Pyridine derivatives with N-linked cyclic substituents as cGAS inhibitors

Abstract

The present invention relates to novel proline derivatives of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and G are as defined in claim 1, as cGAS inhibitors, and prodrugs or pharmaceutically acceptable salts of these compounds for the treatment of diseases such as systemic lupus erythematosus, systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202280032800.4 (application date: May 9, 2022, invention name: Pyridine derivatives with N-linked cyclic substituents as cGAS inhibitors). Background Art

[0002] 1.1 cGAS inhibitors

[0003] Innate immunity is considered to be the first-line cell stress response that defends host cells against invading pathogens and initiates adaptive immune system signal transduction. These processes are triggered by conservative pathogen-associated molecular patterns (PAMPs) via multiple pattern recognition receptors (PRRs) perception and subsequent activation of cytokines and type I interferon gene expression. Main antigen presenting cells (such as monocytes, macrophages and dendritic cells) produce type I interferons, and are essential for inducing adaptive T cells and B cell immune system responses. The main PRR detects abnormalities on the cell surface, inside the lysosomal membrane, or in other cell compartments, i.e., mislocalized, immature or unmodified nucleic acids (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)).

[0004] "Cyclic GMP-AMP Synthase" (cGAS, UniProtKB-Q8N884) is a major sensor of abnormal double-stranded DNA (dsDNA), which originates from pathogens or mislocalization or misprocessing of nuclear or mitochondrial cellular dsDNA (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). The binding of dsDNA to cGAS activates the reaction of GTP and ATP to form the cyclic dinucleotide GMP-AMP (called cGAMP). cGAMP then reaches and activates the endoplasmic reticulum membrane-anchored adapter protein "Stimulator of Interferon Genes" (STING). Activated STING recruits and activates TANK-binding kinase 1 (TBK1), which in turn phosphorylates the transcription factor family of interferon regulatory factors (IRFs), thereby inducing cytokine and type I interferon mRNA expression.

[0005] The key role of cGAS in dsDNA sensing has been established in different pathogenic bacteria (Hansen et al., EMBO J. 33, 1654 (2014)), viruses (Ma et al., PNAS 112, E4306 (2015)) and retroviruses (Gao et al., Science 341, 903-906 (2013)). In addition, cGAS is essential in various other biological processes, such as cell senescence (Yang et al., PNAS 114, E4612 (2017), Gluck et al., Nat. Cell Biol. 19, 1061-1070 (2017)) and the recognition of disrupted micronuclei in potential cancer cell monitoring (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)).

[0006] Although the cGAS pathway is important for host defense against invading pathogens, cellular stress and genetic factors can also lead to the production of abnormal cellular dsDNA effects, such as through nuclear or mitochondrial leakage, and thereby trigger autoinflammatory responses. Aicardi-Goutieres syndrome (AGS; Crow et al., Nat. Genet. 38, 917-920 (2006)), a lupus-like severe autoinflammatory immune-mediated disorder, is caused by loss-of-function mutations in TREX1, a major DNA exonuclease responsible for degrading abnormal DNA in the cytosol. Knockout of cGAS in TREX1-deficient mice prevents otherwise lethal autoimmune reactions, supporting cGAS as a driver of interferon disease (Gray et al., J. Immunol. 195, 1939-1943 (2015); Gao et al., PNAS 112, E5699-E5705 (2015)). Likewise, embryonic lethality caused by deficiency in DNAse2, an endonuclease responsible for degrading excess DNA in lysosomes during endocytosis, was completely rescued by additional knockout of cGAS (Gao et al., PNAS 112, E5699-E5705 (2015)) or STING (Ahn et al., PNAS 109, 19386-19391 (2012)). These observations support cGAS as a drug target, and inhibition of cGAS may provide a therapeutic strategy for preventing autoinflammation and treating diseases such as systemic lupus erythematosus (SLE) involving anti-dsDNA antibodies (Pisetsky et al., Nat. Rev. Rheumatol. 12, 102-110 (2016)).

[0007] 1.2 Prior Art

[0008] Since the observation that inhibition of the cGAS-pathway may provide a therapeutic strategy for preventing autoinflammation and treating, for example, autoimmune diseases, many efforts have been made to develop cGAS inhibitors.

[0009] For example, in WO 2019 / 241787, methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylate (e.g. CU-32 and CU-76) has been disclosed as cGAS-inhibitors whose "in vitro hcGAS IC50-values" are slightly lower than 1 μM (IC50(CU-32)=0.66 μM and IC50(CU-76)=0.27 μM).

[0010] In Hall et al., PLoS ONE 12(9); e0184843 (2017), compound PF-06928215 has been disclosed as a cGAS inhibitor with an "in vitro hcGAS IC50-value" of 0.049 μM as measured by fluorescence polarization analysis. However, compound PF-06928215 did not show acceptable cellular activity as a cGAS inhibitor.

[0011] In WO 2020 / 142729, (benzofurano[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid derivatives have been disclosed as cGAS inhibitors for the treatment of autoimmune disorders such as Acardi-Gutierrez syndrome (AGS), lupus erythematosus, scleroderma, inflammatory bowel disease, and non-alcoholic steatohepatitis (NASH). However, the compounds of the present invention differ from the (benzofurano[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.

[0012] Recently provided cGAS inhibitors (e.g. those in WO 2020 / 142729) generally show insufficient cellular cGAS inhibitory efficacy (IC50 values ​​for inhibition of the cGAS / STING pathway measured in cell-based assays are generally greater than 1 μM, often greater than 5 μM). However, it is of vital importance to provide therapeutic cGAS inhibitors that not only show satisfactory biochemical (in vitro) inhibitory efficacy ("hcGAS IC50"), but also show satisfactory cellular inhibitory efficacy (e.g. by showing inhibition of IFN-induced in virus-stimulated THP-1 cells (THP1 (vir) IC50)) to ensure that the compound is able to show a therapeutic effect in patients. Other important properties that predict successful development of cGAS inhibitors as therapeutic agents are satisfactory cGAS selectivity (relative to off-target activity) and acceptable inhibitory efficacy in human whole blood.

[0013] Surprisingly, it has now been found that compounds of formula (I) and formula (I') simultaneously exhibit the following three properties:

[0014] A satisfactory "biochemical (in vitro) IC50 value for cGAS inhibition" (hcGAS IC50 ≤ 100 nM, more preferably ≤ 50 nM, in particular ≤ 10 nM),

[0015] "Satisfactory inhibition of IFN induction in virus-stimulated THP-1 cells" (THP1 IC50 (vir) ≤1μM, more preferably ≤500nM, more preferably ≤100nM, specifically ≤50nM)

[0016] and

[0017] Satisfactory selectivity for cGAS inhibition

[0018] (THP1 IC50 (cGAMP) / THP1 IC50 (vir) The ratio is ≥10, more preferably ≥50, more preferably ≥500, specifically ≥1000).

[0019] In addition, the compounds of formula (I) and formula (I') also show acceptable IC50 values ​​for inhibition of IFN induction in dsDNA stimulated human whole blood assay, preferably human whole blood IC50 values ​​(hWB IC50) for cGAS inhibition of ≤5000 nM, more preferably ≤1000 nM, specifically ≤100 nM.

[0020] The cGAS inhibitors of the present invention having this specific pharmacological property combine excellent in vitro inhibitory efficacy and excellent cytostatic efficacy with high selectivity for cGAS inhibition, with a high probability of also showing good therapeutic effects in patients. Due to their high cytostatic efficacy, compounds having this specific pharmacological property should be able to pass the cell membrane barrier and thus reach their intracellular target location, and due to their selectivity for exclusively inhibiting cGAS, these compounds should not show undesirable off-target effects, such as side effects or cytotoxic effects somewhere within the cGAS downstream signaling pathway. Summary of the invention

[0021] The present invention relates to compounds of formula (I),

[0022]

[0023] in

[0024] R 1 is selected from methyl, ethyl, halomethyl, haloethyl and halogen,

[0025] in

[0026] G is selected from O, NR 8 , CH2, C and CR 8 R 9 ,

[0027] in

[0028] R 2 Selected from H, halogen, cyclopropyl, C 1-3 -alkyl, C 2-5 -alkynyl, -S-methyl and CN,

[0029] or where R 2 is a cyclic group, wherein the cyclic group is selected from: phenyl and a five- to six-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, and wherein the cyclic group is composed of one or two identical or different substituents R 10 replace,

[0030] in

[0031] R 3 H or methyl

[0032] R 4 H or methyl

[0033] R 5 is selected from H, methyl, -CN, -methylene-OH and -CF3,

[0034] or R 5 does not exist,

[0035] R 6 is selected from H, methyl, -CN, -methylene-OH and -CF3,

[0036] or R 5 and R 6 Together with the C atoms therebetween, they form a ring selected from oxetane, tetrahydrofuran and cyclopropane

[0037] R 7 Selected from H, halogen, (C 1-3 )-alkyl and halo-(C 1-3 )-alkyl

[0038] R 8 is selected from CN, H and methyl,

[0039] R 9 Selected from H, methyl and halogen

[0040] or R 9 does not exist,

[0041] Each R 10independently selected from the group consisting of 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 ,

[0042] Each R 11 independently selected from a five- or six-membered aromatic or non-aromatic heterocyclic ring having one or two heteroatoms each independently selected from N, O and S,

[0043] or G for CR 8 R 9 , R 5 and R 9 does not exist, and R 8 and R 6 and R 8 With R 6 The two C atoms between them form a cyclic five-membered aromatic or non-aromatic heterocycle containing one, two or three heteroatoms independently selected from N, S and O,

[0044] or G for CR 8 R 9 And R 8 and R 9 With R 8 and R 9 The C atoms between them form a diaziridine ring.

[0045] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0046] A more preferred embodiment of the present invention relates to the above-mentioned compounds, which fall within the scope of formula (I')

[0047]

[0048] 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 is defined as mentioned above

[0049] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0050] Another preferred embodiment of the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0051] Where R 7 is H, F, Cl, methyl, ethyl, halomethyl or haloethyl,

[0052] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0053] In another preferred embodiment, the present invention relates to the compound of formula (I) or formula (I') mentioned above,

[0054] Where R 1 is a halomethyl, a haloethyl or a methyl group,

[0055] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0056] Another preferred embodiment of the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0057] Where R 1 is a fluoromethyl group selected from -CF3, -CHF2 and -CH2F,

[0058] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0059] In another preferred embodiment, the present invention relates to the compound of formula (I) or formula (I') mentioned above, wherein R 3 and R 4 At least one of them is methyl

[0060] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0061] Another preferred embodiment of the present invention relates to the compounds of formula (I) or formula (I') mentioned above, wherein R 3 and R 4 One of them is methyl and the other is H

[0062] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0063] In another preferred embodiment, the present invention relates to the compound of formula (I) or formula (I') mentioned above, wherein G is O

[0064] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0065] Another preferred embodiment of the present invention relates to the compound of formula (I) or formula (I') mentioned above, wherein G is O

[0066] And R 3 and R4 One of them is methyl and the other is H,

[0067] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0068] In another preferred embodiment, the present invention relates to the compound of formula (I) or formula (I') mentioned above,

[0069] Where G is O,

[0070] Where R 4 is methyl and R 3 For H,

[0071] And R 5 and R 6 Together they form an oxetane ring

[0072] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0073] Another preferred embodiment of the present invention relates to the compound of formula (I) or formula (I') mentioned above,

[0074] Where R 2 is selected from: H, ethynyl, 1-propynyl, -S-methyl and halogen,

[0075] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0076] In another preferred embodiment, the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0077] Where R 2 is ethynyl,

[0078] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0079] Another preferred embodiment of the present invention relates to the compound of formula (I) or formula (I') mentioned above,

[0080] Where R 4 is methyl and R 3 For H,

[0081] Where G is O,

[0082] Where R 5 and R 6 Together they form an oxetane ring,

[0083] Where R 2 is selected from: H, ethynyl, 1-propynyl, -S-methyl and halogen,

[0084] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0085] In another preferred embodiment, the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0086] Where R 2 is a cyclic group, wherein the cyclic group is selected from: phenyl or a five- to six-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, S and O, and wherein the cyclic group is composed of one or two identical or different substituents R 10 replace,

[0087] Each R 10 independently selected from: 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 ,

[0088] Each R 11 independently selected from a five- or six-membered aromatic or non-aromatic heterocyclic ring having one or two heteroatoms each independently selected from N and O,

[0089] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0090] Another preferred embodiment of the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0091] Where R 2 is a cyclic group selected from pyrazolyl, pyridyl, imidazolyl, phenyl and isoxazolyl,

[0092] The cyclic group is composed of one or two identical or different substituents R 10 replace

[0093] Each R 10 independently selected from: 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 ,

[0094] Each R 11 Tetrahydropyran

[0095] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0096] In another preferred embodiment, the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0097] Where G is O,

[0098] Where R 3 and R 4 One of them is methyl and the other is H,

[0099] Where R 2 is a cyclic group selected from pyrazolyl, pyridyl, imidazolyl, phenyl and isoxazolyl,

[0100] The cyclic group is composed of one or two identical or different substituents R 10 replace

[0101] Each R 10 independently selected from: 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 ,

[0102] Each R 11 is tetrahydropyran,

[0103] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0104] In another preferred embodiment, the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0105] Where R 2 is a cyclic group selected from pyrazolyl, pyridyl, imidazolyl, phenyl and isoxazolyl,

[0106] The cyclic group is composed of one or two identical or different substituents R 10 replace

[0107] Each R 10 independently selected from: 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 ,

[0108] Each R 11 is tetrahydropyran,

[0109] Where G is O,

[0110] Where R 3 and R 4 One of them is methyl and the other is H,

[0111] And R 5 and R 6 Together they form an oxetane ring,

[0112] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0113] In another preferred embodiment, the present invention refers to the compound of formula (I) or formula (I') mentioned above,

[0114] Where G is CR 8 R 9 ,

[0115] Where R 8 and R 6 and R 8 With R 6 The two C atoms between them form a cyclic five-membered aromatic heterocyclic ring containing one or two heteroatoms independently selected from N and O, which is selected from a cyclic isoxazolyl ring, a cyclic pyrazolyl ring, a cyclic pyrrolyl ring and a cyclic furyl ring,

[0116] And R 9 and R 5 does not exist,

[0117] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0118] Another particularly preferred embodiment of the present invention relates to compounds of formula (I) or formula (I') selected from:

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] and

[0127] and prodrugs or pharmaceutically acceptable salts of these compounds.

[0128] In another embodiment, the present invention relates to the compounds of formula (I) or formula (I') mentioned above for use in the treatment of diseases that can be treated by inhibiting cGAS.

[0129] In a more preferred embodiment, the present invention refers to the compound of formula (I) or formula (I') mentioned above, which is used to treat a disease selected from the following: systemic lupus erythematosus (SLE), interferon disease, Icardi-Gutierrez 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 fibrosing interstitial lung disease (PF-ILD), specifically idiopathic pulmonary fibrosis (IPF).

[0130] In a more preferred embodiment, the present invention relates to a compound of formula (I) or formula (I') as mentioned above, for use in treating a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferon disease, Icardi-Gutierrez syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjögren's syndrome and Parkinson's disease.

[0131] In another more preferred embodiment, the present invention relates to the compound of formula (I) or formula (I') mentioned above, which is used to treat a fibrotic disease selected from the following: systemic sclerosis (SSc), interferon disease, non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), more preferably progressive fibrosing interstitial lung disease (PF-ILD), specifically idiopathic pulmonary fibrosis (IPF).

[0132] In another more preferred embodiment, the present invention relates to a compound of formula (I) or formula (I') mentioned above, for use in treating a disease selected from the following: 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.

[0133] In another embodiment, the present invention relates to a pharmaceutical composition comprising at least one of the compounds of formula (I) or formula (I′) mentioned above and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0134] In another preferred embodiment, the present invention refers to an intermediate of the following formula:

[0135]

[0136] According to the synthetic scheme 1,

[0137] Or formula (V)

[0138]

[0139] According to the synthetic scheme 1,

[0140] Or formula (X)

[0141]

[0142] According to Synthesis Scheme 2,

[0143] Or formula (XI)

[0144]

[0145] According to Synthesis Scheme 2,

[0146] Among them, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As mentioned above the definition

[0147] and wherein X is F or NO2,

[0148] And wherein PG is a protecting group selected from: tert-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluorenylmethyleneoxycarbonyl (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).

[0149] In another preferred embodiment, the present invention relates to a prodrug of any one of the compounds of formula (I) or formula (I') mentioned above,

[0150] Wherein this prodrug is within the scope of formula (A)

[0151]

[0152] or within the range of formula (A')

[0153]

[0154] Among them, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As mentioned above the definition

[0155] And R 12 C 1-4- Alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl.

[0156] Specifically, the present invention relates to the prodrugs of formula (A) or formula (A') mentioned above, wherein R 12 It is methyl.

[0157] In another preferred embodiment, the present invention relates to a combination of a compound of formula (I) or (I') and one or more active agents selected from the following: anti-inflammatory agents, antifibrotic agents, antiallergic agents / antihistamines, bronchodilators, β2 agonists / β mimetics, adrenergic agonists, 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 regulators, anti-TNF antibodies (such as adalimumab), anti-BAFF antibodies (such as belimumab and etanercept).

[0158] In a further particularly preferred embodiment, the present invention relates to a combination of a compound of formula (I) or formula (I') and one or more antifibrotic agents selected from the group consisting of Pirfenidon and Nintedanib.

[0159] In a further particularly preferred embodiment, the present invention relates to a combination of a compound of formula (I) or formula (I') and one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids.

[0160] In a further particularly preferred embodiment, the present invention relates to a combination of a compound of formula (I) or (I') with one or more active agents selected from the group consisting of bronchodilators, beta2 agonists / beta mimetics, adrenergic agonists and anticholinergics.

[0161] In a further particularly preferred embodiment, the present invention relates to a combination of a compound of formula (I) or formula (I') and one or more anti-interleukin antibodies selected from the following: anti-IL23 antibody (e.g., Risankizumab), anti-IL17 antibody, anti-IL1 antibody, anti-IL4 antibody, anti-IL13 antibody, anti-IL-5 antibody, anti-IL-6 antibody (e.g., Tocilizumab), anti-IL-12 antibody and anti-IL-15 antibody.

[0162] In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising a combination of a compound of formula (I) or formula (I') and any one of the above-mentioned active agents. DETAILED DESCRIPTION

[0163] Terms and definitions used

[0164] Unless otherwise stated, all substituents are independent of one another. 1-6 -alkyl is a possible substituent at the radical, then in the case of three substituents, for example, C 1-6 -Alkyl can independently represent methyl, n-propyl and tert-butyl.

[0165] The term "C 1-6 -alkyl" (including those as part of other groups) means branched and unbranched alkyl groups having 1 to 6 carbon atoms, and the term "C 1-3 "-alkyl" means branched and unbranched alkyl groups having 1 to 3 carbon atoms. 1-4 "-alkyl" corresponds to branched and unbranched alkyl groups having 1 to 4 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are more preferred. Examples of these groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may also be optionally used for the groups mentioned above. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl, etc.

[0166] The term "C 1-6-alkylene" (including those as part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, and the term "C 1-4 "-alkylene" means branched and unbranched alkylene groups having 1 to 4 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are more preferred. Examples of these groups 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 having the same carbon number. Thus, for example, propyl also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, etc.

[0167] If the carbon chain is substituted by a radical 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 in particular the following examples of rings:

[0168]

[0169] The term "C 2-6 -alkenyl" (including those as part of other groups) means branched and unbranched alkenyl groups having 2 to 6 carbon atoms, and the term "C 2-4 "-Alkenyl" means 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 more 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. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.

[0170] The term "C 2-5 -alkynyl" (including those as part of other groups) means branched and unbranched alkynyl groups having 2 to 5 carbon atoms, and the term "C 2-4 "-alkynyl" means 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 more preferred.

[0171] The term "C 2-6-alkenylene" (including those as part of other groups) means branched and unbranched alkenylene groups having 2 to 6 carbon atoms, and the term "C 2-4 "-Alkenylene" means branched and unbranched alkenylene groups having 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are more preferred. Examples of these groups include: vinylene, propenylene, 1-methylvinylene, butenylene, 1-methylpropenylene, 1,1-dimethylvinylene, 1,2-dimethylvinylene, 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 having the same carbon number. Thus, for example, propenyl also includes 1-methylvinylene, and butenyl includes 1-methylpropenylene, 1,1-dimethylvinylene, 1,2-dimethylvinylene.

[0172] The term "aryl" (including those that are part of other groups) means an aromatic ring system having 6 or 10 carbon atoms. Examples include phenyl or naphthyl, preferably phenyl. Unless otherwise stated, aromatic groups may be substituted by one or more groups selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[0173] The term "aryl-C 1-6 -alkylene" (including those that are part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted by aromatic ring systems having 6 or 10 carbon atoms. Examples include benzyl, 1- or 2-phenylethyl and 1- or 2-naphthylethyl. Unless otherwise stated, the aromatic group may be substituted by one or more groups selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[0174] The term "heteroaryl-C 1-6 -alkylene" (including those that are part of other groups) means (even if it is already included in the "aryl-C 1-6 -alkylene" (hereinafter "alkylene") is a branched and unbranched alkylene group having 1 to 6 carbon atoms, which is substituted by a heteroaryl group.

[0175] If not specifically defined otherwise, such heteroaryl groups include five- or six-membered heterocyclic aromatic groups or 5-10-membered bicyclic heteroaryl rings, which may contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed. The following are examples of five- or six-membered heterocyclic aromatic groups and bicyclic heteroaryl rings:

[0176]

[0177] Unless otherwise stated, these heteroaryl groups may be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, amino, nitro, alkoxy, fluorine, chlorine, bromine and iodine.

[0178] The following are heteroaryl-C 1-6 Examples of -alkylene groups:

[0179]

[0180] The term "C 1-6 -haloalkyl" (including those that are part of other groups) means branched and unbranched alkyl groups having 1 to 6 carbon atoms, which are substituted by one or more halogen atoms. 1-4 "-Haloalkyl" means branched and unbranched alkyl groups having 1 to 4 carbon atoms, which are substituted by one or more halogen atoms. Alkyl groups having 1 to 4 carbon atoms are more preferred. Examples include: CF3, CHF2, CH2F, CH2CF3.

[0181] Unless otherwise specifically defined, the term “C 3-7 -Cycloalkyl" (including those that are part of other groups) means cyclic alkyl groups having 3 to 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from: methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[0182] Unless otherwise specifically defined, the term “C 3-10 "-Cycloalkyl" also means a monocyclic alkyl group having 3 to 7 carbon atoms and a bicyclic alkyl group having 7 to 10 carbon atoms, or a cycloalkyl group consisting of at least one C 1-3 -carbon bridged monocyclic alkyl.

[0183] Unless otherwise indicated, the term "heterocyclic rings" or "heterocycles" means a five-, six- or seven-membered saturated, partially saturated or unsaturated heterocyclic ring which may contain one, two or three heteroatoms selected from oxygen, sulfur and nitrogen, and the ring may be attached to the molecule via a carbon atom or via a nitrogen atom (if one is present). Although encompassed by the term "heterocyclic rings" or "heterocycles", the term "saturated heterocyclic ring" refers to a five-, six- or seven-membered saturated ring. Examples include:

[0184]

[0185] Although encompassed by the terms "heterocycle" or "heterocyclyl", unless expressly defined otherwise, the term "partially saturated heterocyclyl" refers to a five-, six- or seven-membered partially saturated ring containing one or two double bonds without so many double bonds as to form an aromatic system. Examples include:

[0186]

[0187] Although encompassed by the term "heterocyclic rings or heterocycles", unless expressly defined otherwise, the term "heterocyclic aromatic ring", "unsaturated heterocyclic group" or "heteroaryl" refers to a five- or six-membered heterocyclic aromatic group, or a five- to ten-membered bicyclic heteroaryl ring, which may contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contains so many conjugated double bonds that an aromatic system is formed. Examples of five- or six-membered heterocyclic aromatic groups include:

[0188]

[0189] Unless otherwise mentioned, a heterocyclic ring or heterocycle may be provided with a keto group. Examples include:

[0190]

[0191] Although encompassed by the term "cycloalkyl", the term "bicycloalkyl" generally refers to an eight, nine or ten membered bicyclic carbocyclic ring. Examples include:

[0192]

[0193] Although already included by the term "heterocycle", unless explicitly defined otherwise, the term "bicyclic heterocycle" generally refers to an eight-, nine- or ten-membered bicyclic ring which may contain one or more heteroatoms selected from oxygen, sulfur and nitrogen, more preferably 1-4, more preferably 1-3, even more preferably 1-2, specifically one heteroatom. The ring may be attached to the molecule via a carbon atom of the ring or via a nitrogen atom of the ring (if one is present). Examples include:

[0194]

[0195] Although already encompassed by the term "aryl", the term "bicyclic aryl" refers to a 5-10 membered bicyclic aryl ring containing sufficient conjugated double bonds to form an aromatic system. An example of a bicyclic aryl is naphthyl.

[0196] Although already included under "heteroaryl", unless expressly defined otherwise, the term "bicyclic heteroaryl" means a 5-10 membered bicyclic heteroaryl ring which may contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contains sufficient conjugated double bonds to form an aromatic system.

[0197] Although encompassed by the terms "bicycloalkyl" or "bicycloaryl", the terms "fused cycloalkyl" or "fused aryl" represent a bicyclic ring in which the bridge separating the rings represents a direct single bond. The following are examples of fused bicycloalkyls:

[0198]

[0199] Although encompassed by the terms "bicyclic heterocycle" or "bicyclic heteroaryl", the terms "fused bicyclic heterocycle" or "fused bicyclic heteroaryl" refer to bicyclic 5-10 membered heterocycles containing one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and wherein the bridge separating the rings represents a direct single bond. In addition, "fused bicyclic heteroaryl" contains sufficient conjugated double bonds to form an aromatic system. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

[0200]

[0201] "Halogen" within the scope of the present invention means fluorine, chlorine, bromine or iodine. Unless otherwise specified, fluorine, chlorine and bromine are considered to be the more preferred halogens.

[0202] As previously mentioned, the compound of formula (I) or (I') can be converted into its salt, especially for medical use, into its physiological and pharmacologically acceptable salt. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment and are free of excessive toxicity, irritation, allergic reaction or other problems or complications and are commensurate with a reasonable benefit / risk ratio. On the one hand, these salts can exist as physiological and pharmacologically acceptable acid addition salts of the compound of formula (I) or (I') and inorganic or organic acids. On the other hand, the compound of formula (I) or (I') can be converted into physiological and pharmacologically acceptable salts by reacting with an inorganic base, wherein an alkali metal or alkaline earth metal cation is used as a counter ion. 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. A mixture of the acids mentioned above can also be used. In order to prepare alkali metal and alkaline earth metal salts of compounds of formula (I) or (I'), it is preferred to use alkali metal and alkaline earth metal hydroxides and hydrides, among which alkali metal (specifically sodium, potassium, magnesium, calcium, zinc and diethanolamine) hydroxides and hydrides are more preferred, and sodium hydroxide and potassium hydroxide are particularly preferred.

[0203] The present invention relates to the compounds, optionally in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual mirror isomers or racemates, in the form of tautomers and in the form of free bases or corresponding acid addition salts with pharmacologically acceptable acids, for example acid addition salts with hydrohalic acids such as hydrochloric acid or hydrobromic acid or organic acids such as oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid.

[0204] The compounds of formula (I) or (I') according to the invention may optionally be present as mixtures of diastereomeric isomers, but can also be obtained as pure diastereomeric isomers. More preferred are compounds having a specific stereochemistry of formula (I').

[0205] 4 Synthesis method

[0206] The compounds according to the invention and their intermediates can be obtained using synthesis methods known to the person skilled in the art and described, for example, in the literature of organic synthesis.

[0207] Furthermore, the present invention provides a process for preparing the compound of formula (I) or formula (I').

[0208] Optimum reaction conditions and reaction time can be changed depending on the specific reactant used. Unless otherwise specified, solvents, temperature, pressure and other reaction conditions can be easily selected by those skilled in the art. Specific procedures are provided in the synthetic example section. Generally, if necessary, the reaction process can be monitored by thin layer chromatography (TLC) or liquid chromatography mass spectrometry (LC-MS), and intermediates and products can be purified by chromatography on silica gel, HPLC and / or by recrystallization. The following examples are illustrative, and as those skilled in the art will recognize, specific reagents or conditions can be optionally modified for individual compounds without too much experimentation. The starting materials and intermediates used in the following methods are commercially available or easily prepared by those skilled in the art from commercially available materials.

[0209] Compounds of formula (I) can be prepared by the methods outlined in Schemes 1-4, wherein 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 wherein PG is a preferred protecting group selected from: tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluorenylmethyleneoxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc):

[0210] Scenario 1:

[0211]

[0212] As illustrated in Scheme 1, the reaction of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (III) with chloro-pyrimidine (II) in the presence of a suitable base (e.g., diisopropylethylamine, potassium carbonate, or sodium hydride) in a suitable solvent (e.g., DMSO) provides hydroxyproline derivatives of formula (IV). The reaction of hydroxyproline (IV) with a pyridine of formula (V) (wherein X is F or NO2) in the presence of a suitable base (e.g., NaH) in a suitable solvent (e.g., DMA, DMF, or NMP) provides compounds of formula (I).

[0213] Scenario 2:

[0214]

[0215] As illustrated in Scheme 2, the reaction of fluoronitropyridine (VI) with cyclic amine (VII) in the presence of a suitable base (e.g., KCO) in a suitable solvent (e.g., acetonitrile) provides a nitropyridine of formula (VIII). This nitropyridine (VIII) can be reacted with a hydroxyproline of formula (IX) in the presence of a suitable base (e.g., NaH) in a suitable solvent (e.g., DMF, NMP, or DMA) to provide a compound of formula (X), wherein the protecting group PG can be, for example, tert-butyloxycarbonyl (BOC). Removal of the protecting group PG of (X) under standard conditions provides a proline derivative of formula (XI), i.e., if PG is BOC, deprotection can be performed using TFA in a suitable solvent (e.g., acetonitrile). Reaction of compound (XI) with a chloro-pyrimidine of formula (II) in the presence of a suitable base (e.g., diisopropylethylamine, potassium carbonate, or sodium hydride) in a suitable solvent (e.g., DMSO or DMF) provides a compound of formula (I).

[0216] Following this general reaction scheme 2, the substituent R 2 can be located in compound (VI) from the beginning of the reaction sequence and remain unchanged until compound (I) is obtained (ie, if R 2 is H, Br, Cl, aryl or alkynyl), or it can be introduced at a later stage during the synthesis via Suzuki coupling or some other arylation reaction known to those skilled in the art. For example, a compound of formula (VI), (VIII), (X) or (I) wherein R 2 is Br, I or OTf) can be reacted with a suitable aryl borate (ester / acid) in the presence of a suitable base (e.g., Na2CO3, K3PO4 or KOH) and a suitable catalyst (e.g., Pd(dppf)Cl2 or Pd(PPh3)4 (using a suitable ligand, such as Xphos)) in a suitable solvent (e.g., dioxane or DMF) to give the respective compounds, wherein R 2 It is an aromatic group.

[0217] Alternatively, a compound of formula (VI), (VIII), (X) or (I) (wherein R 2 is halogen or OTf) can be reacted with a borylating agent such as bis(pinacolato)diboron in the presence of a suitable catalyst such as Pd(dppf)Cl2 and a suitable base such as potassium acetate to provide a boronate ester. This boronate ester can be reacted with a suitable aryl-halide 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 in a Suzuki coupling to give the respective compounds wherein R2 is aryl.

[0218] Alternatively, a compound of formula (VI), (VIII), (X) or (I) (wherein R 2 is halogen) can be reacted with a suitable alkyne such as ethynyltris(prop-2-yl)silane in the presence of a suitable catalyst such as PdCl2(PPh3)2 and copper(I) iodide and in the presence of a suitable base such as DIPEA in a suitable solvent such as THF to provide the respective compounds wherein R 2 For alkyne.

[0219] The carboxylic acid function of the proline moiety (i.e., compounds of formula (X) or (I)) may be protected during the specific reaction in this sequence with a suitable protecting group (e.g., an alkyl ester), i.e., tert-butyl ester is a suitable protecting group to protect the proline moiety in R 2 Introducing an aryl moiety.

[0220] Compounds of formula (II) can be prepared as illustrated in Scheme 3.

[0221] Solution 3:

[0222]

[0223] The reaction of a carbonitrile of formula (XII) with an anhydride or corresponding acid of formula (XIII) in a suitable solvent (e.g., pyridine) provides amide (XIV). Upon reaction with a suitable chlorinating agent (e.g., phosphorus pentachloride) in a suitable solvent (e.g., sulfolane), amide (XIV) cyclizes to form a compound of formula (II).

[0224] In an alternative synthetic sequence, a compound of formula (XV) is reacted with 2-bromoacetamide in the presence of a suitable base (e.g., KCO or KOH) in a suitable solvent (e.g., ethanol) to provide a compound of formula (XVII). Compound (XVII) is reacted with a dimethylamide of formula (XVIII) in the presence of a suitable chlorinating agent (e.g., phosphorus oxychloride) to form a compound of formula (II).

[0225] In another alternative synthetic sequence, a compound of formula (XV) is reacted with bromoacetonitrile in the presence of a suitable base (e.g., KCO) in a suitable solvent (e.g., DMF) to produce a compound of formula (XIX). This compound is cyclized in the presence of a suitable base (e.g., tert-butoxide) in a suitable solvent (e.g., THF) to form carbonitrile (XII), and can be converted to a compound of formula (XIV) and subsequently to a compound of formula (II) as described above.

[0226] Compounds of formula (VII) are commercially available or can be prepared according to literature procedures or as illustrated in the experimental section. Compounds of formula (VII) exemplified by compounds of formula (XXIII) can be prepared as illustrated in Scheme 4:

[0227] Solution 4:

[0228]

[0229] Oxo-3-ketone (XXII) reacts with the nitroalkane of formula (XXIII) in a suitable solvent (e.g., methanol) and forms a compound of formula (XXIV). Hydrogenation of compound (XXIV) in a suitable solvent (e.g., ethanol) in the presence of hydrogen and a suitable catalyst (e.g., Pd(OH) / C) provides a compound of formula (XXV). Reaction of compound (XXV) with chloroacetyl chloride in a suitable solvent (e.g., acetonitrile) in the presence of a suitable base (e.g., triethylamine) provides compound (XXVI), which is cyclized in a suitable solvent (e.g., tert-amyl alcohol) to form a lactam of formula (XXVII) under treatment with a suitable base (e.g., tert-butoxide). Reduction of compound (XXVII) with a suitable reducing agent (e.g., lithium aluminum hydride) in a suitable solvent (e.g., diethyl ether) provides a morpholine compound of formula (XXVIII).

[0230] Further modification of the compounds of formula (I) by methods known to those skilled in the art and illustrated in the Examples below can be used to prepare additional compounds of the invention.

[0231] The synthetic pathways present may depend on the use of protecting groups. For example, the potential reactive groups present (e.g., hydroxyl, carbonyl, carboxyl, amino, alkylamino or imino) may be protected by conventional protecting groups during the reaction, which are cleaved again after the reaction. Suitable protecting groups for individual functional groups and their removal are well known to those skilled in the art and are described in the literature of organic synthesis: for example, in "Protecting Groups, 3rd Edition", Philip J. Kocienski, Thieme, 2005 or "Protective Groups in Organic Synthesis, 4th Edition", Peter G. M. Wuts, Theodora W. Greene, John Wiley and Sons, 2007.

[0232] As mentioned below, compounds of general formula (I) can be resolved into their diastereoisomers (ds). Thus, for example, a cis / trans mixture can be resolved into its cis and trans isomers.

[0233] Cis / trans mixtures can be separated into their cis and trans isomers by, for example, chromatography.Diastereomeric mixtures of compounds of the general formula (I) can be separated into their diastereomeric isomers by exploiting their different physicochemical properties using methods known per se, such as chromatography and / or fractional crystallization.

[0234] It is more preferred to resolve the racemic intermediate by column chromatography on a chiral phase or by crystallization from an optically active solvent or by reaction with an optically active substance, which forms a salt or a derivative such as an ester or amide with the racemic compound. Basic compounds can form salts with mirror-image pure acids, and acidic compounds can form salts with mirror-image pure bases. Diastereomeric derivatives are formed with mirror-image pure auxiliary compounds (such as acids, activated derivatives thereof or alcohols). The separation of the diastereomeric mixture of salts or derivatives thus obtained can be achieved by utilizing their different physicochemical properties (such as solubility differences); free mirror images can be released from pure diastereomeric salts or derivatives by the action of suitable reagents. Optically active acids commonly used for this purpose and optically active alcohols suitable for use as auxiliary residues are known to those skilled in the art.

[0235] As mentioned above, the compounds of formula (I) can be converted into salts, especially into pharmaceutically acceptable salts for medical use. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, wherein the parent compound is modified by forming its pharmaceutically acceptable acid or base salt, and the phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic response or other problems or complications and commensurate with a reasonable benefit / risk ratio. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkaline or organic salts of acidic residues (such as carboxylic acids); and the like.

[0236] For example, these salts include those derived from benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gentisic, hydrobromic, hydrochloric, maleic, malic, malonic, mandelic, methanesulfonic, 4-methyl-benzenesulfonic, phosphoric, salicylic, succinic, sulfuric, and tartaric acids.

[0237] Other pharmaceutically acceptable salts can be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminoethane.

[0238] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, these salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of an appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof.

[0239] Salts other than those mentioned above which are useful, for example, for the purification or isolation of the compounds of the invention, such as trifluoroacetate, also form part of the invention.

[0240] The compounds according to the invention can also be obtained advantageously using the methods described in the examples hereinafter, which methods can also be used for this purpose in combination with methods known to the person skilled in the art from the literature.

[0241] General Technical Comments

[0242] The terms "ambient temperature" and "room temperature" are used interchangeably and designate a temperature of about 20°C, such as 15°C to 25°C.

[0243] Typically, the prepared compounds have been obtained 1 H-NMR spectrum and / or mass spectrum. Unless otherwise stated, all chromatographic operations were performed at room temperature.

[0244] Synthesis of intermediates

[0245] Intermediate 1.1.I

[0246] N-(2-Cyano-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide

[0247]

[0248] To a mixture of 3-amino-1-benzofuran-2-carbonitrile (4.00 g, 25.3 mmol) in pyridine (40.0 mL) was added TFAA (5.31 g, 25.3 mmol) 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 layers were 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 to 5 / 1).

[0249] ESI-MS: 254.9[M+H] +

[0250] R t (HPLC): 0.56 min (Method A)

[0251] The following intermediates were prepared according to the general procedure above (Intermediate 1.1.I):

[0252]

[0253]

[0254] Intermediate 1.1.III

[0255] N-(2-Cyano-1-benzofuran-3-yl)-2,2-difluoropropionamide

[0256]

[0257] 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 DMF was added HATU (1.04 g, 2.73 mmol) followed by 3-amino-1-benzofuran-2-carbonitrile (474 ​​mg, 3.00 mmol) at RT. After the reaction was stirred at RT for 1.5 h, 2.0 mL of 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) was added to the reaction mixture and stirring was continued. DCM and water were added to the reaction mixture and the product was extracted. The phases were separated and concentrated in vacuo, and the crude product was purified by RP-HPLC (X-Bridge C18, ACN / H2O / TFA).

[0258] ESI-MS: 249[MH]-

[0259] R t (HPLC): 0.53 min (Method A)

[0260] Intermediate 1.2.I

[0261] 6-Chloro-4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]13-1(9),2(7),3,5,10,12-hexaene

[0262]

[0263] 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 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were 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 to 10 / 1).

[0264] ESI-MS: 273[M+H] +

[0265] R t (HPLC): 0.71 min (Method A)

[0266] The following compounds were prepared according to the general procedure above (Intermediate 1.2.I):

[0267]

[0268]

[0269] Intermediate 1.3.I

[0270] (2S,4S)-4-hydroxy-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]-Tridecan-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0271]

[0272] To a preheated mixture of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (1.44 g, 11.0 mmol) in DMSO (25.0 mL) 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 ]13-1(9),2(7),3,5,10,12-hexaene (Intermediate 1.2.I, 2.73 g, 10.0 mmol). Stirring was continued at 110°C for 10 min, after which the reaction mixture was added dropwise to water and acidified with 4M HCl. The precipitate was filtered and dried.

[0273] ESI-MS: 368[M+H] +

[0274] R t (HPLC): 0.50 min (Method A)

[0275] The following compounds were prepared according to the general procedure above (Intermediate 1.3.I):

[0276]

[0277]

[0278] Intermediate 2.1

[0279] 3-(1-Nitroethyl)oxetan-3-ol

[0280] 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, the reaction mixture was stirred at RT for 1 h and then concentrated. The residue was purified by column chromatography (silica gel; CH / EtOAc=75 / 25 to 50 / 50).

[0281] ESI-MS: r 146[MH]-

[0282] R t (EI): 3.38min

[0283] Intermediate 2.2

[0284] 3-(1-Aminoethyl)oxetan-3-ol

[0285]

[0286] A mixture of 3-(1-nitroethyl)oxetan-3-ol (Intermediate 2.1, 24.5 g, 157 mmol), 280 mL of ethanol and Pd(OH)2 / C 5 mol% (5.52 g, 7.87 mmol) was placed in a Parr apparatus under hydrogen pressure (50 psi) for 16 h. The reaction mixture was filtered and concentrated under reduced pressure and used in the next step without further purification.

[0287] ESI-MS: 118 [M+H] +

[0288] R f (TLC): 0.20 (PE / EtOAc=0 / 1)

[0289] Intermediate 2.3

[0290] 2-Chloro-N-[1-(3-hydroxyoxetan-3-yl)ethyl]acetamide

[0291]

[0292] A mixture of 3-(1-aminoethyl)oxetan-3-ol (Intermediate 2.2, 32.4 g, 262 mmol) in 500 mL 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 reach 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 to 85 / 15).

[0293] ESI-MS: 194 [M+H] +

[0294] R t (HPLC): 0.27 min (Method E)

[0295] The following compounds were prepared according to the general procedure above (Intermediate 2.3):

[0296]

[0297] Intermediate 2.4

[0298] 9-Methyl-2,5-dioxa-8-azaspiro[3.5]nonan-7-one

[0299]

[0300] To a stirred, degassed solution of potassium tert-butoxide (1.01 g, 9.03 mmol) in 12.0 mL of tert-amyl alcohol was added 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 at RT under argon over 30 min. After complete addition, 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 to 90 / 10).

[0301] ESI-MS: 158 [M+H] +

[0302] R t (HPLC): 0.24 min (Method E)

[0303] The following compounds were prepared according to the general procedure above (Intermediate 2.4):

[0304]

[0305]

[0306] Intermediate 2.5

[0307] 9-Methyl-2,5-dioxa-8-azaspiro[3.5]nonane

[0308]

[0309] 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 THF under argon was added a 1.0 M solution of LiAlH4 in diethyl ether dropwise while keeping 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 another 16 h.

[0310] The reaction mixture is cooled to 0 ℃, diluted with 60mL anhydrous diethyl ether and continuously treated with 1.33mL water, 1.33mL 4NNaOH aqueous solution and finally 4mL water. Make the reaction mixture reach room temperature and stir for 15min. The mixture is dried over sodium sulfate, then filtered and evaporated in a vacuum solvent. The gained residue is coevaporated twice with ACN to remove residual water.

[0311] ESI-MS: 144 [M+H] +

[0312] R t (HPLC): 0.17 min (Method E)

[0313] The following compounds were prepared according to the general procedure above (Intermediate 2.5):

[0314]

[0315] Intermediate 2.6.I

[0316] 8-(5-Bromo-2-nitropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane

[0317]

[0318] To a mixture of 5-bromo-3-fluoro-2-nitropyridine (1.00 g, 4.53 mmol) in 20.0 mL ACN was added KCO (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 phases were dried over NaSO and concentrated.

[0319] ESI-MS: 344 / 346 [M+H] +

[0320] R t (HPLC): 0.85 min (Method B)

[0321] The following compounds were prepared according to the general procedure above (Intermediate 2.6.I):

[0322]

[0323]

[0324]

[0325]

[0326] Intermediate 2.7.I

[0327] 9-Methyl-8-(2-nitro-5-{2-[tri(prop-2-yl)silyl]ethynyl}pyridin-3-yl)-2,5-dioxa-8-azaspiro[3.5]nonane

[0328]

[0329] To a degassed solution of 8-(5-bromo-2-nitropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane (Intermediate 2.6.1, 584 mg, 1.70 mmol) in 6.80 mL of THF under argon was added DIPEA (2.31 mL, 12.8 mmol) followed by (triisopropylsilyl)-acetylene (0.780 mL, 3.40 mmol), PdCl2(PPh3)2 (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 / EtOAc=50 / 50 to 60 / 40).

[0330] ESI-MS: 446[M+H] +

[0331] R t (HPLC): 0.66 min (Method G)

[0332] The following compounds were prepared according to the general procedure described above (Intermediate 2.7.I):

[0333]

[0334]

[0335] Intermediate 3.1.I(a)

[0336] (a): (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-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-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0337]

[0338] At RT, (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 To a mixture of 1-(tridecyl-1(9),2(7),3,5,10,12-hexen-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) in 20 mL of DMA was added NaH (326 mg, 8.16 mmol). The mixture was stirred overnight at RT. 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 provide two diastereomers (a) and (b). The diastereomer (a) was carried forward to the next step.

[0339] ESI-MS: 646 / 648 [M+H] +

[0340] R t (HPLC): 1.03 min (Method C) - diastereomer (a)

[0341] 1.08min (Method C) - Diastereomer (b)

[0342] The following compounds were prepared according to the general procedure above (Intermediate 3.1.I):

[0343]

[0344] Intermediate 3.2

[0345] (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-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-hexen-6-yl]pyrrolidine-2-carboxylic acid tert-butyl ester

[0346]

[0347] To a solution of (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ] 13-1 (9), 2 (7), 3, 5, 10, 12-hexene-6-yl] pyrrolidine-2-carboxylic acid (Intermediate 3.1.I (a), 110 mg, 0.170 mmol) was added 2-tert-butyl-1, 3-diisopropylisourea (162 μL, 0.68 mmol). The reaction mixture was stirred at 70 ° C in a microwave oven for 1 h. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; CH / EtOAc = 93 / 7 to 60 / 40).

[0348] ESI-MS: 702 / 704 [M+H] +

[0349] R t (HPLC): 0.87 min (Method A)

[0350] Intermediate 3.3

[0351] (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-hexen-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-carboxylic acid tert-butyl ester

[0352]

[0353] Under argon, (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]13-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid tert-butyl ester (Intermediate 3.2, 132 mg, 0.150 mmol) was added with bis(pinacol)-diboron (113 mg, 0.445 mmol), Pd(dppf)Cl2 (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 treated with a phase separator and concentrated under reduced pressure.

[0354] ESI-MS: 750[M+H] +

[0355] R t (HPLC): 0.90 min (Method A)

[0356] Intermediate 3.4.I

[0357] (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-hexen-6-yl]-4-({N,N-dimethyl-5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]-[3,4'-bipyridyl]-2'-yl}oxy)pyrrolidine-2-carboxylic acid tert-butyl ester

[0358]

[0359] Under argon, (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-hexen-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-carboxylic acid tert-butyl ester (Intermediate 3.3, 105 mg, 0.0700 mmol) were added 4-bromo-N,N-dimethylpyridin-2-amine (22.0 mg, 0.109 mmol), Pd(PPh3)4 (9.7 mg, 0.0080 mmol), third generation Xphos (6.0 mg, 0.0070 mmol) and sodium carbonate solution 2 mol / L (105 μL, 0.210 mmol). The reaction mixture was at 100° C. for 1.5 h. The reaction mixture was diluted with ACN / water, filtered and purified by RP-HPLC (Xbridge-C18, ACN / H 2 O / 0.1% NH 4 OH).

[0360] ESI-MS: 744[M+H] +

[0361] R t (HPLC): 0.64 min (Method A)

[0362] The following compounds were prepared according to the general procedure above (Intermediate 3.4.I):

[0363]

[0364] Intermediate 4.1

[0365] 4-Bromo-3-methoxy-N,N-dimethylpyridin-2-amine

[0366]

[0367] 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.

[0368] ESI-MS: 231 / 233 [M+H] +

[0369] R t (HPLC): 0.30 min (Method A)

[0370] Intermediate 5.1

[0371] 4-iodo-3-methoxy-N-methylpyridin-2-amine

[0372]

[0373] 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 h and then concentrated under reduced pressure.

[0374] ESI-MS: 265[M+H] +

[0375] R t (HPLC): 0.26 min (Method A)

[0376] Intermediate 6.1

[0377] 8-(2,5-difluoropyridin-3-yl)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonane

[0378]

[0379] Under 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. Then, a solution of isopropylmagnesium chloride lithium chloride complex in THF (1.92 mL; 2.5 mmol) was added dropwise. The reaction mixture was allowed to reach 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 another 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 at -78 °C with stirring. After completion of the addition, the reaction mixture was warmed to 0 °C, stirred for 30 min, then warmed to RT and stirred for an additional 1 h. The reaction mixture was poured into a saturated NH4Cl solution 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 / H2O, filtered and purified by RP-HPLC.

[0380] ESI-MS: 257 [M+H] +

[0381] R t (HPLC): 0.45 min (Method A)

[0382] Intermediate 7.1.I

[0383] 5-Chloro-2-fluoro-3-{4H,5H,6H,7H-[1,2]oxazolo[4,3-c]pyridin-5-yl}pyridine

[0384]

[0385] 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 at RT for 30 min and then at 50 °C for 3 h. Again, TBAF (1.50 mL, 1.50 mmol) was added and the reaction mixture was stirred at 50 °C for 5 h. ACN / water was added to the reaction mixture, the precipitate was collected by filtration and purified by RP-HPLC (Xbridge C18, ACN / HO / TFA).

[0386] ESI-MS: 254 / 256 [M+H] +

[0387] R t (HPLC): 0.77 min (Method E)

[0388] The following compounds were prepared according to the general procedure above (Intermediate 7.1.1):

[0389]

[0390] Intermediate 8.1

[0391] (2S,4S)-4-{[5-ethynyl-3-(morpholin-4-yl)pyridin-2-yl]oxy}pyrrolidine-2-carboxylic acid

[0392]

[0393] To (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (202 mg, 0.83 mmol) in 3.00 mL DMA was added NaH (99.8 mg, 2.50 mmol). This mixture was stirred at RT for 30 min before 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 DMA was added. After the reaction mixture was stirred at RT for 2 h, 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 in 10.0 mL DCM and 1.00 ml TFA was added. The reaction mixture was stirred overnight at RT and concentrated to give the title compound.

[0394] ESI-MS: 318[M+H] +

[0395] R t (HPLC): 0.67 min (Method C)

[0396] Intermediate 9.1(a)

[0397] (2S,4S)-1-[(tert-Butyloxy)carbonyl]-4-({5-ethynyl-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid

[0398]

[0399] 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-[tri(propan-2-yl)silyl]ethynyl}pyridin-3-yl)-2,5-dioxa-8-azaspiro[3.5]nonane (Intermediate 2.7.1, 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 h 20 min. The reaction mixture was quenched with water, acidified with 1 N HCl, filtered and extracted three times with EtOAc. The organic phases were combined and 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 with a saturated solution of NH4Cl. The organic phases were combined and dried over sodium sulfate, filtered and evaporated. The residue was purified by HPLC (Xbridge, ACN / H2O / TFA).

[0400] ESI-MS: 474[M+H] +

[0401] R t (HPLC): 0.63 min (Method A) - diastereomer (a)

[0402] 0.66min (Method A) -Diastereomer (b)

[0403] Intermediate 9.2

[0404] (2S,4S)-4-({5-ethynyl-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid

[0405]

[0406] To (2S,4S)-1-[(tert-butoxy)carbonyl]-4-({5-ethynyl-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid (Intermediate 9.1(a), 40 mg, 0.080 mmol) in 3.00 mL 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.

[0407] ESI-MS: 374[M+H] +

[0408] R t (HPLC): 0.36 min (Method A)

[0409] Intermediate 10.1

[0410] 4-(Difluoromethyl)-2-methoxybenzonitrile

[0411]

[0412] To 4-formyl-2-methoxybenzonitrile (806 mg, 5.00 mmol) in 3.00 mL of DCM was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (50% solution in toluene, 3.13 mL, 8.50 mmol) and ethanol (1.00 mmol, 57.6 μL). 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 this mixture at RT for 1 h, it was poured into saturated aqueous NaHCO3 solution 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 as is in the next step.

[0413] R t (HPLC): 0.49min (Method A)

[0414] Intermediate 10.2

[0415] 4-(Difluoromethyl)-2-hydroxybenzonitrile

[0416]

[0417] A mixture of 2-(diethylamino)ethanethiol (300 mg, 1.77 mmol) in 3.00 mL 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 reach RT. A solution of 4-(difluoromethyl)-2-methoxybenzonitrile (intermediate 10.1, 50.0 mg, 0.270 mmol) in 2.00 mL DMF was added at RT and the resulting mixture was heated to 160 ° C and maintained for 1.5 h under stirring. The reaction mixture was then cooled to 0 ° C and acidified with 1N HCl aqueous solution. 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).

[0418] ESI-MS: 170 [M+H]+

[0419] R t (HPLC): 0.41 min (Method A)

[0420] Intermediate 10.3.I

[0421] 3-Amino-6-(difluoromethyl)-1-benzofuran-2-carboxamide

[0422]

[0423] To 4-(difluoromethyl)-2-hydroxybenzonitrile (120 mg, 0.71 mmol) in 5.00 mL of ethanol was added KCO (Intermediate 10.2, 150 mg, 1.09 mmol) and 2-bromoacetamide (119 mg, 0.87 mmol). The reaction mixture was heated at reflux for 2 h. The reaction mixture was allowed to reach RT and KOH (95.1 mg, 1.44 mmol) was added. The mixture was then heated at reflux for 2 h. After cooling to RT, the reaction mixture was diluted with water. The ethanol was evaporated in vacuo, the precipitate was collected by filtration, washed with water and dried.

[0424] ESI-MS: 227 [M+H] +

[0425] R t (HPLC): 0.39 min (Method A)

[0426] The following compounds were prepared according to the general procedure above (Intermediate 10.3.I):

[0427]

[0428] Intermediate 10.4.I

[0429] 6-Chloro-11-(difluoromethyl)-4-methyl-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]13-1(9),2(7),3,5,10,12-hexaene

[0430]

[0431] 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 argon atmosphere. The mixture was diluted with 0.5 mL of phosphorus oxychloride and then added dropwise to 3-amino-6-(difluoromethyl)-1-benzofuran-2-carboxamide (Intermediate 10.3.1, 76.0 mg, 0.34 mmol). After the addition was complete, the mixture was heated to 50 °C and stirred for 3 h. Again, phosphorus oxychloride (184 μL, 2.02 mmol) was added 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, the organic phase was dried, filtered and evaporated.

[0432] ESI-MS: 269[M+H] +

[0433] R t (HPLC): 0.62min (Method A)

[0434] The following compounds were prepared according to the general procedure above (Intermediate 10.4.I):

[0435]

[0436]

[0437] Intermediate 11.1

[0438] (2S)-1-(5-Bromo-2-nitropyridin-3-yl)-2-methylhexahydropyrazine

[0439]

[0440] To 5-bromo-3-fluoro-2-nitropyridine (200 mg, 0.91 mmol) in 4.00 mL of ACN was added tert-butyl (3S)-3-methylhexahydropyrazine-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 NaHCO3l solution and saturated NaCl solution. The organic phase was dried, filtered and concentrated. The residue was diluted in 4N HCl in dioxane, stirred at RT for 45 min and concentrated to give the title compound as a salt.

[0441] ESI-MS: 301 / 303 [M+H] +

[0442] R t(HPLC): 0.70 min (Method C)

[0443] Intermediate 11.2

[0444] (3S)-4-(5-Bromo-2-nitropyridin-3-yl)-3-methylhexahydropyrazine-1-carbonitrile

[0445]

[0446] To (2S)-1-(5-bromo-2-nitropyridin-3-yl)-2-methylhexahydropyrazine hydrochloride (Intermediate 11.1, 80.0 mg, 0.24 mmol) in 2.00 mL of DCM was 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. Again, cyanogen bromide (3 mol / L in DCM, 86.9 μL, 0.261 mmol) was added to the reaction mixture and stirring was continued at RT for 1 h. The reaction mixture was quenched with half-saturated aqueous NaHCO3. The phases were separated and extracted with DCM. The combined organic phases were purified by HPLC. The phases were separated and dried and evaporated.

[0447] ESI-MS: 326 / 328 [M+H] +

[0448] R t (HPLC): 0.83 min (Method C)

[0449] Intermediate 12.1

[0450] (5S)-5-Methyl-1,2,6-triazaspiro[2.5]oct-1-ene-6-carboxylic acid tert-butyl ester

[0451]

[0452] To (2S)-2-methyl-4-oxopyridine-1-carboxylic acid tert-butyl ester (1.00 g, 4.69 mmol) was added 6.70 mL of ammonia (7N in methanol) at 0 °C. The reaction mixture was stirred and allowed to reach 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 reach 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 mL72 mL) and extracted with 10% Na2CO3 aqueous solution (15 mL). The organic phase was extracted with water and The phase separator was dried.

[0453] 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 reach RT. The reaction mixture was quenched with 5% sodium sulfite solution and extracted with 10% NaCl aqueous solution. The organic phase was dried over Na2SO4, filtered and evaporated. The product was purified by HPLC (Sunfire, ACN / H2O / TFA).

[0454] ESI-MS: 248[M+Na] +

[0455] R t (HPLC): 1.09 min (Method C)

[0456] Intermediate 12.2

[0457] (5S)-5-Methyl-1,2,6-triazaspiro[2.5]oct-1-ene

[0458]

[0459] 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.

[0460] ESI-MS: 126[M+H] +

[0461] R t (HPLC): 0.11 min (Method C)

[0462] Intermediate 13.1

[0463] 2-Methylpiperidinium 3-carboxylic acid methyl ester acetate

[0464]

[0465] 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 80°C under 3 bar for 12 h. The reaction mixture was filtered and concentrated under reduced pressure and used in the next step without further purification.

[0466] ESI-MS: 158 [M+H] +

[0467] Rt (HPLC): 0.27 min (Method N)

[0468] Intermediate 13.2

[0469] 2-Methylpiperidinium-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester

[0470]

[0471] To methyl 2-methylpiperidine-3-carboxylate (Intermediate 13.1, 15.0 g, 60.4 mmol) in 90.0 mL 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 half-saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (silica gel; CH / EtOAc=99 / 1 to 1 / 99).

[0472] ESI-MS: 258[M+H] +

[0473] R t (HPLC): 0.65 min (Method F)

[0474] Intermediate 13.3

[0475] 2-Methylpiperidinium-1,3,3-tricarboxylic acid 1-tert-butyl ester 3,3-dimethyl ester

[0476]

[0477] To a solution of lithium diisopropylamide (2 mol / L, 11.1 mL, 22.2 mmol) in 32.5 mL THF was added 2-methylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (intermediate 13.2, 5.00 g, 18.5 mmol) in 20.0 mL THF at -78 ° C under argon. The reaction mixture was allowed to reach -20 ° C and stirred for 30 min. 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 THF was added dropwise to the reaction mixture. During the addition, the temperature was kept below -65 ° C. After complete addition, the reaction mixture was allowed to reach RT and stirred at RT for 2 h. The reaction mixture was quenched with a saturated NH4Cl solution and stirred at RT for 10 min. The mixture was diluted with water and extracted with DCM. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel; CH / EtOAc=95 / 5 to 60 / 40).

[0478] ESI-MS: 316[M+H] +

[0479] R f (TLC): 0.29 (CH / EtOAc=20 / 80)

[0480] Intermediate 13.4

[0481] tert-Butyl 3,3-bis(hydroxymethyl)-2-methylpiperidinium-1-carboxylate

[0482]

[0483] To a degassed solution of 2-methylpiperidin-1,3,3-tricarboxylic acid 1-tert-butyl ester 3,3-dimethyl ester (Intermediate 13.3, 5.60 g, 16.9 mmol) in 44.8 mL THF was added dropwise LiAlH4 (2.3 mol / L in 2-methyltetrahydrofuran, 14.6 mL, 33.7 mmol) at RT under argon and this mixture was stirred at RT for 1.5 h. The reaction mixture was cooled to 0°C, diluted with 80.0 mL diethyl ether and carefully treated with 1.25 mL water, then 1.25 mL 4N NaOH and finally 3.75 mL water. The reaction mixture was allowed to reach RT and stirred for 15 min. The mixture was dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH / EtOAc=75 / 25 to 0 / 100).

[0484] ESI-MS: 260 [M+H] +

[0485] R f (TLC): 0.14 (CH / EtOAc=50 / 50)

[0486] Intermediate 13.5

[0487] tert-Butyl 5-methyl-2-oxa-6-azaspiro[3.5]nonane-6-carboxylate

[0488]

[0489] To tert-butyl 3,3-bis(hydroxymethyl)-2-methylpiperidin-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. Ziram (483 mg, 1.50 mmol) and diisopropyl azodicarboxylate (413 μL, 2.00 mmol) were then 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% NH3 aqueous solution. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; DCM / EtOAc=95 / 5 to 70 / 30). The residue was purified by HPLC (Sunfire, ACN / H2O / TFA).

[0490] ESI-MS: 242 [M+H] +

[0491] R t (HPLC): 0.80 min (Method E)

[0492] Intermediate 13.6

[0493] 5-Methyl-2-oxa-6-azaspiro[3.5]nonane

[0494]

[0495] 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.

[0496] ESI-MS: 142 [M+H] +

[0497] R t(HPLC): 0.17 min (Method E)

[0498] Intermediate 14.1

[0499] 2-(Cyanomethoxy)-4-ethylbenzonitrile

[0500]

[0501] To a mixture of 4-ethyl-2-hydroxy-benzonitrile (2.34 g, 16.2 mmol) and potassium carbonate (4.83 g, 35.0 mmol) in 40.0 mL of DMF was added bromoacetonitrile (1.22 mL, 17.5 mmol) 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.

[0502] Intermediate 14.2

[0503] 3-Amino-6-ethyl-1-benzofuran-2-carbonitrile

[0504]

[0505] To a mixture of 2-(cyanomethoxy)-4-ethylbenzonitrile (Intermediate 14.1, 1.79 g, 10.0 mmol) in 40.0 mL THF was added potassium tert-butoxide (108 mg, 0.964 mmol) and the mixture was stirred overnight at RT. The solvent was evaporated in vacuo and the product was purified by column chromatography and used as such in the next step.

[0506] Intermediate 14.3

[0507] N-(2-Cyano-6-ethyl-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide

[0508]

[0509] 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.

[0510] Intermediate 14.4

[0511] 6-Chloro-11-ethyl-4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]13-1(13),2,4,6,9,11-hexaene

[0512]

[0513] 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 into water and extracted with EtOAc. The combined organic layers were washed with brine and evaporated. The residue was purified by column chromatography (silica gel; CH / EtOAc=100 / 0 to 95 / 5).

[0514] ESI-MS: 301 / 303 [M+H] +

[0515] R t (HPLC): 0.79 min (Method A)

[0516] Intermediate 15.1

[0517] 3-(2-Chloroacetylamino)-1-benzofuran-2-carboxamide

[0518]

[0519] 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 min. Chloroacetyl chloride (4.00 mL, 50 mmol) was added and stirring was continued at 60 °C for 20 min. The reaction mixture was poured into water, the precipitate was collected by filtration, resuspended in water, filtered and washed with water. The crude product was used as is in the next step without further purification.

[0520] ESI-MS: 253 [M+H] +

[0521] R t (HPLC): 0.41 min (Method A)

[0522] Intermediate 15.2

[0523] 4-(Hydroxymethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,10,12-penten-6-one

[0524]

[0525] A mixture of 3-(2-chloroacetylamino)-1-benzofuran-2-carboxamide (Intermediate 15.1, 5.80 g, 23.0 mmol) in 2M aqueous NaOH solution was stirred at 60° C. for 10 min. After cooling to RT, stirring was continued for 10 h, and then the pH was adjusted to 1 by adding concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and dried.

[0526] ESI-MS: 217 [M+H] +

[0527] R t (HPLC): 0.59 min (Method C)

[0528] Intermediate 15.3

[0529] 6-Chloro-4-(chloromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]13-1(9),2(7),3,5,10,12-hexaene

[0530]

[0531] Phosphorus oxychloride (30 mL, 328 mmol) was added to 4-(hydroxymethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]tridec-1(9),2(7),3,10,12-pentene-6-one (Intermediate 15.2, 5.00 g, 17.3 mmol) with stirring and the resulting mixture was heated at 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 solution. The mixture was filtered through 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).

[0532] ESI-MS: 253 [M+H] +

[0533] R t (HPLC): 1.07 min (Method C)

[0534] Intermediate 16.1

[0535] (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]-Tridecan-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0536]

[0537] To a degassed mixture of Example 1.10 (1.50 g, 2.26 mmol), bis-(pinacol)-diboron (630 mg, 2.48 mmol) and potassium acetate (670 mg, 6.93 mmol) in 30 mL of dioxane was added Pd(dppf)Cl2 (165 mg, 0.226 mmol) under argon atmosphere. The reaction mixture was heated to 90 ° C and maintained for 3 h, then cooled to RT, poured into 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).

[0538] ESI-MS: 712[M+H] +

[0539] R t (HPLC): 1.05 min (Method A)

[0540] Preparation of final compounds

[0541] Example 1.01 (General Approach)

[0542] (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 ]tridecyl-1(13),2,4,6,9,11-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0543]

[0544] To 2.00 mL of DMA was added (2S,4S)-4-hydroxy-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,74-(5-chloro-2-nitropyridin-3-yl)morpholine-2-carbonitrile (Intermediate 2.6.III, 80.6 mg, 0.30 mmol, 2.0 eq) and NaH (18.0 mg, 0.45 mmol, 3.0 eq) were added to 13-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid (Intermediate 1.3.I, 58.0 mg, 0.15 mmol). 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 / H2O / TFA). The product was obtained as a mixture of two diastereomers.

[0545] ESI-MS: 589[M+H] +

[0546] R t (HPLC): 1.05 min (Method H)

[0547] The compounds listed in the table below were prepared according to the general procedure described above (Example 1.01). Where indicated in the table, the example compounds were isolated as a diastereomeric mixture (ds-mixture) or as pure diastereoisomers (Rt is given for both the isolated diastereoisomers (Example and the 2nd diastereoisomer (2nd ds)).

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557] The absolute stereochemistry of Example 1.10 was confirmed via small molecule X-ray as illustrated below:

[0558]

[0559] The absolute stereochemistry of Example 1.28 was confirmed via small molecule X-ray as illustrated below:

[0560]

[0561] Example 2.01 (General Approach)

[0562] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]13-1(13),2,4,6,9,11-hexen-6-yl]-4-{[5-ethynyl-3-(morpholin-4-yl)pyridin-2-yl]oxy}-pyrrolidine-2-carboxylic acid

[0563]

[0564] To 6-chloro-4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ] tridecan-1(9),2(7),3,5,10,12-hexaene (Intermediate 1.2.II, 30.0 mg, 0.12 mmol) was added with (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 / H2O / TFA).

[0565] ESI-MS: 536[M+H] +

[0566] R t (HPLC): 1.08 min (Method C)

[0567] The following examples were prepared according to the general procedure described above (Example 2.1):

[0568]

[0569]

[0570]

[0571] Example 3.01 (General Approach)

[0572] (2S,4S)-4-({5-[(3S)-3-methylmorpholin-4-yl]-[3,4'-bipyridyl]-6-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7 ]tridecyl-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0573]

[0574] Under argon, (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 To a mixture of 1-(9), 2-(7), 3, 5, 10, 12-hexen-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), 3rd generation Xphos (3.40 mg) and Pd(PPh3)4 (4.64 mg) 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).

[0575] ESI-MS: 621[M+H] +

[0576] R t (HPLC): 0.818 min (Method B)

[0577] The following examples were prepared according to the general procedure described above (Example 3.01). The boronate esters or boronic acids used were commercially available or easily prepared as described in the literature (Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 1 and 2, 2nd edition, ISBN 9783527325986).

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587] Example 4.01 (General Approach)

[0588] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]13-1(9),2(7),3,5,10,12-hexen-6-yl]-4-({N,N-dimethyl-5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]-[3,4'-bipyridyl]-2'-yl}oxy)pyrrolidine-2-carboxylic acid

[0589]

[0590] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 To tert-butyl]-1(9),2(7),3,5,10,12-hexen-6-yl]-4-({N,N-dimethyl-5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]-[3,4'-bipyridyl]-2'-yl}oxy)pyrrolidine-2-carboxylate (Intermediate 3.4.1, 13 mg, 0.020 mmol) was added trifluoroacetic acid (650 μL, 8.49 mmol). The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The crude product was purified by HPLC (Xbridge, ACN / H2O / TFA).

[0591] ESI-MS: 688[M+H] +

[0592] R t (HPLC): 0.51 min (Method A)

[0593] The following examples were prepared according to the general procedure described above (Example 4.1):

[0594]

[0595]

[0596] Example 5.01

[0597] (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]13-1(9),2(7),3,5,10,12-hexen-6-yl]-4-({2'-methanesulfinyl-5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]-[3,4'-bipyridinyl]-6-yl}oxy)pyrrolidine-2-carboxylic acid

[0598]

[0599] At -15°C, (2S,4S)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 To a cooled solution of 1-(1-(9),2-(7),3,5,10,12-hexen-6-yl)-4-({5-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]nonan-8-yl]-2'-(methylthio)-[3,4'-bipyridyl]-6-yl}oxy)-pyrrolidine-2-carboxylic acid (Example 3.16, 25.0 mg, 0.04 mmol) in 1.00 mL of DCM was added meta-chloroperbenzoic acid (7.30 mg, 0.03 mmol). The reaction mixture was stirred at -15 °C for 10 min and then purified by HPLC (Xbridge, ACN / H2O / TFA).

[0600] ESI-MS: 707[M+H] +

[0601] R t (HPLC): 0.85 min (Method H)

[0602] Example 6.01

[0603] (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-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 ]Tridecan-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0604]

[0605] To (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 To a degassed solution of 1-(9),2(7),3,5,10,12-hexen-6-yl)pyrrolidine-2-carboxylic acid (Example 1.10, 150 mg, 0.230 mmol) in 5.00 mL of THF was added copper (I) iodide (4.3 mg, 0.023 mmol) followed by Pd (dppf) Cl 2 (33 mg, 0.050 mmol). After stirring for a few 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 / H 2 O / TFA).

[0606] ESI-MS: 624[M+H] +

[0607] R t (HPLC): 1.08 min (Method E)

[0608] The following examples were prepared according to the general procedure above (Example 6.01):

[0609]

[0610]

[0611] Example 7.01

[0612] (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]-5-(pyrimidin-5-yl)pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]tridecyl-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0613]

[0614] To (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-[7.4.0.02,7]-trideca-1(9),2(7),3,5,1 0,12-hexen-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) in a degassed mixture of 5.00 mL dioxane were added 3rd generation Xphos (15 mg, 0.018 mmol). The reaction mixture was heated to 80 ° C and maintained for 2 h, then 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 layers were washed with saturated ammonium chloride solution and dried over sodium sulfate, filtered, evaporated and purified by HPLC (Sunfire, ACN / H2O / TFA).

[0615] ESI-MS: 692[M+H] +

[0616] R t (HPLC): 1.01min (E)

[0617] The following examples were prepared according to the general procedure above (Example 7.01):

[0618]

[0619]

[0620] Example 8.01

[0621] (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[7.4.0.0 2,7 ]tridecyl-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0622]

[0623] 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 DMSO and 0.10 mL water was stirred at RT for 1 h. Then, 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 / H2O, acidified with TFA, filtered and purified by HPLC.

[0624] ESI-MS: 667[M+H] +

[0625] R t (HPLC): 0.87 min (Method P)

[0626] Example 9.01

[0627] (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-hexen-6-yl]-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]-5-(methylthio)pyridin-2-yl}oxy)pyrrolidine-2-carboxylic acid

[0628]

[0629] (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-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-hexen-6-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 Pd2(dba)3 (16 mg, 0.017 mmol) in 8.00 mL of dioxane were 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, H2O / ACN / TFA).

[0630] ESI-MS: 614[M+H] +

[0631] Rt (HPLC): 1.01 min (Method C)

[0632] Example 10.01

[0633] (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 ]Tridecyl-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid

[0634]

[0635] Under an argon atmosphere, (2S,4S)-4-({5-bromo-3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 To a degassed mixture of 1-tridecyl-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid (Example 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) in 1.50 mL of dioxane 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.

[0636] ESI-MS: 652[M+H] +

[0637] Rt (HPLC): 1.01 min (method P)

[0638] Preparation of prodrugs:

[0639] Prodrug P01

[0640] (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]pyridin-2-yl}oxy)-1-[4-(difluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]tridecyl-1(9),2(7),3,5,10,12-hexen-6-yl]pyrrolidine-2-carboxylic acid methyl ester

[0641]

[0642] To 1.0 mL of THF was added (2S,4S)-4-({3-[(9S)-9-methyl-2,5-dioxa-8-azaspiro[3.5]non-8-yl]-pyridin-2-yl}-oxy)1-[4-(difluoro-methyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 To 1-(13-(2,4,6,9,11-hexen-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 / H2O / TFA).

[0643] ESI-MS: 582[M+H] +

[0644] R t (HPLC): 0.69 min (Method A)

[0645] The following compounds were prepared according to the general procedure described above (prodrug P01):

[0646]

[0647]

[0648] List of abbreviations

[0649] ACN Acetonitrile

[0650] aq. water-based

[0651] ℃ Celsius

[0652] CH Cyclohexane

[0653] DBU diazabicyclo[5.4.0]undec-7-ene

[0654] DCM Dichloromethane

[0655] DIPEA Diisopropylethylamine

[0656] DMA Dimethylacetamide

[0657] DMF N,N-Dimethylformamide

[0658] ds diastereomer

[0659] ESI-MS Electrospray ionization mass spectrometry

[0660] EtOAc Ethyl acetate

[0661] eq equivalent

[0662] FA Formic acid

[0663] FC Flash chromatography, if no other details are given, using SiO2 h hour

[0664] HCl Hydrogen chloride

[0665] HATU [Dimethylamino-(1,2,3-triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate

[0666] HPLC High Performance Liquid Chromatography

[0667] K2CO3 Potassium carbonate

[0668] KOH Potassium Hydroxide

[0669] L Liter

[0670] LiAlH4 Lithium Aluminum Hydride

[0671] LiHMDS Lithium Hexamethyldisilazide

[0672] MeOH Methanol

[0673] min

[0674] mL milliliters

[0675] M Moore

[0676] MS

[0677] nd Not determined

[0678] NH4OH NH3 solution in water

[0679] Pd2(dba)3-(dibenzylideneacetone)dipalladium(0)

[0680] Pd(dppf)Cl2 (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)

[0681] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0682] Pd(OH)2 / C Palladium hydroxide on carbon 20%

[0683] RT Room temperature (about 20℃)

[0684] Sol

[0685] tBuBrettPhos (Propan-2-en-1-yl)palladium[3,6-dimethoxy-2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane trifluoromethanesulfonic acid di-tert-butyl ester TBS tert-Butyl-dimethylsilyl

[0686] TBAF Tetrabutylammonium fluoride

[0687] TEA Triethylamine

[0688] TFA Trifluoroacetic acid

[0689] TFAA Trifluoroacetic anhydride

[0690] THF Tetrahydrofuran

[0691] TIPS Triisopropylsilyl

[0692] TMS Trimethylsilyl

[0693] TosOH p-Toluenesulfonic acid monohydrate

[0694] TLC Thin Layer Chromatography

[0695] RP-HPLC Reverse Phase HPLC R f Delay Factor (TLC)

[0696] R t Residence time (minutes)

[0697] Vol% Volume Percentage

[0698] The third generation Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-

[0699] (2'-amino-1,1'-biphenyl)-methanesulfonate palladium(II)

[0700] Ziram dimethyl dithiocarbamate zinc salt

[0701] Analytical HPLC Method:

[0702] Method A

[0703] Time (min) Vol% Water (including 0.1% TFA) Vol%ACN Flow rate [mL / min] 0.00 99 1 1.6 0.02 99 1 1.6 1.00 0 100 1.6 1.10 0 100 1.6

[0704] Analytical column: XBridge BEH C18_2.1x 30mm, 1.7μm; column temperature: 60℃

[0705] Method B

[0706]

[0707] Analytical column: Stable Bond (Agilent) 1.8 μm; 3.0 x 30 mm; column temperature: 60 °C

[0708] Method C

[0709]

[0710] Analytical column: Sunfire (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0711] Method D

[0712]

[0713] Analytical column: XBridge C18_3.0x 30mm_2.5μm (Waters); column temperature: 60°C

[0714] Method E

[0715]

[0716]

[0717] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0718] Method F

[0719] Time (min) Vol% water (including 0.1% NH3) Vol%ACN Flow rate [mL / min] 0.00 95 5 1.3 0.02 95 5 1.3 1.00 0 100 1.3 1.30 0 100 1.3

[0720] Analytical column: XBridge BEH (Waters) C18_2.1x 30mm, 2.5μm; column temperature: 60°C

[0721] Method G

[0722] Time (min) Vol% Water (including 0.1% TFA) Vol%ACN Flow rate [mL / min] 0.00 50 50 1.6 0.02 50 50 1.6 1.00 0 100 1.6 1.10 0 100 1.6

[0723] Analytical column: XBridge BEH (Waters) C18_2.1x 30mm, 1.7μm; column temperature: 60°C

[0724] Method H

[0725]

[0726] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C Method I

[0727] Time (min) Vol% water (including 0.1% NH3) Vol%ACN Flow rate [mL / min] 0.00 97 3 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0

[0728] Analytical column: XBridge (Waters) C18_3.0x 30mm, 2.5μm; column temperature: 60°C

[0729] Method J

[0730]

[0731]

[0732] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0733] Method K

[0734]

[0735] Analytical column: Xbridge C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0736] Method L

[0737] Time (min) Vol.% Carbon dioxide Vol.%Methanol Flow rate [mL / min] 0.00 97 3 1.3 2.50 55 45 1.3 3.50 55 45 1.3 3.51 97 3 1.3 4.00 97 3 1.3

[0738] Analytical column: Acquity UPC2 Torus 2-PIC (Waters) 1.7 μm; 3.0×100 mm; column temperature: 30°C

[0739] Method M

[0740] Time (min) Vol.% Water (including 0.1% FA) Vol. %ACN Flow rate [mL / min] 0.00 97 3 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0

[0741] Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60 °C

[0742] Method N

[0743]

[0744] Analytical column: XSelect HSS PFP (Waters) 1.8 μm; 2.1 x 30 mm; column temperature: 60 °C

[0745] Method O

[0746]

[0747] Analytical column: Acquity UPLC BEH C18 (Waters) 1.7 μm; 2.1×100 mm; column temperature: 40°

[0748] Method P

[0749]

[0750] Column: Sunfire C18 (Waters) 2.5 μm; 3.0 x 30 mm; CT: 60°C

[0751] Example

[0752] 5.1 Example compounds

[0753] The following example compounds of formula (I) or formula (I') as summarized in Table 1 have been synthesized and tested for their pharmacological properties with respect to their efficacy in inhibiting cGAS activity.

[0754] Specifically, the "biochemical (in vitro) IC50 value" for cGAS inhibition (hcGAS IC50), 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) IC50) and "IC50 values ​​for inhibition of IFN induction in dsDNA stimulated human whole blood" (hWB IC50) have been experimentally determined according to the analytical methods described in Section 6 below. The results are summarized in Table 1.

[0755] The example compounds of formula (I) or formula (I') as summarized in Table 1 simultaneously exhibit the following three properties:

[0756] A satisfactory "biochemical (in vitro) IC50 value for cGAS inhibition" (hcGAS IC50 ≤ 100 nM, more preferably ≤ 50 nM, in particular ≤ 10 nM),

[0757] Satisfactory "Cellular IC50 values ​​for cGAS inhibition" (THP1 (vir) IC50 ≤ 1 μM, more preferably ≤ 500 nM, more preferably ≤ 100 nM, specifically ≤ 50 nM)

[0758] and

[0759] Satisfactory selectivity for cGAS inhibition

[0760] (THP1(cGAMP) IC50 / THP1 (vir) The IC50 ratio is ≥10, more preferably ≥50, more preferably ≥500, specifically ≥1000).

[0761] In addition, the example compounds of formula (I) or formula (I') also showed acceptable IC50 values ​​for the inhibition of IFN induction in dsDNA-stimulated human whole blood (hWB IC50).

[0762] Table 1: Pharmacological properties of the example compounds of the present invention

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784] 5.2 Comparison of Example Compounds with Prior Art Compounds

[0785] 5.2.1 Compounds of WO 2020 / 142729

[0786] In WO 2020 / 142729, cGAS inhibitors with potential similar structures have been disclosed. On pages 44 and 45 of WO 2020 / 142729, "biochemical (in vitro) IC50 values" (corresponding to "hcGASIC50") for cGAS inhibition have been disclosed. Therefore, compounds with "biochemical (in vitro) IC50 values" less than 100nM are named "Group A", compounds with "biochemical (in vitro) IC50 values" greater than 100nM and less than 500nM are named "Group B", compounds with "biochemical (in vitro) IC50 values" greater than 500nM and less than 1μM are named "Group C", compounds with "biochemical (in vitro) IC50 values" greater than 1μM and less than 10μM are named "Group D", and compounds with "biochemical (in vitro) IC50 values" greater than 10μM are named "Group E" (see page 44 of WO 2020 / 142729).

[0787] On page 45 of WO 2020 / 142729, it is disclosed that only compound No. 25 can be named as "Group A" with a "biochemical (in vitro) IC50 value of less than 100 nM". All other example compounds of WO 2020 / 142729 show a "biochemical (in vitro) IC50 value" greater than 100 nM.

[0788] 5.2.2 Comparison between the embodiments of the present invention and the embodiments of WO 2020 / 142729

[0789] Selected prior art compounds of WO 2020 / 142729 have been synthesized and then tested for their pharmacological properties regarding their efficacy in inhibiting the cGAS / STING pathway. Specifically, the "biochemical (in vitro) IC50 value" for cGAS inhibition (hcGAS IC50), the "cellular IC50 value for inhibition of IFN-induced in virus-stimulated THP1 cells" (THP1 (vir) IC50), "Cellular IC50 values ​​for inhibition of IFN induction in cGAMP-stimulated THP1 cells" (THP1 (cGAMP)IC50) and "IC50 value for inhibition of IFN induction in human whole blood" (hWB) have been experimentally determined for the structurally most compact embodiments of WO 2020 / 142729 according to the analytical method described in Section 6 below (see Table 2).

[0790] Table 2: Selected pharmacological properties of example compounds of WO 2020 / 142729

[0791]

[0792]

[0793] As summarized in Table 1, the pharmacological properties of the example compounds of the present invention and the respective pharmacological properties of the compounds of WO 2020 / 142729 can be compared with each other because they are experimentally determined according to the same analytical procedure as described in Section 6 below.

[0794] As can be seen from the data shown in Table 2, all example compounds of WO 2020 / 142729 show a "biochemical (in vitro) IC50 value" (= hcGAS IC50) significantly greater than 100 nM - the only exception is Example No. 25 of WO 2020 / 142729 (in WO 2020 / 142729, named "Group A" with a "biochemical (in vitro) IC50 value" (= hcGAS IC50) of less than 100 nM). In contrast, the example compounds of the present invention all have a "biochemical (in vitro) IC50 value" (hcGAS IC50) of less than 100 nM. However, Example No. 25 of WO 2020 / 142729 with a "biochemical (in vitro) IC50 value" (hcGASIC50) of 55 nM does not meet the requirements of the embodiment of THP1 at all. (vir) The selection criteria of "satisfactory cell inhibition efficacy" indicated by IC50 being lower than 1 μM is due to the fact that THP1 of Example No. 25 of WO 2020 / 142729 (vir) IC50 is 17 μM.

[0795] 5.3 Prodrugs

[0796] It is known that esters of active agents with carboxylic acid groups may represent viable prodrugs that may show improved oral absorption / bioavailability compared to the respective active agent. Commonly used prodrugs of active agents with carboxylic acid groups are, for example, methyl esters, ethyl esters, isopropyl esters, etc. (see Beaumont et al., Current Drug Metabolism, 2003, Vol. 4, No. 6, 461-485).

[0797] In addition, Nakamura et al., Bioorganic & Medicinal Chem., Vol. 15, No. 24, pp. 7720-7725 (2007), described that N-acylsulfonamide derivatives and N-acylsulfonylurea derivatives of specific active agents having a free carboxylic acid group also have the potential to become viable prodrugs.

[0798] Furthermore, it has been found that experimentally suggest that methyl esters of example compounds of formula (I) or formula (I') also represent viable prodrugs of cGAS inhibitors of formula (I) or formula (I').

[0799] Compounds P01, P02, P03 and P04 are methyl esters of Example compounds 4.04, 1.10, 1.12 and 3.14, respectively, and thus may represent viable prodrugs of the respective Example compounds.

[0800] P01, P02, P03 and P04 have been synthesized and tested for their pharmacological properties for their efficacy in inhibiting the cGAS / STING pathway. The pharmacological properties of the experimentally determined prodrugs P01, P02, P03 and P04 were then compared to the corresponding pharmacological properties of the respective example compounds 4.04, 1.10, 1.12 and 3.14 as summarized in Table 3.

[0801] This comparison between the example compounds and their corresponding prodrugs shows that the hcGAS IC50 values ​​of the example compounds are always around 10 nM or even less than 10 nM, while the hcGAS IC50 values ​​of the corresponding prodrugs are always very large, meaning usually greater than 9000 nM. For the individual THP1 (vir) With respect to IC50 values, such large differences between the example compounds on the one hand and their corresponding prodrugs on the other hand have never been observed (see Table 3 for Example 4.04 and its corresponding prodrug P01).

[0802] One possible explanation for this observation is that the example compounds (which represent "drugs") all have a free carboxyl group, which seems to be essential for inhibiting cGAS activity, whereas in all "prodrugs" the carboxyl group is masked by a carboxyl-methyl ester group. Therefore, the prodrugs lose their inhibitory efficacy in the "in vitro human cGAS enzyme assay" (see Section 6.1 below), since there is no intracellular enzyme that cleaves the carboxyl-methyl ester group in this assay. Therefore, in this "in vitro human cGAS enzyme assay", the prodrugs show very large "biochemical (in vitro) IC50 values" (=hcGAS IC50), while the corresponding example compounds (which represent drugs or active agents) show small "biochemical (in vitro) IC50 values" (=hcGAS IC50).

[0803] In the "Human cGAS Cell and Trans-Cell Assays" (see Section 6.2 below), there are endogenous cellular enzymes that cleave the carboxyl-methyl ester group. Therefore, not only the example compounds themselves (which means the drug or active agent itself) show small THP1 (vir) IC50 values, and the corresponding prodrugs also showed relatively small "THP1 (vir) IC50 values" because in this "human cGAS cell assay" the methyl ester of the prodrug can be cleaved by endogenous intracellular enzymes to the corresponding drug / agent which again exhibits inhibitory efficacy.

[0804] This explanation, together with the measurement results shown in Table 3, indicates that the methyl ester derivatives of the compounds of Formula (I) or Formula (I') do appear to represent viable prodrugs of the compounds of Formula (I) or Formula (I'), which themselves have no inhibitory efficacy with respect to in vitro human biochemical cGAS inhibition. However, when the methyl ester is cleaved by endogenous intracellular enzymes, the compounds of Formula (I) or Formula (I') (active agents) are formed, which again exhibit inhibitory efficacy with respect to the cGAS / STING pathway.

[0805] Table 3: Comparison between selected example compounds of the invention (=active agents) and their respective methyl ester prodrugs:

[0806]

[0807]

[0808]

[0809] 6 Biological experiments

[0810] The activity of the compounds of the invention can be demonstrated using the following in vitro cGAS enzyme and cell assays:

[0811] 6.1 Methods: Human cGAS Enzyme Assay (hcGAS IC50 (in vitro))

[0812] The human cGAS enzyme was incubated in the presence of 45 base pair double stranded DNA for activation and GTP and ATP as substrates. The activity of the compound was determined by measuring the effect of the compound on the formation of the enzyme reaction product cGAMP, which was measured by mass spectrometry.

[0813] Enzyme preparation:

[0814] 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 at 18°C ​​for 16 hours. The cells were cultured in a 25 mM Tris (pH 8), 300 mM NaCl, 10 mM imidazole, 10% glycerol, and a protease inhibitor cocktail (cOmplete TM , EDTA-free, Roche) and DNase (5 μg / mL) buffer. cGAS protein was isolated by affinity chromatography on Ni-NTA agarose resin and further purified by size exclusion chromatography using a Superdex 200 column (GE Healthcare) equilibrated in 20 mM Tris (pH 7.5), 500 mM KCl and 1 mM TCEP. The purified protein was concentrated to 1.7 mg / mL and stored at -80°C.

[0815] Analytical methods

[0816] Compounds were delivered in 10 mM DMSO solutions, serially diluted and transferred to 384-well assay plates (Greiner #781201) using an Echo acoustic dispenser. Typically, 8 concentrations were used in the final assay volume, with the highest concentration being 10 μM, followed by approximately 1:5 dilution steps. The DMSO concentration in the final assay volume was set to 1%. The 384-well assay plate contained 22 test compounds (columns 1-22) and DMSO in columns 23 and 24.

[0817] 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 from columns 1 to 23. In column 24, 15 μL of assay buffer without enzyme / DNA was added as a low control.

[0818] The plates were then pre-incubated at room temperature for 60 min.

[0819] Thereafter, 10 μL of GTP (ThermoFisher #R0461)-ATP (Promega #V915B) was added to the assay plate (columns 1-24, 30 μM final concentration each) using a Multidrop Combi.

[0820] The plates were incubated again at room temperature for 90 min.

[0821] After incubation, the reaction was terminated with 80 μL of 0.1% formic acid in assay buffer containing 5 nM cyclic-di-GMP (Sigma #SML1228) as an internal standard for mass spectrometry. The total volume / well was 105 μL.

[0822] Rapidfire MS Assay

[0823] The plate was centrifuged at 4000 rpm, 4°C for 5 min.

[0824] The RapidFire autosampler was coupled to a binary pump (Agilent 1290) and a Triple Quad 6500 (ABSciex, Toronto, Canada). The system was equipped with a 10 μL loop, C18 [12 μL bed volume] column (Agilent, part number G9210A) containing 10 mM NH4Ac(aq) water (pH 7.4) as eluent A (pump 1 at 1.5 mL / min, pump 2 at 1.25 mL / min) and 10 mM NH4Ac (pH 7.4) in v / v / v 47.5 / 47.5 / 5 ACN / MeOH / H2O as eluent B (pump 3 at 1.25 mL / min). Aspiration time: 250 ms; Loading time: 3000 ms; Elution time: 3000 ms; Wash volume: 500 μL.

[0825] MS was operated in positive ion mode with a HESI ion source, source temperature of 550°C, curtain gas = 35, gas 1 = 65, and gas 2 = 80. Unit mass resolution in SRM mode. The following transitions and MS parameters (DP: declustering potential, and CE: collision energy) were determined for cGAMP and DicGMP:

[0826] Analytes: cGAMP, 675.1 / 524, DP=130, CE=30 and

[0827] Internal standard: cyclo-di-GMP, 690.1 / 540, DP=130, CE=30.

[0828] The formation of cGAMP was monitored and assessed as a ratio to cyclic-di-GMP.

[0829] Data evaluation and calculation:

[0830] For data evaluation and calculations, the measured value of the low control was set as 0% control, and the measured value of the high control was set as 100% control. IC50 values ​​were calculated using the standard 4-parameter logistic regression formula. Calculation: [y = (ad) / (1 + (x / c) ^ b) + d], a = low value, d = high value; x = conc M; c = IC50 M; b = slope

[0831] 6.2 Methods: Human cGAS Cell Analysis and cGAMP-Stimulated Transfection Cell Analysis (THP1 (vir) IC50 and THP1 (cGAMP) IC50)

[0832] Using THP1-Dual expressing the IRF-dependent Lucia luciferase reporter gene TM Cells (InvivoGen #thpd-nfis) served as the basis for both assays. For the detection of cellular cGAS activity, stimulator cells (THP1 (vir) IC50 measurement).

[0833] For the reverse analysis, cells were stimulated with cGAMP (SigmaAldrich #SML1232) to activate the same pathway independent of cGAS and directly downstream of cGAS (THP1 (cGAMP) IC50 measurement).

[0834] By measuring cGAS enzyme activity stimulated by DNA (THP1 (vir) IC50 measurement) or directly from cGAMP (THP1 (cGAMP) IC50 measurement, reverse transcriptase analysis)-induced Lucia luciferase activity was used to monitor pathway activity.

[0835] Analytical methods

[0836] Compounds were delivered in 10 mM DMSO solutions, serially diluted and transferred to 384-well assay plates (Greiner #781201) using an Echo acoustic dispenser. Typically, 8 concentrations were used in the final assay volume, with the highest concentration being 10 μM, followed by approximately 1:5 dilution steps. The DMSO concentration in the final assay volume was set to 1%. The 384-well assay plate contained 21 test compounds (columns 1-22) and DMSO in columns 23 and 24.

[0837] Cells cultured according to the manufacturer's conditions were harvested by centrifugation at 300 g / 10 min and then resuspended and diluted to 1.66E5 cells / ml 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)). The baculovirus solution was then added to the cells at 1:200 (varied depending on the virus batch) (THP1 (vir) Alternatively, for the counter analysis, cGAMP was added to the cells at a final concentration of 10 μM (THP1 (cGAMP) IC50 measurement).

[0838] 30 μL of cell / virus mixture was added via MultiDrop Combi dispenser (5000 cells / well) to each well of the composite plate from columns 1 to 23. In column 24, 30 μl / 5000 cells / well without virus were added as a low control.

[0839] The plates were then incubated at 37°C in a humidified incubator for 18 h.

[0840] Afterwards, 15 μL of QuantiLuc detection reagent (InvivoGen #rep-qlcg5) was added to each well using a MultiDrop Combi and immediately measured using an EnVision reader (US luminescence reading mode).

[0841] Data evaluation and calculation:

[0842] For data evaluation and calculations, the measured value of the low control was set as 0% control, and the measured value of the high control was set as 100% control. IC50 values ​​were calculated using the standard 4-parameter logistic regression formula. Calculation: [y = (ad) / (1 + (x / c) ^ b) + d], a = low value, d = high value; x = conc M; c = IC50 M; b = slope

[0843] 6.3 Method: Human Whole Blood Analysis (Human WB IC50)

[0844] For the detection of cellular cGAS activity, human whole blood was stimulated by transfection with double-stranded DNA. Pathway activity was monitored by measuring IFNα2α production.

[0845] Analytical methods

[0846] Compounds were delivered as 10 mM DMSO solutions and serially diluted and transferred to 96-well cell culture plates (Corning #3595) pre-filled with 20 μl OptiMEM (Gibco, #11058-021) in each well using an Echo acoustic dispenser. Typically, 8 concentrations were used in the final assay volume, with the highest concentration being 10 μM, followed by approximately 1:5 dilution steps. The DMSO concentration in the final assay volume was set to 0.1%. The 96-well assay plate contained 10 test compounds and DMSO in the control wells.

[0847] Human whole blood from 3 or more healthy donors (male or female, drug-free for 7 days except birth control pills and thyroxine) is collected in parallel as sodium citrate blood (e.g., 3.8% in Monovettes from Sarstedt). Whole blood is kept at room temperature for a maximum of 3 hours after collection until used for analysis.

[0848] 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 at room temperature for 60 minutes with continuous shaking at 450 rpm, covered with a lid but not sealed.

[0849] Prepare DNA-Fugene mixture (Herring DNA, Sigma Aldrich #D6898-1G, Fugene (5 x 1 mL), Promega #E2312) in OptiMEM and incubate at RT for 10 min (125 ng DNA / 20 μl and Fugene ratio of 9.6:1). Add 20 μl DNA-Fugene mixture to each well, resulting in 125 ng DNA / well / 200 μl and Fugene ratio of 9.6:1. Add 20 μl OptiMEM and 9.6:1 Fugene to all low control wells.

[0850] After covering the assay plate with the zone seal and lid, the blood plate was kept at room temperature for 30 minutes with continuous shaking at 450 rpm, followed by overnight incubation at 37°C in an incubator for 22 h without shaking.

[0851] For the detection of IFNα-2α in human plasma, the biotinylated capture antibody (antibody set IFNA2, Meso Scale Diagnostics #B21VH-3, including coating and capture antibody) was diluted 1:17.5 in diluent 100 (Meso Scale Diagnostics #R50AA-4) according to the manufacturer's instructions. U-PlexMSD GOLD 96-well small spot streptavidin SECTOR plates (Meso Scale Diagnostics #L45SA-5) were coated with 25 μl of the diluted capture antibody. The coated plates were incubated for 60 min at room temperature with continuous shaking at 700 rpm. The MSD IFNα-2α plates were washed three times with 150 μl of wash buffer (1x HBSS, 0.05% Tween).

[0852] After blocking the plates with 100 μl blocking solution / well (1x HBSS with 0.2% Tween, 2% BSA) for 60 min at room temperature and continuous shaking at 700 rpm, the plates were emptied as dryly as possible by pouring just before proceeding with human plasma.

[0853] The whole blood assay plate was centrifuged at 1600 rpm for 10 minutes. 25 μl of supernatant was transferred from each whole blood plate to the corresponding IFNα-2α plate using a pipetting robot. The plate was sealed with a microplate sealer and again kept at room temperature for 2 hours with continuous shaking at 700 rpm.

[0854] Next, the MSD IFNα-2α plates were washed three times with 150 μl wash buffer (1x HBSS, 0.05% Tween) before adding 25 μl of MSD Sulfo-TAG IFNα-2α antibody solution (diluted 1:100 in Diluent 3 (MesoScale Diagnostics #R50AP-2)) to each well of the plate.

[0855] Afterwards, the plate was sealed with a microplate sealer and kept again at room temperature for 2 hours with continuous shaking at 700 rpm. Finally, the MSD IFNα-2α plate was washed 3 times with 150 μl wash buffer (1x HBSS, 0.05% Tween). 150 μl 2x read buffer was added to each well and the plate was immediately measured with an MSD Sector S600 reader using the vendor barcode.

[0856] Data evaluation and calculation:

[0857] For data evaluation and calculations, the % control for each well was calculated based on the average of the high control (DNA stimulated control) and the low control (unstimulated control) by using the following formula:

[0858] [Counts(Sample)-Counts(Low)) / (Counts(High)-Counts(Low))]*100

[0859] IC50 values ​​were calculated using a standard 4-parameter logistic regression formula. Calculation: [y = (ad) / (1+(x / c)^b)+d], a = low value, d = high value; x = conc M; c = IC50 M; b = slope

[0860] 7 Indications

[0861] It has been found that the compounds of formula (I) or (I') are characterized by their range of applications in therapeutic areas. Particular mention should be made of those applications in which the compounds of formula (I) or (I') according to the present invention are preferably used based on their pharmaceutical activity as cGAS inhibitors. Although the cGAS pathway is important for host defense against invading pathogens (e.g., viral infections and invasion of some intracellular bacteria), cellular stress and genetic factors can also cause the production of abnormal cellular dsDNA (e.g., through nuclear or mitochondrial leakage), and thus trigger autoinflammatory responses. Therefore, cGAS inhibitors have a strong therapeutic potential for the treatment of a variety of autoinflammatory and autoimmune diseases.

[0862] An et al., Arthritis Rheumatol. 2017 April; 69(4): 800-807 disclose that cGAS expression in peripheral blood mononuclear cells (PBMCs) is 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 tested SLE patients, but not in normal or rheumatoid arthritis controls. Disease activity was higher in SLE patients with cGAMP compared to SLE patients without cGAMP. While higher cGAS expression may be a result of exposure to type I interferons (IFNs), detection of cGAMP in SLE patients with increased disease activity indicates that the cGAS pathway may be involved in disease manifestation.

[0863] Park et al., Ann Rheum Dis. 2018 Oct;77(10):1507-1515, also disclosed that the cGAS pathway is involved in the development of SLE.

[0864] Thim-Uam et al., iScience 2020 Sep 4;23(9),101530 (doi:10.1016 / j.isci.2020.101530) disclosed that the STING pathway mediates lupus via activation of common dendritic cell maturation and plasmacytoid dendritic cell differentiation.

[0865] Gao et al., Proc. Natl. Acad. Sci. USA. 2015 Oct 20;112(42):E5699-705, describe that activation of cGAS by autologous DNA leads to certain autoimmune diseases, such as interferonopathy.

[0866] Tonduti et al., Expert Rev. Clin. Immunol. 2020 Feb;16(2):189-198, disclose that cGAS inhibitors have particular therapeutic potential in Icardi-Gutierrez syndrome, a lupus-like severe autoinflammatory immune-mediated disease.

[0867] In Yu et al., Cell 2020 Oct 29;183(3):636-649, we describe the link between TDP-43-triggered mitochondrial DNA and activation of the cGAS / STING pathway in amyotrophic lateral sclerosis (ALS).

[0868] 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 disease (ILD), progressive fibrosing interstitial lung disease (PF-ILD), and idiopathic pulmonary fibrosis (IPF).

[0869] In Schuliga et al., Clin. Sci. (Lond). 2020 Apr 17;134(7):889-905, it is described that autologous DNA perpetuates senescence of IPF lung fibroblasts in a cGAS-dependent manner.

[0870] Other scientific clues linking the etiology 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.

[0871] Nascimento et al., Sci. Rep. 2019 Oct 16;9(1):14848, published that autologous DNA release and STING-dependent sensing drive inflammation in mice in response to cigarette smoke, suggesting a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD).

[0872] Ma et al., Sci. Adv. 2020 May 20;6(21):eaaz6717, disclose that ulcerative colitis and inflammatory bowel disease (IBD) can be inhibited by controlling cGAS-mediated inflammation.

[0873] Gratia et al., J. Exp. Med. 2019 May 6;216(5):1199-1213 showed that Bloom's syndrome protein inhibits cGAS innate immune sensing of micronuclei. Therefore, cGAS inhibitors have therapeutic potential in the treatment of Bloom's syndrome.

[0874] Kerur et al., Nat. Med. 2018 Jan;24(1):50-61, demonstrated that cGAS plays an important role in atypical inflammasome activation in age-related macular degeneration (AMD).

[0875] In addition, cGAS inhibitors of formula (I) or formula (I') also have therapeutic potential in cancer treatment (see Hoong et al., Oncotarget. 2020 Jul 28; 11(30): 2930-2955, and Chen et al., Sci. Adv. 2020 Oct 14; 6(42): eabb8941).

[0876] In addition, cGAS inhibitors of formula (I) or formula (I') also have therapeutic potential in the treatment of heart failure (Hu et al., Am. J. Physiol. Heart Circ. Physiol. 2020 Jun 1; 318(6): H1525-H1537).

[0877] There are further scientific clues of the correlation between Parkinson's disease and the cGAS / STING pathway (Sliter et al., Nature. 2018 Sep;561(7722):258-262) and between Sjögren's syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res. 2018 Jul;97(8):893-900).

[0878] In addition, cGAS inhibitors of formula (I) or formula (I') also have therapeutic potential in the treatment of COVID-19 / SARS-CoV-2 infection, as shown in: Di Domizio et al., Nature. 2022 January 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 January 12; 5(1):45. doi:10.1038 / s42003-021-02983-5: "SARS-CoV-2 infection induces a pro-inflammatory cytokiner response through cGAS-STING and NF-kappaB".

[0879] In addition, cGAS inhibitors of Formula (I) or Formula (I') have therapeutic potential in the treatment of renal inflammation and renal fibrosis, as shown in: Chung et al., Cell Metab. 2019 30:784-799: "Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis", and Maekawa et al., Cell Rep. 2019 29:1261-1273: "Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury".

[0880] In addition, 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: "Chromosomalinstability 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".

[0881] In addition, cGAS inhibitors of Formula (I) or Formula (I') have therapeutic potential in treating metabolic disorders due to STING gt Animals showed reduced macrophage infiltration in adipose tissue and STING expression in response to subchronic high-calorie diet (HFD). gt And IRF 3-deficiency leads to lower blood glucose and insulin and weight loss (Mao et al., Arterioscler Thromb VascBiol, 2017; 37(5): 920-929).

[0882] In addition, cGAS inhibitors of formula (I) or formula (I') have therapeutic potential in treating vascular diseases and lead to vascular repair / regeneration, because the release of mitochondrial DNA into the cytosol of endothelial cells leads to activation of the cGAS / STING pathway and inhibition of endothelial proliferation. In addition, cGAS gene knockout restores endothelial repair / regeneration in a mouse model of inflammatory lung injury (Huang et al., Immunity, 2020, March 2017; 52(3):475-486.e5.doi:10.1016 / j.immuni.2020,02.002).

[0883] In addition, cGAS inhibitors of Formula (I) or Formula (I') have therapeutic potential in the treatment of age-related and obesity-related cardiovascular diseases (Hamann et al., Immun Ageing, 2020 Mar 14; 17:7; doi: 10.1186 / s12979-020-00176-y.eCollection 2020).

[0884] Therefore, 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), interferon disease, Icardi-Gutierrez syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjögren's syndrome and Parkinson's disease.

[0885] In addition, compounds of formula (I) or formula (I') as cGAS inhibitors can be used in the treatment of fibrotic diseases (e.g., systemic sclerosis (SSc), interferon disease, non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), specifically idiopathic pulmonary fibrosis (IPF)).

[0886] In addition, compounds of formula (I) or formula (I') as cGAS inhibitors can be used in the treatment 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.

[0887] 8 combinations

[0888] 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.

[0889] In a preferred embodiment of the present invention, the compound of formula (I) or formula (I') can be combined with one or more pharmacologically active agents selected from the following: anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / antihistamines, bronchodilators, β2 agonists / β mimetics, adrenergic agonists, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics (such as interferons or other cytokines / chemokines), cytokine / chemokine receptor modulators (i.e., cytokine receptor agonists or antagonists), toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies (Adalimumab) and anti-BAFF agents (Belimumab and Etanercept).

[0890] The antifibrotic agent is preferably selected from bifenidone and tyrosine kinase inhibitors (such as nintedanib), among which nintedanib is particularly preferred.

[0891] Preferred examples of anti-inflammatory agents are NSAIDs and corticosteroids.

[0892] NSAID is preferably selected from ibuprofen, naproxen, diclofenac, meloxicam, celecoxib, acetylsalicylic acid, aspirin TM ), indomethacin, mefenamic acid and etoricoxib.

[0893] The corticosteroid is preferably selected from Flunisolide, Beclomethasone, Triamcinolone, Budesonide, Fluticasone, Mometasone, Ciclesonide, Rofleponide and Dexamethasone.

[0894] The antiallergic agent / antihistamine is preferably selected from Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Ebastine, Desloratidine and Mizolastine.

[0895] The β2 agonist / β mimetic may be a long-acting β2 agonist (LABA) or a short-acting β2 agonist (SABA). Particularly preferred β2 agonists / β mimetics are selected from Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenalin, Ibuterol, Pirbuterol, Procaterol, Reproterol, Salmeterol, Sulfonterol, Terbutalin, Tolubuterol, Olodaterol and Salbutamol, specifically Olodaterol.

[0896] The anticholinergic agent is preferably selected from ipratropium salt, tiotropium salt, glycopyrronium salt and theophylline, among which tiotropium bromide is particularly preferred.

[0897] The leukotriene modifier is preferably selected from Montelukast, Pranlukast, Zafirlukast, Ibudilast and Zileuton.

[0898] The JAK inhibitor is preferably selected from Baricitinib, Cerdulatinib, Fedratinib, Filgotinib, Gandotinib, Lestaurtinib, Molotinib, Pacritinib, Pefitinib, Ruxolitinib, Tofacitinib and Upadacitinib.

[0899] The anti-interleukin antibody is preferably selected from anti-IL23 antibody (e.g., Risankizumab), anti-IL17 antibody, anti-IL1 antibody, anti-IL4 antibody, anti-IL13 antibody, anti-IL-5 antibody, anti-IL-6 antibody (e.g., Tocilizumab), anti-IL-12 antibody, and anti-IL-15 antibody.

[0900] 9 Preparations

[0901] The compounds of the present invention can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration and administration by inhalation. Parenteral administration refers to administration routes other than enteral, transdermal or by inhalation, and is usually 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 by inhalation through the mouth or through the nasal passages. Topical administration includes application to the skin. The compounds of the present invention can be administered via eye drops to treat Sjögren's syndrome.

[0902] Suitable administration forms are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. In each case, the content of the pharmaceutically effective compound should be in the range of 0.1 to 90 wt.%, more preferably 0.5 to 50 wt.%, of the total composition, i.e., an amount sufficient to achieve the dosage range specified below.

[0903] The preparations can be administered orally in the form of tablets, powders, powders in capsules (eg hard gelatin capsules), solutions or suspensions. When administered by inhalation, the active substance combination can be administered as a powder, an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.

[0904] Therefore, preferably, the pharmaceutical preparation is characterized by the content of one or more compounds of formula (I) or formula (I') according to the above-mentioned more preferred embodiments.

[0905] It is particularly preferred if the compound of formula (I) or formula (I') is administered orally, and it is also particularly preferred if it is administered 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 tablets may also comprise some layers.

[0906] Thus, coated tablets can be prepared by coating cores produced in a manner similar to the tablets with substances commonly used for tablet coatings, such as kollidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core can also consist of a number of layers. Similarly, the tablet coating can consist of a number of layers to achieve delayed release, possibly using the above-mentioned excipients for tablets.

[0907] Syrups containing the active substances of the invention or their combination may additionally contain sweeteners, such as saccharin, cyclamate, glycerol or sugar, and flavor enhancers, such as flavoring agents, such as vanillin or citrus extracts. They may also contain suspension adjuvants or thickeners (e.g. sodium carboxymethylcellulose), wetting agents (e.g. condensation products of fatty alcohols with ethylene oxide) or preservatives (e.g. parabens).

[0908] Capsules containing one or more active substances or active substance combinations can be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and placing them in gelatin capsules. Suitable suppositories can be prepared, for example, by mixing them with carriers provided for this purpose such as neutral fats or polyethylene glycol or its derivatives.

[0909] Excipients that can be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffins (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, sulfite waste liquor, methylcellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0910] For oral administration, in addition to the above-mentioned carriers, the tablets may of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate and various additives such as starch (preferably potato starch), gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, in addition to the above-mentioned excipients, the active substance may also be combined with various flavor enhancers or colorants.

[0911] 1. A compound of formula (I),

[0912]

[0913] in

[0914] R 1 is selected from methyl, ethyl, halomethyl, haloethyl and halogen,

[0915] in

[0916] G is selected from O, NR 8 , CH2, C and CR 8 R 9 ,

[0917] in

[0918] R 2 Selected from H, halogen, cyclopropyl, C 1-3 -alkyl, -C 2-5 -alkynyl, -S-methyl and CN,

[0919] or where R 2 is a cyclic group, wherein the cyclic group is selected from: phenyl or a five- to six-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the cyclic group is composed of one or two identical or different substituents R 10 replace,

[0920] in

[0921] R 3 is H or methyl,

[0922] R 4 is H or methyl,

[0923] R 5 is selected from H, methyl, -CN, -methylene-OH and -CF3,

[0924] or R 5 But it doesn't exist.

[0925] R 6is selected from H, methyl, -CN, -methylene-OH and -CF3,

[0926] or R 5 and R 6 Together with the C atoms therebetween, they form a ring selected from oxetane, tetrahydrofuran and cyclopropane,

[0927] R 7 Selected from H, halogen, (C 1-3 )-alkyl and halo-(C 1-3 )-alkyl,

[0928] R 8 is selected from CN, H and methyl,

[0929] R 9 Selected from H, methyl and halogen

[0930] or R 9 But it doesn't exist.

[0931] Each R 10 independently selected from the group consisting of 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 ,

[0932] Where R 11 is a five- or six-membered heterocyclic ring having one or two heteroatoms independently selected from N, O and S,

[0933] or G for CR 8 R 9 , R 5 and R 9 does not exist, and R 8 and R 6 With R 8 and R 6 The two C atoms between them form a cyclic five-membered aromatic or non-aromatic heterocycle containing one, two or three heteroatoms independently selected from N, S and O,

[0934] or G for CR 8 R 9 , and R 8 and R 9 With R 8 and R 9 The C atoms between them together form a diaziridine ring, and a prodrug or a pharmaceutically acceptable salt thereof.

[0935] 2. The compound according to item 1, which has formula (I'):

[0936]

[0937] 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 is defined as in item 1,

[0938] and prodrugs or pharmaceutically acceptable salts thereof.

[0939] 3. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein R 7 is selected from H, F, Cl, methyl, ethyl, halomethyl and haloethyl,

[0940] and prodrugs or pharmaceutically acceptable salts thereof.

[0941] 4. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein R 1 is selected from halomethyl, haloethyl and methyl,

[0942] and prodrugs or pharmaceutically acceptable salts thereof.

[0943] 5. The compound according to item 3, wherein R 1 It is a fluoromethyl group selected from -CF3, -CHF2 and -CH2F, and a prodrug or a pharmaceutically acceptable salt thereof.

[0944] 6. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein R 3 and R 4 At least one of is methyl,

[0945] and prodrugs or pharmaceutically acceptable salts thereof.

[0946] 7. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein R 3 and R 4 One of them is methyl and the other is H,

[0947] and prodrugs or pharmaceutically acceptable salts thereof.

[0948] 8. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein G is O

[0949] and prodrugs or pharmaceutically acceptable salts thereof.

[0950] 9. A compound according to formula (I) according to item 1 or formula (I') according to item 2,

[0951] Where G is O,

[0952] And R 3 or R 4 One of them is methyl and the other is H

[0953] and prodrugs or pharmaceutically acceptable salts thereof.

[0954] 10. The compound according to item 8,

[0955] Where R 4 is methyl and R 3 For H,

[0956] Where R 5 and R 6 Together with the C atoms between them, they form an oxetane ring.

[0957] and prodrugs or pharmaceutically acceptable salts thereof.

[0958] 11. A compound according to formula (I) according to item 1 or formula (I') according to item 2,

[0959] Where R 2 is selected from: H, ethynyl, 1-propynyl, -S-methyl, halogen,

[0960] and prodrugs or pharmaceutically acceptable salts thereof.

[0961] 12. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein R 2 is ethynyl and its prodrug or pharmaceutically acceptable salt.

[0962] 13. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein R 4 is methyl and R 3 For H,

[0963] Where G is O,

[0964] Where R 5 and R 6 Together they form an oxetane ring

[0965] Where R 2 is selected from: H, ethynyl, 1-propynyl, -S-methyl, halogen,

[0966] and prodrugs or pharmaceutically acceptable salts thereof.

[0967] 14. A compound according to formula (I) according to item 1 or formula (I') according to item 2,

[0968] Where R 2 is a cyclic group, wherein the cyclic group is selected from: phenyl or a five- to six-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, S and O, wherein the cyclic group is composed of one or two identical or different substituents R 10 replace,

[0969] Each R 10 independently selected from: 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 ,

[0970] Each R 11 is selected from a five- or six-membered heterocyclic ring having one or two heteroatoms each independently selected from N and O,

[0971] and prodrugs or pharmaceutically acceptable salts thereof.

[0972] 15. The compound according to item 14, wherein R 2 is a cyclic group selected from pyrazolyl, pyridyl, imidazolyl, phenyl and isoxazolyl,

[0973] The cyclic group is composed of one or two identical or different substituents R 10 replace,

[0974] Each R 10 independently selected from: 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 ,

[0975] Each R 11 is tetrahydropyran,

[0976] and prodrugs or pharmaceutically acceptable salts thereof.

[0977] 16. The compound according to item 15,

[0978] Where G is O,

[0979] Where R 3 or R 4 One of them is methyl and the other is H,

[0980] and prodrugs or pharmaceutically acceptable salts thereof.

[0981] 17. The compound according to item 16,

[0982] Where R 4 is methyl and R 3 For H,

[0983] Where R 5 and R 6 Together with the C atoms between them, they form an oxetane ring.

[0984] and prodrugs or pharmaceutically acceptable salts thereof.

[0985] 18. A compound according to formula (I) of item 1 or formula (I') of item 2, wherein

[0986] G is CR 8 R 9

[0987] And among them

[0988] R 8 and R 6 With R 8 and R 6 The two C atoms between them form a cyclic five-membered aromatic heterocyclic ring containing one or two heteroatoms independently selected from N and O, which is selected from a cyclic isoxazolyl ring, a cyclic pyrazolyl ring, a cyclic pyrrolyl ring and a cyclic furyl ring,

[0989] Where R 9 and R 5 does not exist,

[0990] and prodrugs or pharmaceutically acceptable salts thereof.

[0991] 19. A compound of formula (I) according to item 1 or formula (I') according to item 2, which is selected from:

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999] and its prodrugs or pharmaceutically acceptable salts. 20. An intermediate having the formula (IV)

[1000]

[1001] Or formula (V)

[1002]

[1003] Or formula (X)

[1004]

[1005] Or formula (XI)

[1006]

[1007] Among them, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 According to the definition in item 1

[1008] and wherein X is F or NO2,

[1009] wherein PG is a protecting group selected from tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), fluorenylmethyleneoxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc).

[1010] 21. A prodrug of any one of the compounds according to any one of items 1 to 19, having formula (A)

[1011]

[1012] Or formula (A')

[1013]

[1014] Where R 12 C 1-4 -alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl.

[1015] 22. The prodrug of formula (A) or (A') according to item 21, wherein R 12 It is methyl.

[1016] 23. A compound of formula (I) or formula (I') according to any one of items 1 to 19 for use in treating a disease that can be treated by inhibition of cGAS.

[1017] 24. A compound of formula (I) or formula (I') according to any one of items 1 to 19, for use in treating a disease selected from systemic lupus erythematosus (SLE), interferon disease, Aicardi-Goutières 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 fibrosing interstitial lung disease (PF-ILD), specifically idiopathic pulmonary fibrosis (IPF).

[1018] 25. A compound of formula (I) or formula (I') according to any one of items 1 to 19, for use in treating a disease selected from systemic lupus erythematosus (SLE), interferon disease, Icardi-Gutierrez syndrome, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjögren's syndrome and Parkinson's disease.

[1019] 26. A compound of formula (I) or formula (I') according to any one of items 1 to 19, which is used to treat a fibrotic disease selected from the following: systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interferon disease, interstitial lung disease (ILD), more preferably progressive fibrosing interstitial lung disease (PF-ILD), specifically idiopathic pulmonary fibrosis (IPF).

[1020] 27. A compound of formula (I) or formula (I') according to any one of items 1 to 19, for use in treating a disease selected from: 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.

[1021] 28. A pharmaceutical composition comprising a compound of formula (I) or formula (I') according to any one of items 1 to 19 and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[1022] 29. A pharmaceutical composition comprising a compound of formula (I) or (I') according to any one of items 1 to 19 in combination with one or more active agents selected from the following: anti-inflammatory agents, antifibrotic agents, antiallergic agents / antihistamines, bronchodilators, β2 agonists / β mimetics, adrenergic agonists, 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 regulators; anti-TNF antibodies, such as adalimumab; anti-BAFF antibodies, such as Belimumab and Etanercept.

[1023] 30. The pharmaceutical composition according to item 29, wherein the compound of formula (I) or formula (I') is combined with one or more anti-fibrotic agents selected from the group consisting of pirfenidon and nintedanib.

[1024] 31. The pharmaceutical composition according to item 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.

[1025] 32. A pharmaceutical composition according to claim 29, wherein the compound of formula (I) or formula (I') is combined with one or more active agents selected from bronchodilators, β2 agonists / β mimetics, adrenergic agonists and anticholinergics.

[1026] 33. A pharmaceutical composition according to claim 29, wherein the compound of formula (I) or formula (I') is combined with one or more anti-interleukin antibodies selected from the following: anti-IL-23, such as Risankizumab; anti-IL-17 antibody, anti-IL-1 antibody, anti-IL-4 antibody, anti-IL-13 antibody, anti-IL-5 antibody; anti-IL-6 antibody, such as Tocilizumab; anti-IL-12 antibody and anti-IL-15 antibody.

Claims

1. A formula (I) or a compound of formula (I') in R 1 is selected from methyl, ethyl, halomethyl, haloethyl and halogen, in G is selected from O, NR 8 , CH2, C and CR 8 R 9 , in R 2 Selected from H, halogen, cyclopropyl, C 1-3 -alkyl, -C 2-5 -alkynyl, -S-methyl and CN, or where R 2 is a cyclic group, wherein the cyclic group is selected from: phenyl or a five- to six-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the cyclic group is composed of one or two identical or different substituents R 10 replace, in 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 But it doesn't exist. R 6 is selected from H, methyl, -CN, -methylene-OH and -CF3, or R 5 and R 6 Together with the C atoms therebetween, they form a ring selected from oxetane, tetrahydrofuran and cyclopropane, R 7 Selected from H, halogen, (C 1-3 )-alkyl and halo-(C 1-3 )-alkyl, R 8 is selected from CN, H and methyl, R 9 Selected from H, methyl and halogen or R 9 But it doesn't exist. Each R 10independently selected from the group consisting of 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 , Where R 11 is a five- or six-membered heterocyclic ring having one or two heteroatoms independently selected from N, O and S, or G for CR 8 R 9 , R 5 and R 9 does not exist, and R 8 and R 6 With R 8 and R 6 The two C atoms between them form a cyclic five-membered aromatic or non-aromatic heterocycle containing one, two or three heteroatoms independently selected from N, S and O, or G for CR 8 R 9 , and R 8 and R 9 With R 8 and R 9 The C atoms between them form a diaziridine ring. and prodrugs or pharmaceutically acceptable salts thereof.

2. The compound of formula (I) or formula (I') according to claim 1, which is selected from: and prodrugs or pharmaceutically acceptable salts thereof.

3. Formula (I) according to claim 1 or 2 or a compound of formula (I') in R 1 is selected from methyl, ethyl, halomethyl, haloethyl and halogen, wherein G is selected from O, NR 8 , CH2 and CR 8 R 9 , in R 2 Selected from H, halogen, cyclopropyl, C 1-3 -alkyl, -C 2-5 -alkynyl, -S-methyl and CN, wherein R 3 is H or methyl, R 4 is H or methyl, R 5 Selected from H, methyl, -CN, -methylene-OH and -CF3 or R 5 But it doesn't exist. R 6 is selected from H, methyl, -CN, -methylene-OH and -CF3, or R 5 and R 6 Together with the C atoms therebetween, they form a ring selected from oxetane, tetrahydrofuran and cyclopropane, R 7 Selected from H, halogen, (C 1-3 )-alkyl and halo-(C 1-3 )-alkyl, R 8 is selected from CN, H and methyl, R 9 Selected from H, methyl and halogen or R 9 But it doesn't exist. Each R 10 independently selected from the group consisting of 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 , Where R 11 is a five- or six-membered heterocyclic ring having one or two heteroatoms independently selected from N, O and S, or G for CR 8 R 9 , R 5 and R 9 does not exist, and R 8 and R 6 With R 8 and R6 The two C atoms between them form a cyclic five-membered aromatic or non-aromatic heterocycle containing one, two or three heteroatoms independently selected from N, S and O, or G for CR 8 R 9 , and R 8 and R 9 With R 8 and R 9 The C atoms between them together form a diaziridine ring; Wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

5. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

6. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

7. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

8. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

9. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

10. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

11. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

12. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound: or a pharmaceutically acceptable salt thereof.

13. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

14. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

15. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

16. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

17. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

18. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

19. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

20. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

21. A compound of formula (I) or formula (I') according to claims 1 to 3, which is the following compound:

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