾイル)ピペラジン-1-カルボキサミド (Compound 48)

change

[0149] Example 50 (4-(methylsulfonyl)piperazine-1-yl)(5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)pyridine-2-yl)methanone (compound 49) [ka] 1 H NMR(500MHz, DMSO)δ 8.80(dd, J=2.2, 0.9 Hz, 1H), 8.58(s, 1H), 8.18(dd, J=8.0, 2.2 Hz, 1H), 7.87(q, J=9.1 Hz, 2H), 7.74(dd, J=7.9, 0.8 Hz, 1H), 3.82 - 3.77(m, 2H), 3.64(t, J=5.0 Hz, 2H), 3.40 - 3.32(m, 3H), 3.25(t, J=5.2 Hz, 2H), 3.17(t, J=5.0 Hz, 2H), 2.92(s, 3H), 2.89 - 2.81(m, 3H), 2.08 - 1.98(m, 2H), 1.77(tt, J=8.8, 5.4 Hz, 2H); 13 C NMR (126MHz, DMSO)δ 167.2, 153.3, 153.0, 148.9, 143.8, 142.9, 138.8, 138.3, 137.6, 136.5, 129.8, 12 9.6, 123.3, 122.3, 116.4, 114.8, 46.7, 46.2, 45.7, 34.6, 29.7, 28.7, 22.5, 22.4. HRMS(ESI), m / z calculated value C 25 H 26 N6O3S [M+H] + 491.1865, measured value 491.1863.

[0150] Example 51 N-(2-sulfamoylethyl)-5-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)picolinamide (compound 50) [ka] 1H NMR (500MHz, DMSO) δ 9.10 (t, J=6.0 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.22 (dd, J=8.0, 2.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.86 (q, J=9.2 Hz, 2H), 6.99 (s, 2H), 3.76 (q, J=6.7 Hz, 2H), 3.29 (t, J=7.0 Hz, 4H), 2.80 (t, J=6.1 Hz, 2H), 2.05 - 1.96 (m, 2H), 1.81 - 1.72 (m, 2H); 13 C NMR(126MHz, DMSO)δ 164.3, 153.1, 149.2, 149.1, 143.9, 143.0, 139.4, 138.7, 129.7, 129.6, 122.4, 121.8, 116.3, 114.9, 54.1, 34.8, 29.7, 28.6, 22.5, 22.4. HRMS (ESI), m / z calculation value C 22 H 22 N6O3S [M+H] + 451.1552, measured value 451.1551.

[0151] Example 52 (4-(メチルスルホニル)ピペラジン-1-イル)(6-(8,9,10,11-テトラヒドロ-3H -ピラゾロ[4,3-a]フェナントリジン-7-イル)ピリジン-3-イル)メタノン (Compound 51)

change

[0152] Example 53 N-(2-sulfamoylethyl)-6-(8,9,10,11-tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-7-yl)nicotinamide (compound 52) [ka] 1 H NMR(500MHz, DMSO)δ 9.07(dd, J=2.3, 0.9 Hz, 1H), 8.91(t, J=5.7 Hz, 1H), 8.58(s, 1H), 8.33(dd, J=8.2, 2.3 Hz, 1H), 7.93(dd, J=8.1, 0.8 Hz, 1H), 7.90 - 7.82(m, 2H), 6.97(s, 2H), 3.75 - 3.67(m, 2H), 3.33 - 3.26(m, 4H), 2.95(t, J=6.2 Hz, 2H), 2.06(s, 1H), 1.98(qt, J=6.5, 3.3 Hz, 2H), 1.79 - 1.71(m, 2H); 13 C NMR (126MHz, DMSO)δ 165.4, 161.7, 153.9, 147.4, 143.0, 136.6, 136.1, 130.1, 129.6, 128.9, 124.6, 122.6, 116.4, 114.7, 54.0, 35.3, 31.2, 28.2, 22.5, 22.3. HRMS(ESI), m / z calculated value C 22 H 22 N6O3S [M+H] + 451.1552, measured value 451.1553.

[0153] The following terms and phrases used herein shall have the meanings set forth below. Unless otherwise defined, all technical and scientific terms used herein shall have the same meanings as those commonly understood by those skilled in the art.

[0154] The term "approximately" allows for a certain degree of variation in the value or range (for example, within 10%, 5%, or 1% of the stated limit of the stated value or range).

[0155] The term “substantially” allows for some variation in the value or range (e.g., within 90%, 95%, or 99% of the stated limit value or range).

[0156] The terms “a,” “an,” or “the” are used to include one or more unless the context clearly indicates otherwise. The term “or” is used to refer to a non-exclusive “or” unless otherwise specified. Furthermore, any expressions or terms used herein that are not defined elsewhere are for illustrative purposes only and not for limitation. Any use of section headings is intended to aid the reading framework of the document and should not be interpreted as limitation. Furthermore, information related to a section heading may be located within or outside that particular section. The terms “including” and “having” are defined as “comprising” (i.e., non-limiting words).

[0157] Those skilled in the art will understand that this disclosure is not limited to what is specifically shown and described above. Rather, the scope of this disclosure includes combinations and partial combinations of the various features described above, as well as variations and modifications that a person skilled in the art could conceive of by reading the specification and that are not included in the prior art.

[0158] All patents, patent application publications, academic articles, textbooks, and other publications referenced herein represent the state of the art for those skilled in the art. All such publications are incorporated herein by reference to the same extent that each individual publication is explicitly indicated as being incorporated by reference.

Claims

1. A method for treating or suppressing diseases associated with interferon gene-stimulating factor (STING) hyperactivity, wherein the therapeutically effective dose is given by formula (I): 【Chemistry 1】 [In the formula, R １ is selected from H, alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolineamide, pyrimidine carboxamide, imidazole carboxamide, pyrazole carboxamide, and any of the aforementioned derivatives; R ２ The elements are selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R ３ is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, and alkynyl; and Each X is independently O, S, SO, SO ２ , CRR’, CNRR’, COR’, NR’, and X ｎ selected from, where n is 0 to 2; each R and R’ is independently H, halogen, CF ３ , CN, alkyl, aryl, heteroalkyl, heteroaryl, CONRR ２ R ２ , COR ２ , SO ２ R ２ , (C=O)NR ２ , (C=NH)R ２ , (C=O)OR ２ , C ６ H ５ R ２ , morpholine, and piperazine, where R ２ is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle. A method comprising administering to a patient a compound represented by, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

2. Diseases associated with STING hyperactivity are selected from inflammatory diseases, autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis. The method according to claim 1.

3. Diseases associated with STING hyperactivity are inflammatory diseases. The method according to claim 2.

4. Formula (IA): 【Chemistry 2】 [In the formula, R ２ The elements are selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R ４ is selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolineamide, and any of the aforementioned derivatives; and R ４ OH, OR ２ , halogen, CF ３ ,CN,NRR',CONRR',SO ２ R ２ SO ２ NRR', NCOR ２ , or NSO ２ R ２ They may be substituted with H, halogen, CF ３ CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR ２ R ２ COR ２ SO ２ R ２ (C=O)NR ２ (C=NH)R ２ , (C=O) OR ２ , C ６ H ５ R ２ Selected from morpholine and piperazine, the R ２ is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle; R ５ is selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, wherein the amide is selected from sulfonamide, benzamide, nicotinamide, picolineamide, and any of the aforementioned derivatives; and R ５ OH, OR ２ , halogen, CF ３ ,CN,NRR',CONRR',SO ２ R ２ SO ２ NRR', NCOR ２ , or NSO ２ R ２ It may be replaced with, and the R ２ , R, and R' are as defined above; however, R ５ H, methyl, CF ３ ,CH ２ -CH ２ -OH, CH ２ -CH ２ - Rather than a phenyl group which may be substituted with Cl, COOH, or substituents OMe, COOMe, or amino; R ４ and R ５ They may be the same or different; and Each X is independently O, S, SO, SO ２ , CRR', CNRR', COR', NR', and X ｎ Selected from, where n is 0 to 2; each R and R' is independently H, halogen, CF ３ CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR ２ R ２ COR ２ SO ２ R ２ (C=O)NR ２ (C=NH)R ２ , (C=O) OR ２ , C ６ H ５ R ２ Selected from morpholine and piperazine, the R ２ is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle. The compound represented by, or its pharmaceutically acceptable salts, hydrates, tautomers, or optical isomers.

5. The compound represented by formula (IA) 【Transformation 3】 【Chemistry 4】 or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, The compound according to claim 4.

6. The compound represented by formula (IA) 【Transformation 5】 [In the formula, R ２ The elements are selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; Each R ４ and R ５ are independently selected from H, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkenyl, alkynyl, and amide, where the amide is selected from sulfonamide, benzamide, nicotinamide, picolinamide, and derivatives of any of the foregoing, and the alkyl is OH, OR ２ , halogen, CF ３ , CN, NRR', CONRR', SO ２ R ２ , SO ２ NRR', NCOR ２ , or NSO ２ R ２ and may be substituted with, and each R and R' are independently H, halogen, CF ３ , CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR ２ R ２ , COR ２ , SO ２ R ２ , (C=O)NR ２ , (C=NH)R ２ , (C=O)OR ２ , C ６ H ５ R ２ , morpholine, and piperazine, where the R ２ is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle; Each R ８ and R ９ These are independently selected from H, methyl, alkyl, and heteroalkyl; Each R １０ , R １１ , R １２ , and R １３ is independently selected from H, methyl, alkyl, and heteroalkyl; or R １０ and R １２ Together with the bonded atoms, they form a 4- to 6-membered ring or heterocycle; or R １１ and R １３ Together with the bonded atoms, they form a 4- to 6-membered ring or heterocycle; Z is O, S, SO, SO ２ Selected from CRR', CNRR', COR', and NR', where each R and R' is as defined above; Y is COR ２ SO ２ R ２ (C=O)NR ２ (C=NH)R ２ , (C=O) OR ２ , and C ６ H ５ R ２ Selected from, the R ２ [This is defined above.] or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, The compound according to claim 4.

7. Formula (IB): 【Transformation 6】 [In the formula, R ２ The elements are selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, alkynyl, and halogen; R ３ is selected from H, alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, and alkynyl; Each X is independently O, S, SO, SO ２ , CRR', CNRR', COR', NR', and X ｎ Selected from, where n is 0 to 2; each R and R' is independently H, halogen, CF ３ CN, alkyl, aryl, heteroalkyl, heteroaryl, CONR ２ R ２ COR ２ SO ２ R ２ (C=O)NR ２ (C=NH)R ２ , (C=O) OR ２ , C ６ H ５ R ２ Selected from morpholine and piperazine, the R ２ is as defined above; or R and R', together with the bonded atoms, form a 4- to 6-membered ring or heterocycle; Y is N or CR ２ And R ２ It is defined as above; n is either 0 or 1; Q is NR'', CR ２ R ２ , N (COR ２ ), N (SO ２ ) R ２ , N(C=O)NR ２ , N(C=NH)R ２ , and N(C=O)OR ２ Selected from, however, if Q is NR'', then R'' is H, methyl, isopropyl, CH ２ CH ２ OH, COCH ３ , or SO ２ - Not methyl; and Q is CR ２ R ２ If R ２ [It is not H or dimethylamine] The compound represented by, or its pharmaceutically acceptable salts, hydrates, tautomers, or optical isomers.

8. The compound represented by formula (IB) 【Transformation 7】 【Transformation 8】 【Chemistry 9】 or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, The compound according to claim 7.

9. structure: 【Chemistry 10】 The compound represented by formula (I) shown in , or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

10. A pharmaceutical composition comprising a compound represented by formula (I) as described in claim 9, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

11. A pharmaceutical composition comprising a compound represented by formula (IA) as described in any one of claims 4 to 6, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

12. A pharmaceutical composition comprising a compound represented by formula (IB) as described in any one of claims 7 to 8, or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

13. A method for treating or suppressing a disease associated with the hyperactivity of interferon gene stimulating factor (STING), comprising administering to a patient a therapeutically effective amount of a compound represented by formula (IA) as described in any one of claims 4 to 6, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

14. Diseases associated with excessive STING activity are selected from inflammatory diseases, autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis. The method according to claim 13.

15. Diseases associated with excessive STING activity are inflammatory diseases. The method according to claim 14.

16. A method for treating or suppressing a disease associated with the hyperactivity of interferon gene stimulating factor (STING), comprising administering to a patient a therapeutically effective amount of a compound represented by formula (IB) as described in any one of claims 7 to 8, or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, excipient, or diluent.

17. Diseases associated with excessive STING activity are selected from inflammatory diseases, autoimmune diseases, diabetes, cancer, traumatic brain injury, and fibrosis. The method according to claim 16.

18. Diseases associated with excessive STING activity are inflammatory diseases. The method according to claim 17.

Images