PYRIDINE DERIVATIVES WITH N-LINKED CYCLIC SUBSTITUENTS AS cGAS INHIBITORS

Abstract

To provide compounds as new proline derivatives, and to provide a pharmaceutical composition comprising the compounds for the treatment of diseases such as systemic lupus erythematosus, systemic sclerosis, non-alcoholic steatohepatitis, interstitial lung disease and idiopathic pulmonary fibrosis.SOLUTION: There are provided new proline derivatives of formula (I) as cGAS inhibitors, or pharmaceutical compositions comprising a prodrug, a pharmaceutically acceptable salt, or a stereoisomer of the compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] 1. Background of the Invention 1.1 cGAS inhibitors Innate immunity is considered the most important stress response, defending host cells against invading pathogens and triggering 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. Primary antigen-presenting cells, such as monocytes, macrophages, and dendritic cells, produce type I interferons, which are crucial for triggering adaptive T cell and B cell immune system responses. Primary PRRs detect abnormal, i.e., mislocated, immature or unmodified nucleic acids either on the cell surface, inside the lysosomal membrane, or within other cellular compartments (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)). "Cyclic GMP-AMP synthase" (cGAS, UniProtKB - Q8N884) is a master sensor of aberrant double-stranded DNA (dsDNA) derived from pathogens or resulting from mislocalization or misprocessing of cellular dsDNA in the nucleus or mitochondria (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). Binding of dsDNA to cGAS activates the reaction of GTP and ATP to form the cyclic dinucleotide GMP-AMP (termed cGAMP). cGAMP then translocates to and activates the endoplasmic reticulum membrane-anchored adaptor protein, "stimulator of interferon genes" (STING). Activated STING recruits and activates TANK-binding kinase 1 (TBK1), which then phosphorylates the transcription factor family of interferon regulatory factors (IRFs) to induce cytokine and type I interferon mRNA expression.

[0002] The essential role of cGAS in dsDNA sensing has been confirmed in various pathogens (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)). Furthermore, cGAS is essential for various other biological processes, such as 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)). The cGAS pathway is important for host defense against invading pathogens; however, cellular stress and genetic factors can trigger the production of abnormal cellular dsDNA, for example, through nuclear or mitochondrial leakage, thereby initiating an autoinflammatory response. Aicardi-Goutières syndrome (AGS; Crow et al., Nat. Genet. 38, 917-920 (2006)), a severe autoimmune-mediated disorder similar to lupus, is caused by loss-of-function mutations in TREX1, the main DNA exonuclease responsible for degrading abnormal DNA in the cytosol. Knockout of cGAS in TREX1-deficient mice prevented the lethal autoimmune response that otherwise supports cGAS as a driver of interferonopathy (Gray et al., J. Immunol. 195, 1939-1943 (2015); Gao et al., PNAS 112, E5699-E5705 (2015)). Similarly, embryonic lethality caused by the deletion of DNAse2, an endonuclease responsible for the degradation of excess DNA in lysosomes during endocytosis, was fully rescued by further knockout of cGAS (Gao et al., PNAS 112, E5699-E5705 (2015)) or STING (Ahn et al., PNAS 109, 19386-19391 (2012)). These findings support cGAS as a drug target, and its inhibition could prevent autoinflammation through the involvement of anti-dsDNA antibodies and provide a therapeutic strategy for treating diseases such as systemic lupus erythematosus (SLE) (Pisetsky et al., Nat. Rev. Rheumatol. 12, 102-110 (2016)). [Background technology]

[0003] 1.2 Prior art Due to the knowledge that inhibition of the cGAS pathway can prevent autoinflammation and provide a therapeutic strategy for treating, for example, autoimmune diseases, many efforts have been undertaken to develop cGAS inhibitors. For example, WO 2019 / 241787 disclosed methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylate, e.g., CU-32 and CU-76, as cGAS inhibitors with "in vitro hcGAS IC50 values" of slightly less than 1 μM (IC50(CU-32)=0.66 μM and IC50(CU-76=0.27 μM). Hall et al., PLoS ONE 12(9); e0184843 (2017) published compound PF-06928215 as a cGAS inhibitor with an "in vitro hcGAS IC50 value" of 0.049 μM as measured by a fluorescence polarization assay. However, compound PF-06928215 did not exhibit acceptable cellular activity as a cGAS inhibitor. WO 2020 / 142729 discloses (benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid derivatives as cGAS inhibitors for the treatment of autoimmune disorders such as Aicardi-Goutieres syndrome (AGS), lupus erythematosus, scleroderma, inflammatory bowel disease, and nonalcoholic steatohepatitis (NASH). However, the compounds of the present invention differ from the (benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid derivatives of WO 2020 / 142729 in their completely different substitution pattern at the 4-position of the pyrrolidine ring.

[0004] Recently provided cGAS inhibitors, such as those described in WO 2020 / 142729, typically exhibit insufficient cellular cGAS inhibitory potency (IC50 values for inhibition of the cGAS / STING pathway, as measured in cellular assays, are generally greater than 1 μM, and often greater than 5 μM). However, to ensure that a compound can have a therapeutic effect in patients, it is necessary to not only exhibit satisfactory biochemical (in vitro) inhibitory potency ("hcGAS IC50"), but also satisfactory cellular inhibitory potency (e.g., inhibition of IFN induction in virus-stimulated THP-1 cells (THP1 (vir)It is important to provide therapeutic cGAS inhibitors (by demonstrating IC50). Other important properties that can predict successful development of cGAS inhibitors as therapeutics are satisfactory cGAS selectivity (versus off-target activity) and acceptable inhibitory potency in human whole blood.

[0005] Surprisingly, it has now been found that compounds of formula (I) and formula (I') simultaneously exhibit the following three properties: a satisfactory "biochemical (in vitro) IC50 value for cGAS inhibition" (hcGAS IC50 of ≦100 nM, preferably ≦50 nM, in particular ≦10 nM), Satisfactory "inhibition of IFN induction in virus-stimulated THP-1 cells" (THP1 IC50 of ≦1 μM, preferably ≦500 nM, more preferably ≦100 nM, especially ≦50 nM) (vir) ) and Satisfactory selectivity for cGAS inhibition (a ratio of THP1 IC50 of ≧10, more preferably ≧50, even more preferably ≧500, especially ≧1000) (cGAMP) / THP1 IC50 (vir) ). Furthermore, the compounds of formula (I) and formula (I') also exhibit acceptable IC50 values for inhibition of IFN induction in a dsDNA stimulated human whole blood assay, preferably human whole blood IC50 values (hWB IC50) for cGAS inhibition of ≦5000 nM, more preferably ≦1000 nM, especially ≦100 nM.

[0006] The cGAS compounds of the present invention having this particular pharmacological profile, which combines high selectivity for cGAS inhibition with excellent in vitro inhibitory potency and excellent cellular inhibitory potency, are also likely to show good therapeutic effects in patients. Because of their high cellular inhibitory potency, compounds with this particular pharmacological profile cross the cell membrane barrier and thus reach their intracellular target location. Because of their selectivity to exclusively inhibit cGAS activity, these compounds should not show undesirable off-target effects, such as side effects or cytotoxic effects elsewhere in the signaling pathway downstream of cGAS. Summary of the Invention

[0007] 2. Description of the invention The present invention relates to a compound represented by the following formula (I): [ka]

[0008] (In the formula, R 1 is selected from methyl, ethyl, halomethyl, haloethyl, and halogen; G, O, NR 8 , CH2, C and CR 8 R 9 is selected from R 2 is H, halogen, cyclopropyl, C 1-3 -Alkyl, -C 2-5 -alkynyl, -S-methyl and CN; or R 2 is a cyclic group selected from the group consisting of phenyl or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms each independently selected from N, S, and O, and the cyclic group is substituted with one or two identical or different substituents R 10 is replaced by R 3 is H or methyl, R 4 is H or methyl, R 5 is selected from H, methyl, —CN, -methylene-OH and —CF3; or R 5 may not exist, R 6 is selected from H, methyl, —CN, -methylene-OH and —CF3; or R 5 and R 6 together with the middle C atom form a ring selected from oxetane, tetrahydrofuran and cyclopropane, R 7 is H, halogen, (C 1-3)-alkyl and halo-(C 1-3 )-alkyl; R 8 is selected from CN, H and methyl; R 9 is selected from H, methyl and halogen; or R 9 may not exist, Here, each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH3)2, -CH2-OH, -NH(CH3), -O-(C 1-3 -alkyl), -CN, -S-CH3, -CO-NH2, -CH2-NH(CH3), -CH2-NH2, -SO-(CH3), cyclopropyl and -OR 11 are independently selected from the group consisting of Each R 11 are independently selected from 5- or 6-membered heterocycles having 1 or 2 heteroatoms each independently selected from N, O and S; Or G is CR 8 R 9 and R 5 and R 9 does not exist and R 8 and R 6 and R 8 and R 6 and the two middle C atoms form a fused 5-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, S and O, Or G is CR 8 R 9 and R 8 and R 9 But R 8 and R 9 (together with the middle C atom of the Compounds of and prodrugs or pharmaceutically acceptable salts of these compounds.

[0009] A preferred embodiment of the present invention is a compound represented by the following formula (I'): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and G as defined above) The above compounds falling within the range and prodrugs or pharmaceutically acceptable salts of these compounds.

[0010] Another preferred embodiment of the present invention comprises: R 7 is H, F, Cl, methyl, ethyl, halomethyl or haloethyl; The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. In another preferred embodiment, the present invention provides R 1 is halomethyl, haloethyl or methyl; The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. A further preferred embodiment of the present invention comprises: R 1 is a fluoromethyl selected from the group consisting of -CF3, -CHF2, and -CH2F; The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. In another preferred embodiment, the present invention provides R 3 and R 4 at least one of is methyl; The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds.

[0011] Another preferred embodiment of the present invention comprises: R 3 and R 4 one of which is methyl and the other is H, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. In another preferred embodiment, the present invention provides G is O, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. Another preferred embodiment of the present invention comprises: G is O, And R 3 and R 4 one of which is methyl and the other is H, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. In another preferred embodiment, the present invention provides G is O, R 4 is methyl and R 3 is H, And R 5 and R 6 together form an oxetane ring, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds.

[0012] Another preferred embodiment of the present invention comprises: R 2 is selected from the group consisting of H, ethynyl, 1-propynyl, -S-methyl and halogen; The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. In another preferred embodiment, the present invention provides R 2 is ethynyl, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. Another preferred embodiment of the present invention comprises: R 4 is methyl and R 3 is H, G is O, R 5 and R 6 together form an oxetane ring, R 2 is selected from the group consisting of H, ethynyl, 1-propynyl, -S-methyl and halogen; The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds.

[0013] In another preferred embodiment, the present invention provides R 2 is a cyclic group selected from the group consisting of phenyl or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, S, and O; The cyclic group may be substituted with one or two identical or different substituents R 10 is replaced by Each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH3)2, -CH2-OH, -NH(CH3), -O-CH3, -CN, -S-CH3, -CO-NH2, -CH2-NH(CH3), -CH2-NH2, -SO-(CH3), cyclopropyl and -OR 11 are independently selected from the group consisting of Each R 11 are independently selected from 5- or 6-membered aromatic or non-aromatic heterocycles having 1 or 2 heteroatoms each independently selected from N and O; The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. A further preferred embodiment of the present invention comprises: R2 is a cyclic group selected from the group consisting of pyrazolyl, pyridinyl, imidazolyl, phenyl, and isoxazolyl; The cyclic group may be substituted with one or two identical or different substituents R 10 is replaced by Each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH3)2, -CH2-OH, -NH(CH3), -O-CH3, -CN, -S-CH3, -CO-NH2, -CH2-NH(CH3), -CH2-NH2, -SO-(CH3), cyclopropyl and -OR 11 are independently selected from the group consisting of Each R 11 is tetrahydropyran, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds.

[0014] In another preferred embodiment, the present invention provides G is O, R 3 and R 4 One of the is methyl and the other is H, R 2 is a cyclic group selected from the group consisting of pyrazolyl, pyridinyl, imidazolyl, phenyl, and isoxazolyl; The cyclic group may be substituted with one or two identical or different substituents R 10 is replaced by Each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH3)2, -CH2-OH, -NH(CH3), -O-CH3, -CN, -S-CH3, -CO-NH2, -CH2-NH(CH3), -CH2-NH2, -SO-(CH3), cyclopropyl and -OR 11 are independently selected from the group consisting of Each R 11 is tetrahydropyran, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds. In another preferred embodiment, the present invention provides R 2 is a cyclic group selected from the group consisting of pyrazolyl, pyridinyl, imidazolyl, phenyl, and isoxazolyl; The cyclic group may be substituted with one or two identical or different substituents R 10 is replaced by Each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH3)2, -CH2-OH, -NH(CH3), -O-CH3, -CN, -S-CH3, -CO-NH2, -CH2-NH(CH3), -CH2-NH2, -SO-(CH3), cyclopropyl and -OR 11 are independently selected from the group consisting of Each R 11 is tetrahydropyran, G is O, R 3 and R 4 One of the is methyl and the other is H, And R 5 and R 6 together form an oxetane ring, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds.

[0015] In another preferred embodiment, the present invention provides G is CR 8 R 9 and R 8 and R 6 and R 8 and R 6 and the two middle C atoms form a fused 5-membered aromatic heterocycle containing 1 or 2 heteroatoms independently selected from N and O, which is selected from a fused isoxazolyl ring, a fused pyrazolyl ring, a fused pyrrolyl ring and a fused furanyl ring; And R 9 and R 5 does not exist, The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds.

[0016] Another particularly preferred embodiment of the present invention is the compound [ka]

[0017] [ka]

[0018] [ka]

[0019] [ka]

[0020] [ka]

[0021] [ka]

[0022] [ka]

[0023] [ka] selected from the group consisting of The above compound of formula (I) or formula (I') and prodrugs or pharmaceutically acceptable salts of these compounds.

[0024] In another embodiment, the present invention provides For use in treating a disease treatable by an inhibitor of cGAS, The present invention relates to the above compounds of formula (I) or formula (I'). In a preferred embodiment, the present invention refers to a compound of formula (I) or formula (I') as defined above for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathy, Aicardi-Goutieres syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, Parkinson's disease, heart failure and cancer, systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably progressive fibrotic interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).

[0025] In a further preferred embodiment, the present invention relates to the above-mentioned compounds of formula (I) or formula (I') for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathy, Aicardi-Goutieres syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome and Parkinson's disease. In another further preferred embodiment, the present invention relates to the above-mentioned compounds of formula (I) or formula (I') for use in the treatment of fibrotic diseases selected from the group consisting of systemic sclerosis (SSc), interferonopathies, non-alcoholic steatohepatitis (NASH), interstitial lung diseases (ILDs), preferably progressive fibrotic interstitial lung diseases (PF-ILDs), in particular idiopathic pulmonary fibrosis (IPF). In another further preferred embodiment, the present invention relates to the above-mentioned compound of formula (I) or formula (I') for use in the treatment of a disease selected from the group consisting of age-related macular degeneration (AMD), heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, dysmetabolism, vascular diseases, cardiovascular diseases and cancer.

[0026] In another embodiment, the present invention relates to a pharmaceutical composition comprising at least one of the above compounds of formula (I) or formula (I') and, optionally, one or more pharmaceutically acceptable carriers and / or excipients.

[0027] In another preferred embodiment, the present invention provides a compound represented by the following formula (IV) according to Synthesis Scheme 1: [ka] or the following formula (V) according to Synthesis Scheme 1

[0028] [ka] or the following formula (X) according to Synthesis Scheme 2

[0029] [ka] or the following formula (XI) according to Synthesis Scheme 2

[0030] [ka] refers to the intermediate where G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined above, X is F or NO2, PG is a protecting group selected from the group consisting of tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluorenylmethylenoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-methoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trichloroethyl chloroformate (Troc), acetyl (Ac), or benzoyl (Bn).

[0031] In a further preferred embodiment, the present invention relates to a prodrug of any of the above compounds of formula (I) or formula (I'), wherein the prodrug is within the scope of the following formula (A):

[0032] [ka] Or within the range of the following formula (A')

[0033] [ka] (In the formula, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined above, R 12 is C 1-4- Alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl) Enter. In particular, the present invention provides R 12 is methyl.

[0034] In another preferred embodiment, the present invention relates to the combination of a compound of formula (I) or formula (I') with one or more active agents selected from the group consisting of anti-inflammatory agents, antifibrotic agents, antiallergics / antihistamines, bronchodilators, beta2 agonists / betamimetics, adrenergics, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint modulators, anti-TNF antibodies such as Humira™, anti-BAFF antibodies such as Belimumab and Etanercept. In a further particularly preferred embodiment, the present invention relates to a combination of a compound of formula (I) or formula (I') with one or more antifibrotic agents selected from the group consisting of pirfenidone and nintedanib. In a further particularly preferred embodiment, the present invention relates to the combination of a compound of formula (I) or formula (I') with one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids. In a further particularly preferred embodiment, the present invention relates to a combination of a compound of formula (I) or formula (I') with one or more active agents selected from the group consisting of bronchodilators, beta-2 agonists / betamimetics, adrenergic agonists and anticholinergics. In a further particularly preferred embodiment, the present invention relates to a combination of a compound of formula (I) or formula (I') with one or more anti-interleukin antibodies selected from the group consisting of anti-IL23 antibodies, such as risankizumab, anti-IL17 antibodies, anti-IL1 antibodies, anti-IL4 antibodies, anti-IL13 antibodies, anti-IL-5 antibodies, anti-IL-6 antibodies, such as Actemra™, anti-IL-12 antibodies and anti-IL-15 antibodies. In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (I') in combination with any of the above active agents. DETAILED DESCRIPTION OF THE INVENTION

[0035] 3. Terms and definitions used Unless otherwise specified, all substituents are independent of one another. For example, a group may have several C 1-6 - When alkyl groups are possible substituents, e.g., in the case of three substituents, C 1-6 -Alkyl may independently of one another represent methyl, n-propyl and tert-butyl. The term “C 1-6 -Alkyl" (including those that are part of other groups) means branched and unbranched alkyl groups having 1 to 6 carbon atoms, and the term "C 1-3 "-alkyl" refers to branched and unbranched alkyl groups having 1 to 3 carbon atoms. 1-4 "-Alkyl" denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples of these include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. Optionally, the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may be used for the above groups. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl, etc.

[0036] 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 1-4"-Alkylene" denotes branched and unbranched alkylene groups having 1 to 4 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are preferred. Examples thereof 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 propylene, butylene, pentylene and hexylene include all possible isomeric forms of the groups in question having the same number of carbons. Thus, for example, propyl also includes 1-methylethylene, butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, etc.

[0037] When the carbon chain is substituted with a group which, together with one or two carbon atoms of the alkylene chain, forms a carbocyclic ring having 3, 5 or 6 carbon atoms, this includes, among others, the following example rings: [ka]

[0038] The term “C 2-6 -alkenyl" (including those that are part of other groups) means branched and unbranched alkenyl groups having 2 to 6 carbon atoms, provided that they have at least one double bond, and the term "C 2-4"-Alkenyl" refers to branched and unbranched alkenyl groups having 2 to 4 carbon atoms, provided that 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 propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-butenyl, 2-butenyl and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc. The term “C 2-5 -alkynyl" (including those that are part of other groups) means branched and unbranched alkynyl groups having 2 to 5 carbon atoms, provided that they have at least one triple bond, and the term "C 2-4 "-Alkynyl" refers to branched and unbranched alkynyl groups having 2 to 4 carbon atoms, provided that they have at least one triple bond. Alkynyl groups having 2 to 4 carbon atoms are preferred. The term “C 2-6 -Alkenylene" (including those that are part of other groups) means branched and unbranched alkenylene groups having 2 to 6 carbon atoms, and the term "C 2-4"-Alkenylene" denotes branched and unbranched alkylene groups having 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are preferred. Examples thereof 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 propenylene, butenylene, pentenylene and hexenylene include all possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propenyl also includes 1-methylethenylene, and butenylene also includes 1-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.

[0039] The term "aryl" (including those that are part of other groups) refers to an aromatic ring system having 6 or 10 carbon atoms. Examples include phenyl or naphthyl, with phenyl being the preferred aryl group. Unless otherwise specified, the aromatic group may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. The term "aryl-C 1-6 "-Alkylene" (including those that are part of other groups) refers to branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted with an aromatic ring system having 6 or 10 carbon atoms. Examples include benzyl, 1-phenylethyl or 2-phenylethyl, and 1-naphthylethyl or 2-naphthylethyl. Unless otherwise specified, the aromatic group may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine. The term "heteroaryl-C 1-6 -alkylene" (including those that are part of other groups) is "aryl-C 1-6Although already included within "-alkylene", it refers to branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted with heteroaryl. Unless specifically stated otherwise, this type of heteroaryl includes a 5- or 6-membered heteroaromatic group or a 5- to 10-membered bicyclic heteroaryl ring, which may contain 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and which contain enough conjugated double bonds to form an aromatic system. The following are examples of 5- or 6-membered heteroaromatic groups and bicyclic heteroaryl rings:

[0040] [ka]

[0041] Unless otherwise specified, these heteroaryls may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, amino, nitro, alkoxy, fluorine, chlorine, bromine and iodine. The following is a heteroaryl-C 1-6 - is an example of alkylene.

[0042] [ka]

[0043] The term “C 1-6 The term "C -haloalkyl" (including those that are part of other groups) refers to branched and unbranched alkyl groups having 1 to 6 carbon atoms, which are substituted with one or more halogen atoms. 1-4 "-Haloalkyl" refers to branched and unbranched alkyl groups having 1 to 4 carbon atoms, substituted with one or more halogen atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples include CF3, CHF2, CH2F, and CH2CF3. The term “C 3-7"-cycloalkyl" (including those that are part of other groups) means, unless specifically stated otherwise, a cyclic alkyl group having 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise stated, the cyclic alkyl group may be optionally substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. Unless specifically stated otherwise, the term "C 3-10 -cycloalkyl" refers to monocyclic alkyl groups having 3 to 7 carbon atoms and bicyclic alkyl groups having 7 to 10 carbon atoms, or to a group having at least one C 1-3 It also refers to monocyclic alkyl groups bridged by a -carbon bridge. The term "heterocyclic ring" or "heterocycle", unless otherwise specified, means a 5-, 6-, or 7-membered saturated, partially saturated, or unsaturated heterocyclic ring that may contain 1, 2, or 3 heteroatoms selected from among oxygen, sulfur, and nitrogen, and the ring may be linked to the molecule through a carbon atom or, if present, a nitrogen atom. Although encompassed by the term "heterocyclic ring" or "heterocycle," the term "saturated heterocyclic ring" refers to a 5-, 6-, or 7-membered saturated ring. Examples include:

[0044] [ka]

[0045] Although encompassed by the term "heterocyclic ring" or "heterocyclic group," the term "partially saturated heterocyclic ring" refers to a 5-, 6-, or 7-membered partially saturated ring containing one or two double bonds, unless specifically defined otherwise, without creating so many double bonds that an aromatic system is formed. Examples include:

[0046] [ka]

[0047] The terms "heterocyclic aromatic ring," "unsaturated heterocyclic group," or "heteroaryl," although encompassed by the term "heterocyclic ring" or "heterocycle," refer to a 5- or 6-membered heterocyclic aromatic group or a 5- to 10-membered bicyclic heteroaryl ring, which may contain 1, 2, 3, or 4 heteroatoms selected from among oxygen, sulfur, and nitrogen, and which contain so many conjugated double bonds that an aromatic system is formed, unless specifically defined otherwise. Examples of 5- or 6-membered heterocyclic aromatic groups include:

[0048] [ka]

[0049] Unless otherwise specified, the heterocyclic ring (or heterocycles) may carry a keto group. Examples include:

[0050] [ka]

[0051] Although encompassed by the term "cycloalkyl," the term "bicyclic cycloalkyl" generally refers to an 8-, 9-, or 10-membered bicyclic carbocyclic ring. Examples include:

[0052] [ka]

[0053] Although already encompassed by the term "heterocycle," the term "bicyclic heterocycle," unless specifically defined otherwise, generally refers to an 8-, 9-, or 10-membered bicyclic ring that may contain one or more, preferably 1 to 4, more preferably 1 to 3, even more preferably 1 to 2, and especially 1 heteroatom selected from among oxygen, sulfur, and nitrogen. The ring may be linked to the molecule via a carbon atom in the ring or, if present, via a nitrogen atom in the ring. Examples include:

[0054] [ka]

[0055] Although already encompassed by the term "aryl," the term "bicyclic aryl" refers to a 5- to 10-membered bicyclic aryl ring containing sufficient conjugated double bonds to form an aromatic system. An example of a bicyclic aryl is naphthyl. Although already included within "heteroaryl," the term "bicyclic heteroaryl" means, unless specifically defined otherwise, a 5- to 10-membered bicyclic heteroaryl ring that may contain 1, 2, 3, or 4 heteroatoms selected from among oxygen, sulfur, and nitrogen, and that contains sufficient conjugated double bonds to form an aromatic system. The terms "fused cycloalkyl" or "fused aryl" refer to bicyclic rings in which the bridge separating the rings represents a direct single bond, as encompassed by the terms "bicyclic cycloalkyl" or "bicyclic aryl." Below are examples of fused bicyclic cycloalkyls:

[0056] [ka]

[0057] The terms "fused bicyclic heterocycle" or "fused bicyclic heteroaryl," as encompassed by the terms "bicyclic heterocycle" or "bicyclic heteroaryl," refer to a bicyclic 5- to 10-membered heterocycle containing 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and in which the bridge separating the rings represents a direct single bond. A "fused bicyclic heteroaryl" further contains sufficient conjugated double bonds to form an aromatic system. Examples include pyrrolidine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

[0058] [ka] Examples include:

[0059] "Halogen" within the scope of the present invention means fluorine, chlorine, bromine or iodine. Unless otherwise stated, fluorine, chlorine and bromine are considered to be the preferred halogens. As mentioned above, the compounds of formula (I) or (I') may be converted into their salts, particularly physiologically and pharmacologically acceptable salts for pharmaceutical use. The term "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. These salts may exist, on the one hand, as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) or (I') with inorganic or organic acids. On the other hand, the compounds of formula (I) or (I') may be converted into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as counterions by reaction with inorganic bases. 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. To prepare the alkali metal and alkaline earth metal salts of the compounds of formula (I) or (I'), it is preferred to use the hydroxides and hydrides of alkali metals and alkaline earth metals, among which the hydroxides and hydrides of alkali metals, in particular sodium, potassium, magnesium, calcium, zinc, and diethanolamine, with sodium hydroxide and potassium hydroxide being particularly preferred.

[0060] The present invention relates to the compounds in question, optionally in the form of individual optical isomers, diastereomers, diastereomeric mixtures, individual enantiomer or racemic mixtures, in the form of tautomers as well as in the form of the free base or in the form of a corresponding acid addition salt with a pharmacologically acceptable acid, such as a hydrohalic acid, e.g. hydrochloric acid or hydrobromic acid, or an organic acid, e.g. oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid. The compounds of formula (I) or (I') of the present invention may in some cases exist as mixtures of diastereoisomeric isomers, but may also be obtained as pure diastereomers. Compounds with specific stereochemistry of formula (I') are preferred.

[0061] 4 Synthesis method The compounds of the invention and intermediates thereto can be obtained, for example, using synthetic methods known to those skilled in the art and described in the organic synthesis literature. The present invention further provides a process for preparing a compound of formula (I) or formula (I'). Optimal reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress can be monitored by thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and intermediates and products can be purified, if necessary, by silica gel chromatography, HPLC, and / or recrystallization. The following examples are illustrative, and one of ordinary skill in the art will recognize that specific reagents or conditions can be modified, as needed, to suit individual compounds without undue experimentation. The starting materials and intermediates used in the methods described below are commercially available or readily prepared from commercially available materials by one of ordinary skill in the art. Compounds of formula (I) can be prepared by the methods outlined in Schemes 1-4, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, R 8 , R 9 , R 10 , R 11 and G are as defined above, and PG is a protecting group preferably selected from the group consisting of tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluorenylmethylenoxycarbonyl (Fmoc), and allyloxycarbonyl (Alloc).

[0062] Scheme 1: [ka]

[0063] As shown in Scheme 1, reaction of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (III) with chloro-pyrimidine (II) in the presence of a suitable base such as diisopropylethylamine, potassium carbonate, or sodium hydride in a suitable solvent such as DMSO provides the hydroxyproline derivative of formula (IV). Reaction of hydroxyproline (IV) with pyridine of formula (V) (wherein X is F or NO) in the presence of a suitable base such as NaH in a suitable solvent such as DMA, DMF, or NMP provides the compound of formula (I).

[0064] Scheme 2: [ka]

[0065] As shown in Scheme 2, reaction of fluoronitropyridine (VI) with cyclic amine (VII) in the presence of a suitable base, such as KCO, in a suitable solvent, such as acetonitrile, provides a nitropyridine of formula (VIII). This nitropyridine (VIII) can be reacted with a hydroxyproline of formula (IX), where the protecting group PG can be, for example, tert-butoxycarbonyl (BOC), in the presence of a suitable base, such as NaH, in a suitable solvent, such as DMF, NMP, or DMA, to provide a compound of formula (X). Removal of the protecting group PG in (X) under standard conditions provides a proline derivative of formula (XI). That is, when PG is BOC, deprotection can be achieved using TFA in a suitable solvent, such as acetonitrile. Reaction of compound (XI) with a chloro-pyrimidine of formula (II) in the presence of a suitable base, such as diisopropylethylamine, potassium carbonate, or sodium hydride, in a suitable solvent, such as DMSO or DMF, provides a compound of formula (I). Following this general reaction scheme 2, the substituent R 2 is in place from the beginning of the reaction sequence of compound (VI) and remains unchanged until compound (I) is obtained (i.e., R 2 is H, Br, Cl, aryl or alkynyl), or the substituent R 2 may be introduced at a later stage during the synthesis via Suzuki coupling or other arylation reactions known to those skilled in the art. For example, R 2 Compounds of formula (VI), (VIII), (X) or (I), where R is Br, I or OTf, can be reacted with an appropriate aryl boronate (ester / acid) in the presence of a suitable base such as Na2CO3, K3PO4 or KOH and a suitable catalyst such as Pd(dppf)Cl2 or Pd(PPh3)4 (using a suitable ligand such as Xphos) in a suitable solvent such as dioxane or DMF to give R 2 is aryl.

[0066] Apart from this, R 2Compounds of formula (VI), (VIII), (X), or (I) where R is halogen or OTf can be reacted with a boronating reagent such as bis(pinacolato)diboron in the presence of a suitable catalyst such as Pd(dppf)Cl and a suitable base such as potassium acetate to give a boronic ester. This boronic ester can be reacted with an appropriate aryl halide in a Suzuki coupling in the presence of a suitable base such as NaCO, KPO, or KOH and a suitable catalyst such as Pd(dppf)Cl or Pd(PPh) (using a suitable ligand such as Xphos) in a suitable solvent such as dioxane or DMF to give the respective compound where R is aryl. Apart from this, R 2 Compounds of formula (VI), (VIII), (X) or (I), where R is a halogen, can be reacted with a suitable alkyne, such as ethynyltris(propan-2-yl)silane, in the presence of a suitable catalyst, such as PdCl(PPh) and copper(I) iodide, and a suitable base, such as DIPEA, in a suitable solvent, such as THF, to give R 2 is an alkyne, the respective compounds can be given. The carboxylic acid functionality of the proline motif (i.e., in compounds of formula (X) or (I)) can be protected with a suitable protecting group such as an alkyl ester during the reaction specific to this sequence, i.e., a tert-butyl ester can be used to form R 2 is a suitable protecting group for introducing an aryl moiety into

[0067] Compounds of formula (II) can be prepared as shown in Scheme 3. Scheme 3: [ka]

[0068] Reaction of a carbonitrile of formula (XII) with an anhydride of formula (XIII) or the corresponding acid in a suitable solvent such as pyridine gives the amide (XIV), which upon reaction with a suitable chlorinating agent such as phosphorus pentachloride in a suitable solvent such as sulfolane, cyclizes to form a compound of formula (II). In an alternative synthetic sequence, a compound of formula (XV) is reacted with 2-bromoacetamide in the presence of a suitable base, such as KCO or KOH, in a suitable solvent, such as ethanol, to give a compound of formula (XVII). Compound (XVII) is reacted with a dimethylamide of formula (XVIII) in the presence of a suitable chlorinating reagent, such as phosphorus oxychloride, to form a compound of formula (II). In another alternative synthetic sequence, a compound of formula (XV) is reacted with bromoacetonitrile in the presence of a suitable base, such as K2CO3, in a suitable solvent, such as DMF, to give a compound of formula (XIX), which is cyclized in the presence of a suitable base, such as tert-butoxide, in a suitable solvent, such as THF, to form carbonitrile (XII), which can be converted to a compound of formula (XIV) as described above and subsequently to a compound of formula (II). Compounds of formula (VII) are commercially available or can be prepared according to literature procedures or are described by way of example in the experimental section. Compounds of formula (VII), exemplified by compounds of formula (XXIII), can be prepared as shown in Scheme 4.

[0069] Scheme 4: [ka]

[0070] Oxetan-3-one (XXII) reacts with a nitroalkane of formula (XXIII) in a suitable solvent, such as methanol, to form a compound of formula (XXIV). Hydrogenation of compound (XXIV) in the presence of hydrogen and a suitable catalyst, such as Pd(OH)2 / C, in a suitable solvent, such as ethanol, gives a compound of formula (XXV). Reaction of compound (XXV) with chloroacetyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as acetonitrile, gives compound (XXVI), which cyclizes to form a lactam of formula (XXVII) upon treatment with a suitable base, such as tert-butoxide, in a suitable solvent, such as tert-amyl alcohol. Reduction of compound (XXVII) with a suitable reducing agent, such as lithium aluminum hydride, in a suitable solvent, such as diethyl ether, gives a morpholine compound of formula (XXVIII). Further modification of compounds of formula (I) by methods known to those skilled in the art and as illustrated in the Examples below can be used to prepare additional compounds of the present invention. The proposed synthetic routes may rely on the use of protecting groups. For example, potentially present reactive groups, such as hydroxyl, carbonyl, carboxy, amino, alkylamino, or imino, may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. The respective functionalities and the protecting groups suitable for their removal are well known to those skilled in the art and can be found in the literature of organic synthesis, for example in "Protecting Groups, 3 rd Edition”, Philip J. Kocienski, Thieme, 2005 or “Protective Groups in Organic Synthesis, 4 th Edition”, Peter GM Wuts, Theodora W. Greene, John Wiley and Sons, 2007.

[0071] Compounds of general formula (I) may be resolved into their diastereomers (ds) as described below, thus, for example, cis / trans mixtures may be resolved into their cis and trans isomers. Cis / trans mixtures can be separated into their cis and trans isomers, for example, by chromatography. Diastereomeric mixtures of compounds of general formula (I) can be separated into their diastereomers by taking into account their different physicochemical properties, using methods known per se, for example, chromatography and / or fractional crystallization. Racemic intermediates are preferably resolved by chiral-phase column chromatography or crystallization from optically active solvents, or by reaction with an optically active substance that forms a salt or a derivative, such as an ester or amide, with the racemate. Salts can be formed with enantiomerically pure acids for basic compounds, and with enantiomerically pure bases for acidic compounds. Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, such as acids, their activated derivatives, or alcohols. Separation of diastereomeric mixtures of salts or derivatives thus obtained can be achieved by taking into account their different physicochemical properties, such as differences in solubility; free enantiomers can be liberated from the pure diastereomeric salts or derivatives by the action of appropriate agents. Those skilled in the art are familiar with optically active acids commonly used for such purposes, as well as optically active alcohols that can be used as auxiliary residues.

[0072] As mentioned above, the compounds of formula (I) can be converted into salts, particularly pharmaceutically acceptable salts for pharmaceutical use. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by forming a pharmaceutically acceptable acid or base salt thereof. The term "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali salts or organic salts of acidic residues such as carboxylic acids; and the like. For example, the salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Additional pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, the salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of the appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Other acid salts than those mentioned above, which are useful, for example, in the purification or isolation of the compounds of the invention (eg, trifluoroacetates), also form part of the invention. The compounds of the invention can also be advantageously obtained using the methods described in the examples below, which may be used in conjunction with methods known to those skilled in the art from the literature for this purpose.

[0073] General technical findings The terms "ambient temperature" and "room temperature" are used interchangeably to designate a temperature of about 20°C, e.g., 15-25°C. In principle, the temperature of the compound prepared 1 H NMR and / or mass spectra were obtained. Unless otherwise stated, all chromatographic runs were carried out at room temperature.

[0074] Synthesis of intermediates Intermediate 1.1.I N-(2-cyano-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide [ka]

[0075] TFAA (5.31 g, 25.3 mmol) was added to a mixture of 3-amino-1-benzofuran-2-carbonitrile (4.00 g, 25.3 mmol) in pyridine (40.0 mL) at RT. The mixture was stirred at 25 °C for 12 h, then concentrated under reduced pressure, diluted with 20 mL of water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; PE / EtOAc = 20 / 1 → 5 / 1). ESI-MS: 254.9 [M+H] + R t (HPLC): 0.56 min (Method A)

[0076] The following intermediates were prepared according to the general procedure above (Intermediate 1.1.I). [ka]

[0077] Intermediate 1.1.III N-(2-cyano-1-benzofuran-3-yl)-2,2-difluoropropanamide [ka]

[0078] To a mixture of 2,2-difluoropropionic acid (300 mg, 2.73 mmol) and DIPEA (1.41 mL, 8.18 mmol) in 2.00 mL of DMF at RT was added HATU (1.04 g, 2.73 mmol), followed by 3-amino-1-benzofuran-2-carbonitrile (474 mg, 3.00 mmol). After stirring the reaction at RT for 1.5 h, a mixture of 2,2-difluoropropionic acid (300 mg, 2.73 mmol), DIPEA (1.41 mL, 8.18 mmol), and HATU (1.04 g, 2.73 mmol) in 2.0 mL of DMF was added to the reaction mixture and stirring was continued. DCM and water were added to the reaction mixture to extract the product. The phases were separated and concentrated in vacuo, and the crude product was purified by RP-HPLC (X-Bridge C18, ACN / HO / TFA). ESI-MS:249 [MH] - R t (HPLC): 0.53 min (Method A)

[0079] Intermediate 1.2.I 6-chloro-4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaene [ka]

[0080] To a solution of N-(2-cyano-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide (Intermediate 1.1.I, 4.00 g, 15.7 mmol) in sulfolane (10.0 mL) was added phosphorus pentachloride (13.1 g, 63.0 mmol). The mixture was stirred at 110 °C for 16 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; PE / EtOAc = 20 / 1 → 10 / 1). ESI-MS: 273 [M+H] + Rt (HPLC): 0.71 min (Method A)

[0081] The following compounds were prepared according to the general procedure above (Intermediate 1.2.I): [ka]

[0082] Intermediate 1.3.I (2S,4S)-4-Hydroxy-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]-Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0083] To a mixture of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (1.44 g, 11.0 mmol) in DMSO (25.0 mL) preheated at 110 °C was added DIPEA (3.90 g, 30.0 mmol) and 6-chloro-4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaene (Intermediate 1.2.I, 2.73 g, 10.0 mmol) was added. Stirring was continued at 110 °C for 10 min, after which the reaction mixture was added dropwise to water and acidified with 4 M HCl. The precipitate was filtered and dried. ESI-MS: 368 [M+H] + R t (HPLC): 0.50 min (Method A)

[0084] The following compounds were prepared following the general procedure above (Intermediate 1.3.I). [ka] [ka]

[0085] Intermediate 2.1 3-(1-nitroethyl)oxetan-3-ol [ka]

[0086] A mixture of nitroethane (27.3 g, 364 mmol) in 50 mL of methanol was cooled to 0 °C. TEA (9.74 mL, 69.4 mmol) was added dropwise under cooling, followed by oxetan-3-one (25.0 g, 347 mmol). The cooling was removed, and the reaction mixture was stirred at RT for 1 h and then concentrated. The residue was purified by column chromatography (silica gel; CH / Et0Ac = 75 / 25 → 50 / 50). ESI-MS: r 146 [MH] - R t (EI): 3.38 minutes

[0087] Intermediate 2.2 3-(1-aminoethyl)oxetan-3-ol [ka]

[0088] A mixture of 3-(1-nitroethyl)oxetan-3-ol (Intermediate 2.1, 24.5 g, 157 mmol), 280 mL of ethanol, and 5 mol% Pd(OH) / C (5.52 g, 7.87 mmol) was heated in a Parr apparatus under hydrogen pressure (50 psi (3.4 × 10 5 The reaction mixture was filtered, concentrated under reduced pressure and used in the next step without further purification. ESI-MS: 118 [M+H] + R f (TLC): 0.20 (PE / EtOAc = 0 / 1)

[0089] Intermediate 2.3 2-chloro-N-[1-(3-hydroxyoxetan-3-yl)ethyl]acetamide [ka]

[0090] A mixture of 3-(1-aminoethyl)oxetan-3-ol (Intermediate 2.2, 32.4 g, 262 mmol) in 500 mL of ACN was cooled to 0 °C, and TEA (44.2 mL, 315 mmol) was added, followed by dropwise addition of chloroacetyl chloride (23.0 mL, 289 mmol). The mixture was allowed to warm to RT and stirred for 3 h. The precipitate was removed by filtration, and the filtrate was diluted with 50 mL of methanol and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM / methanol = 97 / 3 → 85 / 15). ESI-MS: 194 [M+H] + R t (HPLC): 0.27 min (Method E)

[0091] The following compounds were prepared according to the general procedure above (Intermediate 2.3). [ka]

[0092] Intermediate 2.4 9-Methyl-2,5-dioxa-8-azaspiro[3.5]nonan-7-one [ka]

[0093] At RT under argon, a degassed solution of 2-chloro-N-[1-(3-hydroxyoxetan-3-yl)ethyl]acetamide (Intermediate 2.3, 1.24 g, 6.02 mmol) in 24.0 mL of tert-amyl alcohol was added dropwise within 30 min to a stirred, degassed solution of potassium tert-butoxide (1.01 g, 9.03 mmol) in 12.0 mL of tert-amyl alcohol. After the addition was complete, the reaction mixture was stirred for another 1 h at RT. Then, MeOH (5.0 mL) and water (0.5 mL) were added, and the mixture was stirred for 20 min at RT. After evaporation of the volatiles, the residue was taken up in DCM and purified by column chromatography (silica gel; DCM / methanol = 99 / 1 → 90 / 10). ESI-MS: 158 [M+H] + R t (HPLC): 0.24 min (Method E)

[0094] The following compounds were prepared according to the general procedure above (Intermediate 2.4). [ka]

[0095] Intermediate 2.5 9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane [ka]

[0096] Under argon, a 1.0 M solution of LiAlH in diethyl ether was added dropwise to a degassed mixture of 9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-7-one (Intermediate 2.4, 3.80 g, 23.0 mmol) in 90.0 mL of THF, maintaining the temperature below 0° C. After the addition was complete, the reaction mixture was allowed to warm to RT and stirred at this temperature for an additional 16 h. The reaction mixture was cooled to 0°C, diluted with 60 mL of anhydrous diethyl ether, and treated successively with 1.33 mL of water, 1.33 mL of 4 N aqueous NaOH, and finally with 4 mL of water. The reaction mixture was allowed to warm to room temperature and stirred for an additional 15 minutes. The mixture was dried over sodium sulfate, filtered, and the solvent evaporated in vacuo. The remaining residue was coevaporated twice with ACN to remove residual water. ESI-MS: 144 [M+H] + R t (HPLC): 0.17 min (Method E)

[0097] The following compounds were prepared according to the general procedure above (Intermediate 2.5). [ka]

[0098] Intermediate 2.6.I 8-(5-Bromo-2-nitropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane [ka]

[0099] To a mixture of 5-bromo-3-fluoro-2-nitropyridine (1.00 g, 4.53 mmol) in 20.0 mL of ACN was added K2CO3 (1.88 g, 13.58 mmol) and 9-methyl-2,5-dioxa-8-azaspiro[3.5]-nonane (Intermediate 2.5, 777 mg, 5.43 mmol). The mixture was heated to 60 °C and stirred for 16.5 h. The reaction was diluted with EtOAc and water was added. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated. ESI-MS: 344 / 346 [M+H] + R t (HPLC): 0.85 min (Method B)

[0100] The following compounds were prepared according to the general procedure above (Intermediate 2.6.I): [ka] [ka] [ka]

[0101] Intermediate 2.7.I 9-Methyl-8-(2-nitro-5-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-3-yl)-2,5-dioxa-8-azaspiro[3.5]nonane [ka]

[0102] To a degassed solution of 8-(5-bromo-2-nitropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane (Intermediate 2.6.I, 584 mg, 1.70 mmol) in 6.80 mL of THF under argon, DIPEA (2.31 mL, 12.8 mmol) was added, followed by (triisopropylsilyl)-acetylene (0.780 mL, 3.40 mmol), PdCl(PPh) (60 mg, 0.085 mmol), and copper(I) iodide (49 mg, 0.25 mmol). The mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with ACN, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; CH / Et0Ac = 50 / 50 → 60 / 40). ESI-MS: 446 [M+H] + R t (HPLC): 0.66 min (Method G)

[0103] The following compounds were prepared according to the general procedure above (Intermediate 2.7.I): [ka]

[0104] Intermediate 3.1.I(a) (a): (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]-trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0105] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] in 20 mL of DMA at RT 2,7 To a mixture of ]-trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylic acid (Intermediate 1.3.II, 1.00 g, 2.72 mmol) and 8-(5-bromo-2-nitropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane (Intermediate 2.6.I, 2.00 g, 5.44 mmol) was added NaH (326 mg, 8.16 mmol). The mixture was stirred at RT overnight. Water was added and the mixture was acidified with TFA. The precipitate was collected by filtration and dried in vacuo. The crude product was purified by RP-HPLC (Sunfire C18, ACN / HO / TFA) to give two diastereomers (a) and (b). Diastereomer (a) was carried on to the next step. ESI-MS: 646 / 648 [M+H] + R t (HPLC): 1.03 min (Method C) - Diastereomer (a) 1.08 min (Method C) - Diastereomer (b)

[0106] The following compounds were prepared according to the general procedure above (Intermediate 3.1.I). [ka]

[0107] Intermediate 3.2 (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]-trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylate tert-butyl ester [ka]

[0108] (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] 2,7 To ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid (Intermediate 3.1.I(a), 110 mg, 0.170 mmol) was added 2-tert-butyl-1,3-disopropylisourea (162 μL, 0.68 mmol). The reaction mixture was stirred at 70 °C for 1 h in a microwave oven. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; CH / Et0Ac = 93 / 7 to 60 / 40). ESI-MS:702 / 704 [M+H] + R t (HPLC): 0.87 min (Method A)

[0109] Intermediate 3.3 (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]-trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl}oxy)pyrrolidine-2-carboxylate tert-butyl ester [ka]

[0110] (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] in 2.00 mL of dioxane under argon. 2,7 To tert-butyl 2-[(2-hydroxy-1,2-diyl)-2-pyrrolidine-2-carboxylate (Intermediate 3.2, 132 mg, 0.150 mmol) was added bis(pinacolato)-diboron (113 mg, 0.445 mmol), Pd(dppf)Cl (12.0 mg, 0.0160 mmol), and potassium acetate (58.0 mg, 0.591 mmol). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with DCM / methanol. The organic phase was run through an ISOLUTE® Phase Separator and concentrated under reduced pressure. ESI-MS: 750 [M+H] + R t (HPLC): 0.90 min (Method A)

[0111] Intermediate 3.4.I (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-({N,N-dimethyl-5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-[3,4'-bipyridin]-2'-yl}oxy)pyrrolidine-2-carboxylate tert-butyl ester [ka]

[0112] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] in 2.00 mL of dioxane under argon 2,7 tert-Butyl]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl}oxy)pyrrolidine-2-carboxylate (Intermediate 3.3, 105 mg, 0.0700 mmol), 4-bromo-N,N-dimethylpyridin-2-amine (22.0 mg, 0.109 mmol), Pd(PPh3)4 (9.7 mg, 0.0080 mmol), and Xphos 3 rd Gen (6.0 mg, 0.0070 mmol) and 2 mol / L sodium carbonate solution (105 μL, 0.210 mmol) were added. The reaction mixture was stirred at 100 °C for 1.5 h. The reaction mixture was diluted with ACN / water, filtered, and purified by RP-HPLC (Xbridge-C18, ACN / H2O / 0.1% NH4OH). ESI-MS: 744 [M+H] + R t (HPLC): 0.64 min (Method A)

[0113] The following compounds were prepared according to the general procedure above (Intermediate 3.4.I). [ka]

[0114] Intermediate 4.1 4-Bromo-3-methoxy-N,N-dimethylpyridin-2-amine [ka]

[0115] To 4-bromo-2-fluoro-3-methoxypyridine (200 mg, 0.97 mmol) in 3.00 mL of THF was added dimethylamine (3.64 mL, 7.28 mmol). The reaction mixture was stirred at 50° C. overnight and then concentrated under reduced pressure to give the title compound. ESI-MS: 231 / 233 [M+H] + R t (HPLC): 0.30 min (Method A)

[0116] Intermediate 5.1 4-Iodo-3-methoxy-N-methylpyridin-2-amine [ka]

[0117] To 2-fluoro-4-iodo-3-methoxypyridine (500 mg, 1.98 mmol) in 8.00 mL of THF was added a 2.0 M solution of methylamine in THF (7.90 mL, 15.8 mmol). The reaction mixture was stirred at 55° C. for 48 hours and then concentrated under reduced pressure. ESI-MS: 265 [M+H] + R t (HPLC): 0.26 min (Method A)

[0118] Intermediate 6.1 8-(2,5-Difluoropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane [ka]

[0119] Under an argon atmosphere, a degassed solution of 8-(5-bromo-2-fluoropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane (Intermediate 7.1.III, 668 mg; 2.00 mmol) in THF (13.4 mL) was cooled to 0 °C. A solution of isopropylmagnesium chloride·lithium chloride complex in THF (1.92 mL; 2.5 mmol) was then added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 h. Additional isopropylmagnesium chloride·lithium chloride complex in THF (0.45 mL; 0.59 mmol) was added and stirring was continued for an additional 1.5 h. The mixture was concentrated in vacuo, then taken up in DCM (5.00 mL) and cooled to −78 °C. A solution of N-fluorobenzenesulfonamide (863 mg, 2.60 mmol) in a mixture of DCM (7.50 mL) and perfluorodecalin (2.50 mL) was added dropwise with stirring at −78 °C. After the addition was complete, the reaction mixture was warmed to 0 °C and stirred for 30 min, then warmed to RT and stirred for an additional 1 h. The reaction mixture was poured into a saturated solution of NH4Cl and stirred for 5 min. The mixture was filtered through Celite, and after phase separation, the aqueous phase was extracted with DCM, and the combined organic phases were dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in ACN / HO, filtered, and purified by RP-HPLC. ESI-MS: 257 [M+H] + R t (HPLC): 0.45 min (Method A)

[0120] Intermediate 7.1.I 5-chloro-2-fluoro-3-{4H,5H,6H,7H-[1,2]oxazolo[4,3-c]pyridin-5-yl}pyridine [ka]

[0121] To 5-chloro-2-nitro-3-{4H,5H,6H,7H-[1,2]oxazolo[4,3-c]pyridin-5-yl}pyridine (Intermediate 2.6.VII, 210 mg, 0.750 mmol) in 2.00 mL of DMF was added a 1.0 M solution of TBAF in THF (1.50 mL, 1.50 mmol). The reaction mixture was stirred for 30 min at RT and then for 3 h at 50 °C. Again, TBAF was added (1.50 mL, 1.50 mmol), and the reaction mixture was stirred at 50 °C for 5 h. ACN / water was added to the reaction mixture, and the precipitate was collected by filtration and purified by RP-HPLC (Xbridge C18, ACN / HO / TFA). ESI-MS: 254 / 256 [M+H] + R t (HPLC): 0.77 min (Method E)

[0122] The following compounds were prepared according to the general procedure above (Intermediate 7.1.I). [ka]

[0123] Intermediate 8.1 (2S,4S)-4-{[5-ethynyl-3-(morpholin-4-yl)pyridin-2-yl]oxy}pyrrolidine-2-carboxylic acid [ka]

[0124] To (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (202 mg, 0.83 mmol) in 3.00 mL of DMA was added NaH (99.8 mg, 2.50 mmol). After stirring this mixture at RT for 30 minutes, a solution of 4-{2-nitro-5-[2-(trimethylsilyl)ethynyl]-pyridin-3-yl}morpholine (Intermediate 2.7.II, 127 mg, 0.42 mmol) in 2.00 mL of DMA was added. After stirring the reaction mixture at RT for 2 hours, it was diluted with ACN and acidified with TFA. The precipitate was collected by filtration and purified by RP-HPLC (Sunfire, ACN / HO / TFA). The residue was diluted with 10.0 mL of DCM, and 1.00 mL of TFA was added. The reaction mixture was stirred at RT overnight and concentrated to give the title compound. ESI-MS: 318 [M+H] + R t (HPLC): 0.67 min (Method C)

[0125] Intermediate 9.1(a) (2S,4S)-1-[(tert-butoxy)carbonyl]-4-({5-ethynyl-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid [ka]

[0126] To a mixture of (2S,4S)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (800 mg, 3.30 mmol) and 9-methyl-8-(2-nitro-5-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-3-yl)-2,5-dioxa-8-azaspiro[3.5]nonane (Intermediate 2.7.I, 1.55 g, 3.30 mmol) in 31.0 mL of NMP was added NaH (660 mg, 16.5 mmol). The reaction mixture was stirred at RT for 1 hour and 20 minutes. The reaction mixture was quenched with water, acidified with 1N HCl, filtered, and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and evaporated. The crude product was dissolved in 10 mL of THF, 2 mL of TBAF solution (1.0 M in THF) was added, and the reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was diluted with EtOAc and extracted twice with saturated NH Cl solution. The combined organic phases were dried over sodium sulfate, filtered, and evaporated. The residue was purified by HPLC (Xbridge, ACN / H O / TFA). ESI-MS: 474 [M+H] + R t (HPLC): 0.63 min (Method A) - Diastereomer (a) 0.66 min (Method A) - Diastereomer (b)

[0127] Intermediate 9.2 (2S,4S)-4-({5-ethynyl-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid [ka]

[0128] To (2S,4S)-1-[(tert-butoxy)carbonyl]-4-({5-ethynyl-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid (Intermediate 9.1(a), 40 mg, 0.080 mmol) in 3.00 mL of ACN was added TosOH (35 mg, 0.18 mmol). The reaction mixture was stirred at RT for 48 h. The reaction mixture was evaporated and used in the next step without further purification. ESI-MS: 374 [M+H] + R t (HPLC): 0.36 min (Method A)

[0129] Intermediate 10.1 4-(Difluoromethyl)-2-methoxybenzonitrile [ka]

[0130] To 4-formyl-2-methoxybenzonitrile (806 mg, 5.00 mmol) in 3.00 mL of DCM, bis(2-methoxyethyl)aminosulfur trifluoride (50% solution in toluene, 3.13 mL, 8.50 mmol) and ethanol (1.00 mmol, 57.6 μL) were slowly added. The reaction mixture was stirred overnight at RT. Again, bis(2-methoxyethyl)aminosulfur trifluoride (920 μL, 2.5 mmol) was added, followed by ethanol (20.0 μL, 0.5 mmol). After stirring the mixture for 1 h at RT, it was poured onto saturated aqueous NaHCO3 and stirred for 5 min. The phases were separated, and the aqueous phase was extracted with DCM. The organic phases were combined, washed with water, dried, and evaporated. The crude product was used directly in the next step. R t (HPLC): 0.49 min (Method A)

[0131] Intermediate 10.2 4-(Difluoromethyl)-2-hydroxybenzonitrile [ka]

[0132] A mixture of 2-(diethylamino)ethanethiol (300 mg, 1.77 mmol) in 3.00 mL of DMF was cooled to 0 °C, and sodium tert-butoxide (340 mg, 3.54 mmol) was added. The reaction mixture was stirred at 0 °C for 5 min. The cooling bath was then removed, and the mixture was allowed to warm to RT. A solution of 4-(difluoromethyl)-2-methoxybenzonitrile (Intermediate 10.1, 50.0 mg, 0.270 mmol) in 2.00 mL of DMF was added at RT, and the resulting mixture was heated to 160 °C with stirring for 1.5 h. The reaction mixture was then cooled to 0 °C and acidified with 1 N aqueous HCl. The reaction mixture was extracted with EtOAc, and the combined organic layers were dried and evaporated. The crude product was purified by RP-HPLC (Xbridge, ACN / H2O / TFA). ESI-MS: 170 [M+H] + R t (HPLC): 0.41 min (Method A)

[0133] Intermediate 10.3.I 3-Amino-6-(difluoromethyl)-1-benzofuran-2-carboxamide [ka]

[0134] To 4-(difluoromethyl)-2-hydroxybenzonitrile (Intermediate 10.2, 120 mg, 0.71 mmol) in 5.00 mL of ethanol was added K2CO3 (150 mg, 1.09 mmol) and 2-bromoacetamide (119 mg, 0.87 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was allowed to return to RT, and KOH (95.1 mg, 1.44 mmol) was added. The mixture was then heated to reflux for 2 h. After cooling to RT, the reaction mixture was diluted with water. The ethanol was evaporated in vacuo, and the precipitate was collected by filtration, washed with water, and dried. ESI-MS: 227 [M+H] + R t (HPLC): 0.39 min (Method A)

[0135] The following compounds were prepared according to the general procedure above (Intermediate 10.3.I). [ka]

[0136] Intermediate 10.4.I 6-chloro-11-(difluoromethyl)-4-methyl-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaene [ka]

[0137] A mixture of phosphorus oxychloride (92.0 μL, 1.01 mmol) and DMA (39.0 μL, 0.40 mmol) was stirred for 30 min at 0 °C under an argon atmosphere. This mixture was diluted with 0.5 mL of phosphorus oxychloride and then added dropwise to 3-amino-6-(difluoromethyl)-1-benzofuran-2-carboxamide (Intermediate 10.3.I, 76.0 mg, 0.34 mmol). After the addition was complete, the mixture was heated to 50 °C and stirred for 3 h. Phosphorus oxychloride (184 μL, 2.02 mmol) was added again, and the reaction mixture was stirred at 50 °C overnight. The reaction mixture was cooled to RT, diluted with ice water, and neutralized with aqueous NaHCO3. The mixture was extracted with DCM, and the organic phase was dried, filtered, and evaporated. ESI-MS: 269 [M+H] + R t (HPLC): 0.62 min (Method A)

[0138] The following compounds were prepared according to the general procedure above (Intermediate 10.4.I): [ka]

[0139] Intermediate 11.1 (2S)-1-(5-bromo-2-nitropyridin-3-yl)-2-methylpiperazine [ka]

[0140] To 5-bromo-3-fluoro-2-nitropyridine (200 mg, 0.91 mmol) in 4.00 mL of ACN was added tert-butyl (3S)-3-methylpiperazine-1-carboxylate (272 mg, 1.36 mmol) and TEA (635 μL, 4.53 mmol). The reaction mixture was stirred at 80° C. for 2.75 h. The reaction mixture was quenched with EtOAc and extracted with half-saturated NH4Cl solution, half-saturated NaHCO3 solution, and saturated NaCl solution. The organic phase was dried, filtered, and concentrated. The residue was diluted with 4 N HCl in dioxane, stirred at RT for 45 min, and concentrated to give the title compound as a salt. ESI-MS:301 / 303 [M+H] + R t (HPLC): 0.70 min (Method C)

[0141] Intermediate 11.2 (3S)-4-(5-Bromo-2-nitropyridin-3-yl)-3-methylpiperazine-1-carbonitrile [ka]

[0142] To (2S)-1-(5-bromo-2-nitropyridin-3-yl)-2-methylpiperazine hydrochloride (Intermediate 11.1, 80.0 mg, 0.24 mmol) in 2.00 mL of DCM were added DIPEA (103 μL, 0.592 mmol) and cyanogen bromide (3 mol / L in DCM, 86.9 μL, 0.261 mmol). The reaction mixture was stirred overnight at RT. Cyanogen bromide (3 mol / L in DCM, 86.9 μL, 0.261 mmol) was again added to the reaction mixture, and stirring was continued at RT for 1 h. The reaction mixture was quenched with half-saturated aqueous NaHCO3 solution. The phases were separated and extracted with DCM. The combined organic phase was dried through an ISOLUTE® Phase Separator and evaporated. ESI-MS: 326 / 328 [M+H] + R t (HPLC): 0.83 min (Method C)

[0143] Intermediate 12.1 tert-Butyl (5S)-5-methyl-1,2,6-triazaspiro[2.5]oct-1-ene-6-carboxylate [ka]

[0144] At 0°C, 6.70 mL of ammonia (7N in methanol) was added to tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (1.00 g, 4.69 mmol). The reaction mixture was stirred and allowed to warm to RT overnight. The mixture was then cooled to -20°C, and hydroxylamine-O-sulfonic acid (1.33 g, 11.7 mmol) was added portionwise. The reaction mixture was allowed to warm to RT and stirred for 1 h. The precipitate was filtered off, washed with methanol, and the filtrate was concentrated in vacuo. The concentrate was taken up in EtOAc / TEA (20 mL / 72 mL) and extracted with 10% aqueous Na2CO3 (15 mL). The organic phase was extracted with water and dried by passing through an ISOLUTE® phase separator. The organic layer was diluted with 10 mL of methanol and then cooled to -10 °C. Iodine (1.31 g, 5.16 mmol) was added and the reaction mixture was allowed to warm to RT. The reaction mixture was quenched with 5% sodium sulfite solution and extracted with 10% aqueous NaCl solution. The organic phase was dried over Na2SO4, filtered and evaporated. The product was purified by HPLC (Sunfire, ACN / H2O / TFA). ESI-MS: 248 [M+Na] + R t (HPLC): 1.09 min (Method C)

[0145] Intermediate 12.2 (5S)-5-Methyl-1,2,6-triazaspiro[2.5]oct-1-ene [ka]

[0146] To tert-butyl (5S)-5-methyl-1,2,6-triazaspiro[2.5]oct-1-ene-6-carboxylate (Intermediate 12.1, 440 mg, 1.95 mmol) in 5.00 mL of DCM was added TFA (0.50 mL, 3.00 mmol). The reaction mixture was stirred at RT for 6 h, then concentrated and used in the next step without further purification. ESI-MS: 126 [M+H] + R t (HPLC): 0.11 min (Method C)

[0147] Intermediate 13.1 2-Methylpiperidine-3-carboxylic acid methyl acetate [ka]

[0148] To methyl 2-methylpyridine-3-carboxylate (10.0 g, 66.2 mmol) in 80.0 mL of acetic acid was added Pd(OH)2 / C (1.00 g), and the mixture was hydrogenated at 3 bar and 80° C. for 12 h. The reaction mixture was filtered, concentrated under reduced pressure, and used in the next step without further purification. ESI-MS: 158 [M+H] + R t (HPLC): 0.27 min (Method N)

[0149] Intermediate 13.2 2-Methylpiperidine-1,3-dicarboxylate 1-tert-butyl 3-methyl [ka]

[0150] To methyl 2-methylpiperidine-3-carboxylate (Intermediate 13.1, 15.0 g, 60.4 mmol) in 90.0 mL of THF was added TEA (8.49 mL, 60.4 mmol) and di-tert-butyl dicarbonate (13.2 g, 60.4 mmol), and the reaction mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with EtOAc and extracted with a semi-saturated NaHCO solution. The organic phase was dried over NaSO, filtered, and evaporated. The crude product was purified by column chromatography (silica gel; CH / EtOAc = 99 / 1 → 1 / 99). ESI-MS: 258 [M+H] + R t (HPLC): 0.65 min (Method F)

[0151] Intermediate 13.3 2-Methylpiperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3,3-dimethyl [ka]

[0152] A solution of 1-tert-butyl 3-methyl 2-methylpiperidine-1,3-dicarboxylate (Intermediate 13.2, 5.00 g, 18.5 mmol) in 20.0 mL of THF was added to a solution of lithium diisopropylamide (2 mol / L, 11.1 mL, 22.2 mmol) in 32.5 mL of THF at −78° C. under argon. The reaction mixture was brought to −20° C. and stirred for 30 minutes. The reaction mixture was then cooled to −78° C., and a solution of methyl chloroformate (2.25 mL, 27.7 mmol) in 10.0 mL of THF was added dropwise to the reaction mixture. The temperature was maintained below −65° C. during the addition. After the addition was complete, the reaction mixture was allowed to warm to RT and stirred at RT for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and stirred at RT for 10 minutes. The mixture was diluted with water and extracted with DCM. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; CH / Et0Ac=95 / 5→60 / 40). ESI-MS: 316 [M+H] + R f (TLC): 0.29 (CH / EtOAc=20 / 80)

[0153] Intermediate 13.4 tert-Butyl 3,3-bis(hydroxymethyl)-2-methylpiperidine-1-carboxylate [ka]

[0154] To a degassed solution of 1-tert-butyl 3,3-dimethyl 2-methylpiperidine-1,3,3-tricarboxylate (Intermediate 13.3, 5.60 g, 16.9 mmol) in 44.8 mL of THF at RT under argon, LiAlH4 (2.3 mol / L in 2-methyltetrahydrofuran, 14.6 mL, 33.7 mmol) was added dropwise, and the mixture was stirred at RT for 1.5 h. The reaction mixture was cooled to 0 °C, diluted with 80.0 mL of diethyl ether, and carefully treated with 1.25 mL of water, then 1.25 mL of 4 N NaOH, and finally 3.75 mL of water. The reaction mixture was allowed to warm to RT and stirred for 15 min. The mixture was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (silica gel; CH4 / Et0Ac = 75 / 25 → 0 / 100). ESI-MS: 260 [M+H] + R f (TLC): 0.14 (CH / EtOAc=50 / 50)

[0155] Intermediate 13.5 tert-Butyl 5-methyl-2-oxa-6-azaspiro[3.5]nonane-6-carboxylate [ka]

[0156] To tert-butyl 3,3-bis(hydroxymethyl)-2-methylpiperidine-1-carboxylate (Intermediate 13.4, 259 mg, 1.00 mmol) in 6.00 mL of THF was added triphenylphosphine (525 mg, 2.00 mmol). The reaction mixture was stirred at RT for 5 min. Then, ziram (483 mg, 1.50 mmol) and diisopropyl azodicarboxylate (413 μL, 2.00 mmol) were added and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with EtOAc, filtered through a Celite pad, and washed with EtOAc. The filtrate was washed with 5% aqueous NH3 solution. The organic phase was dried, filtered, and evaporated. The residue was purified by column chromatography (silica gel; DCM / EtOAc = 95 / 5 → 70 / 30). The residue was purified by HPLC (Sunfire, ACN / H2O / TFA). ESI-MS: 242 [M+H] + R t (HPLC): 0.80 min (Method E)

[0157] Intermediate 13.6 5-methyl-2-oxa-6-azaspiro[3.5]nonane [ka]

[0158] To tert-butyl 5-methyl-2-oxa-6-azaspiro[3.5]nonane-6-carboxylate (Intermediate 13.5, 134 mg, 0.56 mmol) in 2.00 mL of DCM was added TFA (500 mL, 6.48 mmol). The reaction mixture was stirred at RT for 30 min, then concentrated under reduced pressure and used in the next step without further purification. ESI-MS: 142 [M+H] + R t (HPLC): 0.17 min (Method E)

[0159] Intermediate 14.1 2-(cyanomethoxy)-4-ethylbenzonitrile [ka]

[0160] Bromoacetonitrile (1.22 mL, 17.5 mmol) was added to a mixture of 4-ethyl-2-hydroxybenzonitrile (2.34 g, 16.2 mmol) and potassium carbonate (4.83 g, 35.0 mmol) in 40.0 mL of DMF, and the reaction mixture was stirred at 50 °C overnight. The reaction mixture was poured into water and extracted with DCM. The organic phase was concentrated in vacuo, and the crude product was used in the next step without further purification.

[0161] Intermediate 14.2 3-Amino-6-ethyl-1-benzofuran-2-carbonitrile [ka]

[0162] To a mixture of 2-(cyanomethoxy)-4-ethylbenzonitrile (Intermediate 14.1, 1.79 g, 10.0 mmol) in 40.0 mL of THF was added potassium tert-butoxide (108 mg, 0.964 mmol), and the mixture was stirred at RT overnight. The solvent was evaporated in vacuo, and the product was purified by column chromatography and used directly in the next step.

[0163] Intermediate 14.3 N-(2-cyano-6-ethyl-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide [ka]

[0164] A mixture of 3-amino-6-ethyl-1-benzofuran-2-carbonitrile (Intermediate 14.2, 1.40 g, 7.51 mmol) in 20 mL of TFAA was stirred at 50 °C for 3 h. The solvent was evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate, and the organic phase was washed with water and concentrated in vacuo. The crude product was used in the next step without further purification.

[0165] Intermediate 14.4 6-chloro-11-ethyl-4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(13),2,4,6,9,11-hexaene [ka]

[0166] To a mixture of N-(2-cyano-6-ethyl-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide (Intermediate 14.3, 2.00 g, 7.09 mmol) in 5.0 mL of sulfolane was added phosphorus pentachloride (5.90 g, 28.3 mmol) at 45 °C. The mixture was stirred at 110 °C for 16 h, then poured onto ice water and extracted with EtOAc. The combined organic layer was washed with brine and evaporated. The residue was purified by column chromatography (silica gel; CH / EtOAc = 100 / 0 to 95 / 5). ESI-MS:301 / 303 [M+H] + R t (HPLC): 0.79 min (Method A)

[0167] Intermediate 15.1 3-(2-chloroacetamido)-1-benzofuran-2-carboxamide [ka]

[0168] A mixture of 3-aminobenzofuran-2-carboxamide (3.52 g, 176 mmol) in chloroacetyl chloride (6.00 mL, 75 mmol) was stirred at 60° C. for 10 minutes. Chloroacetyl chloride (4.00 mL, 50 mmol) was added and stirring was continued at 60° C. for 20 minutes. The reaction mixture was poured onto ice water, and the precipitate was collected by filtration, resuspended in water, filtered, and washed with water. The crude product was used directly in the next step without further purification. ESI-MS: 253 [M+H]+ R t (HPLC): 0.41 min (Method A)

[0169] Intermediate 15.2 4-(Hydroxymethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,10,12-pentaen-6-one [ka]

[0170] A mixture of 3-(2-chloroacetamido)-1-benzofuran-2-carboxamide (Intermediate 15.1, 5.80 g, 23.0 mmol) in 2 M aqueous NaOH was stirred at 60° C. for 10 min. After cooling to RT, stirring was continued for 10 h before the pH was adjusted to 1 by the addition of concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried. ESI-MS: 217 [M+H] + R t (HPLC): 0.59 min (Method C)

[0171] Intermediate 15.3 6-chloro-4-(chloromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaene [ka]

[0172] Phosphorus oxychloride (30 mL, 328 mmol) was added to 4-(hydroxymethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,10,12-pentaen-6-one (Intermediate 15.2, 5.00 g, 17.3 mmol) under stirring, and the resulting mixture was heated to reflux for 1.5 h. The reaction mixture was cooled to RT and concentrated in vacuo. Ethyl acetate was added to the residue, and the mixture was neutralized by adding saturated aqueous sodium bicarbonate. The mixture was filtered over Celite, the phases were separated, and the organic phase was dried over magnesium sulfate and evaporated. The crude product was purified by flash column chromatography (cyclohexane / EtOAc = 88 / 12 → 0 / 100). ESI-MS: 253 [M+H] + R t (HPLC): 1.07 min (Method C)

[0173] Intermediate 16.1 (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]-Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0174] To a degassed mixture of Ex.1.10 (1.50 g, 2.26 mmol), bis-(pinacolato)-diboron (630 mg, 2.48 mmol), and potassium acetate (670 mg, 6.93 mmol) in 30 mL of dioxane under an argon atmosphere was added Pd(dppf)Cl2 (165 mg, 0.226 mmol). The reaction mixture was heated to 90 °C for 3 h, then cooled to RT, poured onto ice water, and extracted with diethyl ether / THF. The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc / MeOH = 10:1). ESI-MS: 712 [M+H] + R t (HPLC): 1.05 min (Method A)

[0175] Preparation of final compounds Example 1.01 (general route) (2S,4S)-4-{[5-chloro-3-(2-cyanomorpholin-4-yl)pyridin-2-yl]oxy}-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0176] (2S,4S)-4-hydroxy-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] in 2.00 mL of DMA 2,7To 4-(5-chloro-2-nitropyridin-3-yl)morpholine-2-carbonitrile (Intermediate 2.6.III, 80.6 mg, 0.30 mmol, 2.0 equiv.) and NaH (18.0 mg, 0.45 mmol, 3.0 equiv.) were added 4-(5-chloro-2-nitropyridin-3-yl)morpholine-2-carbonitrile (Intermediate 2.6.III, 80.6 mg, 0.30 mmol, 2.0 equiv.). The reaction mixture was stirred at 80° C. for 20 min. The reaction mixture was diluted with ACN / water, acidified with TFA, filtered, and purified by HPLC (ACN / HO / TFA). The product was obtained as a mixture of two diastereomers. ESI-MS: 589 [M+H] + R t (HPLC): 1.05 min (Method H)

[0177] Following the general procedure above (Example 1.01), the compounds listed in the table below were prepared. Where indicated in the table, the example compound was isolated as a diastereomeric mixture (ds-mix) or as a pure diastereomer (both isolated diastereomers (example 1.01) and the second diastereomer (2 nd ds) gives Rt). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0178] The absolute stereochemistry of Example 1.10 was confirmed by small molecule X-rays shown below. [ka]

[0179] The absolute stereochemistry of Example 1.28 was confirmed by small molecule X-rays shown below. [ka]

[0180] Example 2.01 (general route) (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]-4-{[5-ethynyl-3-(morpholin-4-yl)pyridin-2-yl]oxy}-pyrrolidine-2-carboxylic acid [ka]

[0181] 6-chloro-4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] in 1.50 mL of DMSO 2,7To ]trideca-1(9),2(7),3,5,10,12-hexaene (Intermediate 1.2.II, 30.0 mg, 0.12 mmol) was added (2S,4S)-4-{[5-ethynyl-3-(morpholin-4-yl)pyridin-2-yl]oxy}pyrrolidine-2-carboxylic acid (Intermediate 8.1, 55.9 mg, 0.13 mmol) and DIPEA (60.8 μL, 0.35 mmol). The reaction mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with ACN, acidified with TFA, filtered, and purified by HPLC (ACN / HO / TFA). ESI-MS: 536 [M+H] + R t (HPLC): 1.08 min (Method C)

[0182] The following examples were prepared according to the general procedure above (Example 2.1). [ka] [ka] [ka]

[0183] Example 3.01 (general route) (2S,4S)-4-({5-[(3S)-3-methylmorpholin-4-yl]-[3,4'-bipyridin]-6-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0184] (2S,4S)-4-({5-bromo-3-[(3S)-3-methylmorpholin-4-yl]pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid (Intermediate 3.1.II, 50.0 mg, 0.08 mmol), (pyridin-4-yl)boronic acid (24.7 mg, 0.20 mmol), Na2CO3 solution (2.0 M, 100 μL, 0.20 mmol), Xphos 3 rd To a mixture of gen (3.40 mg) and Pd(PPh3)4 (4.64 mg) under argon was added 2.00 mL of dioxane. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was filtered, diluted with ACN / methanol, and purified by HPLC (Xbridge, ACN / H2O / TFA). ESI-MS: 621 [M+H] + R t (HPLC): 0.818 min (Method B)

[0185] The following examples were prepared according to the general procedure described above (Example 3.01). The boronates or boronic acids used were either commercially available or easily prepared as described in the literature (Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 1&2, 2 nd Edition, ISBN 9783527325986). [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0186] Example 4.01 (general route) (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-({N,N-dimethyl-5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-[3,4'-bipyridin]-2'-yl}oxy)pyrrolidine-2-carboxylic acid [ka]

[0187] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] in 2.00 mL of DCM 2,7To tert-butyl 4-({N,N-dimethyl-5-[(9S)-9-methyl-2,5-dioxaspiro[3.5]nonan-8-yl]-[3,4'-bipyridin]-2'-yl}oxy)pyrrolidine-2-carboxylate (Intermediate 3.4.I, 13 mg, 0.020 mmol) was added trifluoroacetic acid (650 μL, 8.49 mmol) over one day. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The crude product was purified by HPLC (Xbridge, ACN / HO / TFA). ESI-MS: 688 [M+H] + R t (HPLC): 0.51 min (Method A)

[0188] The following examples were prepared according to the general procedure above (Example 4.1). [ka]

[0189] Example 5.01 (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-({2'-methanesulfinyl-5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-[3,4'-bipyridin]-6-yl}oxy)pyrrolidine-2-carboxylic acid [ka]

[0190] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7To a cooled solution of [(5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-2'-(methylsulfanyl)-[3,4'-bipyridin]-6-yl}oxy)-pyrrolidine-2-carboxylic acid (Example 3.16, 25.0 mg, 0.04 mmol) was added meta-chloroperoxybenzoic acid (7.30 mg, 0.03 mmol) at −15 °C. The reaction mixture was stirred at −15 °C for 10 min and then purified by HPLC (Xbridge, ACN / HO / TFA). ESI-MS: 707 [M+H] + R t (HPLC): 0.85 min (Method H)

[0191] Example 6.01 (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(prop-1-yn-1-yl)pyridin-2-yl}-oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0192] (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] 2,7To a degassed solution of [trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid (Example 1.10, 150 mg, 0.230 mmol) was added copper(I) iodide (4.3 mg, 0.023 mmol), followed by Pd(dppf)Cl (33 mg, 0.050 mmol). After stirring for several minutes, a 1 M solution of methylacetylene in THF (1.35 mL, 1.35 mmol) was added and the mixture was heated to 75 °C for 4 h. The reaction mixture was diluted with ACN, acidified with acetic acid, filtered, and purified by HPLC (Xbridge, ACN / HO / TFA). ESI-MS: 624 [M+H] + R t (HPLC): 1.08 min (Method E)

[0193] The following examples were prepared according to the general procedure above (Example 6.01). [ka]

[0194] Example 7.01 (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(pyrimidin-5-yl)pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0195] (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo-[7.4.0.0]pyridin-2-yl]oxy] ... To a degassed mixture of 2,7]-trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid (Intermediate 16.1, 220 mg, 0.309 mmol), potassium carbonate solution (2.0 mol / L, 0.463 mL, 0.928 mmol), and 4-bromo-1-cyclopropyl-1H-pyrazole (119 mg, 618 mmol) was added Xphos 3rd gen (15 mg, 0.018 mmol). The reaction mixture was heated to 80 °C for 2 h, cooled to RT, and diluted with ethyl acetate. Saturated aqueous ammonium chloride solution and water were added. The phases were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated ammonium chloride solution, dried over sodium sulfate, filtered, evaporated, and purified by HPLC (Sunfire, ACN / H2O / TFA). ESI-MS: 692 [M+H] + R t (HPLC): 1.01 min (E)

[0196] The following examples were prepared according to the general procedure above (Example 7.01). [ka] [ka]

[0197] Example 8.01 (2S,4S)-4-{[5-(1-methyl-1H-1,2,3-triazol-4-yl)-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl]oxy}-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7 ]Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0198] A mixture of Example 1.12 (75 mg, 0.12 mmol), trimethylsilylmethyl azide (16 mg, 0.012 mmol), copper(II) sulfate (20 mg, 0.12 mmol), and L-ascorbic acid sodium salt (49 mg, 0.24 mmol) in a mixture of 1.00 mL of DMSO and 0.10 mL of water was stirred at RT for 1 h. Next, 1 M TBAF solution (240 μL) was added, and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with ACN / HO, acidified with TFA, filtered, and purified by HPLC. ESI-MS: 667 [M+H] + R t (HPLC): 0.87 min (Method P)

[0199] Example 9.01 (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(methylsulfanyl)pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid [ka]

[0200] (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]-trideca-1(9),2(7),3,5,10,12-hexaene-6 in 8.00 mL of dioxane A degassed mixture of [-yl]pyrrolidine-2-carboxylic acid (Intermediate 3.1.I(a), 160 mg, 0.25 mmol), XANTPHOS (20 mg, 0.035 mmol), sodium methanethiolate (0.25 mL, 0.59 mmol), DIPEA (0.100 mL, 0.58 mmol), and Pd(dba) (16 mg, 0.017 mmol) was heated at 110 °C overnight. After cooling to RT, ethyl acetate and water were added to the reaction mixture. The organic layer was separated, dried, concentrated in vacuo, and purified by HPLC (Sunfire C-18, HO / ACN / TFA). ESI-MS: 614 [M+H] + Rt (HPLC): 1.01 min (Method C)

[0201] Example 10.01 (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-5-(1H-pyrazol-1-yl)pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]Trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid [ka]

[0202] (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] methyl]pyridin-2-yl}oxy] ... 2,7 To a degassed mixture of ]-trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid (Ex. 1.10, 30 mg, 0.045 mmol), LiHMDS (1 M in THF, 0.120 mL, 0.120 mmol), and pyrazole (5.00 mg, 0.073 mmol) was added tBuBrettPhos (5.00 mg, 0.006 mmol), and the mixture was heated at 80° C. for 5 h. After cooling to RT, the mixture was diluted with methanol, concentrated in vacuo, and purified by HPLC. ESI-MS: 652 [M+H] + Rt (HPLC): 1.01 min (Method P)

[0203] Preparation of prodrugs: Prodrug P01 (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylate methyl [ka]

[0204] (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-pyridin-2-yl}-oxy)1-[4-(difluoro-methyl)-8-oxa-3,5-diazatricyclo[7.4.0.0] in 1.0 mL of THF 2,7To ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-2-carboxylic acid (Example 4.04, 15 mg, 0.020 mmol) was added O-methyl-N,N'-diisopropylurea (41 μL, 0.25 mmol). The reaction mixture was stirred at RT for 60 h, then diluted with ACN / water and purified by HPLC (ACN / HO / TFA). ESI-MS: 582 [M+H] + R t (HPLC): 0.69 min (Method A)

[0205] The following compounds were prepared according to the general procedure above (prodrug P01). [ka]

[0206] List of abbreviations [Table 2-1] [Table 2-2]

[0207] Analytical HPLC method: [Table 3]

[0208] [Table 4]

[0209] [Table 5]

[0210] [Table 6]

[0211]

Table 7

[0212]

Table 8

[0213]

Table 9

[0214]

Table 10

[0215]

Table 11

[0216]

Table 12

[0217]

Table 13

[0218]

Table 14

[0219]

Table 15

[0220] [Table 16]

[0221] [Table 17]

[0222] [Table 18] [Example]

[0223] 5 Examples 5.1 Compound examples The following exemplary compounds of formula (I) or formula (I'), summarized in Table 1 below, were synthesized and tested for their pharmacological properties with respect to their potency in inhibiting cGAS activity. In particular, the "biochemical (in vitro) IC50 value" for cGAS inhibition (hcGAS IC50) and the "IC50 value for inhibition of IFN induction in virus-stimulated THP1 cells" (THP (vir) IC50), "IC50 value for inhibition of IFN induction in cGAMP-stimulated THP1 cells" (THP (cGAMP) The "IC50" and "IC50 values for inhibition of IFN induction in dsDNA-stimulated human whole blood" (hWB IC50) were experimentally determined according to the assay method described in Section 6 below. The results are summarized in Table 1 below.

[0224] The exemplary compounds of formula (I) or formula (I') summarized in Table 1 simultaneously exhibit the following properties: a satisfactory biochemical (in vitro) IC50 value for cGAS inhibition (hcGAS IC50 of ≦100 nM, preferably ≦50 nM, in particular ≦10 nM); a satisfactory "cellular IC50 value for cGAS inhibition" (≤ 1 μM, preferably ≤ 500 nM, more preferably ≤ 100 nM, especially ≤ 50 nM THP1 (vir) IC50) and Satisfactory selectivity for cGAS inhibition (Ratio THP1 of ≧10, more preferably ≧50, even more preferably ≧500, in particular ≧1000) (cGAMP) IC50 / THP1 (vir) IC50). Furthermore, exemplary compounds of Formula (I) or Formula (I') also exhibit acceptable IC50 values for inhibition of IFN induction in dsDNA-stimulated human whole blood (hWB IC50).

[0225] Table 1: Pharmacological properties of exemplary compounds of the present invention [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5] [Table 19-6] [Table 19-7] [Table 19-8] [Table 19-9] [Table 19-10] [Table 19-11] [Table 19-12] [Table 19-13] [Table 19-14] [Table 19-15] [Table 19-16] [Table 19-17] [Table 19-18] [Table 19-19]

[0226] 5.2 Comparison of Example Compounds with Prior Art Compounds 5.2.1 Compounds of WO 2020 / 142729 WO 2020 / 142729 discloses cGAS inhibitors with a partially similar structure. On pages 44 and 45 of WO 2020 / 142729, "biochemical (in vitro) IC50 values" (equivalent to "hcGAS IC50") for cGAS inhibition are disclosed. Compounds with a "biochemical (in vitro) IC50 value" of less than 100 nM were designated as "Group A," compounds with a "biochemical (in vitro) IC50 value" of greater than 100 nM and less than 500 nM were designated as "Group B," compounds with a "biochemical (in vitro) IC50 value" of greater than 500 nM and less than 1 μM were designated as "Group C," compounds with a "biochemical (in vitro) IC50 value" of greater than 1 μM and less than 10 μM were designated as "Group D," and compounds with a "biochemical (in vitro) IC50 value" of greater than 10 μM were designated as "Group E" (see page 44 of WO 2020 / 142729). Page 45 of WO 2020 / 142729 discloses that only compound number 25 could be assigned to "Group A" having a "biochemical (in vitro) IC50 value" of less than 100 nM. All other compound examples in WO 2020 / 142729 exhibit "biochemical (in vitro) IC50 values" greater than 100 nM.

[0227] 5.2.2 Comparison of the present example with the example in WO 2020 / 142729 Selected prior art compounds of WO 2020 / 142729 were synthesized and then tested for their pharmacological properties with respect to their potency in inhibiting the cGAS / STING pathway. In particular, for the structurally closest examples of WO 2020 / 142729, "biochemical (in vitro) IC50 values" for cGAS inhibition (hcGAS IC50) and "cellular IC50 values for inhibition of IFN induction in virus-stimulated THP1 cells" (THP1 IC50) were measured according to the assay methods described in Section 6 below. (vir) IC50), "Cellular IC50 value for inhibition of IFN induction in cGAMP-stimulated THP1 cells" (THP1 (cGAMP)The "IC50" and "IC50 values for inhibition of IFN induction in human whole blood" (hWB) were experimentally determined (see Table 2 below).

[0228] Table 2: Pharmacological properties of selected example compounds from WO 2020 / 142729 [Table 20]

[0229] The pharmacological properties for the exemplary compounds of the present invention summarized in Table 1 and the respective pharmacological properties for the compounds of WO 2020 / 142729 were experimentally determined according to the same assay procedures described in Section 6 below and can therefore be compared to each other. From the data shown in Table 2, it is clear that all of the compound examples in WO 2020 / 142729, with the sole exception of Example No. 25 of WO 2020 / 142729 (designated as "Group A" in WO 2020 / 142729, having a "biochemical (in vitro) IC50 value" (= hcGAS IC50) of less than 100 nM, exhibit "biochemical (in vitro) IC50 values" (= hcGAS IC50) significantly greater than 100 nM. This is in contrast to the compound examples of the present invention, all of which have "biochemical (in vitro) IC50 values" (= hcGAS IC50) of less than 100 nM. However, the compound of Example No. 25 of WO 2020 / 142729, which has a "biochemical (in vitro) IC50 value" (= hcGAS IC50) of 55 nM, exhibits a significant increase in the THP1 activity of Example No. 25 of WO 2020 / 142729. (vir) The IC50 is 17 μM, so less than 1 μM of THP1 (vir) It never meets the selection criterion of "satisfactory cell inhibitory potency" as indicated by IC50.

[0230] 5.3 Prodrugs It is known that esters of active drugs having a carboxylic acid group can be viable prodrugs, i.e., can exhibit improved oral absorption / bioavailability compared to the respective active drugs. Frequently used prodrugs of active drugs having a carboxylic acid group include, for example, methyl esters, ethyl esters, isopropyl esters, etc. (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, pp. 7720-7725 (2007) describe that N-acylsulfonamide and N-acylsulfonylurea derivatives of certain active drugs having a free carboxylic acid group may also be viable prodrugs.

[0231] Furthermore, experimental evidence indicates that methyl esters of exemplary compounds of Formula (I) or Formula (I') also represent viable prodrugs of cGAS inhibitors of Formula (I) or Formula (I'). Compounds P01, P02, P03 and P04 are the methyl esters of compound examples 4.04, 1.10, 1.12 and 3.14, respectively, and therefore may be viable prodrugs of each of the respective compound examples. P01, P02, P03, and P04 were synthesized and tested for their pharmacological properties with respect to their potency in inhibiting the cGAS / STING pathway. The experimentally determined pharmacological properties of prodrugs P01, P02, P03, and P04 were then compared to the corresponding pharmacological properties of the respective compound examples 4.04, 1.10, 1.12, and 3.14, as summarized in Table 3 below. This comparison between the example compounds and their corresponding prodrugs shows that the hcGAS IC50 values for the example compounds are always around 10 nM or even smaller, while the hcGAS IC50 values for the corresponding prodrugs are always extremely large, generally greater than 9000 nM. This large difference between the example compounds on the one hand and their corresponding prodrugs on the other hand means that the respective THP1 values always remain within the same range between the example compounds and their corresponding prodrugs. (vir) No IC50 values are observed (see Table 3 for example number 4.04 and its respective prodrug P01).

[0232] One possible explanation for this finding is that the example compounds (which would be the "drugs") all have a free carboxyl group, which appears to be crucial for inhibiting cGAS activity, whereas in all "prodrugs," the carboxyl group is masked by a carboxy-methyl ester group. As a result, the prodrugs lose their inhibitory potency in the "in vitro human cGAS enzyme assay" (see Section 6.1 below) because no intracellular enzyme is present to cleave the carboxy-methyl ester group. Thus, the prodrugs exhibit extremely large "biochemical (in vitro) IC50 values" (= hcGAS IC50) in this "in vitro human cGAS enzyme assay," whereas the corresponding example compounds (which would be the drugs or active agents) exhibit small "biochemical (in vitro) IC50 values" (= hcGAS IC50). In the "Human cGAS Cellular Assay and Competitive Cellular Assay" (see Section 6.2 below), there are endogenous cellular enzymes that cleave the carboxy-methyl ester group. As a result, the example compound itself (meaning the drug or active agent itself) is a small THP1 (vir) Not only does it show a relatively small IC50 value, but the corresponding prodrug also has a relatively small IC50 value. (vir) IC50 values are shown because in this Human cGAS Cell Assay the methyl ester of the prodrug is cleaved by endogenous intracellular enzymes to the corresponding drug / active agent, which again exhibits inhibitory potency. This explanation, along with the measurements shown in Table 3, means that methyl ester derivatives of compounds of Formula (I) or Formula (I') are indeed likely to be viable prodrugs of compounds of Formula (I) or Formula (I'), but by themselves lack inhibitory potency with respect to in vitro human biochemical cGAS inhibition. However, upon cleavage of the methyl ester by endogenous intracellular enzymes, compounds of Formula (I) or Formula (I') (active drugs) are formed, again demonstrating inhibitory potency with respect to the cGAS / STING pathway.

[0233] Table 3: Comparison of selected exemplary compounds of the present invention (=active drugs) with their respective methyl ester prodrugs: [Table 21-1] [Table 21-2]

[0234] 6. Biological Experiments The activity of the compounds of the invention can be demonstrated using the in vitro cGAS enzyme assay and cellular assay described below. 6.1 Method: Human cGAS Enzyme Assay (hcGAS IC50 (in vitro)) The human cGAS enzyme was activated in the presence of 45 base pair double-stranded DNA and GTP and ATP as substrates. Compound activity was determined by measuring the compound's effect on the formation of the enzymatic reaction product, cGAMP, by mass spectrometry. Enzyme preparation: Human cGAS (amino acids 1-522) with an N-terminal 6x-His tag and a SUMO tag was expressed in E. coli BL21(DE3)pLysS (Novagen) cells for 16 hours at 18°C. Cells were lysed 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). cGAS protein was isolated by affinity chromatography on Ni-NTA agarose resin and purified by size-exclusion chromatography using a Superdex 200 column (GE Healthcare) equilibrated with 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.

[0235] Assay Method Compounds were supplied in 10 mM DMSO solution, serially diluted, and transferred to a 384-well assay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, eight concentrations were used with approximately 1:5 dilution steps after a top concentration of 10 μM in the final assay volume. The DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 22 test compounds (columns 1-22), with columns 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, in assay buffer, 10 mM Tris pH 7.5 / 10 mM KCl / 5 mM MgCl2 / 1 mM DTT) was added via a MultiDrop Combi dispenser to each well in columns 1 through 23. To column 24, 15 μL of assay buffer without enzyme / DNA was added as a low control. The plates were then pre-incubated at room temperature for 60 minutes. Then, 10 μL of GTP (ThermoFisher #R0461)-ATP (Promega #V915B) mix in assay buffer was added to the assay plate using a Multidrop Combi (columns 1-24, final concentration of 30 μM each). The plates were again incubated 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), used as an internal standard for mass spectrometry. The total volume per well was 105 μL.

[0236] 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). The system was equipped with a 10 μL loop and a C18 [12 μL bed volume] cartridge (Agilent, part number G9210A) containing 10 mM NH4Ac(aq) aqueous solution (pH 7.4) as eluent A (pump 1, 1.5 mL / min; pump 2, 1.25 mL / min) and 10 mM NH4Ac in 47.5 / 47.5 / 5 v / v / v ACN / MeOH / HO (pH 7.4) as eluent B (pump 3, 1.25 mL / min). Aspiration time: 250 ms; load time: 3000 ms; elution time: 3000 ms; wash volume: 500 μL. The MS was operated in positive ion mode using a HESI ion source, a source temperature of 550 °C, curtain gas = 35, gas 1 = 65, and gas 2 = 80, and unit mass resolution in SRM mode. The following transition and MS parameters (DP: declustering potential and CE: collision energy) were determined for cGAMP and DicGMP: Analyte: cGAMP, 675.1 / 524, DP=130, CE=30 and Internal standard: cyclic di-GMP, 690.1 / 540, DP=130, CE=30. The formation of cGAMP was monitored and assessed as a ratio to cyclic di-GMP. Data evaluation and calculation: For data evaluation and calculation, the low control measurement was set as the 0% control and the high control measurement was set as the 100% control. IC50 values were calculated using a standard four-parameter logistic regression equation: [y = (ad) / (1 + (x / c)^b) + d], where a = low value, d = high value; x = conc M; c = IC50 M; b = slope

[0237] 6.2 Methods: Human cGAS Cellular Assay and cGAMP-Stimulated Counter Cellular Assay (THP1 (vir) IC50 and THP1 (cGAMP) IC50) Both assays used THP1-Dual™ cells (InvivoGen #thpd-nfis) expressing an IRF-dependent Lucia luciferase reporter. To detect cellular cGAS activity, cells were stimulated by infection with a baculovirus (pFastbac-1, Invitrogen, no coding insert) that delivers the cGAS enzyme, which primes double-stranded DNA (THP1 (vir) (measurement of IC50). For the counter assay, cells were stimulated with cGAMP (SigmaAldrich #SML1232) to activate the same pathway that is independent of and immediately downstream of cGAS (THP1 (cGAMP) (measurement of IC50). DNA-stimulated cGAS enzyme activity (THP1 (vir) IC50 measurement) or direct cGAMP (THP1 (cGAMP) Pathway activity was monitored by measuring induced Lucia luciferase activity (measurement of IC50, counter assay).

[0238] Assay Method Compounds were supplied in 10 mM DMSO solution, serially diluted, and transferred to a 384-well assay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, eight concentrations were used with approximately 1:5 dilution steps after a top concentration of 10 μM in the final assay volume. The DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 21 test compounds (columns 1-22), with columns 23 and 24 containing DMSO. Cells cultured according to the manufacturer's instructions were harvested by centrifugation at 300g / 10 min and resuspended in fresh cell culture medium (RPMI 1640 (Gibco #A10491-01), 10% FCS (Gibco #10500), 1x GlutaMax (Gibco #35050-061), 1x 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. Baculovirus solution was then added to the cells at a ratio of 1:200 (varied depending on the virus batch) (THP1). (vir) Alternatively, for counter assays, cGAMP was added to cells at a final concentration of 10 μM (THP1 (cGAMP) (measurement of IC50). 30 μL of the cell / virus mix was added with a MultiDrop Combi dispenser (5000 cells / well) to each well of the compound plate in columns 1 to 23. To column 24, 30 μl / 5000 cells / well (no virus) was added as a low control. The plates were then incubated for 18 hours at 37°C in a humidified incubator. Then, 15 μL of QuantiLuc detection reagent (InvivoGen #rep-qlcg5) was added to each well using a MultiDrop Combi, and measurements were taken immediately after addition using an EnVision reader (US luminescence reading mode). Data evaluation and calculation: For data evaluation and calculation, the low control measurement was set as the 0% control and the high control measurement was set as the 100% control. IC50 values were calculated using a standard four-parameter logistic regression equation: [y = (ad) / (1 + (x / c)^b) + d], where a = low value, d = high value; x = conc M; c = IC50 M; b = slope

[0239] 6.3 Method: Human Whole Blood Assay (Human WB IC50) To detect cellular cGAS activity, human whole blood was stimulated by transfection with double-stranded DNA, and pathway activity was monitored by measuring IFNα2α production. Assay Method Compounds were supplied in 10 mM DMSO solution, serially diluted, and transferred to a 96-well cell culture plate (Corning #3595) using an Echo acoustic dispenser, with 20 μl of OptiMEM (Gibco, #11058-021) pre-filled into each well. Typically, eight concentrations were used with approximately 1:5 dilution steps after a top concentration of 10 μM in the final assay volume. The DMSO concentration was set to 1% in the final assay volume. The 96-well assay plate contained 10 test compounds, with DMSO in control wells. Human whole blood was collected in parallel from three or more healthy donors (female or male, medication-free for 7 days except for contraceptives and thyroxine) as sodium citrated blood (e.g., 3.8% in Mononovettes from Sarstedt). After collection, the whole blood was stored at room temperature for a maximum of 3 hours before use in the assay. 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 in duplicate with blood from different donors. The blood plates were kept covered but unsealed at room temperature for 60 minutes with constant shaking at 450 rpm. A DNA-Fugene mix (Herring DNA, Sigma Aldrich #D6898-1G, Fugene (5x1mL), Promega #E2312) was prepared in OptiMEM and incubated for 10 minutes at RT (125ng DNA / 20µl to a 9.6:1 Fugene ratio). 20µl of DNA-Fugene mix was added to each well, resulting in 125ng DNA / well / 200µl to a 9.6:1 Fugene ratio. All low control wells received 20µl OptiMEM and 9.6:1 Fugene. After covering the assay plate with a vented seal and lid, the blood plate was kept at room temperature with constant shaking at 450 rpm for 30 minutes, followed by overnight incubation at 37°C in an incubator without shaking for 22 hours.

[0240] For detection of IFNα-2α in human plasma, biotinylated capture antibodies (antibody set IFNA2, Meso Scale Diagnostics #B21VH-3, including coating and capture antibodies) were diluted 1:17.5 in Diluent 100 (Meso Scale Diagnostics #R50AA-4) according to the manufacturer's instructions. U-Plex MSD GOLD 96-well Small Spot Strepavidin SECTOR plates (Meso Scale Diagnostics #L45SA-5) were coated with 25 μl of diluted capture antibody. The coated plates were incubated at room temperature for 60 minutes at 700 rpm with constant shaking. The MSD IFNα-2α plates were washed three times with 150 μl of wash buffer (1x HBSS, 0.05% Tween). Plates were blocked with 100 μl of blocking solution / well (1×HBSS with 0.2% Tween, 2% BSA) for 60 minutes at room temperature with constant shaking at 700 rpm, then emptied as dry as possible by removing the plates immediately before continuing with human plasma. The whole blood assay plates were centrifuged at 1600 rpm for 10 minutes. A pipetting robot was used to transfer 25 μl of supernatant from each whole blood plate to the corresponding IFNα-2α plate. The plates were sealed with a microplate seal and again maintained at room temperature with constant shaking at 700 rpm for 2 hours. The MSD IFNα-2α plate was then washed three times with 150 μl of wash buffer (1xHBSS, 0.05% Tween), after which 25 μL of MSD SULFO-TAG IFNα-2α antibody solution (diluted 1:100 in Diluent 3 (Meso Scale Diagnostics # R50AP-2)) was added to the wells of the plate. The plate was then sealed with a microplate seal and again maintained at room temperature for 2 hours with constant shaking at 700 rpm. Finally, the MSD IFNα-2α plate was washed three times with 150 μl of wash buffer (1x HBSS, 0.05% Tween). 150 μl of 2x Read buffer was added to each well, and the plate was immediately read using the vendor barcode on an MSD Sector S600 reader. Data evaluation and calculation: For data evaluation and calculation, the % control calculation for each well was 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 IC50 values were calculated using a standard four-parameter logistic regression equation. Calculation: [y=(ad) / (1+(x / c)^b)+d], where a=low value, d=high value; x=conc M; c=IC50 M; b=slope

[0241] 7. Indications As has become clear, the compounds of formula (I) or formula (I') are characterized by their wide range of applications in the therapeutic field. Particular mention should be made of the applications in which the compounds of formula (I) or formula (I') of the present invention are preferably used as cGAS inhibitors based on their pharmaceutical activity. The cGAS pathway is important for host defense against pathogen invasion, such as viral infection and invasion by some intracellular bacteria. However, cellular stress and genetic factors can also lead to the production of abnormal cellular dsDNA, e.g., due to nuclear or mitochondrial leakage, thereby triggering an autoinflammatory response. As a result, cGAS inhibitors have strong 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, reported that cGAS expression in peripheral blood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of SLE patients tested but not in normal or rheumatoid arthritis controls. SLE patients with cGAMP had higher disease activity than patients without cGAMP. While higher cGAS expression may be the result of exposure to type I interferon (IFN), the detection of cGAMP in SLE patients with high disease activity suggests the potential for modification of the cGAS pathway in disease development.

[0242] Park et al., Ann Rheum Dis. 2018 Oct;77(10):1507-1515 also discloses the improvement 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) discloses that the STING pathway mediates lupus by activating conventional dendritic cell maturation and plasmacytoid dendritic cell differentiation. Gao et al., Proc. Natl. Acad. Sci. USA. 2015 Oct 20;112(42):E5699-705, state that activation of cGAS by self-DNA causes certain autoimmune diseases, such as interferonopathies. Tonduti et al., Expert Rev. Clin. Immunol. 2020 Feb;16(2):189-198, discloses that cGAS inhibitors have particular therapeutic potential for Aicardi-Goutières syndrome, a severe autoinflammatory immune-mediated disorder similar to lupus. Yu et al., Cell 2020 Oct 29;183(3):636-649, describes a link between TDP-43-induced mitochondrial DNA and activation of the cGAS / STING pathway in amyotrophic lateral sclerosis (ALS). Ryu et al., Arthritis Rheumatol. 2020 Nov;72(11):1905-1915, also showed that bioactive plasma mitochondrial DNA is associated with disease progression in specific fibrotic diseases, such as systemic sclerosis (SSc) or interstitial lung diseases (ILDs), progressive fibrotic interstitial lung diseases (PF-ILDs), and idiopathic pulmonary fibrosis (IPF). Schuliga et al., Clin. Sci. (Lond). 2020 Apr 17;134(7):889-905, describes how self-DNA perpetuates senescence in IPF lung fibroblasts in a cGAS-dependent manner.

[0243] Further scientific hints linking the pathogenesis of other fibrotic diseases, such as nonalcoholic steatohepatitis (NASH), to 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, reported that self-DNA release and STING-dependent sensing lead to cigarette smoke-induced inflammation in mice, 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, reported that controlling cGAS-mediated inflammation may suppress ulcerative colitis and inflammatory bowel disease (IBD). Gratia et al., J. Exp. Med. 2019 May 6;216(5):1199-1213, show that Bloom syndrome proteins suppress innate immune sensing of micronuclei by cGAS. Consequently, cGAS inhibitors have therapeutic potential for the treatment of Bloom syndrome. Kerur et al., Nat. Med. 2018 Jan;24(1):50-61, states that cGAS plays an important role in non-canonical inflammasome activation in age-related macular degeneration (AMD).

[0244] Additionally, cGAS inhibitors of Formula (I) or Formula (I') 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 Formula (I) or Formula (I') 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). There are further scientific hints about a correlation between Parkinson's disease and the cGAS / STING pathway (Sliter et al., Nature. 2018 Sep;561(7722):258-262) and Sjögren's syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res. 2018 Jul;97(8):893-900). Furthermore, cGAS inhibitors of Formula (I) or Formula (I') 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". Furthermore, cGAS inhibitors of Formula (I) or Formula (I') have therapeutic potential in treating renal inflammation and 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."

[0245] Furthermore, cGAS inhibitors of Formula (I) or Formula (I') 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." Furthermore, cGAS inhibitors of Formula (I) or Formula (I') have therapeutic potential in the treatment of metabolic disorders because STING gt Animals under subchronic high-calorie diet (HFD) showed reduced macrophage infiltration in adipose tissue, and STING gt and IRF3 deficiency leads to decreased blood glucose and insulin levels and weight loss (Mao et al, Arterioscler Thromb Vasc Biol, 2017;37 (5): 920-929). Furthermore, cGAS inhibitors of Formula (I) or Formula (I') have therapeutic potential in the treatment of vascular diseases, resulting in vascular repair / regeneration, because release of mitochondrial DNA into the cytosol of endothelial cells leads to cGAS / STING pathway activation and suppression of endothelial proliferation. Furthermore, 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). Furthermore, cGAS inhibitors of Formula (I) or Formula (I') have therapeutic potential in the treatment of age- and obesity-related cardiovascular disease (Hamann et al, Immun Ageing, 2020, Mar 14; 17: 7; doi: 10.1186 / s12979-020-00176-y.eCollection 2020).

[0246] As a result, the compounds of formula (I) or formula (I') as cGAS inhibitors can be used to treat autoinflammatory and autoimmune diseases, such as systemic lupus erythematosus (SLE), interferonopathies, Aicardi-Goutieres syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, and Parkinson's disease. Furthermore, the compounds of formula (I) or formula (I') as cGAS inhibitors can be used to treat fibrotic diseases such as systemic sclerosis (SSc), interferonopathies, non-alcoholic steatohepatitis (NASH), interstitial lung diseases (ILDs), preferably progressive fibrotic interstitial lung diseases (PF-ILDs), in particular idiopathic pulmonary fibrosis (IPF). Furthermore, the compounds of formula (I) or formula (I') as cGAS inhibitors can be used to treat age-related macular degeneration (AMD), heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases and cancer.

[0247] 8 Combinations The compounds of formula (I) or formula (I') may be administered to a patient alone or in combination with one or more other pharmacologically active agents. In a preferred embodiment of the invention, the compounds of formula (I) or (I') may be used in combination with one or more pharmacologically active agents selected from the group consisting of anti-inflammatory agents, antifibrotic agents, antiallergics / antihistamines, bronchodilators, beta2 agonists / betamimetics, adrenergics, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, non-specific 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 modulators, anti-TNF antibodies such as Adalimumab (Humira™), and anti-BAFF agents (Belimumab and Etanercept).

[0248] The antifibrotic agent is preferably selected from pirfenidone and tyrosine kinase inhibitors such as nintedanib, with nintedanib being particularly preferred. Preferred examples of anti-inflammatory drugs 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, Rofleponide and Dexamethasone. The antiallergic / antihistamine is preferably selected from Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Ebastine, Desloratidine and Mizolastine.

[0249] The beta2 agonist / betamimetics may be a long-acting beta2 agonist (LABA) or a short-acting beta agonist (SABA). Particularly preferred β2 agonists / mimetics are selected from Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenalin, Ibuterol, Pirbuterol, Procaterol, Reproterol, Salmeterol, Sulfonterol, Terbutaline, Tolubuterol, Olodaterol, and Salbutamol, especially Olodaterol. The anticholinergic agent is preferably selected from ipratropium salts, tiotropium salts, glycopyrronium salts, and theophylline, with tiotropium bromide being particularly preferred. The leukotriene modifier is preferably selected from Montelukast, Pranlukast, Zafirlukast, Ibudilast and Zileuton. The JAK inhibitor is preferably selected from baricitinib, cerdulatinib, fedratinib, filgotinib, gandotinib, lestaurtinib, momelotinib, 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, anti-IL-6 antibodies such as Tocilizumab (Actemra™), anti-IL-12 antibodies, and anti-IL-15 antibodies.

[0250] 9. Preparations The compounds of the present invention may be administered by any suitable route, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, rectal, and inhalation administration. Parenteral administration refers to a route of administration other than enteral, transdermal, or inhalation administration, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs, whether inhaled through the mouth or nasal passages. Topical administration includes application to the skin. The compounds of the present invention may also be administered by eye drops to treat Sjögren's syndrome. Suitable forms for administration include, for example, tablets, capsules, liquids, syrups, emulsions, or inhalable powders or sprays. In any case, the content of the pharmaceutically active compound should be within the range of 0.1 to 90 wt.%, preferably 0.5 to 50 wt.%, of the total composition, i.e., within the range sufficient to achieve the dosage range described below. The formulation may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g., a hard gelatin capsule), as a solution or suspension. When administered by inhalation, the active substance combination may be administered as a powder, as an aqueous or aqueous ethanolic solution, or by means of a propellant gas formulation.

[0251] Thus, preferably, the pharmaceutical formulation is characterized by the content of one or more compounds of formula (I) or formula (I') according to the above preferred embodiments. It is particularly preferred to administer the compound of formula (I) or formula (I') orally, and it is particularly preferred to administer the compound of formula (I) or formula (I') once or twice a day. 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 delayed-release agents such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablet may comprise several layers. Thus, coated tablets can be prepared by coating a core made similarly to a tablet with a substance commonly used in tablet coatings, such as Kollidon or shellac, gum arabic, talc, titanium dioxide, or sugar. The core may consist of several layers to achieve delayed release or to prevent incompatibilities. Similarly, tablet coatings can consist of several layers to achieve delayed release, possibly using the excipients mentioned above for tablets. Syrups containing the active substances or combinations thereof according to the invention may additionally contain sweetening agents such as saccharine, cyclamate, glycerol or sugar and flavour enhancers, for example flavourings, such as vanillin or orange extract, etc. They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide or preservatives such as p-hydroxybenzoates.

[0252] Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatin capsules. Suitable suppositories can be prepared, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof. 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 oil 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 dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite liquor, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate). For oral administration, tablets may naturally contain, apart from the above carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin, etc. Furthermore, for the tabletting process, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used at the same time, and in the case of aqueous suspensions, the active substance may be combined with various flavor enhancers or coloring agents in addition to the above excipients.

Claims

1. The following formula (I) 【Chemical 1】 (In the formula, R 1 is selected from methyl, ethyl, halomethyl, haloethyl, and halogen; G, O, NR 8 , C.H. 2 , C and CR 8 R 9 is selected from R 2 is H, halogen, cyclopropyl, C 1-3 -Alkyl, -C 2-5 -alkynyl, -S-methyl and CN; or R 2 is a cyclic group selected from the group consisting of phenyl or 5- to 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms each independently selected from N, S and O, and the cyclic group is substituted with one or two identical or different substituents R 10 is replaced by R 3 is H or methyl, R 4 is H or methyl, R 5 -H, methyl, -CN, -methylene, -OH and -CF 3 is selected from or R 5 may not exist, R 6 -H, methyl, -CN, -methylene, -OH and -CF 3 is selected from or R 5 and R 6 together with the middle C atom form a ring selected from oxetane, tetrahydrofuran and cyclopropane, R 7 is H, halogen, (C 1-3 )-alkyl and halo-(C 1-3 )-alkyl; R 8 is selected from CN, H and methyl; R 9 is selected from H, methyl and halogen; or R 9 may not exist, Here, each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH 3 ) 2 , -CH 2 -OH, -NH(CH 3 ), -O-(C 1-3 -Alkyl), -CN, -S-CH 3 , -CO-NH 2 , -CH 2 -NH(CH 3 ), -CH 2 -NH 2 , -SO-(CH 3 ), cyclopropyl and -OR 11 are independently selected from the group consisting of R 11 is a 5- or 6-membered heterocycle having 1 or 2 heteroatoms independently selected from N, O and S; Or G is CR 8 R 9 and R 5 and R 9 does not exist and R 8 and R 6 and R 8 and R 6 and the two middle C atoms form a fused 5-membered aromatic or non-aromatic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, S and O, Or G is CR 8 R 9 and R 8 and R 9 But R 8 and R 9 forms a diazirine ring together with the middle C atom of Compounds of and prodrugs or pharmaceutically acceptable salts thereof.

2. The following formula (I') 【Chemistry 2】 (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and G are as defined in claim 1) The compound according to claim 1, and prodrugs or pharmaceutically acceptable salts thereof.

3. R 7 is selected from H, F, Cl, methyl, ethyl, halomethyl and haloethyl; A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

4. R 1 is selected from halomethyl, haloethyl and methyl; A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

5. R 1 But -CF 3 , -CHF 2 and -CH 2 F is a fluoromethyl selected from the group consisting of The compound according to claim 3, and prodrugs or pharmaceutically acceptable salts thereof.

6. R 3 and R 4 at least one of is methyl; A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

7. R 3 and R 4 one of which is methyl and the other is H, A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

8. G is O, A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

9. G is O, And R 3 or R 4 one of which is methyl and the other is H, A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

10. R 4 is methyl and R 3 is H, R 5 and R 6 forms an oxetane ring together with the middle C atom, The compound according to claim 8, and prodrugs or pharmaceutically acceptable salts thereof.

11. R 2 is selected from the group consisting of H, ethynyl, 1-propynyl, -S-methyl, and halogen; A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

12. R 2 is ethynyl, A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

13. R 4 is methyl and R 3 is H, G is O, R 5 and R 6 together form an oxetane ring, R 2 is selected from the group consisting of H, ethynyl, 1-propynyl, -S-methyl, and halogen; A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

14. R 2 is a cyclic group selected from the group consisting of phenyl or 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, S and O, and the cyclic group is substituted with one or two identical or different substituents R 10 is replaced by Each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH 3 ) 2 , -CH 2 -OH, -NH(CH 3 ), -O-CH 3 , -CN, -S-CH 3 , -CO-NH 2 , -CH 2 -NH(CH 3 ), -CH 2 -NH 2 , -SO-(CH 3 ), cyclopropyl and -OR 11 are independently selected from the group consisting of Each R 11 is selected from 5- or 6-membered heterocycles having 1 or 2 heteroatoms each independently selected from N and O; A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

15. R 2 is a cyclic group selected from the group consisting of pyrazolyl, pyridinyl, imidazolyl, phenyl, and isoxazolyl; The cyclic group may be substituted with one or two identical or different substituents R 10 is replaced by Each R 10 is hydrogen, halogen, haloalkyl, -methyl, -ethyl, -NH-CO-methyl, -N(CH 3 ) 2 , -CH 2 -OH, -NH(CH 3 ), -O-CH 3 , -CN, -S-CH 3 , -CO-NH 2 , -CH 2 -NH(CH 3 ), -CH 2 -NH 2 , -SO-(CH 3 ), cyclopropyl and -OR 11 are independently selected from the group consisting of Each R 11 is tetrahydropyran, The compound of claim 14, and prodrugs or pharmaceutically acceptable salts thereof.

16. G is O, R 3 or R 4 one of which is methyl and the other is H, The compound of claim 15, and prodrugs or pharmaceutically acceptable salts thereof.

17. R 4 is methyl and R 3 is H, R 5 and R 6 forms an oxetane ring together with the middle C atom, The compound of claim 16, and prodrugs or pharmaceutically acceptable salts thereof.

18. G is R 8 R 9 and R 8 and R 6 and R 8 and R 6 and the two middle C atoms form a fused 5-membered aromatic heterocycle containing 1 or 2 heteroatoms independently selected from N and O, and the ring is selected from a fused isoxazolyl ring, a fused pyrazolyl ring, a fused pyrrolyl ring and a fused furanyl ring; R 9 and R 5 does not exist, A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

19. the below described 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 selected from the group consisting of A compound of formula (I) according to claim 1 or a compound of formula (I') according to claim 2, and prodrugs or pharmaceutically acceptable salts thereof.

20. The following formula (IV) 【Chemistry 10】 or the following formula (V): 【Chemistry 11】 Or the following formula (X) 【Chemistry 12】 or the following formula (XI) 【Chemistry 13】 (In the formula, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is as defined in claim 1, X is F or NO 2 and PG is a protecting group selected from the group consisting of tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluorenylmethylenoxycarbonyl (Fmoc), and allyloxycarbonyl (Alloc). Intermediate.

21. The following formula (A) 【Chemistry 14】 Or the following formula (A') 【Chemistry 15】 (In the formula, R 12 is C 1-4 -Alkyl, aryl, -CH 2 -aryl, NH-SO 2 -C 1-3 -alkyl), A prodrug of any of the compounds of any one of claims 1 to 19.

22. R 12 22. The prodrug of formula (A) or formula (A') of claim 21, wherein is methyl.

23. A compound of formula (I) or formula (I') according to any one of claims 1 to 19 for use in the treatment of a disease treatable by the inhibition of cGAS.

24. 20. A compound of formula (I) or formula (I') according to any one of claims 1 to 19 for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathies, Aicardi-Goutieres syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, Parkinson's disease, heart failure and cancer, systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably progressive fibrotic interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).

25. 20. A compound of formula (I) or formula (I') according to any one of claims 1 to 19 for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathy, Aicardi-Goutieres syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome and Parkinson's disease.

26. A compound of formula (I) or formula (I') according to any one of claims 1 to 19 for use in the treatment of a disease selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interferonopathies, interstitial lung diseases (ILDs), preferably progressive fibrotic interstitial lung diseases (PF-ILDs), in particular idiopathic pulmonary fibrosis (IPF).

27. 20. A compound of formula (I) or formula (I') according to any one of claims 1 to 19 for use in the treatment of a disease selected from the group consisting of age-related macular degeneration (AMD), heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases and cancer.

28. A pharmaceutical composition comprising a compound of formula (I) or formula (I') according to any one of claims 1 to 19, optionally together with one or more pharmaceutically acceptable carriers and / or excipients.

29. 20. A pharmaceutical composition comprising a compound of formula (I) or formula (I') according to any one of claims 1 to 19 in combination with one or more active agents selected from the group consisting of anti-inflammatory agents, antifibrotic agents, antiallergics / antihistamines, bronchodilators, beta2 agonists / betamimetics, adrenergics, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint modulators, anti-TNF antibodies such as adalimumab, anti-BAFF antibodies such as belimumab, and etanercept.

30. 30. The pharmaceutical composition of claim 29, wherein the compound of formula (I) or formula (I') is combined with one or more antifibrotic agents selected from the group consisting of pirfenidone and nintedanib.

31. 30. The pharmaceutical composition of claim 29, wherein the compound of formula (I) or formula (I') is combined with one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids.

32. 30. The pharmaceutical composition of claim 29, wherein the compound of formula (I) or formula (I') is combined with one or more active agents selected from the group consisting of bronchodilators, beta-2 agonists / betamimetics, adrenergic agonists and anticholinergics.

33. 30. The pharmaceutical composition of claim 29, wherein the compound of formula (I) or formula (I') is combined with one or more anti-interleukin antibodies selected from the group consisting of anti-IL-23 antibodies, such as risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies, anti-IL-4 antibodies, anti-IL-13 antibodies, anti-IL-5 antibodies, anti-IL-6 antibodies, such as tocilizumab, anti-IL-12 antibodies, and anti-IL-15 antibodies.

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