Cyclic benzimidazole derivatives as cGAS inhibitors

Abstract

The present invention provides compounds of formula I for the treatment of diseases such as systemic lupus erythematosus, systemic sclerosis (SSc), interferonosis, nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), and idiopathic pulmonary fibrosis (IPF). JPEG2025537531000121.jpg96150 (in the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are as defined in claim 1), and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

Description

[Background technology]

[0001] 1. Background of the Invention 1.1 cGAS inhibitors Innate immunity is considered the frontline cellular stress response, defending host cells from invading pathogens and initiating signaling to the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diverse pattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene expression. Major antigen-presenting cells, such as monocytes, macrophages, and dendritic cells, are critically important for producing type I interferons and inducing the adaptive immune system response in T and B cells. Major PRRs detect abnormal nucleic acids—that is, nucleic acids that are mislocalized, immature, or unmodified—on the cell surface, within the lysosomal membrane, or in other cellular compartments (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)).

[0002] "Cyclic GMP-AMP synthetase ( C yclic G MP- A MP S Synthase)" cGASUniProtKB-Q8N884)) is a major sensor for abnormal double-stranded DNA (dsDNA) originating from pathogens or from abnormal localization or processing of nuclear or mitochondrial cellular dsDNA (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). When dsDNA binds to cGAS, the reaction of GTP and ATP is activated to form a cyclic dinucleotide GMP-AMP (called cGAMP). Then, cGAMP becomes an interferon gene stimulator of an endoplasmic reticulum membrane-bound adapter protein. In terferon G enes)" STING It moves to ) and activates that protein. The activated STING then activates TANK-binding kinase ( T ANK- b inding k (inase) 1 ( TBK1 TBK1 mobilizes and activates interferon regulators that induce mRNA expression of cytokines and type I interferons. i nterferon r egulatory f actor) IRF It phosphorylates (phosphorylates) the transcription factor family of ).

[0003] The critically important role of cGAS in dsDNA sensing has been demonstrated in various pathogenic bacteria (Hansen et al., EMBOJ. 33, 1654 (2014)), viruses (Ma et al., PNAS 112, E4306 (2015)), and retroviruses (Gao et al., Science 341, 903-906 (2013)). In addition, cGAS is essential in various other biological processes, including cellular senescence (Yang et al., PNAS 114, E4612 (2017), Gluck et al., Nat. Cell Biol. 19, 1061-1070 (2017)) and the recognition of ruptured micronuclei in the surveillance of potential cancer cells (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)). While the cGAS pathway is important for host defense against invading pathogens, cellular stress and genetic factors can also trigger the production of abnormal cellular dsDNA, such as nuclear or mitochondrial leakage, which can lead to autoinflammatory responses. Eicardi-Gutierre syndrome (AGS; Crow et al., Nat. Genet. 38, 917-920 (2006)), a lupus-like severe autoinflammatory immune-mediated disorder, arises from loss-of-function mutations in the major DNA exonuclease TREX1, which causes the degradation of abnormal DNA in the cytosol. Knocking out cGAS in TREX1-deficient mice prevents an otherwise lethal autoimmune response, supporting the idea that cGAS is a driver of interferonosis (Gray et al., J. Immunol. 195, 1939-1943 (2015); Gao et al., PNAS 112, E5699-E5705 (2015)). Similarly, embryonic lethality caused by deficiency of DNAse2, an endonuclease responsible for the degradation of excess DNA in lysosomes during endocytosis, was completely rescued by additionally knocking out cGAS (Gao et al., PNAS 112, E5699-E5705 (2015)) or STING (Ahn et al., PNAS 109, 19386-19391 (2012)). These observations support cGAS as a drug target, suggesting that inhibiting cGAS could provide a therapeutic strategy to prevent autoinflammation and treat diseases such as systemic lupus erythematosus (SLE) involving anti-dsDNA antibodies (Pisetsky et al., Nat. Rev. Rheumatol. 12, 102-110 (2016)).

[0004] 1.2 Prior art Due to the observation that inhibiting the cGAS pathway can prevent autoinflammation and lead to therapeutic strategies for treating autoimmune diseases, for example, many attempts have been made to develop cGAS inhibitors. For example, in International Publication No. 2019 / 241787, methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylates such as CU-32 and CU-76 were found to be slightly below 1 μM in "in vitro hcGAS IC 50 Value (IC 50 (CU-32) = 0.66 μM and IC 50 It was disclosed as a cGAS inhibitor having (CU-76 = 0.27 μM). In Hall et al., PLoS ONE 12(9); e0184843 (2017), compound PF-06928215 was found to have a concentration of 0.049 μM in vitro hcGAS IC50 when measured by fluorescence polarization assay. 50 It was published as a cGAS inhibitor with a "-value". However, compound PF-06928215 did not exhibit the cellular activity acceptable for a cGAS inhibitor.

[0005] In International Publication Nos. 2020 / 142729 and 2022 / 174012, (benzoflo[3,2-d]pyrimidine-4-yl)pyrrolidine-2-carboxylic acid derivatives were disclosed as cGAS inhibitors for the treatment of autoimmune disorders such as Eicardi-Gutierre syndrome (AGS), lupus erythematosus, scleroderma, inflammatory bowel disease, and non-alcoholic steatohepatitis (NASH). However, the compounds of the present invention differ from the (benzoflo[3,2-d]pyrimidine-4-yl)pyrrolidine-2-carboxylic acid derivatives of International Publication No. 2020 / 142729, which have a completely different substitution pattern at the 4-position of the pyrrolidine ring. Recently provided cGAS inhibitors, such as those described in International Publication No. 2020 / 142729 or 2022 / 174012, typically exhibit insufficient cellular cGAS inhibitory efficacy (IC regarding inhibition of the cGAS / STING pathway). 50 The value is usually higher than 1 μM and often higher than 5 μM when measured in cell assays. However, to ensure that the compound can exert a therapeutic effect in patients, satisfactory biochemical (in vitro) inhibitory efficacy ("hcGAS IC") is required. 50) not only exhibit, but also exhibit satisfactory cell inhibitory potency (e.g., inhibition of IFN induction in virus-stimulated THP-1 cells (THP1 (vir) IC 50 )), it is critically important to provide therapeutic cGAS inhibitors. Another important property that allows one to anticipate successful development of cGAS inhibitors as therapeutic agents is satisfactory cGAS selectivity (against off-target activity) and acceptable inhibitory potency in human whole blood.

[0006] Surprisingly, it has now been found that the compounds of Formula I, II, or III simultaneously exhibit the following three properties: ·Satisfactory "biochemical (in vitro) IC for cGAS inhibition 50 value" (hcGAS IC of ≤100 nM, preferably ≤50 nM, particularly ≤10 nM 50 ), ·Satisfactory "inhibition of IFN induction in virus-stimulated THP-1 cells (THP1 IC of ≤1 μM, preferably ≤500 nM, more preferably ≤100 nM, particularly ≤50 nM 50(vir) ), and ·Satisfactory selectivity for cGAS inhibition (THP1 IC of ≥10, more preferably ≥50, more preferably ≥500, particularly ≥1000 50(cGAMP) / THP1 IC 50(vir) ratio).

[0007] In addition, the compounds of Formula I, II, or III also exhibit an acceptable IC for inhibition of IFN induction in a dsDNA-stimulated human whole blood assay 50 value, preferably a human whole blood IC for cGAS inhibition of ≤5000 nM, more preferably ≤1000 nM, particularly ≤100 nM 50 value (hWB IC 50 ).

[0008] The cGAS inhibitors of the present invention, possessing a pharmacological profile that combines excellent in vitro inhibitory efficacy and superior cell inhibitory efficacy with high selectivity for cGAS inhibition, are particularly likely to exhibit favorable therapeutic effects in patients. Due to their high cell inhibitory efficacy, compounds with this pharmacological profile, in particular, should be able to cross the cell membrane barrier and thus reach their intracellular target sites. Furthermore, due to their selectivity to exclusively inhibit cGAS activity, these compounds should not exhibit undesirable off-target effects, such as side effects or cytotoxic effects anywhere in the signaling pathway downstream of cGAS. [Overview of the project]

[0009] 2. Description of the present invention This invention relates to the compound of formula I, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. [ka] (In the formula, R 1 This is selected from the group consisting of hydrogen, halogen, methyl, ethyl, -CF3, -CHF2, CFH2, and methoxy. R 2 It is selected from the group consisting of hydrogen and methyl, R 3 It is selected from the group consisting of hydrogen, methyl, and halogen, A is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, -N(CH3)-, -NH-, and -CHCH3-. D is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, and -CHCH3-. E is selected from the group consisting of -CH2-, -O-, -C(CH3)2-, -CHF-, CF2-, and -CHCH3-. G is selected from the group consisting of -NH-, -NCH3-, -CH2-, -O-, -CF2-, -CHF-, -CHCH3-, and -C(CH3)2. J is selected from the group consisting of -CO-, -CH2-, -O-, -CHF-, -CF2-, and -CHCH3-. K is selected from the group consisting of -CH2-, -CF2-, and -O-, or is absent. L is selected from the group consisting of -CH2-, -O-, -CHCH3-, -CHF-, and -CF2-, or is absent.

[0010] This ensures that variables A, D, E, G, J, K, and L are preferably selected such that no two or more heteroatoms are directly adjacent to each other. In a preferred embodiment, the present invention is R 1 However, it is selected from the group consisting of hydrogen, Cl, and F, R 2 However, selected from the group consisting of hydrogen and methyl, R 3 However, it is selected from the group consisting of hydrogen, methyl, Cl, and F, A is selected from the group consisting of -CH2-, -O-, -CF2-, and -N(CH3)-. D is selected from the group consisting of -CH2-, -O-, and -CHCH3-. E is selected from the group consisting of -CH2-, -O-, and -C(CH3)2-. G is selected from the group consisting of -NH-, -CH2-, -O-, and -CHCH3-. J is selected from the group consisting of -CO-, -CH2-, -O-, and -CHCH3-. K is selected from the group consisting of -CH2-, -CF2-, and -O-, or is absent. The present invention relates to the compound of formula I, in which L is selected from the group consisting of -CH2- and -CF2-, or is absent, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0011] This ensures that variables A, D, E, G, J, K, and L are preferably selected such that no two or more heteroatoms are directly adjacent to each other. In a further preferred embodiment, the present invention relates to the above compound of formula I in which L is absent, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In a further preferred embodiment, the present invention relates to the compound of formula I, wherein L is absent and A is selected from the group consisting of -CH2- and -CF2-, as well as its prodrug, its pharmaceutically acceptable salt, or its deuterated analog. In a further preferred embodiment, the present invention relates to the compound of formula I, wherein L is absent and K is -CF2-, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In another preferred embodiment, the present invention is R 3 This invention relates to the above-mentioned compound of formula I, wherein is a halogen, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. This allows R 3 It is particularly preferable that the element is a halogen atom selected from the group consisting of Cl and F.

[0012] In a further preferred embodiment, the present invention is R 3 The present invention relates to the compound of formula I, wherein the compound is Cl or F and is located at the 5-position of the benzimidazole moiety, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In a further preferred embodiment, the present invention is R 1 This invention relates to the above-mentioned compound of formula I, wherein is a halogen, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In another preferred embodiment, the present invention is R 1 The present invention relates to the above-mentioned compound of formula I, wherein the compound is Cl or F, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In a further preferred embodiment, the present invention is R 1 This invention relates to the above compound of formula I, wherein the anode is hydrogen, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In another particularly preferred embodiment, the present invention [ka] [ka] This invention relates to the above compound of formula I, selected from the group consisting of the above, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0013] In a further preferred embodiment, the present invention is A is selected from the group consisting of -CH2- and -CF2-, D and E are -CH2-, G is selected from the group consisting of -CH2- and -O-. J is selected from the group consisting of -CH2- and -O-, K is selected from the group consisting of -CF2- and -CH2-, This invention relates to the above compound of formula I in which L is absent, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0014] In another particularly preferred embodiment, the present invention [ka] This invention relates to the above compound of formula I, selected from the group consisting of the above, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0015] In a further preferred embodiment, the present invention relates to the above compound of formula I, wherein R2 is methyl, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0016] In another particularly preferred embodiment, the present invention relates to a compound of formula II. [ka] or compounds of formula III, [ka] The present invention relates to its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. (In the formula, R 1 It is selected from the group consisting of hydrogen and halogens, R 3 It is selected from the group consisting of hydrogen, methyl, and halogen, A is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, -N(CH3)-, -NH-, and -CHCH3-. D is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, and -CHCH3-. E is selected from the group consisting of -CH2-, -O-, -C(CH3)2-, -CHF-, CF2-, and -CHCH3-. G is selected from the group consisting of -NH-, -NCH3-, -CH2-, -O-, -CF2-, -CHF-, -CHCH3-, and -C(CH3)2. J is selected from the group consisting of -CO-, -CH2-, -O-, -CHF-, -CF2-, and -CHCH3-. K is selected from the group consisting of -CH2-, -CF2-, and -O-, or is absent. L is selected from the group consisting of -CH2-, -O-, -CHCH3-, -CHF-, and -CF2-, or is absent.

[0017] This ensures that variables A, D, E, G, J, K, and L are preferably selected such that no two or more heteroatoms are directly adjacent to each other. R 1 However, it is selected from the group consisting of hydrogen, Cl, and F, R 3 However, it is selected from the group consisting of hydrogen, methyl, Cl, and F, A is selected from the group consisting of -CH2-, -O-, -CF2-, and -N(CH3)-, D is selected from the group consisting of -CH2-, -O-, and -CHCH3-. E is selected from the group consisting of -CH2-, -O-, and -C(CH3)2-. G is selected from the group consisting of -NH-, -CH2-, -O-, and -CHCH3-. J is selected from the group consisting of -CO-, -CH2-, -O-, and -CHCH3-. K is selected from the group consisting of -CH2-, -CF2-, and -O-, or is absent. The compounds of formula II or III, in which L is selected from the group consisting of -CH2- and -CF2-, or is absent, as well as their prodrugs, deuterated analogs, and pharmaceutically acceptable salts, are more preferred.

[0018] This ensures that variables A, D, E, G, J, K, and L are preferably selected such that no two or more heteroatoms are directly adjacent to each other.

[0019] The above-mentioned compounds of formula II, as well as their prodrugs, deuterated analogs, and pharmaceutically acceptable salts, are particularly preferred. [ka] (In the formula, R 1 It is selected from the group consisting of hydrogen, Cl, and F. R 3 It is selected from the group consisting of hydrogen, methyl, Cl, and F. A is selected from the group consisting of -CH2-, -O-, -CF2-, and -N(CH3)-, D is selected from the group consisting of -CH2-, -O-, and -CHCH3-. E is selected from the group consisting of -CH2-, -O-, and -C(CH3)2-, G is selected from the group consisting of -NH-, -CH2-, -O-, and -CHCH3-. J is selected from the group consisting of -CO-, -CH2-, -O-, and -CHCH3-. K is selected from the group consisting of -CH2-, -CF2-, and -O-, or is absent. L is selected from the group consisting of -CH2- and -CF2-, or is absent.

[0020] This ensures that variables A, D, E, G, J, K, and L are preferably selected such that no two or more heteroatoms are directly adjacent to each other. In another preferred embodiment, the present invention relates to the above compound of formula II or the above compound of formula III in which L is absent, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In a further preferred embodiment, the present invention relates to the compound of formula II or the compound of formula III, wherein L is absent and K is -CF2-, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In another preferred embodiment, the present invention is R 3 The present invention relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein the halogen is present, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0021] In a further preferred embodiment, the present invention is R 3 The present invention relates to the above-mentioned compounds of formula II or formula III, wherein the compound is Cl or F, as well as their prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In a particularly preferred embodiment, the present invention is R 3 The present invention relates to the above compound of formula II or formula III, wherein the compound is Cl or F and is located at the 5-position of the benzimidazole moiety, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In another preferred embodiment, the present invention is R 3 The present invention relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein the element is hydrogen, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0022] In a further preferred embodiment, the present invention is R 1 This invention relates to the above-mentioned compound of formula II or formula III, wherein the halogen is a halogen, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In a particularly preferred embodiment, the present invention is R 1The present invention relates to the above-mentioned compound of formula II or formula III, selected from the group consisting of Cl or F, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In another preferred embodiment, the present invention is R 1 The present invention relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein the element is hydrogen, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts. In a further preferred embodiment, the present invention is A is selected from the group consisting of -CH2- and -CF2-, D and E are -CH2-, G is selected from the group consisting of -CH2- and -O-. J is selected from the group consisting of -CH2- and -O-, K is selected from the group consisting of -CF2- and -CH2-, The present invention relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III in which L is absent, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0023] In another particularly preferred embodiment, the present invention [ka] This invention relates to the above-mentioned compound of formula II, selected from the group consisting of the above-mentioned compounds, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0024] In a further particularly preferred embodiment, the present invention is A is selected from the group consisting of -CH2- and -CF2-, D, E, and G are each -CH2-, J is selected from the group consisting of -CH2- and -O-, K is -CF2-, The present invention relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III in which L is absent, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0025] In another particularly preferred embodiment, the present invention [ka] This invention relates to the above-mentioned compound of formula II, selected from the group consisting of the above-mentioned compounds, as well as its prodrugs, deuterated analogs, and pharmaceutically acceptable salts.

[0026] The compound prodrug of formula I is preferably the compound of formula Ia. [ka] (In the formula, the variable R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as above. R 4 C 1-4 -alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -It is alkyl.)

[0027] Variable R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as above, R 4 A prodrug of formula Ia, in which is methyl, is particularly preferred.

[0028] The prodrug of the compound of formula II is preferably the compound of formula IIa. [ka] (In the formula, the variable R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as above. R 4 C 1-4 -alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -It is alkyl.)

[0029] Variable R 1 , R 2 , R3 A, D, E, G, J, K, and L are defined as above, R 4 A prodrug of formula IIa, in which is methyl, is particularly preferred.

[0030] The prodrug of the compound of formula III is preferably the compound of formula IIIa. [ka] (In the formula, the variable R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as above. R 4 C 1-4 -alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -It is alkyl.)

[0031] Variable R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as above, R 4 A prodrug of formula IIIa, in which is methyl, is particularly preferred.

[0032] In another preferred embodiment, the present invention is a) Intermediate compound of formula (AI) [ka] (In the formula, R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as described above, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl. b) Intermediate compound of formula (A-II) [ka] (In the formula, R 1 , R 2 , R 3A, D, E, G, J, K, and L are defined as described above, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl. R is either hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl, and benzyl. c) Intermediate compound of formula (BI) [ka] (In the formula, R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as described above, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), or d) Intermediate compound of formula (B-II) [ka] (In the formula, R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as described above, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl. Regarding.

[0033] In a further preferred embodiment, the present invention relates to the compounds of formula I, II, or III, or to prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of formula Ia, IIa, or IIIa, for use in the treatment of diseases that can be treated by inhibition of cGAS. In a further preferred embodiment, the present invention relates to systemic lupus erythematosus (SLE), interferonosis, Eicardi-Gutierre syndrome (AGS), COPA syndrome, familial lupus frostbite, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes mellitus, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjögren's syndrome, Parkinson's disease, heart failure, and cancer, systemic sclerosis (SSc), dermatomyositis, and non-alcoholic diseases. The present invention relates to the compounds of formula I, II, or III, or to prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of formula Ia, IIa, or IIIa, for use in the treatment of diseases selected from the group consisting of cholangiopathic steatohepatitis (NASH), interstitial lung disease (ILD), preferably interstitial lung disease with progressive fibrosis (PF-ILD), particularly idiopathic pulmonary fibrosis (IPF), aging, myopathy, sepsis, rheumatoid arthritis, osteoarthritis, and COVID-19.

[0034] In another preferred embodiment, the present invention relates to the compounds of formula I, II, or III, or to prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of formula Ia, IIa, or IIIa, for use in the treatment of diseases selected from the group consisting of systemic lupus erythematosus (SLE), interferonosis, Eicardi-Gutierre syndrome (AGS), COPA syndrome, familial lupus frostbite, dermatomyositis, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjögren's syndrome, rheumatoid arthritis, and Parkinson's disease. In a further preferred embodiment, the present invention relates to the compounds of formula I, II, or III, or to prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of formula Ia, IIa, or IIIa, for use in the treatment of diseases selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interferonosis, interstitial lung disease (ILD), preferably interstitial lung disease with progressive fibrosis (PF-ILD), and particularly idiopathic pulmonary fibrosis (IPF).

[0035] In another preferred embodiment, the present invention relates to the compounds of formula I, II, or III, or to prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of formula Ia, IIa, or IIIa, for use in the treatment of diseases selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes mellitus, obesity, aging, muscle disorders, sepsis, osteoarthritis, heart failure, COVID-19 / SARS-CoV-2 infection, nephritis, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, and cancer. In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above-mentioned compounds of formula I, II, or III, or a prodrug, deuterated analog thereof of formula Ia, IIa, or IIIa, and a pharmaceutically acceptable salt, which may also comprise one or more pharmaceutically acceptable carriers and / or excipients. In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising one or more active agents selected from the group consisting of the above compounds of formula I, II, or III, or the prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of formula Ia, IIa, or IIIa, in combination with anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / antihistamines, bronchodilators, β2 agonists / beta-mimetics, adrenaline agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, nonspecific immunotherapeutic agents such as interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, Toll-like receptor agonists, immune checkpoint regulators, anti-TNF antibodies such as Humira®, and anti-BAFF antibodies such as belimumab and etanercept, and may also comprise one or more pharmaceutically acceptable carriers and / or excipients.

[0036] In a further preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above compound of formula I, II, or III, or a prodrug, deuterated analog thereof of formula Ia, IIa, or IIIa, and a pharmaceutically acceptable salt thereof, and one or more antifibrotic agents selected from the group consisting of pirfenidone and nintedanib, and may also comprise one or more pharmaceutically acceptable carriers and / or excipients. In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above compound of formula I, II, or III, or a prodrug, deuterated analog thereof of formula Ia, IIa, or IIIa, and a pharmaceutically acceptable salt thereof, and one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids, and may also comprise one or more pharmaceutically acceptable carriers and / or excipients. In a further preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above compound of formula I, II, or III, or a prodrug, deuterated analog, and pharmaceutically acceptable salt thereof of formula Ia, IIa, or IIIa, and one or more active agents selected from the group consisting of bronchodilators, β2 agonists / beta-mimetics, adrenaline agonists, and anticholinergics, and may also comprise one or more pharmaceutically acceptable carriers and / or excipients.

[0037] In another preferred embodiment, the present invention relates to a pharmaceutical combination comprising the above-mentioned compound of formula I, II, or III, or its prodrug, deuterated analog, and pharmaceutically acceptable salt of formula Ia, IIa, or IIIa, and one or more anti-interleukin antibodies selected from the group consisting of anti-IL-23, anti-IL-17, anti-IL-1, anti-IL-4, anti-IL-13, anti-IL-5 antibodies such as risankizumab, anti-IL-6 antibodies such as Actemra®, anti-IL-12 antibodies, and anti-IL-15 antibodies. [Modes for carrying out the invention]

[0038] 3. Terms and definitions used Unless otherwise stated, all substituents are independent of one another. For example, some C 1-6 -alkyl groups are possible substituents of a certain group, for example in the case of 3 substituents, the C 1-6 -alkyl groups are independent of one another and can represent methyl, n-propyl and tert-butyl. A crossed bond such as the central bond in the following butyl molecule represents

Chemical Formula

[0039] The term "C 1-6 -alkylene" (including those that are part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, and the term "C 1-4The term "-alkylene" refers to branched and unbranched alkylene groups having 1 to 4 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are preferred. Examples of these include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, and hexylene. Unless otherwise stated, the definitions of propylene, butylene, pentylene, and hexylene encompass all possible isomers of the group having the same number of carbon atoms. For example, propyl also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, etc. When a carbon chain is substituted with a group that combines with one or two carbon atoms of an alkylene chain to form a carbocyclic ring having three, five, or six carbon atoms, examples of such rings include, among others, the following: [ka]

[0040] "C 2-6 The term "-alkenyl" (including when it is part of another group) refers to branched and unbranched alkenyl groups having 2 to 6 carbon atoms, and "C 2-4 The term "-alkenyl" refers to branched and unbranched alkenyl groups having 2 to 4 carbon atoms, provided they have at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. Examples include ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise stated, the definitions of propenyl, butenyl, pentenyl, and hexenyl encompass all possible isomers of the group. For example, propenyl includes 1-propenyl and 2-propenyl, and butenyl includes 1-, 2-, and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc. "C 2-5 The term "-alkynyl" (including when it is part of another group) refers to branched and unbranched alkynyl groups having 2 to 5 carbon atoms, and "C 2-4 The term "-alkynyl" refers to branched and unbranched alkynyl groups having 2 to 4 carbon atoms, provided they have at least one triple bond. Alkynyl groups having 2 to 4 carbon atoms are preferred.

[0041] "C 2-6 The term "-alkenylene" (including when it is part of another group) refers to branched and unbranched alkenylene groups having 2 to 6 carbon atoms, and "C 2-4 The term "-alkenylene" refers to branched and unbranched alkylene groups having 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are preferred. Examples of these include ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, and hexenylene. Unless otherwise stated, the definitions of propenylene, butenylene, pentenylene, and hexenylene encompass all possible isomers of the group having the same number of carbon atoms. Therefore, for example, propenyl includes 1-methylethenylene, and butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, and 1,2-dimethylethenylene.

[0042] The term "aryl" (including when it is part of another group) refers to an aromatic ring system having six or ten carbon atoms. Examples include phenyl or naphthyl, with phenyl being the preferred aryl group. Unless otherwise stated, the aromatic group may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. "Aryl-C 1-6 -alkylene" (including those that are part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted by an aromatic ring system having 6 or 10 carbon atoms. Examples include benzyl, 1- or 2-phenylethyl, and 1- or 2-naphthylethyl. Unless otherwise stated, the aromatic group may be substituted with one or more groups selected from methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. "Heteroaryl-C 1-6 -alkylene" (including those that are part of other groups), although already encompassed in the aforementioned "aryl-C 1-6 -alkylene", means branched and unbranched alkylene groups having 1 to 6 carbon atoms which are substituted by heteroaryl.

[0043] Unless specifically defined otherwise, heteroaryls of this class include 5- or 6-membered heterocyclic aromatic groups or 5- to 10-membered bicyclic heteroaryl rings, which may contain 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and may contain a sufficient number of conjugated double bonds to form an aromatic system. The following are examples of 5- or 6-membered heterocyclic aromatic groups and bicyclic heteroaryl rings.

Chemical Formula

[0044] The following are examples of heteroaryl-C 1-6 -alkylene.

Chemical Formula

[0045] "C 3-7 The term "cycloalkyl" (including when it is part of another group) means a cyclic alkyl group having 3 to 7 carbon atoms, unless otherwise specifically defined. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise stated, the cyclic alkyl group may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. Unless specifically defined otherwise, "C 3-10 The term "cycloalkyl" refers to a monocyclic alkyl group having 3 to 7 carbon atoms, a bicyclic alkyl group having 7 to 10 carbon atoms, or at least one C 1-3 -This also refers to monocyclic alkyl groups bridged by carbon bridges. The terms “heterocyclic ring” or “heterocycle” mean a 5-membered, 6-membered, or 7-membered saturated, partially saturated, or unsaturated heterocyclic ring, which may contain one, two, or three heteroatoms selected from oxygen, sulfur, and nitrogen, and which may be linked to the molecule via carbon or nitrogen atoms, if present. The term “saturated heterocyclic ring” is encompassed within the terms “heterocyclic ring” or “heterocycle,” but refers to a 5-membered, 6-membered, or 7-membered saturated ring. For example,

[0046] [ka] These are some examples. While encompassed by the terms "heterocyclic ring" or "heterocyclic group," the term "partially saturated heterocyclic group" refers to a 5-membered, 6-membered, or 7-membered partially saturated ring containing one or two double bonds, but not enough to form an aromatic system, unless specifically defined otherwise. For example,

[0047] [ka] These are some examples.

[0048] The terms "heterocyclic ring" or "heterocycle," but which encompass "heterocyclic aromatic ring," "unsaturated heterocyclic group," or "heteroaryl," refer to a 5- or 6-membered heterocyclic aromatic group or a 5- to 10-membered bicyclic heteroaryl ring, which may contain one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen, and may contain enough conjugated double bonds to form an aromatic system. Examples of 5- or 6-membered heterocyclic aromatic groups include: [ka] These are some examples.

[0049] Unless otherwise specified, heterocyclic rings (or heterocycles) may contain keto groups. For example, [ka] These are some examples.

[0050] Although encompassed by the term "cycloalkyl," the term "bicyclic cycloalkyl" generally refers to a bicyclic carbon ring with 8, 9, or 10 members. For example, [ka] These are some examples. Although already encompassed by the term "heterocycle," the term "bicyclic heterocycle," unless not specifically defined otherwise, generally refers to an 8-membered, 9-membered, or 10-membered bicyclic ring that may contain one or more heteroatoms selected from oxygen, sulfur, and nitrogen, preferably 1 to 4, more preferably 1 to 3, even more preferably 1 to 2, and particularly 1. If carbon atoms or nitrogen atoms of the ring are present, the ring may be linked to a molecule via them. For example,

[0051] [ka] These are some examples. Although already encompassed by the term "aryl," the term "bicyclic aryl" refers to a 5- to 10-membered bicyclic aryl ring containing enough conjugated double bonds to form an aromatic system. An example of a bicyclic aryl is naphthyl. Although already encompassed by "heteroaryl," the term "bicyclic heteroaryl" refers to a 5- to 10-membered bicyclic heteroaryl ring that may contain one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen, and contains enough conjugated double bonds to form an aromatic system, unless otherwise specifically defined.

[0052] The terms "bicyclic cycloalkyl" or "bicyclic aryl" encompass the same concept, but the terms "condensed cycloalkyl" or "condensed aryl" specifically refer to a bicyclic ring where the bridges separating the rings directly represent single bonds. The following are examples of condensed bicyclic cycloalkyls. [ka] The terms "bicyclic heterocycle" or "bicyclic heteroaryl" encompass a 5-10 membered bicyclic heterocycle containing one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen, with the bridges separating the rings directly representing single bonds. "Fused bicyclic heteroaryls" further contain enough conjugated double bonds to form aromatic systems. Examples include pyrrolidine, indole, indidine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyridopyrimidine,

[0053] [ka] These are some examples. Within the scope of this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine. Unless otherwise noted, fluorine, chlorine, and bromine are considered preferred halogens. As mentioned earlier, the compounds of Formula I, II, or III can be converted into their salts, in particular their physiologically and pharmacologically acceptable salts for pharmaceutical use. As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. These salts may, on the one hand, exist as physiologically and pharmacologically acceptable acid addition salts of the compounds of Formula I, II, or III with inorganic or organic acids. On the other hand, the compounds of Formula I, II, or III can be converted by reaction with an inorganic base into physiologically and pharmacologically acceptable salts with alkali metal cations or alkaline earth metal cations as counterions. Acid addition salts can be prepared using, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid. Mixtures of the above acids can also be used. For preparing the alkali metal salts and alkaline earth metal salts of the compounds of Formula I, II, or III, it is preferable to use hydroxides and hydrides of alkali metals and alkaline earth metals, among which the hydroxides and hydrides of alkali metals, particularly sodium, potassium, magnesium, calcium, zinc and diethanolamine are preferred, and sodium hydroxide and potassium hydroxide are particularly preferred.

[0054] The present invention relates to the subject compounds, which may be in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual enantiomers, or racemates, tautomers, and the corresponding acid addition salts with a free base or a pharmacologically acceptable acid, for example acid addition salts with hydrohalic acids such as hydrochloric acid or hydrobromic acid, or organic acids such as oxalic acid, fumaric acid, diglycolic acid, or methanesulfonic acid. Compounds of Formula I, II, or III according to the present invention may exist as a mixture of diastereomeric isomers, but can also be obtained as pure diastereomers. Compounds of Formula II and III with specific stereochemistry, particularly compounds of Formula II with specific stereochemistry, are preferred.

[0055] 4.Synthesis method General Procedure The following methods are suitable for preparing the compounds of General Formula I, II, or III. The compounds according to the present invention can be obtained using synthetic methods known to those skilled in the art and described in organic synthesis literature. General methods for functional group protection and deprotection steps are described, for example, in Greene, T.W. and Wuts, P.G.M. (eds.): Protective Groups in Organic Synthesis, third edition 1999; John Wiley and Sons, Inc. Preferably, the compounds are obtained in the same manner as the preparation methods described in further detail hereinafter, particularly as set forth in the experimental section. The compounds of General Formula (I) can be prepared using several alternative synthetic routes, of which the following routes shall serve as examples.

[0056] Route A: Compounds of general formulas I, II, and III (in particular, where A represents -CH2- or substituted -CH2-) can be obtained from the compound of formula (AI) through a standard amidation procedure. R13 can thereby represent hydrogen or a protecting group such as tert-butyl, which can be removed by a standard deprotection method. Compounds of formula (AI) can be prepared from the compounds of formula (A-II) by applying a standard deprotection method. Compounds of formula (A-II) can be prepared by reacting the compounds of formula (A-III) with the compounds of formula (A-IV) using a strong base such as sodium hydride. Applicable methods for the preparation of compounds (A-III) will become apparent to those skilled in the art by referring to routes B and C described below and the examples described in the experimental section. Compounds of formula (A-IV) can be prepared through the method described below for the synthesis of intermediate B. R in formulas (A-II) and (A-III) can represent hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl, and benzyl.

[0057] [ka]

[0058] Route B: Compounds of general formulas I, II, and III can be prepared by reacting the compound of general formula (BI) in the presence of a strong base, such as sodium hydride. R13 can thereby represent hydrogen or a protecting group, such as tert-butyl, which can be removed by standard deprotection methods. Compound (BI) can be prepared by oxidizing the compound of general formula (B-II) with, for example, 3-chloroperbenzoic acid. Compound (B-II) can be prepared by reacting the compound of general formula (B-III) with the compound of general formula (B-IV) under standard amidation conditions. Applicable methods for the preparation of compound (B-III) will become apparent to those skilled in the art by referring to the synthesis and route C of compound (B-VI) described below, and the examples described in the experimental section. Compound (B-IV) can be prepared through the method described below for the synthesis of intermediate B. Alternatively, compound (B-II) can be prepared by reacting the compound of general formula (BV) with the respective enantiopurine hydroxyproline in the presence of a base. Compound (BV) can be obtained by chlorinating the compound of general formula (B-VI) using phosphoryl chloride. Compound (B-VI) can be prepared from the compound of general formula (B-VII) by applying strongly alkaline conditions, for example, at high temperatures. Compound (B-VII) can be obtained by reacting the compound of general formula (B-VIII) with the compound of general formula (B-IX) by applying a standard amidation procedure. The compound of general formula (B-VIII) can be prepared by the methods exemplified below or by other standard synthesis methods known to those skilled in the art.

[0059] [ka]

[0060] Route C: Compounds of the general formula (CI) can be prepared from compounds of the general formula (CI) by various types of ring-closing reactions, exemplified but not limited to Heck coupling reactions (where R11 represents a bromine or iodine atom and R12 contains a terminal alkene), ring-closing metathesis reactions (where both R11 and R12 contain terminal alkenes), and subsequent hydrogenation and amidation of the resulting alkene (where R11 has a carboxylic acid and R12 has a primary or secondary amino group, or vice versa). R13 can thereby represent hydrogen or a protecting group such as tert-butyl, which can be removed by standard deprotection methods. The method for synthesizing compound (CI) will become apparent to those skilled in the art by referring to routes A and B above and the examples described in the experimental section.

[0061] [ka]

[0062] Synthesis of intermediates Intermediate A Intermediate A-01 (racemic tert-butyltrans-4-amino-3-methylpiperidine-1-carboxylate): [ka]

[0063] Step 1: Lithium tri-sec-butyl (hydride) borate (L-selectride; 1M in THF; 984mL; 0.98mol) was added to a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (175g; 0.82mol) in THF (1.22L) cooled to 0°C. The mixture was stirred for 4 hours while maintaining a temperature of 0°C to 10°C. A 10% aqueous sodium hypochlorite solution (525mL) was added, and the mixture was extracted with  (700mL). The organic layer was separated, washed with brine, dehydrated with sodium sulfate, and evaporated. The crude product was purified by FC (silica gel; petroleum ether /  2% → 50%). 1 H NMR (400 MHz, CDCl3) δ ppm 3.84 - 3.82 (m, 1H), 3.52 (d, J = 6.40 Hz, 2H), 3.29 (d, J = 5.40 Hz, 2H), 3.06 - 3.02 (m, 1H), 1.76 - 1.74 (m, 3H), 1.65 (s, 9H), 1.24 - 0.89 (m, 3H)

[0064] Step 2: Triethylamine (341 g; 3.37 mol) was added to a solution of the product from Step 1 (330 g; 1.53 mol) in THF (1.65 L). Methanesulfonic anhydride (507 g; 2.91 mol) was added at room temperature, and the mixture was stirred at room temperature for 4 hours. Water (550 mL) was added, and the mixture was extracted with RINKAN (1.65 L). The organic layer was separated, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure. The product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 4.74 - 4.71 (m, 1H), 4.23 - 3.95 (m, 1H), 3.17 - 3.04 (m, 2H), 3.04 (s, 3H), 1.95 - 1.92 (m, 1H), 1.83 (s, 1H), 1.83 - 1.82 (m, 1H), 1.32 (s, 9H), 0.91- 0.79 (m, 3H)

[0065] Step 3: Reaction under a nitrogen atmosphere. Sodium azide (186 g; 2.86 mol) was added to a solution of the product from Step 2 (420 g; 1.43 mol) in DMF (2.1 L) at room temperature. The mixture was stirred at 100 °C for 4 hours and then cooled to 0 °C. A saturated solution of sodium carbonate (4.0 L) was added while maintaining the temperature below 10 °C. The mixture was extracted with ethyl acetate, the organic layer was separated, washed with brine, dehydrated with sodium sulfate, and evaporated under reduced pressure. The product was used in the next step without further purification.

[0066] Step 4: A mixture of the product of Step 3 (200 g; 0.83 mol), palladium on charcoal (60 g), and EtOAc (1.0 L) was stirred under hydrogen pressure (50 psi) at room temperature for 2 hours. The catalyst was filtered off with suction and washed with methanol (2 L). The combined filtrates were evaporated under reduced pressure. The crude product was purified by FC (silica gel; petroleum ether / EtOAc 0%→100%) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.85 (s, 1 H) 3.99 - 3.74 (m, 2 H), 2.81 - 2.79 (m, 2H), 2.71 (s, 1 H), 2.72 - 2.70 (m, 1 H), 2.64 - 2.52 (m, 1 H), 2.25 - 2.16 (m, 2 H), 1.66 - 1.57 (m, 1 H), 1.35 - 1.30 (m, 2 H), 1.30 - 1.27 (m, 8 H), 1.17 - 1.06 (m, 2 H), 0.83 - 0.78 (m, 3 H), 0.75 - 0.71 (m, 1 H)

[0067] Intermediate B Intermediate B-01:

Chemical Formula

[0068] Step 1: A mixture of intermediate A-01 (2 g; 9.97 mmol), 5-chloro-2-fluoronitrobenzene (1.21 mL; 9.97 mmol), DIPEA (3.43 mL; 19.9 mmol), and DMF (17 mL) was stirred at 60°C for 10 hours until reaction control by RP HPLC showed significant transformation of the starting materials. The mixture was poured into ice water. Water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with water, then with brine, separated, dehydrated with magnesium sulfate, filtered, and concentrated. The crude product was purified by FC (silica gel; cyclohexane / siRNA 20% → 100%) to obtain tert-butyl(rac-trans)-4-[(4-chloro-2-nitrophenyl)amino]-3-methylpiperidine-1-carboxylate. ESI-MS: 392 [M+Na] + R t (HPLC): 0.83 min (Method A)

[0069] Step 2: In a Parr apparatus, the product from Step 1 (3.25 g; 7.90 mmol), Raney nickel (410 mg), and THF (60 mL) were shaken at room temperature under hydrogen pressure (50 psi) for 5 hours. Further Raney nickel (160 mg) was added multiple times, each time for 10-15 hours, until RP HPLC control showed a high conversion of the starting materials (in this case: 3 catalyst additions). The catalyst was filtered off, and the filtrate was evaporated. The crude product was used in the next step. ESI-MS: 340 [M+H] + R t (HPLC): 0.63 min (Method A)

[0070] Step 3: The mixture of the product from Step 2 (2.16 g; 6.37 mmol), 1-(1H-imidazole-1-carbotioil)-1H-imidazole (1.47 g; 8.25 mmol), and DMF (34 mL) was stirred at room temperature for 2 hours. Ice water (200 mL) was slowly added to the reaction mixture while stirring, and stirring was continued for another 10 minutes. The precipitate was filtered off, washed with water, dried overnight at 50°C, and used in the next step without further purification. ESI-MS: 382 [M+H] + R t (HPLC): 0.71 min (Method A)

[0071] Step 4: Reaction under an argon atmosphere. To a solution of the product from step 3 (2.57 g; 6.26 mmol) in anhydrous DMF, potassium tert-butyrate (1.42 g; 12.7 mmol) was added. The mixture was stirred at room temperature for 15 minutes, then iodomethane (597 μL; 9.49 mmol) was added. The mixture was stirred at room temperature for 2 hours until reaction control by RP HPLC showed almost complete conversion of the starting materials. Ice water (100 mL) was added, and the mixture was maintained overnight at 6°C. The precipitate formed was filtered off, dissolved in siRNA, concentrated under reduced pressure, and dried by co-evaporation with toluene to obtain tert-butyl (racemic trans)-4-[5-chloro-2-(methylsulfanyl)-1H-1,3-benzodiazole-1-yl]-3-methylpiperidine-1-carboxylate. ESI-MS: 396 [M+H] + R t (HPLC): 0.73 min (Method A)

[0072] Step 5: The enantiomer mixture from Step 4 was separated by preparative SFC (instrument: Sepiatec 2 Prep SFC 100; column: Lux Cellulose-2 (21.2 mm × 250 mm, 5 μm); mobile phase: A CO2 and B IPA; gradient: B % = 20% isocratic elution mode; flow rate: 60 mL / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 150 bar). The absolute configurations of the two separated enantiomers were assigned according to the method described by DJ Patel et al, PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116), based on the cocrystal structure with human cGAS protein in Example 1.01. (The first isomer to elute) 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.69 (m, 1 H), 7.10 - 7.26 (m, 1 H), 7.17 (br d, J=6.84 Hz, 1 H), 3.87 - 4.22 (m, 3 H), 2.87 - 3.06 (m, 1 H), 2.57 - 2.79 (m, 4 H), 2.31 - 2.45 (m, 1 H), 2.13 - 2.30 (m, 1 H), 1.80 (br d, J=11.79 Hz, 1 H), 1.45 (s, 9 H), 0.58 (d, J=6.46 Hz, 3 H)

[0073] First, the isomer that eluted was selected for the next step. Second, intermediate B-02 was prepared from the isomer that eluted.

[0074] Step 6: To a solution of the isomer to be eluted first in Step 5 (811 mg; 2.05 mmol) in DCM (11.8 mL), 3-chloroperbenzoic acid (77%; 0.987 g; 4.40 mmol) was added. The mixture was stirred for 2 hours, then further diluted with DCM and washed with aqueous potassium carbonate (15%). The aqueous layer was re-extracted with DCM, the combined organic layers were washed with water and separated, dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound. ESI-MS: 428 [M+H] + R t (HPLC): 0.74 min (Method A)

[0075] The following intermediates were prepared from the indicated starting materials in the same manner as intermediate 1.01 described above. This allowed the reaction temperature in step 1 to be adjusted for the reactivity of each nitrobenzene starting material. The absolute configuration of the selected intermediates was assigned from the cocrystal structures of the example compounds prepared from each intermediate with human cGAS protein, according to the method described by DJ Patel et al, PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116). The absolute configurations of the other intermediates and examples were assigned based on the assumption that the utemers share the same absolute stereochemistry in all cases.

[0076] [Table 1-1] [Table 1-2]

[0077] Intermediate B-12 [ka] The product of step 4 of the synthesis of intermediate B-08 was deprotected by BOC according to general procedure D. ESI-MS: 262 [M+H] + Rt (HPLC): 0.47 min (Method E)

[0078] Intermediate B-14 [ka] A mixture of intermediate B-08 (700 mg; 1.78 mmol) and hydrochloric acid in dioxane (4 M; 1.33 mL; 5.45 mmol) was stirred for 2 hours. Tert-butyl methyl ether (20 mL) was added, and the mixture was left to stand for 1 hour without stirring. The precipitate was filtered off and dissolved in methanol. The resulting solution was evaporated under reduced pressure to obtain the title compound. ESI-MS: 294 [M+H] + R t (HPLC): 0.60 min (Method E)

[0079] Intermediate I Intermediate I.01: [ka] Intermediate NR is reacted with intermediate B-5 according to general procedure A to obtain the title compound tert-butyl(3S,4S)-4-(2-{[(3S,5S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}-5-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate. ESI-MS: 747 [M+H] + R t (HPLC): 1.27 minutes (Method B)

[0080] Intermediate I.02: [ka]

[0081] Step 1: The reaction was carried out under an argon atmosphere, the solvent was degassed, and the mixture was dried by adding molecular sieves. Intermediate I.01 (721 mg; 0.916 mmol) in a round-bottom flask was mixed with DMSO (10 ml), methylbromodifluoroacetate (266 μL; 2.42 mmol), and copper powder (291 mg; 4.58 mmol). The mixture was stirred overnight, and then another 1 equivalent of methylbromodifluoroacetate and another 2 equivalents of copper were added. After stirring for a further 72 hours, the mixture was diluted with SiO2, potassium dihydrogen phosphate solution (1.27 M; 20 mL) was added, and the mixture was stirred for another 30 minutes before being filtered. The organic layer of the filtrate was washed with water and concentrated, and the crude product was purified by FC (silica gel; CH / siRNA 10% → 100%) to obtain tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(1,1-difluoro-2-methoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate.

[0082] Step 2: Sodium borohydride (244 mg; 6.40 mmol) was added in small amounts over less than 1 hour to the product (585 mg; 0.647 mmol) from Step 1 in anhydrous ethanol (dehydrated with molecular sieves at 3 Å). The reaction was quenched by the addition of water, the mixture was extracted three times with ethyl acetate, the combined organic layer was washed with water, then washed with brine, separated, dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by FC (silica gel; CH / ethyl acetate 20% → 100%) to obtain tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(1,1-difluoro-2-hydroxyethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate.

[0083] Step 3: Sodium hydride (55% in mineral oil; 47 mg; 1.08 mmol) was added to a solution of the product from Step 2 (269 mg; 0.359 mmol) and allyl bromide (220 μL; 2.52 mmol) in DMA (1.67 mL). The mixture was stirred for 10 minutes and then quenched by adding water. The mixture was extracted three times with Â, the combined organic layers were washed with water and then with brine, separated, dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by FC (silica gel; CH / ELISA 20% → 100%) to obtain the title compound tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-{4-[1,1-difluoro-2-(propa-2-en-1-yloxy)ethyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate. ESI-MS: 789 [M+H] + R t (HPLC): 1.29 minutes (Method B)

[0084] Intermediate I.03: [ka] To a solution of 3-allyloxypropionic acid (38 μL; 0.303 mmol) in DMF (500 μL), EDC hydrochloride (70 mg; 0.364 mmol) and N,N-diisopropylethylamine (105 μL; 0.606 mmol) were added. The mixture was stirred for 10 minutes, then intermediate B-14 (100 mg; 0.303 mmol) was added, and the mixture was stirred for 90 minutes. The mixture was then diluted with methanol (2 mL) and purified by RP HPLC (Sunfire C18; ACN / water, modifier: TFA). ESI-MS: 406 [M+H] + R t (HPLC): 0.88 min (Method E)

[0085] Intermediate N The synthesis described below was partially carried out according to the following general procedures as instructed. General procedure: Hydrogenation using Int-A:Pd / C catalyst (intermediate NA, see step 4) General procedure Int-B: Ring closure under basic conditions (see intermediate NA, step 5) General Procedure Int-C: Chlorination using phosphoryl trichloride (intermediate NA, see step 7) General procedure Int-D: S using hydroxyproline ester N Ar (intermediate NA, see step 8) General procedure Int-E: Ester cleavage using lithium hydroxide (intermediate NF, see step 2) General procedure: Amidation using Int-F:PFTU (intermediate NF, see step 3) General procedure: Int-G:Heck type coupling (intermediate NJ, see step 1)

[0086] Intermediate NA: [ka]

[0087] Step 1: A mixture of tert-butyl 3-(2-oxoethoxy)propanoate (7.25 g; 38.5 mmol) and methyl (triphenylphosphoranylidene) acetate (13.1 g; 38.5 mmol), prepared as described in European Patent Application Publication No. 2409977, was stirred overnight at room temperature in DCM (200 mL). The mixture was evaporated under reduced pressure and dissolved in CH / siRNA (3:1). Insoluble matter was removed by filtration, and the filtrate was evaporated. The crude product was purified by FC (silica gel; CH / siRNA 10% → 45%) to obtain a mixture of cis- and trans-isomers. Step 2: The product from Step 1 (1.50 g; 6.14 mmol) was stirred overnight in a mixture of DCM (15 mL) and TFA (10 mL). The mixture was evaporated and dissolved in methanol (10 mL). Polymer-bound tetraalkylammonium carbonate (2 weight equivalents) was added and the mixture was stirred for 90 minutes. Insoluble matter was filtered off and the filtrate was evaporated.

[0088] Step 3: To a solution of the product from Step 2 (5.00 g; 21.3 mmol) in ACN (140 mL), 1-chloro-N,N,2-trimethylpropenylamine (4.45 mL; 33.6 mmol) was added. The mixture was stirred at room temperature for 10 minutes, then pyridine (5.10 mL; 63.0 mmol) and 3-aminobenzofuran-2-carboxamide (3.70 g; 21.0 mmol) were added. The mixture was stirred overnight at room temperature, then water was added. The mixture was extracted by DCM, the organic layer was separated and evaporated. The crude product was purified first by FC (silica gel; petroleum ether / Â1 40% → 80%), then by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 347 [M+H] + R t (HPLC): 0.80 min (Method E)

[0089] Step 4: General Procedure Int-A: The mixture of the product from Step 3 (3.40 g; 9.73 mmol), charcoal-supported palladium (10%; 350 mg), and ethanol (500 mL) was shaken under hydrogen pressure (50 psi) by RP HPLC until the reaction control showed the transformation of the starting materials (in this case: 90 minutes). The catalyst was filtered off, and the filtrate was evaporated to dryness. ESI-MS: 349 [M+H] + R t (HPLC): 0.81 min (Method E) Step 5: General Procedure Int-B: The mixture of the product from Step 4 (4.55 g; 13.1 mmol) and aqueous sodium hydroxide (4 M; 100 mL; 400 mmol) was stirred at 60°C (60 minutes in this case) until reaction control by RP HPLC showed the transformation of the starting materials. The mixture was allowed to cool to room temperature and then acidified by adding aqueous hydrochloric acid (4 M). The precipitate was collected and dried at 60°C. ESI-MS: 317 [M+H] + R t (HPLC): 0.73 min (Method E) Step 6: To a mixture of the product from Step 5 (3.53 g; 11.2 mmol), DCM (60 mL), and a few drops of DMF, oxalyl chloride (1.24 mL; 14.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, then methanol was added and stirring continued for a further 60 minutes. The mixture was extracted with water to separate the organic layer, which was evaporated to dryness. ESI-MS: 331 [M+H] + R t (HPLC): 0.82 min (Method E)

[0090] Step 7: General procedure Int-C: The mixture of the product from Step 6 (3.70 g; 11.2 mmol) and phosphoroyl trichloride (70 mL) was stirred at 90°C for 4 hours. Excess phosphoroyl trichloride was removed by distillation, and water was carefully added. The resulting mixture was extracted with ethyl acetate, the organic layer was separated, and evaporated. The crude product was used for the next step. ESI-MS: 349 [M+H] + R t (HPLC): 1.02 min (Method E)

[0091] Step 8: General Procedure Int-D: The mixture of the product from Step 7 (300 mg; 0.896 mmol), tert-butyl(2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (253 mg; 1.08 mmol), potassium carbonate (300 mg; 2.06 mmol), and DMF (7.0 mL) was stirred overnight at room temperature. Water was added, and the mixture was acidified by the addition of aqueous hydrochloric acid (1 M). The mixture was extracted with ethyl acetate, the organic layer was evaporated, and the crude product was purified by FC (silica gel; petroleum ether / ethyl acetate 40% → 75%). ESI-MS: 500 [M+H] + R t (HPLC): 0.75 min (Method E)

[0092] Step 9: The product from Step 8 was reacted according to the general procedure Int-E to obtain the ester-cleavage title compound. ESI-MS: 486 [M+H] + R t (HPLC): 0.70 min (Method E)

[0093] Intermediate NB: [ka] In step 3, 3-amino-6-chloro-1-benzofuran-2-carboxamide was applied, and the intermediate NA was prepared in the same manner as described for its synthesis. ESI-MS: 520 [M+H] + R t (HPLC): 0.50 min (Method A)

[0094] Intermediate NC: [ka] A two-step sequence is performed from intermediate NV and 2-(buta-3-en-1-yloxy)acetic acid: Step 1: Comply with General Procedure Int-G Step 2: Comply with General Procedure Int-A The title compound was obtained by applying the following method and performing the preparation. ESI-MS: 504 [M+H] + R t (HPLC): 0.45 min (Method A)

[0095] Intermediate ND: [ka] Starting from tert-butyl 2-(3-oxopropoxy)acetate prepared as described in European Patent Application Publication No. 1939201, the intermediate NA was prepared in the same manner as described in the sequence for its synthesis. ESI-MS: 486 [M+H] + R t (HPLC): 0.71 min (Method E)

[0096] Intermediate NE: [ka] Step 1: A mixture of 3-aminobenzofuran-2-carboxamide (2.00 g; 11.4 mmol), ethyl 2-[2-(2-ethoxy-2-oxoethoxy)ethoxy]acetate (5.32 g; 22.7 mmol), and 1H,2H,3H,4H,6H,7H,8H-[1,3]diazino[1,2-a]pyrimidine (6.45 g; 45.4 mmol) was heated at 120°C for 150 minutes. After cooling to room temperature, aqueous hydrochloric acid (1 M; 70 mL) was added. The precipitate was filtered off by suction, washed with water, and dried in vacuum at 60°C to obtain ethyl 2-[2-({6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 A mixture of trideca-1(9),2(7),3,10,12-pentaen-4-yl}methoxy)ethoxy acetate and their respective free acids was obtained. This mixture was then used in the next step. Step 2: In the acid re-esterification, the mixture from step 1 (2.8 g) was dissolved in DCM (200 mL). Two drops of DMF were added, followed by oxalyl chloride (392 μL, 4.57 mmol). The mixture was stirred overnight, then ethanol (10 mL) was added, and the mixture was stirred for a further 2 hours. The mixture was concentrated under reduced pressure. Methyl tert-butyl ether was added, and the resulting precipitate was washed with methyl tert-butyl ether and dried at 50°C to obtain ethyl 2-[2-({6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 [Trideca-1(9),2(7),3,10,12-pentaen-4-yl]methoxy)ethoxy acetate was obtained.

[0097] The product from Step 2 was further reacted in a two-step sequence using the initial general procedure Int-C, followed by Int-D, to obtain the title compound. ESI-MS: 516 [M+H] + R t (HPLC): 0.80 min (Method E)

[0098] Intermediate NF: [ka] Step 1: The zinc powder to be used was washed with 2% aqueous hydrochloric acid, water, and acetone before use. The purified powder was dried in high vacuum and stored under argon. Zinc powder (2.44 g; 36.9 mmol), nickel(II) chloride hexahydrate (0.754 g; 3.14 mmol), THF (35.0 mL), and 3 drops of water were added to a flask, and the mixture was stirred at room temperature for 10 minutes. Then, tert-butylhexa-5-enoate (4.63 g; 18.5 mmol; prepared as described in International Publication No. 2010 / 15447) was added all at once, and ethyliodofluoroacetate (2.80 mL; 18.5 mmol) was added dropwise while maintaining the temperature below 30°C (exothermic reaction during addition). After the addition was complete, the reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was poured into a mixture of saturated ammonium chloride solution (100 mL) and diethyl ether (100 mL) and stirred for 10 minutes. The mixture was then filtered through a Celite pad, and after phase separation, the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and evaporated. The crude product was purified by FC (silica gel; CH / DCM 10% → 100%). ESI-MS:312 [M+NH4] + R t (HPLC): 0.78 min (Method A)

[0099] Step 2: General Procedure Int-E: Lithium hydroxide (276 mg; 11.0 mmol) was added to the THF / H2O (2:1) solution of the product from Step 1, and the reaction mixture was stirred at room temperature until reaction control by RP HPLC indicated the consumption of the starting material (in this case: 2.5 hours). Volatile substances were removed under vacuum. The residue was acidified to pH=1 by adding 5.50 mL of 1N aqueous hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered, and evaporated. ESI-MS:211 [M-isobutene + H] + R t (HPLC): 0.59 min (Method A)

[0100] Step 3: General procedure Int-F: At room temperature, PFTU (2.40 g; 5.60 mmol) was added to the stirred solution of the product from step 2 (1.40 g; 5.09 mmol) and DIPEA (970 μL; 5.60 mmol) in DMF (21.0 mL), and the mixture was stirred for 30 minutes. Then, 3-aminobenzofuran-2-carboxamide (1.01 g; 5.60 mmol) and another DIPEA (970 μL; 5.60 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was then heated to 50 °C and stirred at this temperature for 16 hours. When reaction control by RP HPLC showed incomplete consumption of the starting materials, additional DIPEA (441 μL; 2.80 mmol) and PFTU (0.86 g; 2.04 mmol) were added, and stirring continued at 50 °C for a further 2.5 hours. The reaction mixture was diluted with water, acidified with TFA, filtered, and purified by RP HPLC (XBridge C18; ACN / water; modifier: TFA). ESI-MS:425 [M+H] + R t (HPLC): 0.72 min (Method A)

[0101] Step 4: At room temperature, chlorotrimethylsilane (4.05 mL; 30.3 mmol) was slowly added to a solution of the product from step 3 (950 mg; 2.13 mmol) and TEA (13.0 mL; 92.4 mmol) in 1,2-dichloroethane (28.5 mL). After the addition was complete, the reaction mixture was heated to 85°C and stirred at this temperature for 24 hours. The reaction mixture was poured into 30 mL of 4 M hydrochloric acid (pH=1) and extracted twice with DCM. The combined organic phases were washed with water, dried over sodium sulfate, filtered, and evaporated to obtain tert-butyl 7,7-difluoro-7-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2(7),3,9,11-pentaen-4-yl}heptanoate. ESI-MS:405 [MH] - Rt (HPLC): 0.44 min (Method F)

[0102] Step 5: The general procedure Int-C was applied to convert the product from step 4 into a chlorinated product, which was then purified by RP-HPLC (XBridge C18; ACN / water; modifier: TFA). ESI-MS: 367 [MH] - R t (HPLC): 0.64 min (Method A)

[0103] Step 6: The product from Step 6 was reacted according to the general procedure Int-D to obtain the title compound. ESI-MS:520 [M+H] + R t (HPLC): 0.61 min (Method A) Intermediate NG: [ka] Preparation is carried out in the same manner as described for the synthesis of intermediate NF, by applying 3-amino-6-fluorobenzofuran-2-carboxamide in step 3. Intermediate NH: [ka] Preparation is carried out in the same manner as the reaction sequence described for the synthesis of intermediate NF, by applying 3-amino-6-chlorobenzofuran-2-carboxamide in step 3. Intermediate NI [ka]

[0104] Step 1: To a solution of magnesium powder (45.0 g; 1.85 mol) in THF (285 mL), iodine (1.00 g; 3.94 mmol) was added, followed by the dropwise addition of a solution of 1-bromo-3-butene (111 g; 821 mmol) in THF (850 mL). The temperature was maintained below 50°C. The resulting mixture was cooled to -75°C, and a solution of diethyl oxalate (100 g; 684 mmol; 93.5 mL) in THF (1.89 L) was added dropwise at -75°C. The mixture was stirred at -75°C for a further 4 hours. The reaction mixture was quenched by adding a saturated aqueous solution of ammonium chloride (900 mL) at 0°C, and then the pH was adjusted to pH 3 by adding aqueous hydrochloric acid (1 M). The mixture was extracted three times with HCl (500 mL). The combined organic layers were washed with brine (900 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by FC (silica gel; petroleum ether / ethyl acetate 0% → 100%). 1 H NMR: (400 MHz, CDCl3) δ = 5.85 - 5.72 (m, 1H), 5.11 - 4.92 (m, 2H), 4.37 - 4.24 (m, 2H), 2.92 (t, J = 7.3 Hz, 2H), 2.36 (q, J = 7.1 Hz, 2H), 1.24 - 1.21 (m, 3H)

[0105] Step 2: To a solution of the product from Step 1 (50.0 g, 320 mmol) in DCM (1000 mL), bis-(2-methoxyethyl)aminosulfur trifluoride (deoxofluor) (120 g, 544 mmol, 119 mL) and ethanol (2.95 g, 64.0 mmol) were added at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by adding 500 mL of saturated aqueous sodium bicarbonate and then extracted three times with DCM (500 mL). The combined organic layer was washed with aqueous hydrochloric acid (1 M; 200 mL) and brine (200 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was distilled under vacuum (30°C, 0.09 MPa / oil pump). 1 H NMR: (400 MHz, CDCl3): δ = 5.80 (br dd, J = 10.3, 16.9 Hz, 1H), 5.13 - 5.00 (m, 2H), 4.39 - 4.28 (m, 2H), 2.30 - 2.12 (m, 4H), 1.43 - 1.34 (m, 3H)

[0106] Step 3: A mixture of zinc powder (8.79 g, 134 mmol) and THF (30.0 mL) was mixed with nickel(II) chloride hexahydrate (804 mg, 3.38 mmol). The mixture was stirred at -65°C for 5 minutes. Then, ethyl difluoroiodoacetate (12.0 g, 48.0 mmol) and the product from step 2 (6.00 g, 33.7 mmol) were added dropwise at -65°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by adding saturated aqueous ammonium chloride (60.0 mL) at 0°C, and then extracted three times with DCM (60.0 mL). The combined organic layers were washed with brine (60.0 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. 1 H NMR: (400 MHz, chloroform-d): δ = 4.33 (q, J = 7.2 Hz, 4H), 2.18 - 1.98 (m, 4H), 1.56 (td, J = 3.8, 8.0 Hz, 4H), 1.36 (t, J = 7.2 Hz, 6H)

[0107] Step 4: To a solution of the product from Step 3 (11.0 g, 36.4 mmol) in dioxane (30.0 mL), 1,5,7-triazabicyclo[4.4.0]deca-5-ene (14.2 g, 102 mmol) and 3-amino-1-benzofuran-2-carboxamide (4.50 g, 25.5 mmol) were added. The mixture was stirred at 110°C for 2 hours, then diluted with water (30.0 mL) and extracted three times with siRNA (30.0 mL). The combined organic layer was washed with brine (30.0 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by RP HPLC (ACN / water, modifier: TFA). 1 H NMR: (400 MHz,DMSO-d): δ = 8.09 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 2.40 - 2.37 (m, 2H), 2.12 - 2.07 (m, 2H), 1.54 - 1.48 (m, 4H). Step 5: The product from Step 4 was chlorinated using the general procedure Int-C.

[0108] Step 6: The product from Step 5 was reacted using the general procedure Int-D to obtain the title compound. ESI-MS:556 [M+H] + R t (HPLC): 0.64 min (Method A) Intermediate NJ: [ka] The intermediate NR was prepared by applying the following three-step sequence:

[0109] Step 1: General Procedure Int-G: Intermediate NR (300 mg; 0.69 mmol) and methyl 5-hexenoate (298 μL; 2.07 mmol) were dissolved in DMF (10 mL; 123 mmol). Triethylamine (0.39 mL, 2.76 mmol) was added, and the mixture was degassed with argon. Palladium(II) acetate (31 mg; 0.14 mmol) and tri-o-tolylphosphine (84 mg; 0.28 mmol) were added under argon. The sealed vial was stirred overnight at 95°C. The mixture was diluted with ACN / water, acidified with TFA, and filtered through a syringe filter. Purification by preparative RP HPLC (Sunfire C18, ACN / water; modifier: TFA) yields tert-butyl(2S,4S)-4-hydroxy-1-{4-[6-methoxy-6-oxohexa-1-en-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidine-2-carboxylate was obtained.

[0110] Step 2: The product of Step 1 is hydrogenated according to the general procedure Int-A to obtain tert-butyl(2S,4S)-4-hydroxy-1-[4-(6-methoxy-6-oxohexyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-2-carboxylate. ESI-MS: 484 [M+H] + R t (HPLC): 0.65 min (Method B)

[0111] Step 3: The product from Step 2 was reacted according to the general procedure Int-E to obtain the ester-cleavage title compound.

[0112] Intermediate NK: [ka] From the intermediate NR and methyl 3-(buta-3-en-2-yloxy)propanoate, the following 3-step sequence is obtained: Step 1: Heck-type coupling compliant with general procedure Int-G Step 2: Hydrogenation in accordance with general procedure Int-A Step 3: Ester cleavage in accordance with the general procedure Int-E. The title compound was obtained by applying the following method (the starting material, methyl 3-(buta-3-en-2-yloxy)propanoate, was prepared by acidic ester cleavage from its respective tert-butyl ester, followed by methyl ester formation (methanol, thionyl chloride)). ESI-MS: 500 [M+H] + R t (HPLC): 1.82 minutes (Method G)

[0113] Intermediate NL: 2-(4-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(13),2,4,6,9,11-hexaen-4-yl}-4,4-difluorobutoxy)acetic acid [ka]

[0114] Step 1: A dry reaction vessel was equipped with a magnetic stirring bar, and tert-butyl 2-allyl oxyacetate (1.00 g; 5.81 mmol), anhydrous nickel(II) chloride (0.038 g; 0.290 mmol), and sodium carbonate (0.61 g; 5.81 mmol) were added. The reaction vessel was then briefly evacuated and refilled with argon (this sequence was repeated a total of three times). Anhydrous DMF (40 mL), ethyl bromodifluoroacetate (1.5 mL, 11.6 mmol), and phenylsilane (2.9 mL; 23.2 mmol) were sequentially added to the reaction vessel via syringe. The vessel was heated in an oil bath at 70°C and stirred until TLC monitoring indicated the consumption of the starting materials (in this case, overnight). The reaction mixture was diluted with 30 mL of siRNA, and the organic layer was washed with 80 mL of saturated sodium chloride aqueous solution. The organic layer was then dehydrated with sulfate, concentrated under reduced pressure, and further purified by FC (silica gel; hexane / ethyl) to obtain ethyl 5-(2-tert-butoxy-2-oxoethoxy)-2,2-difluoropentanoate.

[0115] Step 2: At room temperature, 1,5,7-triazabicyclo[4.4.0]deca-5-ene (0.79 g; 5.68 mmol) was added to a solution of 3-aminobenzofuran-2-carboxamide (0.25 g; 1.42 mmol) in 1,4-dioxane (1 mL). Then, the product from step 1 (0.84 g; 2.84 mmol) was added, and the temperature was raised to 120°C. The mixture was stirred until TLC showed a nearly complete transformation (in this case, 18 hours). The reaction mixture was diluted with water (15 mL) and extracted with DCM (3 times × 7 mL). The pH of the resulting aqueous layer was adjusted to 4-5, and the precipitated solid was filtered off. ESI-MS: 353 [M+H] + R t (HPLC): 1.61 min (Method H)

[0116] Step 3: The product from Step 2 was reacted according to the general procedure Int-C. ESI-MS: 371 [M+H] + R t (HPLC): 1.82 minutes (Method H)

[0117] Step 4: The product from Step 2 was reacted according to the general procedure Int-D to obtain the title compound. ESI-MS: 522.6 [M+H] + R t (HPLC): 2.96 minutes (Method G)

[0118] Intermediate NM: [ka] 3-amino-6-chloro-1-benzofuran-2-carboxamide (prepared as described in European Patent Application Publication No. 1710233) was used as the starting material in step 2, and the intermediate NL was prepared in the same manner as described in the procedure for its synthesis.

[0119] Intermediate NN: [ka] Preparation of intermediate NJ from intermediate NR and methyl 4,4-dimethylhepta-6-enoate was carried out in the same reaction sequence as described for the synthesis of intermediate NJ.

[0120] Intermediate NO: [ka] Preparation of intermediate NJ from intermediate NR and ethyl 6-heptaenoate was carried out in the same reaction sequence as described for the synthesis of intermediate NJ.

[0121] Intermediate NP: [ka] The intermediate NU was reacted according to the general procedure Int-E to obtain the title compound. ESI-MS: 414 [M+H] + R t (HPLC): 0.55 min (Method B) Intermediate NQ: [ka] tert-butyl(2S,4S)-1-[4-(7-ethoxy-7-oxohepta-1-en-2-yl)-8-oxa-3,5-diazatricyclo[7.4.0.0] was formed as a by-product in step 1 of the synthesis of intermediate NO. 2,7 Trideca-1(13),2,4,6,9,11-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate was isolated by RP HPLC and further reacted according to the reaction sequence described for the preparation of intermediate NO to obtain the title compound.

[0122] Intermediate NR: tert-butyl(2S,4S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(13),2(7),3,5,9,11-hexaen-6-yl}-4-hydroxypyrrolidine-2-carboxylate [ka]

[0123] Step 1: 4,6-dibromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(13),2(7),3,5,9,11-hexaene A mixture of 1H-benzo[4,5]fl[3,2-d]pyrimidine-2,4-dione (11.6 g; 0.0573 mol) and phosphoryltribromide (40.8 mL, 0.402 mol) was heated at 150°C for 3 hours. The mixture was cooled to room temperature, and the pH was adjusted to pH=7 while cooling to 0°C using a saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (3 times × 50 mL). The organic layers were combined, dehydrated with sodium sulfate, and evaporated under reduced pressure. The remaining residue was purified by dissolving it in a mixture of DCM (3 volumes relative to the weight of the crude product) and ethyl acetate (3 volumes relative to the weight of the crude product) while stirring. After stirring at room temperature for 30 minutes, the mixture was filtered, and the supernatant was evaporated under reduced pressure. ESI-MS: 327 / 329 / 331 [M+H] + R t (HPLC): 0.67 min (Method A)

[0124] Step 2: tert-butyl(2S,4S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(13),2(7),3,5,9,11-hexaen-6-yl}-4-hydroxypyrrolidine-2-carboxylate To 93 mL of DMF, a mixture of 4,6-dibromo-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene (5.56 g, 16.9 mmol) was added, to which tert-butyl(2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (4.17 g, 16.6 mmol) and potassium carbonate (7.03 g, 50.8 mmol) were added. After stirring overnight at room temperature, the reaction mixture was poured into water and neutralized with 4 M aqueous HCl solution. The precipitate was collected by filtration and vacuum-dried. ESI-MS: 434 / 436 [M+H] + R t (HPLC): 0.64 min (Method A)

[0125] Intermediate NS: [ka]

[0126] Step 1: 9.02 g of 2-allyloxyacetic acid (73.8 mmol) was dissolved in DCM containing one drop of DMF and cooled to 0°C. 23.4 g of oxalyl chloride (184 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 2 hours. The solvent was then evaporated under reduced pressure. The residue was dissolved in DMF and added to a stirred solution of 3-aminobenzofuran-2-carboxamide (13.0 g of 3-aminobenzofuran-2-carboxamide) in DMF. After 2 hours, the mixture was poured into 100 mL of water and stirred for 5 minutes. The resulting solid was collected, dissolved in DCM, and dehydrated with magnesium sulfate. The volatile substances were evaporated, and the solid was triturated with tert-butyl methyl ether to obtain 3-[2-(propa-2-en-1-yloxy)acetamide]-1-benzofuran-2-carboxamide.

[0127] Step 2: The suspension of the product from Step 1 in 4M aqueous sodium hydroxide was stirred at 70°C for 2 hours. The mixture was acidified by adding aqueous hydrochloric acid, and the resulting precipitate was collected and dried to form 4-[(propa-2-en-1-yloxy)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained trideca-1(9),2(7),3,10,12-pentaen-6-one. The product from Step 2 was further reacted using a two-step sequence involving Int-C and then Int-D, as per the general procedure, to obtain the title compound. ESI-MS:426 [M+H] + R t (HPLC): 0.49 min (Method A) Intermediate NT: [ka]

[0128] Step 1: Sodium hydride (60% in mineral oil; 1.73 g, 44.2 mmol) was added in small amounts over 2 minutes to sodium 2-chloro-2,2-difluoroacetate (4.5 g, 29.5 mmol) and propa-2-en-1-ol (2.14 g, 36.8 mmol) in 30 mL of THF under nitrogen at 0°C. The resulting suspension was stirred at 65°C for 16 hours. The reaction mixture was cooled and diluted with aqueous hydrochloric acid (2 M) to a pH of 5-6, and the aqueous layer was extracted twice with DCM (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to obtain the crude product. The crude product was purified by FC (silica gel; petroleum ether / siRNA 0% → 30%) to obtain 2-(allyloxy)-2,2-difluoroacetic acid. 1 H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 6.01 - 5.91 (m, 1H), 5.45 - 5.36 (m, 1H), 5.33 - 5.26 (m, 1H), 4.50 (dt, J = 5.8, 1.2 Hz, 2H) Step 2: To a solution of the product from Step 1 (5 g, 33 mmol) in pyridine (100 mL), 4.63 g, 26 mmol of 3-amino-1-benzofuran-2-carboxamide was added, followed by the dropwise addition of phosphoryl trichloride (15.3 g, 0.1 mol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water (200 mL) and extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine, dehydrated with sodium sulfate, and concentrated. The residue was purified by FC (silica gel; petroleum ether / ethyl acetate 15%) to obtain 3-(2-(allyloxy)-2,2-difluoroacetamide)benzofuran-2-carboxamide. ESI-MS: 311 [M+H] +

[0129] Step 3: The product from Step 2 (3 g, 9.7 mmol) was added to aqueous sodium hydroxide (14.5 mL, 4 M, 58.2 mmol), followed by the addition of THF (1.5 mL). The reaction mixture was stirred at 70°C for 4 hours. The cooled (room temperature) reaction mixture was acidified to pH 5-6 with aqueous hydrochloric acid (2 M), the resulting precipitate was collected and dried to obtain crude 2-((allyloxy)difluoromethyl)benzoflou[3,2-d]pyrimidine-4(3H)-one. This was used in the next step without further purification.

[0130] Step 4: DMF (1.36 g, 18.6 mmol) and DCM (250 mL) were placed in a 0.5 L three-necked flask equipped with a thermometer and a nitrogen balloon. The flask was cooled to 0°C, and a solution of oxalyl chloride (3.54 g, 27.9 mmol) in DCM (5 mL) was added dropwise over 5 minutes while maintaining the temperature at 0-5°C. The mixture was stirred at ambient temperature for 0.5 hours. The reaction was cooled to 0°C in an ice bath, and the product from step 3 (1.8 g, 6.2 mmol) was added in small amounts. The reaction was stirred at room temperature for 15 minutes, then stirred at 40°C for 2 hours. After cooling to room temperature, the reaction was poured onto ice, neutralized with aqueous sodium bicarbonate, and extracted twice with DCM (100 mL). The combined organic phase was washed with water, dried over sodium sulfate, and concentrated. The crude product was purified by FC (silica gel; petroleum ether / RINKAN 2% → 10%) to obtain the title compound 2-((allyloxy)difluoromethyl)-4-chlorobenzofl[3,2-d]pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 - 8.31 (m, 1H), 7.79 (m, 2H), 7.60 - 7.54 (m, 1H), 7.26 (s, 1H), 6.06 (dq, J = 10.8, 6.0 Hz, 1H), 5.45 (dd, J = 17.2, 1.2 Hz, 1H), 5.30 (dd, J = 10.4, 1.0 Hz, 1H), 4.70 (d, J = 6.0 Hz, 2H)

[0131] Step 5: The product from Step 4 was reacted according to the general procedure Int-D to obtain the title compound. ESI-MS: 462 [M+H] + R t (HPLC): 0.68 min (Method A)

[0132] Intermediate NU: tert-butyl(2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate [ka]

[0133] Step 1: Ethyl 2-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(9),2(7),3,10,12-pentaen-4-yl acetate To a mixture of ethyl-3-aminobenzofuran-2-carboxylate (5.00 g; 24.4 mmol) in 4M aqueous hydrochloric acid (50.00 mL; 200 mmol), ethyl cyanoethyl (5.19 mL; 48.7 mmol) was added at room temperature. The mixture was heated at 100°C for 4 hours. After cooling to room temperature, a further 2.6 mL (24.4 mmol) of ethyl cyanoethyl was added, and heating was continued at 100°C for 48 hours. The solvent was evaporated, the crude residue was diluted with 100 mL of MeOH, filtered, and dried. The crude product was used directly in the next step. ESI-MS: 273 [M+H] + R t (HPLC): 0.63 min (Method B)

[0134] Step 2: Ethyl 2-{6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7Trideca-1(9),2(7),3,5,10,12-hexaen-4-yl acetate Phosphoryl trichloride (50.0 mL; 547 mmol) contains ethyl 2-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 A mixture of trideca-1(9),2(7),3,10,12-pentaen-4-yl acetate (3.35 g; 12.3 mmol) was heated at 110°C for 1.5 hours. The reaction mixture was cooled to room temperature and added dropwise over 30 minutes in an ice bath (500 mL) under stirring. Ethyl acetate was added and the mixture was separated. A saturated bicarbonate solution was slowly added to the organic layer, causing phase separation. The organic layer was washed with water and brine, dehydrated with sodium sulfate, filtered, and concentrated under vacuum. ESI-MS: 291 [M+H] + R t (HPLC): 0.43 min (Method A)

[0135] Step 3: tert-butyl(2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate 30 mL of NMP contains ethyl 2-{6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 To trideca-1(9),2(7),3,5,10,12-hexaen-4-yl acetate (8.17 mmol; 1.00 equivalent, 2.50 g), tert-butyl(2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (8.99 mmol; 2.01 g) and DIPEA (27.0 mmol; 4.64 mL) were added, and the resulting mixture was stirred at 70°C for 1.5 hours. The reaction mixture was cooled to room temperature and slowly added to 300 mL of ice water. The precipitate was filtered, washed several times with water, and dried. ESI-MS: 442 [M+H] + R t(HPLC): 0.67 min (Method B)

[0136] Intermediate NV: [ka] 11-Fluoro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Preparation of the intermediate NR from trideca-1(13),2(7),9,11-tetraene-4,6-dione in the same reaction sequence as described for the synthesis of the intermediate NR. Starting material 11-fluoro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(13),2(7),9,11-tetraen-4,6-dione as described in International Publication No. 2019059577, 11-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 It was prepared in the same manner as the synthesis of trideca-1(13),2(7),9,11-tetraene-4,6-zione.

[0137] Preparation of the final compound The absolute configuration of the piperidine moiety of the compound (where R2 is a methyl group) was partially determined (e.g., Example 1.01) from the co-crystal structure with human cGAS protein, according to the method described by DJ Patel et al, PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116). In other cases, the absolute configuration was determined based on the assumption that the stronger diastereoisomer always has the (S,S,S,S)-stereoconfiguration.

[0138] (Example 1.01) (General Procedures A, B, C, D) [ka]

[0139] Step 1 (General Procedure A): Under an argon atmosphere, in oven-dried glassware, intermediate NA (216 mg; 0.418 mmol) and intermediate B-01 (188 mg; 0.439 mmol) were dissolved in DMA (4.05 ml), to which sodium hydride (55% in mineral oil; 73.0 mg; 1.67 mmol) was added. After the foaming subsided, the reaction was heated to 35°C and stirred for a further 25 minutes. The reaction was then quenched by adding ice water, diluted with ethyl acetate, and acidified by adding aqueous hydrochloric acid (1 M; 1.7 mL). The mixture was extracted three times with ethyl acetate, and the combined organic layer was subsequently washed with water and brine and evaporated to dryness. The crude reaction mixture was purified by FC (silica gel; cyclohexane / ethyl acetate 25% → 100%). ESI-MS: 833 [M+H] + R t (HPLC): 0.92 min (Method B)

[0140] Step 2 (General Procedure B): To a mixture of the intermediate from Step 1 (272 mg; 0.326 mmol) and ACN (10 mL), TosOH (124 mg; 0.653 mmol) was added, and the mixture was stirred in a closed vial at room temperature for 3 days. Since the reaction control by HPLC showed a low conversion, TosOH (45.0 mg; 0.237 mmol) was added, and the mixture was further heated at 40°C until the reaction control by HPLC showed a high conversion to the desired product. DMF and one drop of water were added, and the mixture was then filtered and subjected to HPLC purification (Sunfire C18; ACN / water, TFA as a modifier). ESI-MS: 733 [M+H] + R t (HPLC): 0.62 min (Method B)

[0141] Step 3 (General Procedure C): In a furnace-dried glassware under argon, a solution of HATU (81.2 mg; 0.214 mmol) in DMF (4 mL) was slowly added to a solution of the intermediate from step 2 (145 mg; 0.198 mmol) in DMF (12 mL) using a syringe pump under vigorous stirring. The mixture was further stirred until HPLC control of the reaction showed a high conversion to the desired product. The reaction was then quenched by the addition of water, extracted three times with ethyl acetate, and the combined organic layer was subsequently washed with water and brine and evaporated to dryness. The crude reaction mixture was purified by FC (cyclohexane / ethyl acetate 50% → 100%, then ethyl acetate / MeOH 0% → 10%). ESI-MS: 715 [M+H] + R t (HPLC): 0.80 min (Method B)

[0142] Step 4 (General Procedure D): The mixture of the intermediate from Step 3 (79.0 mg; 0.110 mmol), DCM (1.06 ml), and TFA (852 μL) was stirred at room temperature for 90 minutes. Since the reaction control by HPLC showed a low conversion, the temperature was raised to 37°C and stirring continued for 3 hours. Since the reaction control by HPLC still showed a low conversion, the temperature was raised to 45°C and stirring continued until the reaction control by HPLC showed a high conversion to the desired product. The mixture was evaporated, and the crude product was purified by preparative HPLC (Sunfire C18; ACN / water, TFA as modifier). ESI-MS: 659 [M+H] + R t (HPLC): 0.83 min (Method E)

[0143] The following compounds were prepared in the same manner as in Example 1.01 above, following general procedures A, B, C, and D: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0144] (Example 2.01) [ka]

[0145] Step 1: Intermediate B-09 was reacted according to general procedure D to obtain the TFA salt of rac-trans-7-chloro-2-methanesulfonyl-1-[3-methylpiperidine-4-yl]-1H-1,3-benzodiazole.

[0146] Step 2: The product from Step 1 was reacted with 1.2 equivalents of 4-{[(tert-butoxy)carbonyl]amino}butanoic acid according to general procedure C.

[0147] Step 3: The product of Step 2 is reacted with intermediate NP according to general procedure A to obtain 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({1-[1-(4-{[(tert-butoxy)carbonyl]amino}butanoyl)-3-methylpiperidine-4-yl]-7-chloro-1H-1,3-benzodiazole-2-yl}oxy)pyrrolidine-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7Trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid (having a racemic trans configuration of the piperidine moiety) was obtained.

[0148] Step 4: The product from Step 3 was deprotected by BOC by reaction with 1.5 equivalents of hydrochloric acid (4M in dioxane) in dioxane overnight at room temperature. The crude product was purified by RP HPLC (Sunfire C18; ACN / water / modifier: TFA) to obtain 2-{6-[(2S,4S)-4-({1-[1-(4-aminobutanoyl)-3-methylpiperidine-4-yl]-7-chloro-1H-1,3-benzodiazole-2-yl}oxy)-2-[(tert-butoxy)carbonyl]pyrrolidine-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 The TFA salt of ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid (having a racemic trans configuration of the piperidine moiety) was obtained.

[0149] Step 5: The product from Step 4 is reacted according to general procedure C to obtain tert-butyl(12S,14S)-4-chloro-37-methyl-29,34-dioxo-11,18-dioxa-2,9,15,26,30,35,40-heptazaoctacyclo[33.2.2.1 12,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 We obtained hexetetraconta-3,5,7,9,16(40),17(25),19(24),20,22,26-decaene-14-carboxylate (having a racemic trans configuration of the piperidine moiety).

[0150] Step 6: The product of Step 5 is reacted according to general procedure D to obtain the title compound (12S,14S)-4-chloro-37-methyl-29,34-dioxo-11,18-dioxa-2,9,15,26,30,35,40-heptazaoctacyclo[33.2.2.112,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 We obtained hexetetraconta-3,5,7,9,16(40),17(25),19(24),20,22,26-decaene-14-carboxylic acid (having a racemic trans configuration of the piperidine moiety). ESI-MS: 672 [M+H] + R t (HPLC): 0.88 min (Method E)

[0151] (Example 3.01) [ka]

[0152] Step 1: Intermediate I.02 is deprotected by BOC according to general procedure B to obtain tert-butyl(2S,4S)-1-{4-[1,1-difluoro-2-(propa-2-en-1-yloxy)ethyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 The TFA salt of ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}-4-({1-[(3S,4S)-3-methylpiperidine-4-yl]-1H-1,3-benzodiazole-2-yl}oxy)pyrrolidine-2-carboxylate was obtained. ESI-MS: 689 [M+H] + R t (HPLC): 0.62 min (Method A)

[0153] Step 2: General Procedure G: At 0°C, the product from Step 1 (105 mg; 0.127 mmol), vinylacetic acid (14.5 μl; 0.165 mmol), and DMAP (2.0 mg; 0.016 mmol) were mixed in a solution of DCM (1.05 mL), to which DCC (1 M; 165 μL; 0.165 mmol) was added dropwise. The mixture was heated to room temperature with stirring, and then stirred for another hour. The mixture was evaporated to dryness, and the residue was subjected to FC (CH / Â 40% → 100%). The resulting impure product was further purified by RP HPLC (Sunfire C18; ACN / water, modifier: TFA) to obtain tert-butyl(2S,4S)-4-({1-[(3S,4S)-1-(buta-3-eneoyl)-3-methylpiperidine-4-yl]-1H-1,3-benzodiazole-2-yl}oxy)-1-{4-[1,1-difluoro-2-(propa-2-ene-1-yloxy)ethyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidine-2-carboxylate was obtained. ESI-MS: 757 [M+H] + R t (HPLC): 0.77 min (Method A)

[0154] Step 3: General Procedure H: In a furnace-dried glass container, the product from Step 2 (dried by azeotropic co-distillation with toluene; 77.0 mg; 0.102 mmol) was dissolved in 1,2-dichloroethane (degassed; 9.0 ml) and the catalyst Grubbs II (5.0 mg) was added. The mixture was stirred at 80°C for 24 hours, then the same amount of catalyst was added again, and the mixture was stirred for another 24 hours. The reaction was quenched by the addition of imidazole (10 mg) and then allowed to cool to room temperature. The mixture was concentrated and subjected to FC (silica gel; CH / siRNA 20% → 100%) to obtain tert-butyl(1S,12S,14S,32E,38S)-28,28-difluoro-38-methyl-35-oxo-11,18,30-trioxa-2,9,15,26,36,41-hexaazaoctacyclo[34.2.2.1]. 12,15.1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 We obtained dotetraconta-3(8),4,6,9,16(41),17(25),19,21,23,26,32-undecaene-14-carboxylate. ESI-MS: 729 [M+H] + R t (HPLC): 0.73 min (Method A)

[0155] Step 4: The product from Step 3 (22.0 mg; 0.0302 mmol), ethanol (1.5 mL), and a mixture of 10% Pd / C were maintained overnight under hydrogen (5 psi) in a Parr apparatus. The mixture was filtered, evaporated, and used for the next step. ESI-MS: 731 [M+H] + R t (HPLC): 1.09 min (Method E)

[0156] Step 5: The product from Step 4 (22.1 mg) was reacted according to general procedure D. The product was further purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 675 [M+H] + R t (HPLC): 0.60 min (Method A)

[0157] (Example 4.01) [ka]

[0158] Step 1: To a degassed solution of intermediate I.02 (150 mg; 0.190 mmol) in ethyl acrylate (1.56 mL; 14.3 mmol), Grubbs II catalyst (8.1 mg; 0.0095 mmol) was added. The mixture was stirred for 24 hours, then evaporated, and subjected to FC (CH / siRNA 30% → 100%) to obtain tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(2-{[4-ethoxy-4-oxobuta-2-en-1-yl]oxy}-1,1-difluoroethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate. ESI-MS: 861 [M+H] + R t (HPLC): 1.28 minutes (Method B)

[0159] Step 2: General Procedure E The mixture of the product from Step 1 (140 mg; 0.163 mmol), Pd / C 10% (28 mg), and ethanol (2.0 mL) was reacted in a Parr apparatus at room temperature under hydrogen (50 psi) until HPLC control showed the conversion of the starting materials (4 hours). The mixture was filtered, concentrated under reduced pressure, and purified by RP HPLC (XBridge C18, ACN / water, modifier: TFA) to tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-{4-[2-(4-ethoxy-4-oxobutoxy)-1,1-difluoroethyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate. ESI-MS: 863 [M+H] + R t (HPLC): 1.28 minutes (Method B)

[0160] Step 3: General Procedure F The product from Step 2 (118 mg; 0.137 mmol) was dissolved in a mixture of aqueous lithium hydroxide (2 M; 153 μL; 0.306 mmol), MeOH (0.80 mL), and THF (4.0 mL). The mixture was stirred at 40°C for 7 hours until HPLC analysis showed a transformation, concentrated under reduced pressure, diluted with water, and acidified with equimolar aqueous hydrochloric acid. One drop of methanol was added, and the mixture was extracted by DCM. The organic layer was separated, concentrated under reduced pressure, and used in the next step.

[0161] Step 4: The product from Step 3 is reacted according to general procedure B to obtain 4-(2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({1-[(3S,4S)-3-methylpiperidine-4-yl]-1H-1,3-benzodiazole-2-yl}oxy)pyrrolidine-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(13),2,4,6,9,11-hexaen-4-yl}-2,2-difluoroethoxy)butanoic acid was obtained.

[0162] Step 5: The product of Step 4 is reacted according to general procedure C to obtain tert-butyl(1S,12S,14S,37S)-28,28-difluoro-37-methyl-34-oxo-11,18,30-trioxa-2,9,15,26,35,40-hexaazaoctacyclo[33.2.2.1 12,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 We obtained hexetetraconta-3,5,7,9,16,19,21,23,25,27(40)-decaene-14-carboxylate. Step 6: The product from step 5 was reacted according to general procedure D to obtain the title compound. ESI-MS: 661 [M+H] + R t (HPLC): 0.90 min (Method B)

[0163] (Example 5.01) [ka] Starting from intermediates NS and B-11, the synthesis was carried out by applying the following reaction sequence:

[0164] Step 1: Aromatic nucleophilic substitution by applying general procedure A (reagents: NS and B-11) Step 2: Apply General Procedure B to deprotect the BOC Step 3: Reaction with 4-pentenoic acid using general procedure G Step 4: Metathesis applying general procedure H Step 5: Hydrogenation applying General Procedure E Step 6: Apply General Procedure D to deprotect tert-butyl ester ESI-MS: 643 [M+H] + R t (HPLC): 0.58 min (Method A)

[0165] (Example 6.01) [ka] Starting from intermediates NT and B-02, the synthesis was carried out by applying the following reaction sequence:

[0166] Step 1: Aromatic nucleophilic substitution by applying general procedure A (Reagents: NT and B-02) Step 2: Apply the modification of general procedure H, metathesis using methyl 3-butenoate as the second olefin (15 equivalents of methyl 3-butenoate are added in DCM at room temperature to react, and after 24 hours, another 15 equivalents of methyl 3-butenoate are added, and then 0.3 equivalents of catalyst are added in small increments).

[0167] Step 3: Hydrogenation by applying general procedure E (solvent: pharmaceutically acceptable).

[0168] Step 4: Ester saponification using general procedure F (aqueous lithium hydroxide / THF, 50°C, 5 hours) Step 5: Apply General Procedure B to deprotect the BOC Step 6: Ring-closing amidation by applying general procedure C (solvent: DMA) Step 7: Apply general procedure D to deprotect tert-butyl ester. ESI-MS: 695 [M+H] + R t (HPLC): 0.72 min (Method A)

[0169] (Example 7.01) [ka] Starting from intermediates NR and B-10, the synthesis was carried out by applying the following reaction sequence: Step 1: Aromatic nucleophilic substitution by applying general procedure A (Reagents: NR and B-10) Step 2: Apply General Procedure B to deprotect the BOC Step 3: Apply general procedure C, amidation with (3R)-3-propa-3-en-1-yloxy)butanoic acid.

[0170] Step 4: To a dioxane-degassed solution (under argon) of the product from Step 3 (162 mg; 0.213 mmol), cesium carbonate (174 mg; 0.533 mmol), and silver iodide (55.1 mg; 0.235 mmol), the catalyst [1,1'-BIS(di-TERT-butylphosphino)ferrocene]dichloropalladium(II) (21.3 mg; 0.0320 mmol) was added. The mixture was stirred at 120°C for 24 hours and then allowed to cool to room temperature. The mixture was diluted with ACN / methanol, filtered, and purified by preparative RP HPLC (XBridge C18, ACN / water, modifier: TFA) to obtain tert-butyl(12S,14S,32R)-32-methyl-34-oxo-11,18,31-trioxa-2,9,15,26,35,40-hexaazaoctacyclo[33.2.2.1]. 12,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 We obtained hexetetraconta-3(8),4,6,9,16(40),17(25),19(24),20,22,26,28-undecaene-14-carboxylate. ESI-MS: 679 [M+H] + R t (HPLC): 0.60 min (Method A)

[0171] Step 5: Hydrogenation applying General Procedure E

[0172] Step 6: Apply General Procedure D to deprotect tert-butyl ester ESI-MS: 625 [M+H] + R t (HPLC): 0.47 min (Method A) (Example 8.01) [ka] Starting from intermediates NS and B-10, the synthesis was carried out by applying the following reaction sequence:

[0173] Step 1: Aromatic nucleophilic substitution by applying general procedure A (Reagents: NS and B-10)

[0174] Step 2: Reaction under argon. To a degassed mixture of the product from Step 1 (381 mg; 0.500 mmol), nickel(II) chloride (3.3 mg; 0.025 mmol), sodium carbonate (53 mg; 0.50 mmol), and anhydrous DMF (4.77 ml), ethyl bromodifluoroacetate (209 mg; 1.00 mmol) and phenylsilane (223 mg; 2.00 mmol) were added at room temperature. The mixture was stirred in a sealed container at 70°C for 14 hours. The mixture was poured into saturated brine, and the resulting mixture was extracted twice with butyl. The combined organic layer was dried over sodium sulfate, filtered, and evaporated. The crude product was purified by preparative RP HPLC (XBridge C18; ACN / water, modifier: TFA) and tert-butyl 4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-(4-{[(5-ethoxy-4,4-difluoro-5-oxopentyl)oxy]methyl}-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl)pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)piperidine-1-carboxylate. ESI-MS: 649 [M+H] + R t (HPLC): 0.80 min (Method A) Step 3: Ester saponification using general procedure F (aqueous lithium hydroxide / THF, room temperature, 2.5 hours)

[0175] Step 4: Apply General Procedure B to deprotect the BOC Step 5: Apply general procedure C, ring-closing amidation with HATU in DMF. Step 6: Apply General Procedure D to deprotect tert-butyl ester ESI-MS: 647 [M+H] + Rt (HPLC): 0.53 min (Method A) (Example 9.01) [ka] Starting from intermediates NR and B-10, the synthesis was carried out by applying the following reaction sequence:

[0176] Step 1: Aromatic nucleophilic substitution by applying general procedure A (Reagents: NR and B-10) Step 2: General Procedure I: Under argon conditions, palladium(II) acetate (9.0 mg; 0.040 mmol) and tri-o-tolylphosphine (24.4 mg; 0.080 mmol) were added to a degassed solution of the product from Step 1 (326 mg; 0.400 mmol), allyloxyacetic acid (133 μL; 1.20 mmol), and triethylamine (112 μL; 0.800 mmol) in DMF (6.52 mL). The vial was sealed, and the reaction mixture was stirred at 115°C for 2.5 hours. The reaction mixture was diluted with ACN / H2O, filtered, and then purified by preparative RP HPLC (XBridge C18; 30-100% ACN / H2O, modifier: ammonia) to obtain 2-{[(3-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-[(1-{1-[(tert-butoxy)carbonyl]piperidine-4-yl}-1H-1,3-benzodiazole-2-yl)oxy]pyrrolidine-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(13),2,4,6,9,11-hexaen-4-yl}propa-2-en-1-yl]oxyacetic acid was obtained as a mixture of E / Z isomers. ESI-MS: 769 [M+H] + R t (HPLC): 0.57 / 0.58 min (Method F)

[0177] Step 3: Hydrogenation by applying general procedure E (solvent: pharmaceutically acceptable). Step 4: Apply General Procedure B to deprotect the BOC Step 5: Apply general procedure C, ring-closing amidation with HATU in DMF. Step 6: Apply General Procedure D to deprotect tert-butyl ester ESI-MS: 597 [M+H] + R t (HPLC): 0.42 min (Method A)

[0178] (Examples 10.01 and 10.02) [ka] Starting from intermediates NR and I.03, the synthesis was carried out by applying the following reaction sequence:

[0179] Step 1: Aromatic nucleophilic substitution by applying general procedure A (Reagents: NR and I.03) Step 2: Intramolecular Heck coupling by applying General Procedure I (reaction time 17 hours; 100°C) Step 3: Hydrogenation using general procedure E (catalyst: Laney-Ni; solvent: methanol) Step 4: Apply general procedure D to deprotect tert-butyl ester. Step 5: The resulting diastereomer mixture was separated by preparative SFC (instrument: Sepiatec PrepSFC50; column: CHIRAL ART Cellulose-SC (10 mm × 250 mm, 5 μm); mobile phase: A CO2 and B IPA [+20 mM NH3]; gradient: B %=25% isocratic elution mode; flow rate: 15 mL / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 150 bar). Example 10.01 (Firstly, elution) ESI-MS: 625 [M+H] + R t (HPLC): 0.804 min (Method E) Example 10.02 (Second elution) ESI-MS: 625 [M+H] + R t (HPLC): 0.814 min (Method E)

[0180] (Example 11.01) [ka] Starting from intermediates NR and B-10, the synthesis was carried out by applying the following reaction sequence:

[0181] Step 1: Aromatic nucleophilic substitution by applying general procedure A (Reagents: NR and B-10) Step 2: The mixture of the product from Step 1 (500 mg; 0.682 mmol), 1,4-butanediol (1.22 mL; 13.6 mmol), potassium tert-butyrate (229 mg; 2.04 mmol), and ACN (10 mL; dehydrated with molecular sieves) was stirred overnight at 80°C in a sealed vial. The mixture was evaporated, and the residue was purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA) to obtain tert-butyl 4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(4-hydroxybutoxy)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)piperidine-1-carboxylate. ESI-MS: 743 [M+H] + R t (HPLC): 0.70 min (Method A)

[0182] Step 3: The mixture of the product from Step 2 (143 mg; 0.193 mmol), 4-nitrophenyl chloroformate (87.1 mg; 0.424 mmol), pyridine (103 μL; 1.27 mmol), and DCM (6.0 mL) was stirred at room temperature for 4 hours. After evaporating the volatile substances, the crude product was used in the next step without further purification. Step 4: Acidic BOC deprotection was performed using the conditions of general procedure D. Step 5: For carbamate formation and ring closure, the crude product from step 4 was dissolved in excess DIPEA and stirred at 70°C for 90 minutes. The mixture was evaporated and used for the next step without purification.

[0183] Step 6: Step 4: Apply general procedure D to deprotect tert-butyl ester. ESI-MS: 613 [M+H] + R t (HPLC): 0.50 min (Method A)

[0184] (Example 12.01) A racemic mixture of trans isomers: [ka]

[0185] Step 1: A mixture of tert-butyl-3-(2-hydroxyethoxy)propanoate (1.45 g; 7.62 mmol), pyridine (663 mg; 8.38 mmol), and DCM (15 mL), cooled to 0°C, was added dropwise by adding a solution of 4-nitrophenyl-chloroformate (1.54 g; 7.62 mmol) in DCM (15 mL). The mixture was stirred overnight at room temperature, then diluted with DCM and extracted with water. The organic layer was evaporated, and the crude product was used for the next step.

[0186] Step 2: The crude product from Step 1 (686 mg), intermediate B-12 (500 mg), diisopropyl-ethylamine (742 μL), and THF (8.0 mL) were refluxed for 2 hours. The mixture was evaporated, dissolved in ethyl acetate, extracted twice with aqueous sodium hydroxide (1 M), and then washed with water and brine. The organic layer was evaporated to dryness, and the crude reaction product was purified by FC (silica gel; petroleum ether / ethyl acetate 5% → 35%) to obtain racemic trans-tert-butyl 2-{3-[3-methyl-4-[2-(methylsulfanyl)-1H-1,3-benzodiazole-1-yl]piperidine-1-carbonyloxy]propoxy}acetate. ESI-MS: 478 [M+H] + R t (HPLC): 0.85 min (Method E)

[0187] Step 3: Acidic ester cleavage by applying general procedure D without chromatographic purification. Step 4: To a solution of the product from Step 3 (579 mg) in ACN (10 mL), 1-chloro-N,N,2-trimethylpropenylamine (259 μL; 3.92 mmol) was added at room temperature. The mixture was stirred overnight, evaporated, dissolved in DCM, and extracted with water. The organic layer was evaporated and subjected to FC (silica gel; petroleum ether / Âi 45% → 95%). ESI-MS: 580 [M+H] + R t (HPLC): 0.81 min (Method E)

[0188] Step 5: The product from Step 4 (650 mg; 1.12 mmol) was suspended in aqueous sodium hydroxide (4 M; 15 mL). The mixture was stirred at 60°C for 1 hour, then allowed to cool to room temperature, and subsequently acidified by adding aqueous hydrochloric acid (4 M). The supernatant was decanted, and the solid was purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 562 [M+H] + R t (HPLC): 0.76 min (Method E)

[0189] Step 6: The product from Step 5 (390 mg; 0.694 mmol) was suspended in phosphoryl trichloride (6 mL). The mixture was stirred at 90°C for 1 hour and then evaporated. Water was carefully added to the residue, and the resulting mixture was extracted with pharmaceutically acceptable ammonium compounds. The organic layer was separated and evaporated to dryness to obtain the racemic trans-3-({6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 [Trideca-1(9),2(7),3,5,10,12-hexaen-4-yl]methoxy)propyl-3-methyl-4-[2-(methylsulfanyl)-1H-1,3-benzodiazole-1-yl]piperidine-1-carboxylate was obtained. ESI-MS: 580, 582 [M+H] + R t (HPLC): 0.89 min (Method E) Step 7: The mixture of the product from Step 6 (300 mg; 0.517 mmol), tert-butyl(2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (142 mg; 0.621 mmol), potassium carbonate (173 mg; 1.19 mmol), and DMF (7.0 mL) was stirred overnight at room temperature. Water was added, the precipitate was collected, and purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA) to obtain 3-({6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 [Trideca-1(9),2(7),3,5,10,12-hexaen-4-yl]methoxy)propyl-3-methyl-4-[2-(methylsulfanyl)-1H-1,3-benzodiazole-1-yl]piperidine-1-carboxylate (having a racemic trans configuration of the piperidine moiety) was obtained. ESI-MS: 731 [M+H] + R t (HPLC): 0.77 min (Method E)

[0190] Step 8: The product from Step 7 (239 mg; 0.327 mmol) was dissolved in DCM (8.0 mL). m-chloroperbenzoic acid (77%; 161 mg; 0.719 mmol) was added, and the mixture was stirred for 2 hours, then washed with sodium bicarbonate solution. The organic layer was evaporated, and the 3-({6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 Trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}methoxy)propyl-4-(2-methanesulfonyl-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate (having a racemic trans configuration of the piperidine moiety) was obtained. ESI-MS: 763 [M+H] + R t (HPLC): 0.85 min (Method E)

[0191] Step 9: Cyclization by aromatic nucleophilic substitution, applying general procedure A.

[0192] Step 10: The title compound is obtained by acidic tert-butyl ester cleavage using general procedure D. ESI-MS: 627 [M+H] + R t (HPLC): 0.83 min (Method E)

[0193] (Example 13.01) [ka]

[0194] Step 1: N-methyl-(penta-4-en-1-yl)amine (500 mg; 4.79 mmol) was added dropwise to an ice-cold aqueous sodium carbonate (2 M; 4.79 mL; 9.58 mmol) solution to which benzyl chloroformate (774 μL; 5.27 mmol) was added. The mixture was stirred at 0°C for 1 hour, then diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water, then with brine, dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by FC (silica gel; cyclohexane / ethyl acetate 25% → 100%). ESI-MS: 234 [M+H] + R t (HPLC): 0.67 min (Method A)

[0195] Step 2: The reaction was carried out under argon in oven-dried glassware. Triethylamine (180 μL; 1.30 mmol) was added to a mixture of the product from Step 1 (191 mg; 0.778 mmol), intermediate I.01 (200 mg; 0.259 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (20.2 mg; 0.0311 mmol), and pre-degassed DMA (2.4 mL). The reaction mixture was degassed and then heated in a sealed vial at 115 °C for 10 hours. The mixture was evaporated, and the residue was purified by preparative RP HPLC (XBridge C18, ACN / water, modifier: ammonia) to obtain tert-butyl(3S,4S)-4-(2-{[(3S,5S)-1-{4-[5-{[(benzyloxy)carbonyl](methyl)amino}penta-1-en-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}-5-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate.

[0196] Step 3: Hydrogenation (including Cbz deprotection) is performed by applying general procedure E without chromatographic purification. Step 4: To a solution of the crude product (199 mg) from Step 3 in DCM (3 mL), triethylamine (125 μL; 1.04 mmol) and 4-nitrophenyl chloroformate (53 mg; 0.26 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was evaporated and purified by FC (cyclohexane / Â1 20% → 100%) to obtain tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(5-{methyl[(4-nitrophenoxy)carbonyl]amino}pentyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 We obtained ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-3-yl]oxy}-1H-1,3-benzodiazole-1-yl)-3-methylpiperidine-1-carboxylate. Step 5: Apply General Procedure B to deprotect the BOC Step 6: The crude product from Step 5 was added dropwise over 25 minutes to a solution of N,N-diisopropylethylamine (49 μL) in THF (1.5 mL) using a syringe pump. The mixture was stirred at 80°C for 10 hours. The mixture was passed through a sodium bicarbonate cartridge and evaporated. N-methylpyrrolidone (3.0 mL) and DIPEA (100 μL) were added, and the mixture was heated in a microwave oven at 180°C for 30 minutes. The mixture was purified by RP HPLC (XBridge C18, ACN / water, modifier: TFA). ESI-MS: 695 [M+H] + R t (HPLC): 0.61 min (Method A)

[0197] Step 7: The title compound is obtained by tert-butyl ester cleavage using general procedure D. ESI-MS: 638 [M+H]+ R t (HPLC): 0.55 min (Method A)

[0198] General Technical Matters The terms "ambient temperature" and "room temperature" are used synonymously and refer to a temperature of approximately 20°C, for example, 15-25°C. Generally, the prepared compounds 1 1H NMR spectra and / or mass spectra were obtained. Unless otherwise noted, all chromatographic operations were performed at room temperature.

[0199] List of Abbreviations [Table 3]

[0200] Analysis method (HPLC / SFC): [Table 4]

[0201] [Table 5]

[0202] [Table 6]

[0203] [Table 7]

[0204] [Table 8]

[0205] [Table 9]

[0206] [Table 10]

[0207] [Table 11]

[0208] [Table 12] [Examples]

[0209] 4. Examples 5.1 Example Compounds of Formula I, II, or III of the Present Invention The example compounds of formulas I, II, or III summarized in Table 1 were synthesized, and their pharmacological properties regarding their efficacy in inhibiting cGAS activity were tested. In particular, cGAS inhibition (hcGAS IC) 50 Regarding "biochemical (in vitro) IC" 50 "Value," "Regarding the inhibition of IFN induction in virally stimulated THP1 cells, IC 50 Value (THP) (vir) I C 50 ), "Regarding the inhibition of IFN induction in cGAMP-stimulated THP1 cells, IC 50 Value (THP) (cGAMP) I C 50 ), and IC regarding the inhibition of IFN induction in dsDNA-stimulated human whole blood. 50 Value (hWB IC) 50 The result was determined experimentally according to the assay method described in Section 6 below. The results are summarized in Table 1.

[0210] The example compounds of formulas I, II, or III summarized in Table 1 simultaneously exhibit the following three properties: • Satisfactory "biochemical (in vitro) IC regarding cGAS inhibition" 50hcGAS IC with a value of (≤100nM, preferably ≤50nM, especially ≤10nM) 50 ), • Satisfactory "Cellular IC regarding cGAS inhibition" 50 Value (≤1 μM, preferably ≤500 nM, more preferably ≤100 nM, especially ≤50 nM of THP1) (vir) I C 50 ), and • Satisfactory selectivity for cGAS inhibition (≥10, more preferably ≥50, more preferably ≥500, especially for THP1 ≥1000) (cGAMP) I C 50 / THP1 (vir) I C 50 ratio).

[0211] In addition, the example compounds of formula I, II, or III are acceptable ICs for inhibiting IFN induction in dsDNA-stimulated human whole blood. 50 Value (hWB IC) 50 ) also shows.

[0212] [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7]

[0213] 5.2 Comparison of Example Compounds of Formula I, II, or III with Prior Art Compounds 5.2.1 Compounds of International Publication No. 2020 / 142729 International Publication No. 2020 / 142729 disclosed a cGAS inhibitor with a partially similar structure. Pages 44 and 45 of International Publication No. 2020 / 142729 discuss "biochemical (in vitro) IC" regarding cGAS inhibition. 50 Value ("hcGAS IC 50 This disclosed the corresponding "biochemical (in vitro) IC50" of less than 100 nM. 50 Compounds with a "value" are designated as "Group A," and have a "biochemical (in vitro) IC50" that is higher than 100 nM and less than 500 nM. 50 Compounds with a "value" are designated as "Group B," and have a "biochemical (in vitro) IC50" that is higher than 500 nM and less than 1 μM. 50 Compounds with a "value" are designated as "Group C," and have a "biochemical (in vitro) IC50" value higher than 1 μM and less than 10 μM. 50 Compounds with a "value" are designated as "Group D" and have a "biochemical (in vitro) IC" higher than 10 μM. 50 Compounds with the value " were designated as "Group E" (see page 44 of International Publication No. 2020 / 142729).

[0214] On page 45 of International Publication No. 2020 / 142729, only compound No. 25 is listed as having a "biochemical (in vitro) IC2" of less than 100 nM. 50 It is disclosed that it may be designated as "Group A" having a value of ". All other example compounds in International Publication No. 2020 / 142729 have a "biochemical (in vitro) IC" higher than 100 nM. 50 It indicates the value. Selected prior art compounds from International Publication No. 2020 / 142729, including compound No. 25, were synthesized and then tested for their pharmacological properties regarding their efficacy in inhibiting the cGAS / STING pathway using the exact same assays used to test the compounds of the present invention. In particular, for the structurally closest example from International Publication No. 2020 / 142729, a "biochemical (in vitro) IC" was performed for cGAS inhibition. 50 Value (hcGAS IC) 50), "Regarding the inhibition of IFN induction in virus-stimulated THP1 cells, cellular IC 50 Value (THP1) (vir) I C 50 ), "Regarding the inhibition of IFN induction in cGAMP-stimulated THP1 cells, cellular IC 50 Value (THP1) (cGAMP) I C 50 ), and "IC regarding inhibition of IFN induction in human whole blood" 50 The "hWB" value was determined experimentally according to the assay method described in Section 6 below (see Table 2).

[0215] [Table 14-1] [Table 14-2]

[0216] The pharmacological properties of the example compounds of the present invention summarized in Table 1 and the pharmacological properties of the compounds of International Publication No. 2020 / 142729 summarized in Table 2 were determined experimentally according to the same assay procedure described in Section 6 below, and can therefore be compared with each other. From the data shown in Table 2, (International Publication No. 2020 / 142729 defines "biochemical (in vitro) IC2" as less than 100 nM) 50 Value (= hcGAS IC) 50 With the exception of Example No. 25 in International Publication No. 2020 / 142729 (which was designated as "Group A" having ), all example compounds in International Publication No. 2020 / 142729 have a significantly higher "biochemical (in vitro) IC50 than 100 nM". 50 Value (= hcGAS IC) 50 It is clear that the above exhibits a "biochemical (in vitro) IC2" of less than 100 nM. In contrast, all of the example compounds of the present invention exhibit a "biochemical (in vitro) IC2" of less than 100 nM. 50 Value (hcGAS IC) 50 ) has 55 nM "biochemical (in vitro) IC50". 50Value (hcGAS IC) 50 Example No. 25 of International Publication No. 2020 / 142729, which has THP1 (vir) I C 50 Since it is 17 μM, THP1 is lower than 1 μM. (vir) I C 50 It does not meet the selection criteria for "satisfactory cell inhibitory efficacy" as indicated by [the relevant source].

[0217] 5.2.2 Compounds of International Publication No. 2022 / 174012 International Publication No. 2022 / 174012 disclosed a cGAS inhibitor having a partially similar structure. On page 65 of International Publication No. 2022 / 174012, regarding cGAS inhibition, it states "biochemical (in vitro) IC 50 The value, on page 67 of International Publication No. 2022 / 174012, states "Cell IC 50 The value (IFNβ stimulated with THP-1 ELISA) was disclosed. Compound 5 (BBL0100455) in International Publication No. 2022 / 174012 is, a) Biochemical (or enzymatic) (in vitro) IC2 levels lower than 100 nM 50 (In the enzyme assay of International Publication No. 2022 / 174012, compound 5 was measured to obtain an enzyme IC50 nM to 100 nM.) 50 It is included in "Group B" which represents the value. (See Table 2 on page 65 of International Publication No. 2022 / 174012) and b) Cellular IC at concentrations lower than 1 μM 50 "Value" (THP-1 stimulated IFNβ ELISA) (In the "Cell Assay" of International Publication No. 2022 / 174012, compound 5 was measured to obtain a "Cell IC5" value of <1 μM) 50 It is included in "Group A" which represents the value. (See Table 3 on pages 67 and 68 of International Publication No. 2022 / 174012) It appears to be the only compound in International Publication No. 2022 / 174012 that may have the potential to satisfy the selection criteria of the present invention, which means that it is the only compound that can satisfy these criteria.

[0218] However, the biochemical / enzyme assays and cell assays in International Publication No. 2022 / 174012 are not identical to the respective "biochemical / enzyme assays and cell assays" of the present invention, and therefore the measured biochemical / enzyme ICs in International Publication No. 2022 / 174012 are not identical to the "biochemical / enzyme assays and cell assays" of the present invention. 50 Values ​​and Cell IC 50 The values ​​are the IC values ​​measured for each compound of the present invention. 50 The value is not comparable. Therefore, compound 5 of International Publication No. 2022 / 174012 was synthesized and then tested for its pharmacological properties relating to its efficacy in inhibiting the cGAS / STING pathway using the exact same assay used for testing the compounds of the present invention and described in Section 6 below.

[0219] [Table 15] As shown in the data in Table 3, compound No. 5 (BBL0100455) of International Publication No. 2022 / 174012 is acceptable for biochemical / enzymatic IC55 nM. 50 Value (hcGAS IC 50 Cellular IC has a strength of 55nM, but is higher than 10000nM. 50 Value (THP1 (vir) I C 50 It has (=10000nM). As a result, all of the compounds of the present invention have their biochemical / enzymatic IC2. 50 The values ​​are comparable to those of compound No. 5 in International Publication No. 2022 / 174012, but their cellular IC 50 The values ​​are clearly superior to those of compound No. 5 in International Publication No. 2022 / 174012 (all are lower than 1000 nM for compounds of formula I, II, or III of the present invention).

[0220] 5.3 Prodrugs Esters of activators with carboxylic acid groups can represent practical prodrugs, for example, they are known to exhibit improved oral absorption / bioavailability compared to the activators alone. Commonly used prodrugs of activators with carboxylic acid groups include, for example, methyl esters, ethyl esters, and isopropyl esters (see Beaumont et al., Current Drug Metabolism, 2003, Vol. 4, Issue 6, 461-485). Furthermore, Nakamura et al., Bioorganic & Medicinal Chem., Vol. 15, Issue 24, p. 7720-7725 (2007) states that N-acylsulfonamide derivatives and N-acylsulfonylurea derivatives of specific activators and free carboxylic acid groups also have the potential to be practical prodrugs.

[0221] In addition, experimental evidence suggests that the methyl esters of the example compounds of formulas I, II, or III also represent usable prodrugs of the cGAS inhibitors of formulas I, II, or III. International applications PCT / EP2022 / 062480 and PCT / EP2022 / 062496 (both currently unpublished) disclose cGAS inhibitors structurally similar to the cGAS inhibitors of the present invention, all of which include carboxylic acid groups bonded to the pyrrolidine moiety. In both international applications PCT / EP2022 / 062480 and PCT / EP2022 / 062496, methyl ester derivatives of these cGAS inhibitors having carboxylic acid groups bonded to the pyrrolidine moiety have been experimentally shown to function as practical prodrugs of cGAS inhibitors having free carboxylic acid groups. Compounds P01, P02, P03, and P04 of international application PCT / EP2022 / 062480 were methyl ester derivatives and putative prodrugs of example compounds 4.04, 1.10, 1.12, and 3.14 of international application PCT / EP2022 / 062480, respectively (all possessing a free carboxylic acid group and low biochemical IC with respect to cGAS inhibition). 50 Values ​​and low cell IC 50 (It was an active cGAS inhibitor with a value.)

[0222] Compounds P01, P02, and P03 of international application PCT / EP2022 / 062496 were methyl ester derivatives and putative prodrugs of example compounds 2.12, 1.13, and 1.05 of international application PCT / EP2022 / 062496, respectively (all possessing a free carboxylic acid group and exhibiting low biochemical IC50 with respect to cGAS inhibition). 50 Values ​​and low cell IC 50 (It was an active cGAS inhibitor with a value.) In both international applications PCT / EP2022 / 062480 and PCT / EP2022 / 062496, the "active cGAS inhibitors / example compounds having their free carboxylic acids" and their "respective methyl ester derivatives / suggested prodrugs" were synthesized and tested for their pharmacological properties with respect to their potency in inhibiting the cGAS / STING pathway. On the other hand, this comparison of the properties of the example compounds in international applications PCT / EP2022 / 062480 and PCT / EP2022 / 062496, which have these free carboxylic acids, with the properties of their corresponding methyl ester derivatives / suggested prodrugs reveals the "biochemical IC" of the example compounds. 50 Value (hcGAS IC 50 The "biochemical IC50" value is always around 10 nM or much lower than 10 nM, but the corresponding methyl ester derivative / prodrug's "biochemical IC50" 50 Value (hcGAS IC) 50 The IC values ​​are always extremely high, generally meaning higher than 7000 nM. On the other hand, the IC values ​​of the example compounds are shown to be extremely high. 50The IC values ​​of their corresponding methyl ester derivatives / prodrugs 50 Such large differences between the values ​​always remain within the same range between the example compounds and their corresponding prodrugs in each cell IC. 50 Value (THP1 (vir) I C 50 No values ​​were observed (see Table 4 below).

[0223] One possible explanation for this observation is that while all the example compounds possess a free carboxylic acid group, which appears to be crucial for inhibiting cGAS activity, in all "methyl ester derivatives / prodrugs," the carboxyl group is masked by a carboxymethyl ester group. As a result, the methyl ester derivatives / prodrugs lose their inhibitory efficacy in the "in vitro human cGAS enzyme assay" (see Section 6.1 below). This is because, in this assay, there are no intracellular enzymes that cleave the carboxymethyl ester group, and therefore the crucial free carboxylic acid group cannot be restored in the biochemical assay. Consequently, the prodrugs exhibit extremely high "biochemical (in vitro) IC2" in this "in vitro human cGAS enzyme assay." 50 Value (=hcGAS IC) 50 ) shows, but the corresponding example compound (which has a free carboxylic acid group from the beginning) has a low "biochemical (in vitro) IC25" 50 Value (=hcGAS IC) 50 ) indicates.

[0224] In cell assays (= "Human cGAS cell and counter cell assays," see Section 6.2 below), there are endogenous cellular enzymes that cleave carboxymethyl ester groups. As a result, the example compounds in international applications PCT / EP2022 / 062480 and PCT / EP2022 / 062496 themselves (which already have free carboxylic acid groups) exhibit low THP1 (vir) I C 50In addition to showing the value, the corresponding methyl ester derivative / prodrug also has a relatively low "THP1" value. (vir) I C 50 This indicates the value. This is because, in this "human cGAS cell assay," the carboxymethyl ester group of the prodrug can be cleaved by endogenous intracellular enzymes, thereby releasing the "active example compound having a free carboxylic acid group," which then exhibits cGAS inhibitory efficacy again.

[0225] This explanation, along with the measurements shown in Table 4, suggests that the carboxymethyl ester derivatives of the structurally similar example compounds in international applications PCT / EP2022 / 062480 and PCT / EP2022 / 062496 appear to actually represent usable prodrugs of the respective example compounds having a free carboxylic acid group (they themselves do not exhibit inhibitory activity with respect to in vitro human biochemical cGAS inhibition). However, after cleavage of the carboxymethyl ester by endogenous intracellular enzymes present in the cell assay, the "active example compound" is reactivated and again exhibits inhibitory activity with respect to the cGAS / STING pathway. Since the example compounds of formula I, II, or III of the present invention have the exact same free carboxylic acid bonded to the pyrrolidinyl moiety as the example compounds of international application PCT / EP2022 / 062480 or international application PCT / EP2022 / 062496, it can be expected that carboxy-methyl ester derivatives of these compounds of formula I, II, or III will also function as prodrugs.

[0226] [Table 16-1] [Table 16-2] [Table 16-3]

[0227] 5. Biological experiments The activity of the compounds of the present invention can be demonstrated using the following in vitro cGAS enzyme and cell assays: 6.1 Method: Human cGAS enzyme assay (hcGAS IC) 50 (in vitro) Human cGAS enzyme was incubated in the presence of 45-base-pair double-stranded DNA to activate the enzyme, as well as GTP and ATP, as substrates. Compound activity was determined by measuring the effect of the compound on the formation of the enzymatic reaction product cGAMP, which was measured by mass spectrometry.

[0228] Enzyme preparation: Human cGAS (amino acids 1-522) with an N-terminal 6x-His tag and a SUMO tag was expressed in Escherichia coli BL21(DE3) pLysS(Novagen) cells at 18°C ​​for 16 hours. The cells were dissolved in a buffer containing 25 mM Tris (pH 8), 300 mM NaCl, 10 mM imidazole, 10% glycerol, a protease inhibitor cocktail (cOmplete®, EDTA-free, Roche), and DNase (5 μg / mL). The cGAS protein was isolated by affinity chromatography on Ni-NTA agarose resin and further purified by size exclusion chromatography using a Superdex 200 column (GE Healthcare) equilibrated in 20 mM Tris (pH 7.5), 500 mM KCl, and 1 mM TCEP. The purified protein was concentrated to 1.7 mg / mL and stored at -80°C.

[0229] Assay method The compound was provided as a 10 mM DMSO solution, serially diluted, and transferred to a 384-well assay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, the highest concentration was 10 μM in the final assay volume, followed by approximately 1:5 dilution steps to obtain eight different concentrations. The DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 22 test compounds (rows 1-22), with rows 23 and 24 containing DMSO. After compound transfer, 15 μL of enzyme-DNA working solution (12 nM cGAS, 0.32 μM 45 base pair DNA / assay buffer, 10 mM Tris pH 7.5 / 10 mM KCl / 5 mM MgCl2 / 1 mM DTT) was added to each well from row 1 to 23 via a MultiDrop Combi dispenser. In row 24, 15 μL of enzyme / DNA-free assay buffer was added as a low control. Next, the plates were pre-incubated at room temperature for 60 minutes.

[0230] Subsequently, 10 μL of GTP (ThermoFisher #R0461)-ATP (Promega #V915B) mix in assay buffer was added to assay plates (rows 1-24, each at a final concentration of 30 μM) using Multidrop Combi. The plates were incubated again at room temperature for 90 minutes. After incubation, the reaction was stopped with 80 μL of 0.1% formic acid in assay buffer containing 5 nM cyclic di-GMP (Sigma #SML1228), which was used as an internal standard for mass spectrometry. The total volume / well was 105 μL.

[0231] Rapidfire MS Detection The plate was centrifuged at 4000 rpm at 4°C for 5 minutes. A RapidFire autosampler was connected to a binary pump (Agilent 1290) and a Triple Quad 6500 (ABSciex, Toronto, Canada). This system was equipped with a 10 μL loop C18 [12 μL bed volume] cartridge (Agilent, part No. G9210A) containing eluent A: 10 mM NH4Ac (aqueous solution) water (pH 7.4) (pump 1: 1.5 mL / min, pump 2: 1.25 mL / min) and eluent B: 10 mM NH4Ac (pH 7.4) in 47.5 / 47.5 / 5 (v / v / v) ACN / MeOH / H2O (pump 3: 1.25 mL / min). Aspiration time: 250 ms; Loading time: 3000 ms; Elution time: 3000 ms; Washing volume: 500 μL.

[0232] The MS was operated in positive ion mode with a HESI ion source, source temperature 550°C, curtain gas = 35, gas 1 = 65, and gas 2 = 80. Unit mass resolution in SRM mode. The following transitions and MS parameters (DP: declustering voltage and CE: collision energy) were determined for cGAMP and DicGMP: Analyte: cGAMP, 675.1 / 524, DP=130, CE=30 Internal standards: Cyclic-D-GMP, 690.1 / 540, DP=130, CE=30. cGAMP formation was monitored and evaluated as a ratio to cyclic-di-GMP. Data evaluation and calculation: In data evaluation and calculations, measurements with low control were set as 0% control, and measurements with high control were set as 100% control. 50 The values ​​were calculated using the standard four-parameter logistic regression equation. Calculation: [y=(ad) / (1+(x / c)^b)+d], a=low value, d=high value; x=conc M; c=IC 50 M;b=slope

[0233] 6.2 Methods: Human cGAS cell assay and cGAMP-stimulated counter cell assay (THP1 (vir) I C 50 and THP1(cGAMP) I C 50 ) THP1-Dual® cells (InvivoGen #thpd-nfis) expressing an IRF-dependent Lucia luciferase reporter were used as the base for both assays. For the detection of cellular cGAS activity, cells were stimulated by infection with a baculovirus (pFastbac-1, Invitrogen, no coding insertion) that delivers cGAS enzyme-stimulated double-stranded DNA (THP1 (vir) I C 50 (Measurement). In the counterassay, cells were stimulated with cGAMP (SigmaAldrich #SML1232) to activate the same direct downstream pathway independent of cGAS (THP1 (cGAMP) I C 50 (Measurement). Pathway activity is determined by DNA-stimulated cGAS enzyme activity (THP1 (vir) I C 50 (Measurement) or direct cGAMP (THP1 (cGAMP) I C 50 Lucia luciferase activity was monitored by measuring the activity induced by the measurement (counterassay).

[0234] Assay method The compounds were provided as a 10 mM DMSO solution, serially diluted, and transferred to a 384-well assay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, the highest concentration was 10 μM in the final assay volume, followed by approximately 1:5 dilution steps to obtain eight different concentrations. The DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 21 test compounds (rows 1-22), with rows 23 and 24 containing DMSO. Cells cultured according to the manufacturer's conditions were collected by centrifugation at 300 g / 10 min, then resuspended in fresh cell culture medium (RPMI 1640 (Gibco #A10491-01), 10% FCS (Gibco #10500), 1× GlutaMax (Gibco #35050-061), 1× Pen / Strep solution (Gibco #15140-122), 100 μg / ml Normocin (InvivoGen #ant-nr), 100 μg / ml Zeocin (InvivoGen #ant-zn), 10 μg / ml Blasticidin S (Life Technologies #A11139-03)) and diluted to 1.66E5 cells / ml. Then, baculovirus solution was added to the cells at a ratio of 1:200 (varied by virus batch) (THP1 (vir) I C 50 (Measurement of ). Alternatively, in a counterassay, cGAMP was added to cells at a final concentration of 10 μM (THP1 (cGAMP) I C 50 (Measurement).

[0235] 30 μL of cell / virus mix was added to each well of compound plates with 1 to 23 rows via a Multidrop Combi dispenser (5000 cells / well). In row 24, 30 μL of virus-free 5000 cells / well was added as a low control. Next, the plates were incubated in a humidified incubator at 37°C for 18 hours. Subsequently, 15 μL of QuantiLuc detection reagent (InvivoGen #rep-qlcg5) was added to each well using a Multidrop Combi. Immediately after addition, measurements were performed using an EnVision reader (US-luminescence reading mode). Data evaluation and calculation: In data evaluation and calculations, measurements with low control were set as 0% control, and measurements with high control were set as 100% control. 50The values ​​were calculated using the standard four-parameter logistic regression equation. Calculation: [y=(ad) / (1+(x / c)^b)+d], a=low value, d=high value; x=conc M; c=IC 50 M;b=slope

[0236] 6.3 Method: Human whole blood assay (human WB IC) 50 ) For the detection of cellular cGAS activity, human whole blood was stimulated by transfection with double-stranded DNA. Pathway activity was monitored by measuring IFNα2α production. Assay method The compounds were provided as a 10 mM DMSO solution, serially diluted, and transferred to a 96-well cell culture plate (Corning #3595). Each well was pre-filled with 20 μl OptiMEM (Gibco, #11058-021) using an Echo acoustic dispenser. Typically, the highest concentration was 10 μM in the final assay volume, followed by approximately 1:5 dilution steps to obtain eight different concentrations. The DMSO concentration was set to 0.1% in the final assay volume. The 96-well assay plate contained 10 test compounds, with DMSO in the control wells. Human whole blood was collected in parallel from three or more healthy donors (male or female, free from drug treatments other than contraceptives and thyroxine for 7 days) as sodium citrate blood (e.g., 3.8% in Monovettes from Sarstedt). Whole blood was kept at room temperature for up to 3 hours after collection until use in the assay.

[0237] 160 μl of whole blood sample was transferred to each well of a 96-well assay plate filled with compound / OptiMEM. All assay plates were prepared as duplicates using blood from different donors. The blood plates were maintained at room temperature for 60 minutes, continuously shaken at 450 rpm, and then covered but not sealed. A DNA-Fugene mix (Herring DNA, Sigma Aldrich #D6898-1G, Fugene (5×1 mL), Promega #E2312) was prepared in OptiMEM and incubated at room temperature for 10 minutes (125 ng DNA / 20 μl and Fugene ratio 9.6:1). 20 μl of the DNA-Fugene mix was added to each well, resulting in 125 ng DNA / well / 200 μl and a Fugene ratio of 9.6:1. 20 μl of OptiMEM and Fugene at a ratio of 9.6:1 were added to all low control wells. After covering the assay plate with an AERA seal and lid, the blood plate was kept at room temperature for 30 minutes, continuously shaken at 450 rpm, and then incubated overnight at 37°C in an incubator for 22 hours without shaking.

[0238] For the detection of IFNα-2α in human plasma, biotinylated capture antibody (Antibody Set IFNA2, Meso Scale Diagnostics #B21VH-3, including coating and capture antibody) was diluted 1:17.5 in Diluent 100 (Meso Scale Diagnostics #R50AA-4) according to the manufacturer's instructions. A U-Plex MSD GOLD 96-well small-spot streptavidin SECTOR plate (Meso Scale Diagnostics # L45SA-5) was coated with 25 μl of diluted capture antibody. The coated plate was incubated at room temperature for 60 minutes under continuous shaking at 700 rpm. The MSD IFNα-2α plate was washed three times with 150 μl of washing buffer (1×HBSS, 0.05% Tween). The plates were blocked at room temperature for 60 minutes with 100 μl of blocking solution / well (1×HBSS containing 0.2% Tween and 2% BSA), followed by continuous shaking at 700 rpm. Immediately after emptying the plates to the driest possible state by dumping, human plasma was added.

[0239] The whole blood assay plates were centrifuged at 1600 rpm for 10 minutes. 25 μl of supernatant was transferred from each whole blood plate to the corresponding IFNα-2α plate using a pipetting robot. The plates were sealed with microplate seals and maintained at room temperature for 2 hours under continuous shaking at 700 rpm. Next, the MSD IFNα-2α plate was washed three times with 150 μl of washing buffer (1×HBSS, 0.05% Tween), and then 25 μl of MSD SULFO-TAG IFNα-2α antibody solution (diluted 1:100 with Diluent 3 (Meso Scale Diagnostics # R50AP-2)) was added to each well of the plate. The plates were then sealed with microplate seals and maintained at room temperature for 2 hours under continuous shaking at 700 rpm. Finally, the MSD IFNα-2α plates were washed three times with 150 μl of washing buffer (1×HBSS, 0.05% Tween). 150 μl of 2×Read buffer was added to each well, and the plates were immediately measured using an MSD Sector S600 reader with the supplier's barcode. Data evaluation and calculation: In data evaluation and calculation, the control percentage for each well was calculated based on the mean of the high control (DNA-stimulated control) and the mean of the low control (unstimulated control) by using the following formula: [Count (sample) - Count (low)) / (Count (high) - Count (low))] × 100 I C 50 The values ​​were calculated using the standard four-parameter logistic regression equation. Calculation: [y=(ad) / (1+(x / c)^b)+d], a=low value, d=high value; x=conc M; c=IC 50 M;b=slope

[0240] 6. Indications As found, compounds of formulas I, II, or III are characterized by their range of applications in the therapeutic field. Particular attention should be paid to the applications in which compounds of formulas I, II, or III according to the present invention are preferably used as cGAS inhibitors based on their pharmaceutical activity. The cGAS pathway is important for host defense against invading pathogens such as viral infections and invasions by certain intracellular bacteria, while cellular stress and genetic factors can also lead to the production of abnormal cellular dsDNA, for example, through nuclear or mitochondrial leakage, thereby triggering autoinflammatory responses. As a result, cGAS inhibitors have potent therapeutic potential for use in the treatment of a variety of autoinflammatory and autoimmune diseases. An et al., Arthritis Rheumatol. 2017 Apr;69(4):800-807, disclosed that cGAS expression in peripheral blood mononuclear cells (PBMCs) is significantly higher in patients with systemic lupus erythematosus (SLE), an autoimmune disease, than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the SLE patients tested, but not in healthy or rheumatoid arthritis controls. SLE patients with cGAMP had higher disease activity than those without cGAMP. Since elevated cGAS expression can result from exposure to type I interferon (IFN), the detection of cGAMP in SLE patients with increased disease activity suggests a potential involvement of the cGAS pathway in disease manifestation.

[0241] Park et al., Ann Rheum Dis. 2018 Oct;77(10):1507-1515 also disclose the involvement of the cGAS pathway in the development of SLE. Thim-Uam et al., iScience 2020 Sep 4;23(9), 101530 (doi: 10.1016 / j.isci.2020.101530) disclose that the STING pathway mediates lupus through activation of normal dendritic cell maturation and plasmacytoid dendritic cell differentiation. Gao et al., Proc. Natl. Acad. Sci. US A. 2015 Oct 20;112(42):E5699-705, describes how activation of cGAS by autologous DNA can lead to several autoimmune diseases, including interferonosis. Tonduti et al., Expert Rev. Clin. Immunol. 2020 Feb;16(2):189-198 disclose that cGAS inhibitors have specific therapeutic potential in Eicardi-Gutierre syndrome and familial lupus frostbite, which are lupus-like severe autoinflammatory immune-mediated disorders. Steiner et al., Nat Commun. 2022 Apr 28;13(1):232; doi: 10.1038, demonstrate that deficiency of coatmer complex I leads to abnormal activation of STING signaling and COPA syndrome, and that cGAS is required to drive type I IFN signaling in a COPA syndrome cell model.

[0242] Li et al. demonstrated that plasma-derived DNA-containing extracellular vesicles induce a STING-mediated pro-inflammatory response in dermatomyositis (Theranostics. 2021; 11(15): 7144-7158). Zhou et al. (J Clin Lab Anal. 2022 Oct; 36(10): e24631) described the correlation between activation of the cGAS-STING pathway and muscle fiber atrophy / necrosis in dermatomyositis. Yu et al., Cell 2020 Oct 29;183(3):636-649 describes the association between TDP-43-induced mitochondrial DNA and cGAS / STING pathway activation in amyotrophic lateral sclerosis (ALS). Ryu et al., Arthritis Rheumatol. 2020 Nov;72(11):1905-1915 also shows that bioactive plasma mitochondrial DNA is associated with disease progression in certain fibrosis conditions, such as systemic sclerosis (SSc) or interstitial lung disease (ILD), interstitial lung disease with progressive fibrosis (PF-ILD), and idiopathic pulmonary fibrosis (IPF). Schuliga et al., Clin. Sci. (Lond). 2020 Apr 17;134(7):889-905 describes how autoDNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner.

[0243] Additional scientific suggestions linking other causes of fibrosis, such as non-alcoholic steatohepatitis (NASH) associated with the cGAS / STING pathway, are described in Yu et al., J. Clin. Invest. 2019 Feb 1;129(2):546-555 and Cho et al., Hepatology. 2018 Oct;68(4): 1331-1346. Nascimento et al., Sci. Rep. 2019 Oct 16;9(1):14848 disclose that the release of autoDNA and STING-dependent sensing induce inflammation in mice caused by tobacco smoke, suggesting a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD). Ma et al., Sci. Adv. 2020 May 20;6(21):eaaz6717 disclose that ulcerative colitis and inflammatory bowel disease (IBD) can be suppressed by controlling cGAS-mediated inflammation. Gratia et al., J. Exp. Med. 2019 May 6;216(5):1199-1213, demonstrates that Bloom syndrome proteins suppress innate immune sensing of micronuclei by cGAS. Consequently, cGAS inhibitors may have therapeutic potential when treating Bloom syndrome.

[0244] Kerur et al., Nat. Med. 2018 Jan;24(1):50-61 describes that cGAS plays an important role in non-standard inflammasome activation in age-related macular degeneration (AMD). Visitchanakun et al., Int J Mol Sci. 2021 Oct 23;22(21):11450, show that GAS-deficient mice were less severe than wild-type mice in cecal ligation puncture (CLP) and lipopolysaccharide (LPS) injection sepsis models. Wang et al., Mediators Inflamm. 2015;2015:192329, describes how cGAS is necessary for cell proliferation and inflammatory cytokine production in rheumatoid arthritis synovial cells. It has also been reported that cGAS deficiency suppressed interferon response, inflammatory cell infiltration, and joint swelling in a mouse model of inflammatory arthritis (Willemsen et al., Cell Rep. 2021 Nov 9;37(6):109977).

[0245] Guo et al., Osteoarthritis Cartilage. 2021 Aug;29(8):1213-1224, described that damaged DNA is an important pathological factor in osteoarthritis (OA), and that this may be mediated by the cGAS / STING pathway, as STING knockdown mitigates the destabilization of medial meniscus-induced OA development in mice. Mao et al., Arterioscler Thromb Vasc Biol (2017) 37(5):920-929 showed that the cGAS / STING pathway mediates endothelial inflammation in response to free fatty acid-induced mitochondrial damage in diet-induced obesity, suggesting that cGAS inhibitors may have potential in the treatment of obesity and diabetes. Kerur et al, Nat Med. 2018 Jan;24(1):50-61, describe how cGAS levels are elevated in the retinal pigment epithelium of human eyes with geographic atrophy, and how cGAS drives the activation of non-standard inflammasome activation in age-related macular degeneration. cGAS promotes cellular senescence and senescence-related secretory phenomena (Yang et al, Proc Natl Acad Sci USA 2017 Jun 6;114:E4612-E4620). Intracytoplasmic chromatin triggers inflammation in aging through cGAS / STING, and STING null mice showed reduced tissue inflammation and aging (Dou et al, Nature. 2017 550: 402-406). Furthermore, in humans, mutations in the STING gene are associated with healthy aging, most likely due to a reduction in inflammatory aging (Hamann et al, Gerontology 2019;65:145-154). In summary, STING inhibitors reduce senescence-related inflammation and senescent cell accumulation, leading to improvements in aging, muscle disorders, and fibrosis, among other age-related diseases.

[0246] Furthermore, cGAS inhibitors of formulas I, II, or III also have therapeutic potential in the treatment of cancer (see Hoong et al., Oncotarget. 2020 Jul 28;11(30):2930-2955 and Chen et al., Sci. Adv. 2020 Oct 14;6(42):eabb8941). Furthermore, cGAS inhibitors of formulas I, II, or III also have therapeutic potential in the treatment of heart failure (Hu et al., Am. J. Physiol. Heart Circ. Physiol. 2020 Jun 1;318(6):H1525-H1537). Further scientific insights exist regarding the correlation between Parkinson's disease and the cGAS / STING pathway (Sliter et al., Nature. 2018 Sep;561(7722):258-262) and the correlation between Sjögren's syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res. 2018 Jul;97(8):893-900). Furthermore, cGAS inhibitors of formulas I, II, or III also have therapeutic potential in the treatment of COVID-19 / SARS-CoV-2 infection, as shown in Di Domizio et al., Nature. 2022 Jan 19. doi: 10.1038 / s41586-022-04421-w: "The cGAS-STING pathway drives type I IFN immunopathology in COVID-19" and Neufeldt et al., Commun Biol. 2022 Jan 12;5(1):45. doi: 10.1038 / s42003-021-02983-5: "SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-kappaB".

[0247] In addition, cGAS inhibitors of formulas I, II, or III have therapeutic potential in the treatment of renal inflammation and renal fibrosis, as shown in Chung et al., Cell Metab. 2019 30:784-799: "Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis" and Maekawa et al., Cell Rep. 2019 29:1261-1273: "Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury". Furthermore, cGAS inhibitors of formulas I, II, or III have therapeutic potential in the treatment of cancer, as shown in Bakhoum et al., Nature. 2018 Jan 25;553(7689):467-472: "Chromosomal instability drives metastasis through a cytosolic DNA response" and Liu et al., Nature. 2018 Nov;563(7729):131-136: "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis".

[0248] In addition, cGAS inhibitors of formulas I, II, or III have therapeutic potential in the treatment of metabolic disorders. gt Animals showed reduced macrophage infiltration in adipose tissue after subchronic high-calorie intake (HFD), STING gt Furthermore, IRF3 deficiency leads to decreased blood glucose and insulin levels, as well as weight loss (Mao et al, Arterioscler Thromb Vasc Biol, 2017;37 (5): 920-929). Furthermore, cGAS inhibitors of formulas I, II, or III have therapeutic potential in the treatment of vascular diseases and induce vascular repair / regeneration. This is because the release of mitochondrial DNA into the cytosol of endothelial cells activates the cGAS / STING pathway and suppresses endothelial proliferation. Moreover, knockout of the cGAS gene restores endothelial repair / regeneration in a mouse model of inflammatory lung injury (Huang et al, Immunity, 2020, Mar 2017; 52 (3): 475-486.e5. doi: 10.1016 / j.immuni.2020,02.002). In addition, cGAS inhibitors of formulas I, II, or III have therapeutic potential in the treatment of age-related and obesity-related cardiovascular diseases (Hamann et al, Immun Ageing, 2020, Mar 14; 17: 7; doi: 10.1186 / s12979-020-00176-y.eCollection 2020).

[0249] As a result, compounds of formula I, II, or III can be used as cGAS inhibitors in the treatment of autoinflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE), interferonosis, Ecardi-Goutierre syndrome (AGS), COPA syndrome, familial lupus frostbite, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjögren's syndrome, rheumatoid arthritis, and Parkinson's disease. In addition, compounds of formula I, II, or III can be used as cGAS inhibitors in the treatment of systemic sclerosis (SSc), interferonosis, non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably interstitial lung disease with progressive fibrosis (PF-ILD), and especially fibrosis such as idiopathic pulmonary fibrosis (IPF). Furthermore, compounds of formula I, II, or III as cGAS inhibitors can be used in the treatment of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging, muscle disorders, sepsis, osteoarthritis, heart failure, COVID-19 / SARS-CoV-2 infection, nephritis, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, and cancer.

[0250] 7. combination Compounds of formulas I, II, or III may be administered to patients alone or in combination with one or more other pharmacologically active agents. In preferred embodiments of the present invention, compounds of formula I, II, or III may be combined with one or more pharmacologically active agents selected from the group consisting of anti-inflammatory agents, antifibrotic agents, antiallergic agents / antihistamines, bronchodilators, β2 agonists / beta-mimetics, adrenaline agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, nonspecific immunotherapeutic agents such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e., cytokine receptor agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies (Humira®), and anti-BAFF agents (belimumab and etanercept). The antifibrotic agent is preferably selected from tyrosine kinase inhibitors such as pirfenidone and nintedanib, with nintedanib being particularly preferred.

[0251] Preferred examples of anti-inflammatory agents are NSAIDs and corticosteroids. The NSAID is preferably selected from ibuprofen, naproxen, diclofenac, meloxicam, celecoxib, acetylsalicylic acid (aspirin®), indomethacin, mefenamic acid, and etoricoxib. The corticosteroid is preferably selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, lorofreponide, and dexamethasone. The antiallergic agent / antihistamine is preferably selected from epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine, and mizolastine. The β2 agonist / beta-mimetic may be either a long-acting β2 agonist (LABA) or a short-acting β2 agonist (SABA). Particularly preferred β2 agonists / beta-mimetics are selected from bambuterol, vitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, olodaterol, and salbutamol, particularly olodaterol.

[0252] The anticholinergic agent is preferably selected from ipratropium salt, tiotropium salt, glycopyrronium salt, and theophylline, with tiotropium bromide being particularly preferred. The leukotriene modifier is preferably selected from montelukast, pranlukast, zafirlukast, ibudilast, and dileuton. The JAK inhibitor is preferably selected from baricitinib, celzlatinib, fedratinib, filgotinib, gandotinib, restaurtinib, momerotinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The anti-interleukin antibody is preferably selected from anti-IL23 antibodies such as risankizumab, anti-IL17 antibodies, anti-IL1 antibodies, anti-IL4 antibodies, anti-IL13 antibodies, anti-IL-5 antibodies, and anti-IL-6 antibodies such as Actemra®, anti-IL-12 antibodies, and anti-IL-15 antibodies.

[0253] 8. formulation The compounds of the present invention may be administered by any suitable route of administration, including both systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, rectal, and inhalation administration. Parenteral administration refers to any route of administration other than enteral, transdermal, or inhalation, and is typically administered by injection or intravenous infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration to the patient's lungs, whether by inhalation through the mouth or nasal passages. Topical administration includes application to the skin. The compounds of the present invention may be administered via eye drops to treat Sjögren's syndrome. Suitable forms for administration include, for example, tablets, capsules, solutions, syrups, emulsions, or inhalable powders or aerosols. In all cases, the content of the pharmaceutically effective compound should be in the range of 0.1 to 90% by mass, preferably 0.5 to 50% by mass, of the total composition, i.e., an amount sufficient to achieve the dosage range specified below. The preparation may be administered orally in tablet form, powder form, powder form in capsules (e.g., hard gelatin capsules), solution, or suspension. When administered by inhalation, the active substance combination may be administered as a powder, as an aqueous or aqueous-ethanol solution, or using a propellant gas preparation. Preferably, and therefore, the pharmaceutical formulation is characterized by the content of one or more compounds of formula I, II, or III according to the preferred embodiments described above.

[0254] It is particularly preferable that the compound of formula I, II, or III is administered orally, and it is also particularly preferable that it be administered once or twice daily. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as inert diluents such as calcium carbonate, calcium phosphate, or lactose; disintegrants such as corn starch or alginic acid; binders such as starch or gelatin; lubricants such as magnesium stearate or talc; and / or release retarders such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also contain several layers. Coated tablets may be prepared accordingly by coating a core, produced in the same manner as a tablet, with a substance commonly used for tablet coatings, such as coridone or shellac, gum arabic, talc, titanium dioxide, or sugar. To achieve delayed release or prevent inconformity, the core may consist of several layers. Similarly, tablet coatings may consist of several layers to achieve delayed release, possibly using the excipients described above for tablets.

[0255] The syrup formulations containing the active substances or combinations thereof according to the present invention may further contain sweeteners such as saccharin, cyclamate, glycerol, or sugar, and flavor enhancers such as vanillin or orange extract. They may also contain suspension adjuvants or viscosity enhancers such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoate. Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol and filling them into gelatin capsules. Suitable suppositories can be prepared by mixing with a carrier provided for this purpose, such as a neutral fat or polyethylene glycol or derivatives thereof.

[0256] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersible silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, sulfite wastewater, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate). For oral administration, tablets may, in addition to the carrier described above, contain various additives such as sodium citrate, calcium carbonate, and dicalcium phosphate, along with starch, preferably potato starch, gelatin, and other additives. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substance may be combined with various flavor enhancers or colorants in addition to the excipients described above.

Claims

1. A compound of formula I, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt. 【Chemistry 1】 (In the formula, R 1 is hydrogen, halogen, methyl, ethyl, -CF 3 ,-CHF 2 , -CFH 2 Selected from the group consisting of , and methoxy, R 2 It is selected from the group consisting of hydrogen and methyl, R 3 It is selected from the group consisting of hydrogen, methyl, and halogen, A is -CH 2 -, -O-, -CF 2 -, -CHF-, -N(CH 3 )-, -NH-, and -CHCH 3 - selected from the group consisting of D is -CH 2 -, -O-, -CF 2 -, -CHF-, and -CHCH 3 - Selected from the group consisting of, E is -CH 2 -, -O-, -C(CH 3 ) 2 -, -CHF-, CF 2 -, and -CHCH 3 - Selected from the group consisting of, G is -NH-, -NCH 3 -ien-CH 2 -, -O-, -CF 2 -, -CHF-, -CHCH 3 -, and -C(CH 3 ) 2 Selected from the group consisting of, J is -CO-, -CH 2 -, -O-, -CHF-, -CF 2 -, and -CHCH 3 - Selected from the group consisting of, K is -CH 2 -, -CF 2 Either selected from the group consisting of - and -O-, or not present. L is -CH 2 -, -O-, -CHCH 3 -, -CHF-, -CF 2 (either selected from the group consisting of -, or not existing)

2. R 1 However, it is selected from the group consisting of hydrogen, Cl, and F, R 2 However, selected from the group consisting of hydrogen and methyl, R 3 However, it is selected from the group consisting of hydrogen, methyl, Cl, and F, A is -CH 2 -, -O-, -CF 2 -, and -N(CH 3 Selected from the group consisting of ) D is -CH 2 -, -O-, and -CHCH 3 - Selected from the group consisting of, E is -CH 2 -, -O-, and -C(CH 3 ) 2 - Selected from the group consisting of, G is -NH-, -CH 2 -, -O-, -CHCH 3 - Selected from the group consisting of, J is -CO-, -CH 2 -, -O-, and -CHCH 3 - Selected from the group consisting of, K is -CH 2 -, -CF 2 Either selected from the group consisting of - and -O-, or not present. L is -CH 2 -, -CF 2 A compound of formula I according to claim 1, selected from the group consisting of -, or absent therefrom, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated analog of the compound said to be said to be in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

3. A compound of formula I according to claim 1 or 2, in which L is absent, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

4. L is nonexistent, and A is -CH 2 - and -CF 2 A compound of formula I according to claim 1 or 2, selected from the group consisting of -, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

5. L is nonexistent, and K is -CF 2 - A compound of formula I according to claim 1 or 2, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

6. R 3 A compound of formula I according to claim 1 or 2, wherein is a halogen, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

7. R 3 The compound of formula I according to claim 1 or 2, wherein the compound is Cl or F, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

8. R 3 The compound of formula I according to claim 1 or 2, wherein the compound is Cl or F and is located at the 5-position of the benzimidazole moiety, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

9. R 1 A compound of formula I according to claim 1 or 2, wherein is a halogen, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

10. R 1 The compound of formula I according to claim 1 or 2, wherein the compound is Cl or F, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

11. R 1 A compound of formula I according to claim 1 or 2, wherein is hydrogen, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt. 【Request Item 12】 【Chemistry 2-1】 【Chemistry 2-2】 A compound of formula I according to claim 1 or 2, selected from the group consisting of the above, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

13. A is -CH 2 - and -CF 2 - Selected from the group consisting of, D and E are -CH 2 - and G is -CH 2 Selected from the group consisting of - and -O-, J is -CH 2 Selected from the group consisting of - and -O-, K is -CF 2 - and -CH 2 - Selected from the group consisting of, A compound of formula I according to claim 1 or 2, in which L is absent, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt. 【Request Item 14】 【Chemistry 3】 A compound of formula I according to claim 1 or 2, selected from the group consisting of the above, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

15. R 2 A compound of formula I according to claim 1, wherein is methyl, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

16. Compound of formula II as described in claim 15 【Chemistry 4】 or a compound of formula III, 【Transformation 5】 Alternatively, a carboxymethyl ester derivative as a prodrug, or a deuterated form of the compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt thereof.

17. A compound of formula II as described in claim 16, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt. 【Transformation 6】

18. A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, in which L is absent, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

19. L is nonexistent, and K is -CF 2 - A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

20. R 3 A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, wherein is a halogen, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

21. R 3 The compound of formula II according to claim 16 or 17, or the compound of formula III according to claim 16, wherein the compound is Cl or F, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

22. R 3 The compound of formula II according to claim 16 or 17 or the compound of formula III according to claim 16, wherein the compound is Cl or F and is located at the 5-position of the benzimidazole moiety, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

23. R 3 A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, wherein is hydrogen, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

24. R 1 A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, wherein is a halogen, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

25. R 1 The compound of formula II according to claim 16 or 17, or the compound of formula III according to claim 16, selected from the group consisting of Cl or F, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

26. R 1 A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, wherein is hydrogen, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

27. A is -CH 2 - and -CF 2 - Selected from the group consisting of, D and E are -CH 2 - and G is -CH 2 Selected from the group consisting of - and -O-, J is -CH 2 Selected from the group consisting of - and -O-, K is -CF 2 - and -CH 2 - Selected from the group consisting of, A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, in which L is absent, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt. 【Request Item 28】 【Chemistry 7】 A compound of formula II according to claim 16 or 17, selected from the group consisting of the above, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

29. A is -CH 2 - and -CF 2 - Selected from the group consisting of, D, E, and G are each -CH 2 - and J is -CH 2 Selected from the group consisting of - and -O-, K is -CF 2 - and A compound of formula II according to claim 16 or 17, or a compound of formula III according to claim 16, in which L is absent, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated form of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt. 【Request Item 30】 【Transformation 8】 A compound of formula II according to claim 16 or 17, selected from the group consisting of the above, or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms in the formula are substituted with deuterium, or a pharmaceutically acceptable salt.

31. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

32. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

33. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

34. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

35. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

36. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

37. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

38. Formula: A compound of formula II according to claim 16 or 17, represented by [formula], or a carboxymethyl ester derivative thereof as a prodrug, or a deuterated product of the said compound in which one or more hydrogen atoms are substituted with deuterium, or a pharmaceutically acceptable salt.

39. Equation (A - I) 【Chemistry 9】 (wherein, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as set forth in claim 1, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), Equation (A-II) 【Chemistry 10】 (In the formula, R 1 , R 2 , R 3 A, D, E, G, J, K, and L are defined as described in claim 1, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl. R is either hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl, and benzyl. ・Formula (BI) 【Chemistry 11】 (in the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as described in Claim 1, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), or ・Formula (B-II) 【Chemistry 12】 (In the formula, R 1 , R 2 , R 3 (A, D, E, G, J, K, and L are defined as described in claim 1, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl.) An intermediate compound of [the product].

40. Use of a compound of formula I according to claim 1 or 2, or a compound of formula II or III according to claim 16, for the manufacture of a pharmaceutical agent for treating diseases that can be treated by inhibiting cGAS.

41. Use of a compound of formula I according to claim 1 or 2 or a compound of formula II or III according to claim 16 for the manufacture of a pharmaceutical product for the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonosis, Eicardi-Gutierre syndrome (AGS), COPA syndrome, familial lupus frostbite, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), retinopathy, glaucoma, diabetes mellitus, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, dermatomyositis, Sjögren's syndrome, Parkinson's disease, heart failure, cancer, aging, muscle disorders, sepsis, rheumatoid arthritis, osteoarthritis, COVID-19, systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), and interstitial lung disease (ILD).

42. Use of a compound of formula I according to claim 1 or 2 or a compound of formula II or III according to claim 16 for the manufacture of a pharmaceutical product for the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonosis, Eicardi-Gutierre syndrome (AGS), COPA syndrome, familial lupus frostbite, dermatomyositis, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjögren's syndrome, rheumatoid arthritis, and Parkinson's disease.

43. Use of a compound of formula I according to claim 1 or 2, or a compound of formula II or III according to claim 16, for the manufacture of a pharmaceutical product for treating a disease selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interferonosis, and interstitial lung disease (ILD).

44. Use of a compound of formula I according to claim 1 or 2 or a compound of formula II or III according to claim 16 for the manufacture of a pharmaceutical for the treatment of a disease selected from the group consisting of interstitial lung disease with progressive fibrosis (PF-ILD).

45. Use of a compound of formula I according to claim 1 or 2 or a compound of formula II or III according to claim 16 for the manufacture of a pharmaceutical product for the treatment of idiopathic pulmonary fibrosis (IPF).

46. Use of a compound of formula I according to claim 1 or 2 or a compound of formula II or III according to claim 16 for the manufacture of a pharmaceutical product for the treatment of a disease selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging, muscle disorders, sepsis, osteoarthritis, heart failure, COVID-19 / SARS-CoV-2 infection, nephritis, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, and cancer.

47. A pharmaceutical composition comprising a compound of formula I as described in claim 1 or 2, or a compound of formula II or III as described in claim 16, and which may also comprise one or more pharmaceutically acceptable carriers and / or excipients.

48. A compound of formula I according to claim 1 or 2, or a compound of formula II or III according to claim 16, is combined with one or more activators selected from the group consisting of anti-inflammatory agents, antifibrotic agents, anti-allergic agents / antihistamines, bronchodilators, β2 agonists / beta-mimetics, adrenaline agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, nonspecific immunotherapy agents, cytokine / chemokine receptor modulators, Toll-like receptor agonists, immune checkpoint regulators, anti-TNF antibodies, and anti-BAFF antibodies. A pharmaceutical composition which may contain one or more pharmaceutically acceptable carriers and / or excipients.

49. A pharmaceutical composition comprising a compound of formula I according to claim 1 or 2, or a compound of formula II or III according to claim 16, in combination with one or more antifibrotic agents selected from the group consisting of pirfenidone and nintedanib, and which may also comprise one or more pharmaceutically acceptable carriers and / or excipients.

50. A pharmaceutical composition comprising a compound of formula I according to claim 1 or 2, or a compound of formula II or III according to claim 16, in combination with one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids, and which may also comprise one or more pharmaceutically acceptable carriers and / or excipients.

51. A pharmaceutical composition comprising a compound of formula I according to claim 1 or 2, or a compound of formula II or III according to claim 16, in combination with one or more active agents selected from the group consisting of bronchodilators, β2 agonists / beta-mimetics, adrenaline agonists, and anticholinergics, and which may also comprise one or more pharmaceutically acceptable carriers and / or excipients.

52. A pharmaceutical combination comprising a compound of formula I according to claim 1 or 2, or a compound of formula II or III according to claim 16, and one or more anti-interleukin antibodies selected from the group consisting of anti-IL-23, anti-IL-17, anti-IL-1, anti-IL-4, anti-IL-13, anti-IL-5, anti-IL-6, anti-IL-12, and anti-IL-15 antibodies.

53. A pharmaceutical composition comprising a compound of formula I according to claim 1 or 2 or a compound of formula II or III according to claim 16, and one or more activators selected from the group consisting of the anti-TNF antibody Humira (trademark), the anti-IL-23 antibody risankizumab, the anti-IL-6 antibody Actemra (trademark), and the anti-BAFF antibody belimumab or etanercept, and which may also comprise one or more pharmaceutically acceptable carriers and / or excipients.

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