Thienopyrrolotriazine compounds, their preparation and their therapeutic use - Patents.com

Abstract

The present invention relates to thienopyrrolotriazine compounds of formula (I), their preparation and their therapeutic use. [Formula 1] TIFF2025506729000100.tif28170

Description

[Technical field]

[0001] Disclosed herein are thienopyrrolotriazine compounds, their preparation, pharmaceutical compositions containing said compounds, and their therapeutic uses.

[0002] Compounds according to the present disclosure are useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. [Background technology]

[0003] NOD-like receptor protein 3: The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) or NACHT, LRR and PYD domain-containing protein 3 (NALP3), is a cytosolic sensor of diverse pathogen-derived and host-derived molecules. Upon activation, NLRP3 oligomerizes and recruits an adaptor protein called apoptosis-associated speck-like protein (ASC). ASC then polymerizes to form large aggregates known as ASC specks. In turn, polymerized ASC interacts with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This multicomplex protein forms a platform for the binding, dimerization, and activation of the caspase-1 protease. Caspase-1 then cleaves the precursor forms of the proinflammatory cytokines IL1β and IL18 (termed pro-IL1β and pro-IL18), thereby activating an adapted inflammatory response. However, this pathway has been shown to be involved in a variety of inflammation-related processes and diseases, including: - Neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), Alzheimer's disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and brain injury (Guan Y & Han F. Front. Integr., Neurosci. 14: 37, 2020); - Mackle-Wells autoinflammatory disorders (Agostini et al., 2004), cryopyrin-associated periodic fever syndromes (CAPS) (Mortimer et al., Nature Immunol. 2016, 17(10), 1176-1188); sickle cell disease; systemic lupus erythematosus (SLE); liver-related diseases, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease (Petrasek et al., J. Clin. Invest. 2012, 122, 3476-89), and inflammatory arthritis-related disorders, such as gout, pseudogout (chondrocalcinosis), osteoarthritis (Ridker et al., N. Engl. J. Med. 2017, 377, 1119-31), and rheumatoid arthritis (Mathews et al., Nature Immunol. 2016, 17(10), 1176-1188). al., Ann. Rheum. Dis. 2014, 73, 1202-10), acute or chronic arthropathy, as well as kidney-related diseases such as hyperoxaluria (Knaufet et al., Kidney Int. 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al., Br. J. Pharmacol. 2016, 173, 752-10 65), hemodialysis-associated inflammation and diabetic nephropathy (Shahzad et al., Kidney Int. 2015, 87, 74-84); - Obesity & insulin resistance (Rheinheimer J.et al.,Metabolism Clin & Experimental 74:1-9,2017);Pancreatitis (Fu Q.et al.,BioMed Research International Volume 2018,Article ID 12949512018);Myocarditis (Toldo S et al,Int J Cardiol 2014); - Eye diseases in which the NLRP3 inflammasome has been shown to contribute to diabetic retinopathy (Perrone L.et al.,J.Cell.Physiol.221:262-272,2009), acute glaucoma (Chi W.et al.National Academy Science 111:11181-11186,2014), age-related macular degeneration (Tseng WAet al.,Investigative Ophthalmological & Visual Science 54:11-120,2013), Behçet's syndrome and dry eye disease (Zheng Q.et al.,Experimental Eye Research 134:133-140,2015); - Metabolic disorders, heart disease, skin disorders & cancer, e.g. diabetic cardiomyopathy (Luo B.et al.,PLoS ONE 9(8):e104771,2014); Kawasaki disease (Jia et al. Cell Death and Disease 10:778;2019; Anzai F.et al.,J.Molecular & Cell Cardiology 138:185-196,2020); cardiometabolic disorders, atherosclerosis, type I and type II diabetes and associated complications, peripheral arterial disease (PAD), acute heart failure and hypertension (Ridker et al.,N.Engl.J.Med.2017,377,1119-31; wound healing and scar formation; inflammatory skin diseases (Sweeney et al., Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age-related macular degeneration; cancer-related diseases, e.g., myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer, colorectal cancer (Ridker et al., Lancet 2017, 390, 1833-42); and - SARS-Cov-2: The NLRP3 inflammasome is central to the antiviral response (Zhao C. and Zhao W. 11, 211:2020; Freeman & Swartz, Frontiers in Immunol. 11, 1518, 2020).

[0004] Inhibitors of NLRP3 are potential treatments for these conditions with unmet clinical need.

[0005] Therefore, inhibitors of the NLRP3 inflammasome pathway are needed to provide new or alternative therapeutic approaches. Summary of the Invention [Means for solving the problem]

[0006] The present specification provides compounds corresponding to formula (I), [ka] During the ceremony: R1 represents a hydrogen atom, a halogen atom, or a -(C1-C2)-alkyl group; R2 represents a -(C1-C3)alkyl group which is unsubstituted or substituted with 1 to 3 substituents independently selected from a hydroxy group, a -(C1-C3)-alkoxy group, or a -(C3-C4)cycloalkyl group; R3 is - -(C5-C8)bicycloalkyl groups which are unsubstituted or substituted by one -(C1-C3)alkyl group which is unsubstituted or substituted by one or two -NH(CO)Me groups, - unsubstituted or Halogen atoms, Oxo group, -(C1-C4)-alkyl groups which are unsubstituted or substituted by 1 to 3 substituents independently selected from hydroxy groups, -(C1-C2)-alkyl groups, halogen atoms, -(C1-C2)-alkoxy groups, nitrile groups, -C(O)O(C1-C3) groups or -(C3-C8)-cycloalkyl groups which are unsubstituted or substituted by one or more halogen groups, -(C3-C6)-cycloalkyl groups which are unsubstituted or substituted by one or more (C1-C2)alkyl groups, -(CO)-(C1-C2)-alkyl group, Heterocycloalkyl groups, or -(C4-C7)heterocycloalkyl groups having nitrogen as a heteroatom, which are unsubstituted or substituted with one or more substituents independently selected from heteroaryl groups substituted with one or more -(C1-C4)alkyl groups; - Optionally, -(C3-C4) cycloalkyl group, or -(C1-C3) alkyl group a hetero(C6-C9)bicycloalkyl group having a nitrogen atom as a heteroatom, substituted with one or more substituents independently selected from Or, - unsubstituted or - -(C1-C4) alkyl group, - -(C1-C4) alkoxy group, or - Halogen atoms a mono- or bicycloheteroaryl group substituted with one or more substituents independently selected from A compound selected from or a pharma- ceutically acceptable salt thereof is disclosed.

[0007] The compounds of formula (I) may contain one or more asymmetric carbon atoms and therefore may exist in the form of enantiomers, diastereoisomers or mixtures thereof.

[0008] The compounds of formula (I) can exist in the form of bases or addition salts with acids or bases, particularly pharma- ceutically acceptable salts.

[0009] Pharmaceutically acceptable salts of the compounds of formula (I) form part of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] As used herein, certain terms have the following definitions: - a halogen atom: a fluorine, chlorine or bromine atom; - (C1-C4) alkyl group: a linear or branched saturated aliphatic group containing 1-4 carbon atoms. Examples include, but are not limited to, methyl (Me), ethyl, propyl, isopropyl (iPr), butyl, isobutyl, t-butyl, etc.; - Cycloalkyl group: a cyclic alkyl group. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; - Bicycloalkyl group: a cyclic alkyl group, where the cycloalkyl can generally have bonds or carbon atoms. Examples include, but are not limited to, bicyclo[1.1.1]pentane, etc.; - Heterocycloalkyl group: a saturated cyclic group containing 3 to 6 carbon atoms and containing 1 or 2 heteroatoms such as nitrogen. Examples include, but are not limited to, piperidine, azepane, and pyrrolidine; - Heterobicycloalkyl group: a saturated bicyclic group containing 3-4 carbon atoms and containing 1 or 2 heteroatoms such as nitrogen or oxygen. Examples include, but are not limited to, quinuclidine, N-2-azabicyclo[2.2.1]heptan-6-amine, azabicyclo[2.2.1]heptane, and azaspiro[3.3]heptane; - an alkoxy group: a radical -O-alkyl, where the alkyl group is as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, etc. - nitrile group: a group containing -CN; - Hydroxy group: a group containing -OH; - Aryl group: a cyclic aromatic group containing 5 to 10 carbon atoms. Examples of aryl groups include the phenyl group; - Mono- or bicycloheteroaryl group: an unsaturated cyclic group containing 4 to 9 carbon atoms and containing one or two heteroatoms such as sulfur or nitrogen. Examples include, but are not limited to, thiazole, pyrazole, pyrimidine, indazole, benzothiazole, etc.

[0011] In an embodiment, the compound of formula (I) is a compound comprising the formula: R1 represents a hydrogen atom, a halogen atom selected from a group consisting of a bromine atom and a chlorine atom, or a methyl group; R2 represents a -(C1-C3) alkyl group selected from among methyl, ethyl, propyl and isopropyl groups, which is unsubstituted or substituted with one substituent independently selected from a hydroxy group, a methoxy group or a cyclopropyl group; R3 is a bicyclopentyl group, which is unsubstituted or substituted by one -(C1-C3)alkyl group which is substituted by one -NH(CO)Me group, - unsubstituted or Fluorine atoms, Oxo group, -(C1-C4)-alkyl groups which are unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy groups, methyl groups, fluorine atoms, methoxy groups, nitrile groups, -C(O)O(C1-C2) groups or -(C3-C6)-cycloalkyl groups which are unsubstituted or substituted by one fluorine atom, -(C3-C5)-cycloalkyl groups which are unsubstituted or substituted by one or more methyl groups, -(CO)-methyl group, Heterocyclopropyl group, or one or more substituents independently selected from imidazole groups, which are unsubstituted or substituted with one methyl group; -(C4-C6)heterocycloalkyl group having nitrogen as a heteroatom, substituted with - Optionally, -(C3-C4) cycloalkyl group, or Methyl group a hetero(C6-C9)bicycloalkyl group having nitrogen as a heteroatom, substituted with one or more substituents independently selected from or - unsubstituted or - methyl group, - a methoxy group, or - Fluorine atom A mono- or bicycloaryl group substituted with one or two substituents independently selected from A compound selected from or a pharma- ceutically acceptable salt thereof.

[0012] In certain embodiments, the compound of formula (I) is a compound, comprising: R1 represents a hydrogen atom or a halogen atom selected from among bromine and chlorine atoms; R2 represents a -(C1-C3) alkyl group or a -(C3-C4) cycloalkyl group that is unsubstituted or substituted with 1 to 3 hydroxy groups; R3 is - (C5-C8)bicycloalkyl groups which are unsubstituted or substituted by one -(C1-C3)alkyl group which is unsubstituted or substituted by one or two -NH(CO)Me groups, - unsubstituted or -(C1-C4)alkyl groups which are unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy groups, methyl groups, fluorine atoms, methoxy groups, nitrile groups, -C(O)O(C1-C3) groups, or -(C3-C5)cycloalkyl groups which are unsubstituted or substituted with one or more fluorine atoms, (C3-C6)-cycloalkyl groups which are unsubstituted or substituted by one or more -(C1-C2)-alkyl groups, or Heterocycloalkyl groups a (C4-C7) heterocycloalkyl group having a nitrogen atom as a heteroatom, substituted with one or more substituents independently selected from - hetero(C6-C8)bicycloalkyl groups having nitrogen as a heteroatom, optionally substituted with one or more -(C3-C4)cycloalkyl groups, or a mono- or bicycloheteroaryl group which is unsubstituted or substituted by one fluorine atom; A compound selected from or a pharma- ceutically acceptable salt thereof.

[0013] In certain embodiments, the compounds of formula (I) include a third group consisting of compounds wherein R 1 represents a hydrogen atom, or a pharma ceutically acceptable salt thereof.

[0014] In certain embodiments, the compounds of formula (I) include a fourth group consisting of compounds wherein R 1 represents a bromine atom, or a pharma ceutically acceptable salt thereof.

[0015] In certain embodiments, the compounds of formula (I) include a fifth group consisting of compounds wherein R 1 represents a chlorine atom, or a pharma ceutically acceptable salt thereof.

[0016] In certain embodiments, the compounds of formula (I) include a sixth group consisting of compounds wherein R2 represents a -iPr group, or a pharma- ceutically acceptable salt thereof.

[0017] In certain embodiments, the compounds of formula (I) include a seventh group consisting of compounds wherein R2 represents a -cyclopropyl group, or a pharma- ceutically acceptable salt thereof.

[0018] In certain embodiments, the compound of Formula (I) is a compound wherein R3 is unsubstituted or -(C1-C4)-alkyl groups which are unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy groups, -(C1-C2)-alkyl groups, fluorine atoms, -(C1-C2)-alkoxy groups, nitrile groups, -C(O)O(C1-C3) groups or -(C3-C5)-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C3-C6)-cycloalkyl groups which are unsubstituted or substituted by one or more -(C1-C2)-alkyl groups, or Heterocyclopropyl group a compound representing a -(C4-C7)heterocycloalkyl group having nitrogen as a heteroatom, substituted with one or more substituents independently selected from or a pharma- ceutically acceptable salt thereof.

[0019] All of these subgroups, used alone or in combination, are part of this specification.

[0020] Among the compounds of formula (I), particular mention may be made of the following compounds: 1 (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(thiazol-5-yl)acetamide 3 N-((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 4 (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 5 (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 6 (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 7 2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(thiazol-5-yl)acetamide 8 (R)-2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 9 (R)-2-(8-isopropyl-2-methyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 10 (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclobutylpiperidin-3-yl)acetamide formate 11 (R)-N-(1-cyclobutylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 12 N-(benzo[d]thiazol-6-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 13 (R)-2-(2-chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide 14 (R)-N-(1-isobutylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 15 N-(benzo[d]thiazol-5-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 16 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(6-methoxypyridin-3-yl)acetamide 17 (R)-N-(1-(cyclopentylmethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 18 N-((3R)-1-((2,2-difluorocyclopropyl)methyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide combined with formaldehyde 19 (R)-N-(1-(2-hydroxyethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide combined with formaldehyde 20 (R)-N-(1-cyclobutylpiperidin-3-yl)-2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 21 (R)-2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide 22 2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)acetamide 23 (R)-N-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 24 (R)-2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide formate 25 N-((R)-1-Cyclobutylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)propanamide formate 26 N-((R)-1-Cyclopropylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)propanamide formate 27 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methyl-1H-indazol-6-yl)acetamide formate 28 (R)-N-(1-(cyclopropylmethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 29 (R)-2-(2-chloro-8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclobutylpiperidin-3-yl)acetamide formate 30 (R)-2-(2-chloro-8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide formate 31 (R)-2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclobutylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 32 (R)-N-(1-cyclobutylpiperidin-3-yl)-2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 33 (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 2,2,2-trifluoroacetate 34 2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(5,5-difluoro-1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 35 N-(5,5-difluoro-1-methylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 36 (R)-N-(1-(2-fluoroethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 37 N-(1-(tert-butyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide formate 38 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)acetamide 2,2,2-trifluoroacetate 39 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(quinuclidin-3-yl)acetamide 40 (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-(oxetan-3-yl)piperidin-3-yl)acetamide 41 (R)-N-(1-(3-fluoropropyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 42 (R)-N-(1-acetylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 43 (R)-N-(1-((3,3-difluorocyclobutyl)methyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 44 N-((R)-1-Cyclopropylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 45 (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-(1-methyl-1H-imidazol-2-yl)piperidin-3-yl)acetamide 46 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methyl-2-oxopiperidin-4-yl)acetamide 47 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide 48 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-isopropyl-3-piperidyl]acetamide 49 N-[(3R)-1-Cyclopentyl-3-piperidyl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 50 N-((R)-1-Cyclobutylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 51 N-((R)-1-Cyclopropylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2d][1,2,4]triazine-6(5H)-yl)acetamide 52 (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-(2-hydroxypropan-2-yl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 53 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(2-methylpyrazol-3-yl)acetamide 54 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(1-methylpyrazol-3-yl)acetamide 55 N-[(1-tert-butyl-5-oxo-pyrrolidin-3-yl)methyl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 56 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(3-pyridyl)acetamide 57 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[rac-(3R)-1-(2,2-dimethylcyclobutyl)-3-piperidyl]acetamide 58 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(2-pyridyl)acetamide 59 2-(4-bromo-12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(1-tert-butyl-3-piperidyl)acetamide 60 N-[(3R)-1-Cyclopropyl-3-piperidyl]-2-(12-ethyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 61 N-[(3R)-1-cyclopropylazepan-3-yl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 62 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-methylazepan-3-yl]acetamide 63 N-(1-cyclopropyl-5,5-difluoropiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 2,2,2-trifluoroacetate 64 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-((3R)-1-(1-methoxypropan-2-yl)piperidin-3-yl)acetamide 65 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(2-methoxypyridin-4-yl)acetamide 66 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-pyrimidin-4-yl-acetamide 67 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(4-pyridyl)acetamide 68 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(6-methyl-3-pyridyl)acetamide 69 2-(12-ethyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-[(2S)-2-hydroxypropyl]-3-piperidyl]acetamide 70 N-(5-fluoropyrimidin-4-yl)-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 71 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-(1-methylcyclopentyl)-3-piperidyl]acetamide 72 N-[(3R)-1-Cyclopropylpiperidin-3-yl]-2-(9-oxo-12-propyl-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 73 2-(12-ethyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-methyl-3-piperidyl]acetamide 74 N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 75 N-[(3R)-1-(cyanomethyl)piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 76 N-[(3R)-1-Methylpyrrolidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 77 N-[(3R)-1-(2-cyanoethyl)piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 78 N-[(3R)-1-[(2R)-2-hydroxypropyl]piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 79 N-[(3R)-1-(1-hydroxy-2-methylpropan-2-yl)piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 80 Ethyl 2-methyl-2-[3-[[2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetyl]amino]piperidin-1-yl]propanoate 81 N-((R)-1-Cyclobutylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 82 N-[(1R,4R)-2-Methyl-2-azabicyclo[2.2.1]heptan-6-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 83 N-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 84 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-pyrimidin-5-ylacetamide 85 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(2-oxo-4-piperidyl)acetamide 86 N-(1-cyclopropylpyrrolidin-3-yl)-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 87 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[rac-(3R)-1-tert-butylpyrrolidin-3-yl]acetamide 88 N-[(1S,4R)-2-Azabicyclo[2.2.1]heptan-6-yl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide hydrochloride

[0021] According to the present disclosure, the compounds of general formula (I) may be prepared by the following process:

[0022] Unless otherwise specified, R is an alkyl group, X is a halogen atom, and R1-R3 are as previously defined.

[0023] Reaction Scheme 1 (R1=H, Cl, Me) [ka] Compounds of general formula (I) can be prepared by reaction scheme 1, in which a bicyclic thienopyrrole carboxylic acid ester (GS1) is converted with hydrazine to provide a carboxyhydrazide analog (GS2). (GS2) is then reacted with the hydrochloride salt of an amidate (wherein R2 is alkyl, cycloalkyl, alkoxyalkyl or hydroxyalkyl), followed by addition of a base such as tBuOK to obtain a triazinone (GS3) after cyclization. (GS3) is then alkylated with an alkyl haloacetate using a base such as K2CO3 to obtain an ester (GS4), which is then saponified using aqueous base to obtain an acid (GS5), which is subsequently coupled with the appropriate amine H2N-R3 using known standard methods such as EDC / HOBT Et3N, HATU DIPEA to provide a compound of general formula (I).

[0024] Reaction Scheme 2 (R1=Br) [ka] Compounds of the present disclosure having R1=Br may be prepared by reaction scheme 2, in which an ester intermediate (GS4, R1=H) where R1=H is reacted with a brominating agent such as NBS to give the corresponding brominated derivative (GS6), which is then saponified using aqueous base to give the carboxylic acid (GS7), which is subsequently coupled with an appropriate amine H2N-R3 using known standard methods such as EDC / HOBT Et3N, HATU DIPEA to provide compounds of general formula (I').

[0025] Reaction Scheme 3 (R2 = C(OH)(CH3)2) [ka] The modified reaction sequence of Scheme 1 applies when R2 = C(OH)(CH3)2. Compounds of general formula (I) where R2 is 2-hydroxypropan-2-yl can be prepared by reaction scheme 3, where the general structure (GS3 with R2 = CH(OH)-CH3) is oxidized using standard methods such as Swern or Dess-Martin oxidation to provide the ketone (GS8), which is subjected to a Grignard reaction using, for example, MeMgCl to give (GS9). This intermediate is then alkylated with an alkyl haloacetate using a base such as K2CO3 to give the ester (GS10), which is then saponified to the corresponding carboxylic acid (GS11), which is subsequently coupled with the appropriate amine H2N-R3 using known standard methods such as EDC / HOBT Et3N, HATU DIPEA to provide compounds of general formula (I").

[0026] In the schemes that follow, the starting compounds and reagents, unless their preparation is described, are either commercially available or available as described in the literature, or may be prepared according to methods described therein or known to those skilled in the art.

[0027] The following abbreviations and empirical formulas are used: ACN Acetonitrile DAST Diethylaminosulfur trifluoride DCM Dichloromethane Cs2CO3 Cesium carbonate DIPEA Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Et2O Diethyl ether EtOAc Ethyl acetate Et3N Triethylamine EtOH Ethanol FA Formic Acid HATU Hexafluorophosphate azabenzotriazole tetramethyluronium HOBT Hydroxybenzotriazole HCl Hydrochloric acid IL 1b Interleukin 1 beta K2CO3 Potassium Carbonate MeOH Methanol NaHCO3 Sodium Bicarbonate Na2CO3 Sodium Carbonate Na2S2O3 Sodium Thiosulfate Na2SO4 Sodium Sulfate NaOH Sodium hydroxide NBS N-Bromosuccinimide NH4Cl Ammonium chloride TMSO Trimethylsilyloxy P2O5 Diphosphorus pentoxide tBuOK Potassium tert-butylate TFA Trifluoroacetic acid THF Tetrahydrofuran TNF-α tumor necrosis factor α rt room temperature Rt retention time ℃ Celsius temperature ml milliliter mmol min μmol micromol μl microliter h time

[0028] The following examples describe the preparation of certain compounds according to the present disclosure. These examples are not limiting, but merely illustrative of the present disclosure. The numbers of the exemplified compounds are listed in the above list of compounds and in the IC series which illustrate the chemical structures and physical properties of some compounds according to the present disclosure. 50 corresponds to that given in the table of values.

[0029] In the table: NMR: Proton magnetic resonance spectroscopy as described below ( 1H NMR (H NMR) are recorded at 400 MHz or 500 MHz in DMSO-d6 using the DMSO-d6 peak as standard. Chemical shifts (δ) are expressed in parts per million (ppm). The observed signals are designated as follows: s = singlet; d = doublet; t = triplet; m = multiplet or br s = broad singlet; br m = broad multiplet. LCMS: The LCMS profiles as described below indicate the different high performance liquid chromatography analytical methods used.

[0030] LCMS final compound: Method A: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -) Column: ACQUITY CORTECS C18+1.7μm 2.1×50mm; Column temperature: 40℃; Flow rate: 1.0ml / min; Solvent: A=H2O (0.1% formic acid); B=ACN (0.1% formic acid)

[0031] [Table 1]

[0032] Method B: System: Waters UPLC / SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -) Column: ACQUITY CSH C18+1.7μm 2.1×50mm; Column temperature: 60℃; Flow rate: 1.0ml / min; Solvent: A=H2O (0.1% formic acid); B=ACN (0.1% formic acid)

[0033] [Table 2]

[0034] Method C: System: Waters UPLC / SQD; Ionization: Electrospray in positive and / or negative mode (ES+ / -) Column: ACQUITY CORTECS C18+1.7μm 2.1×50mm; Column temperature: 40℃; Flow rate: 1.0ml / min; Solvent: A=H2O (0.1% formic acid); B=ACN (0.1% formic acid)

[0035] [Table 3]

[0036] Method D System: Waters XeVo-Qtof; Ionization: Electrospray in positive and / or negative mode (ES+) Column: ACQUITY CSH C18+1.7μm 2.1×100mm; Column temperature: 45℃; Flow rate: 0.5ml / min; Solvent: A=H2O (0.1% formic acid); B=ACN (0.1% formic acid)

[0037] [Table 4]

[0038] LCMS, intermediates Methods E and F: LC-MS: System Waters UPLC Hclass / SQD2; Ionization: Electrospray in positive and / or negative mode (ES+ / -); Column: Cortecs uplc C18 1.6 μm 2.1 × 50 mm; Column temperature: 55 °C; Flow rate: 0.8 ml / min; Solvents: A = H2O (0.1% formic acid); B = ACN (0.1% formic acid).

[0039] [Table 5]

[0040] Mass spectrometry results are reported as weight to charge ratio. EXAMPLES

[0041] Example 1: (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide [ka] Int 1: 6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] To a solution of methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (15.45 mmol, 2.8 g) in 15 ml of MeOH, add a solution of hydrazine (50-60% in water) (61.13 mmol, 6 ml) and heat the mixture under reflux overnight. After cooling the solution, the precipitate formed is filtered off, washed with Et2O and dried under vacuum. The title compound is obtained as a white solid (2.56 g, 91% yield). LMCS (Method E): Rt=0.61 min; MS m / z[M+H] + 182

[0042] Int 2:8-Isopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] To a solution of 6H-thieno[2,3-b]pyrrole-5-carbohydrazide (1.55 g, 8.55 mmol) in 20 ml of DMF under nitrogen, methyl 2-methylpropanimidate hydrochloride (1.46 g, 10.26 mmol) is added. The mixture is stirred at rt for 30 min. Then, solid tBuOK (2.15 g, 18.82 mmol) is added and the resulting mixture is stirred for 1 h in an oil bath preheated to 90 °C. After cooling to 0 °C, 70 ml of water is added and the mixture is acidified to pH 5 with HCl (1 M). The precipitate formed is filtered off and washed with water and EtOAc / CH2Cl2 (9 / 1). The resulting solid is washed with pentane and dried under vacuum to give the title compound as a beige solid (1.0 g, 50% yield). LMCS (Method E): Rt=1.21 min; MS m / z[M+H] + 234

[0043] Int 3: Ethyl 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrole[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 8-isopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (717 mg, 3.07 mmol) in 10 ml of DMF under nitrogen, K2CO3 (637 mg, 4.61 mmol) is added, followed by dropwise addition of ethyl iodoacetate (557 μl, 4.61 mmol). The resulting mixture is stirred at rt for 1 h. The mixture is then diluted with a saturated aqueous solution of NH4Cl and extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using cyclohexane / EtOAc (0%-50%) to give the title compound as a white solid (620 mg, 63% yield). LMCS (Method E): Rt=1.46 min; MS m / z[M+H] + 320

[0044] Int 4: 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrole[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (620 mg, 1.94 mmol) in 20 ml of dioxane is added a solution of NaOH (1 M) (2.91 ml, 2.91 mmol). The resulting solution is stirred at rt overnight.

[0045] The mixture is acidified with HCl (1M). The precipitate formed is filtered off and washed with water and pentane. After drying overnight under vacuum in the presence of P2O5, the title compound is obtained as a white solid (433 mg, 77% yield). LMCS (Method E): Rt=1.22 min; MS m / z[M+H] + 292

[0046] Example 1: (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide [ka] To a suspension of (3R)-1-methylpiperidin-3-amine dihydrochloride (22 mg, 113 μmol) and 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (30 mg, 103 μmol) in 2 ml of DMF under nitrogen, DIPEA (54 μl, 0.31 mmol) is added followed by HATU (51 mg, 134 μmol). The resulting mixture is stirred at rt for 20 h. The crude mixture is purified by reverse phase chromatography on a Waters SunFire PrepC18 OBD 30 × 100 mm column in water containing 0.1% HCOH with a gradient of 10-80% acetonitrile for 18 min. After evaporation under reduced pressure and drying overnight, the title compound is obtained as a yellow solid (24 mg, 60% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 1.24(m,1H),1.35(d,J=6.8Hz,6H),1.48(qd,J=10.2,3.9Hz,1H),1.62 -1.72(m,2H),1.92(m,1H),2.02(m,1H),2,21(s,3H),2.57(m,1H),2.7 1(m,1H),3.37(m,1H),3.77(m,1H),4.55(s,2H),7.32(d,J=5.5Hz,1H) ,7.36(s,1H),7.58(d,J=5.5Hz,1H),7.92(d,J=7.8Hz,1H),8.14(s,1H) LCMS[M+H] + =388;Rt=0.65;Method A

[0047] The following examples were synthesized similarly to the previous procedure using the appropriate amine.

[0048] [Table 6]

[0049] [Table 7]

[0050] [Table 8]

[0051] [Table 9]

[0052] [Table 10]

[0053] [Table 11]

[0054] [Table 12]

[0055] [Table 13]

[0056] [Table 14]

[0057] Example 5: (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate [ka] Int 5: 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] To a solution of methyl 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate (1.5 g, 6.96 mmol) in 10 ml of MeOH, hydrazine (1.31 ml, 20.87 mmol) is added and the mixture is heated under reflux overnight. After cooling the solution, the precipitate formed is filtered off, washed with ether and dried under vacuum. The title compound is obtained as a beige solid (1.39 g, 92% yield). LCMS (Method F): Rt=1.14 min; MS m / z[M+H] + 216 / 218

[0058] Int 6: 2-Chloro-8-isopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] To a solution of 2-chloro-6H-thieno[2,3-b]pyrrole-5-carbohydrazide (1.39 g, 6.45 mmol) in 20 ml of DMF under nitrogen, methyl 2-methylpropanimidate hydrochloride (1.10 g, 7.73 mmol) is added. The mixture is stirred at rt for 30 min. Solid tBuOK (2.15 g, 18.82 mmol) is then added and the resulting mixture is stirred for 24 h in an oil bath preheated to 90 °C. After cooling to 0 °C, the solution is acidified to pH 5 with saturated aqueous NH4Cl solution. The formed precipitate is filtered off and purified by flash chromatography on silica gel using cyclohexane / EtOAc (10% to 50%) to give the title compound (750 mg, 43% yield) as a brown solid. LCMS (Method F): Rt=1.82 min; MS m / z[M+H] + 268 / 270

[0059] Int 7: Ethyl 2-(2-chloro-8-isobutyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 2-chloro-8-isopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (750 mg, 2.80 mmol) in 20 ml of DMF under nitrogen, K2CO3 (581 mg, 4.20 mmol) is added, followed by dropwise addition of ethyl iodoacetate (508 μl, 4.20 mmol). The mixture is stirred at rt for 12 h.

[0060] The reaction mixture is diluted with water and then extracted twice with EtOAc. The combined organic layers are washed with water, then with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using cyclohexane / EtOAc (10%-30%) to give the title compound as a white solid (800 mg, 80% yield). LCMS (Method F): Rt=2.18 min; MS m / z[M+H] + 354 / 356

[0061] Int 8: 2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(2-chloro-8-isobutyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (808 mg, 2.28 mmol) in 20 ml of dioxane is added a solution of NaOH (1 M) (6.85 ml, 6.85 mmol). The resulting solution is stirred at rt overnight.

[0062] The mixture is acidified with HCl (1M). The precipitate formed is filtered off and washed with water and pentane. After drying overnight under vacuum in the presence of P2O5, the title compound is obtained as a white solid (613 mg, 82% yield). LCMS (Method F): Rt=1.84 min; MS m / z[M+H] + 326 / 328

[0063] Example 5: (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate [ka] To a suspension of (3R)-1-methylpiperidin-3-amine dihydrochloride (73 mg, 368 μmol) and 2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (100 mg, 307 μmol) in 2 ml of DMF under nitrogen, DIPEA (268 μl, 1.53 mmol) is added followed by HATU (175 mg, 460 μmol). The resulting mixture is stirred at rt for 12 h. A few drops of TFA are added and the resulting solution is purified by reverse phase chromatography on a Waters SunFire PrepC18 OBD 30 × 100 mm column with a gradient of acetonitrile 20-80% in water containing 0.1% TFA for 18 min.

[0064] After evaporation under reduced pressure and drying overnight, the title compound is obtained as a solid (116 mg, 71% yield). 1H NMR(400MHz,DMSO-d6)δppm 1.24-1.50(m,7H),1.67(m,1H),1.79-1.95(m,2H),2.64(m,1H),2.73-2.89(m,1H),3.22(sept,J=6.6Hz,1 H),3.32-3.46(m,4H),3.94(m,1H),4.57(s,2H),7.34(s,1H),7.50(s,1H),8.26(d,J=7.5Hz,1H),9.54(br s,1H) LCMS[M+H] + =422;Rt=0.76;Method A

[0065] The following examples were synthesized similarly to the previous procedure using the appropriate amine.

[0066] [Table 15]

[0067] Example 8: (R)-2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide [ka] Int 9: 2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (260 mg, 814 μmol) in 10 ml of CHCl3 under nitrogen, 1 ml of acetic acid and NBS (159 mg, 896 μmol) are added. The mixture is stirred at rt overnight. A solution of Na2S2O3 (1M) is added and the mixture is extracted with DCM. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure.

[0068] The residue obtained is dissolved in 10 ml of THF and 1 ml of MeOH and 0.5 ml of a solution of NaOH (1N) is added. The solution is stirred at rt for 1 h, then the mixture is acidified with a solution of HCl (1N), followed by extraction with EtOAc, drying over Na2SO4, then filtering off and concentrating. The corresponding acid is obtained as a white solid (270 mg, 89% yield). LMCS (Method E): Rt=1.43 min; MS m / z[M+H] + 370 / 372

[0069] Example 8: (R)-2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide [ka] To a suspension of (3R)-1-methylpiperidin-3-amine dihydrochloride (74 mg, 375 μmol) and 2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (126 mg, 340 μmol) in 2 ml of DMF under nitrogen, DIPEA (180 μl, 1.03 mmol) is added followed by HATU (168 mg, 442 μmol). The mixture is stirred at rt for 12 h. The crude mixture is purified by reverse phase chromatography on a Waters SunFire PrepC18 OBD 30 × 100 mm column in water containing 0.1% HCOH with a gradient of 10-80% acetonitrile for 18 min. After evaporation under reduced pressure and drying overnight, the title compound is obtained as a solid (51 mg, 32% yield). 1H NMR(500MHz,DMSO-d6)δ ppm 1.33(d,J=6.8Hz,6H),1.39(m,1H),1.66(m,1H),1.85(m,1H),1.91(m,1H),2.63(m,1H),2.78-2.89(m,4H),3.23(s ept,J=6.8Hz,1H),3.41(m,2H),3.94(m,1H),4.57(s,2H),7.33(s,1H),7.58(s,1H),8.25(d,J=7.6Hz,1H),9.45(br s,1H) LCMS[M+H] + =466 / 468;Rt=0.76;Method A

[0070] The following examples were synthesized similarly to the previous procedure using the appropriate amine.

[0071] [Table 16]

[0072] Example 9: (R)-2-(8-isopropyl-2-methyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate [ka] Int 10: 2-Methyl-6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] Analogously to the synthesis of 6H-thieno[2,3-b]pyrrole-5-carbohydrazide, starting with ethyl 2-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylate (300 mg, 1.43 mmol) and hydrazine (0.270 ml, 4.3 mmol), 150 mg (53% yield) of the title compound is obtained as a solid. LMCS (Method E): Rt=0.96 min; MS m / z[M+H] + 196

[0073] Int 11: 8-Isopropyl-2-methylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] To a solution of 2-methyl-6H-thieno[2,3-b]pyrrole-5-carbohydrazide (100 mg, 512 μmol) in 5 ml of DMF under nitrogen is added methyl 2-methylpropanimidate hydrochloride (87 mg, 615 μmol).

[0074] The mixture is stirred at rt for 30 min. Solid tBuOK (115 mg, 1.02 mmol) is then added and the resulting mixture is stirred for 1 h in an oil bath preheated to 100° C. After cooling to 0° C., the mixture is acidified to pH 5 with (1N) HCl. The formed precipitate is filtered off, washed with water and dried under vacuum to give the title compound as a purple solid (110 mg, 86% yield). LMCS (Method E): Rt=1.33 min; MS m / z[M+H] + 248

[0075] Int 12: Ethyl 2-(8-isopropyl-2-methyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 8-isopropyl-2-methylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (110 mg, 445 μmol) in 5 ml of DMF under nitrogen, K2CO3 (92 mg, 667 μmol) is added, followed by dropwise addition of ethyl iodoacetate (81 μl, 667 μmol). The resulting mixture is stirred at rt for 12 h.

[0076] The reaction mixture is diluted with a saturated aqueous solution of NH4Cl and then extracted twice with EtOAc. The combined organic layers are washed with water, then with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using cyclohexane / EtOAc (10%-100%) to give the title compound as a white solid (71 mg, 48% yield). LMCS (Method E): Rt=1.57 min; MS m / z[M+H] + 334

[0077] Example 9: (R)-2-(8-isopropyl-2-methyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate [ka] Solid NaOH (26 mg, 639 μmol) is added to a solution of ethyl 2-(8-isopropyl-2-methyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (71 mg, 213 μmol) in 2 ml of dioxane and 5 ml of H 2 O. The solution is stirred at rt overnight.

[0078] The mixture is acidified with HCl (1N) and then extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated under vacuum. Under nitrogen, the residue is solubilized in 5 ml of DMF, then (3R)-1-methylpiperidin-3-amine dihydrochloride (50 mg, 256 μmol), DIPEA (149 μl, 852 μmol) and HATU (1221 mg, 319 μmol) are added to the solution. The mixture is stirred at rt for 12 h. The resulting solution is purified by reverse phase chromatography Waters SunFire PrepC18 OBD 30×100 mm column in water containing 0.1% TFA with a gradient of 20-80% acetonitrile in 18 min.

[0079] After evaporation under reduced pressure and drying overnight, the title compound is obtained as a yellow solid (35 mg, 32% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 1.34(d,J=7Hz,7H),1.66(br d,J=14Hz,1H),1.80-1.94(m,2H),2.58(d,J=1Hz,3H),2.63(br d,J=10Hz,1H),2.77-2.85(m,4H),3.26-3.36(m,3H),3.89-3.99(m,1H),4.56(s,2H),7.03(d,J=1Hz,1H),7.26(s,1H),8.24(d,J=8Hz,1H) LCMS[M+H] + =402;Rt=0.71;Method A

[0080] Example 24: (R)-2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide [ka] Int 1: 6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] To a solution of methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (4 g, 22.07 mmol) in 100 ml of EtOH, a hydrazine solution (35% in water) (24.7 ml, 176.59 mmol) is added and the mixture is heated under reflux overnight. After cooling the solution, the precipitate formed is filtered off, washed with ether and dried under vacuum. The title compound is obtained as a white solid (3.4 g, 85% yield). LCMS (Method F): Rt=1.15 min; MS m / z[M+H] + 181.2

[0081] Int 13: 8-Cyclopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] To a solution of 6H-thieno[2,3-b]pyrrole-5-carbohydrazide (1 g, 5.52 mmol) in 40 ml of DMF under nitrogen is added methylcyclopropanecarboximidate hydrochloride (945 mg, 6.62 mmol) and the mixture is stirred at rt for 1 h.

[0082] Solid tBuOK (1.26 g, 11.04 mmol) is then added and the resulting mixture is stirred in a preheated Dry-syn (90° C.) for 1 h. The mixture is cooled to RT, diluted with EtOAc, and washed with a 10% aqueous solution of NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title product (490 mg, 38% yield). LCMS (Method F): Rt=1.41 min; MS m / z[M+H] + 232.2

[0083] Int 14: Ethyl 2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 8-cyclopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (490 mg, 2.12 mmol) in 5 ml of DMF under nitrogen, Cs2CO3 (828 mg, 2.54 mmol) is added, followed by dropwise addition of ethyl iodoacetate (557 μl, 4.61 mmol). The resulting mixture is stirred at rt for 20 h. The mixture is then diluted with water and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using cyclohexane / EtOAc (5%-40%) to give the title compound as a white solid (500 mg, 77% yield). LCMS (Method F): Rt=1.79 min; MS m / z[M+H] + 318.4

[0084] Int 15: 2-(-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (650 mg, 2.14 mmol) in 15 ml of dioxane / MeOH (1 / 1) is added a solution of (1 M) NaOH (6.43 ml, 6.43 mmol). The resulting solution is stirred at rt for 20 h. The mixture is acidified with HCl (1 M) and extracted with DCM. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound as a white solid (500 mg, 80% yield). LCMS (Method F): Rt=1.47 min; MS m / z[M+H] + 290.0

[0085] Example 24: (R)-2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide [ka] To a suspension of (R)-1-methylpiperidin-3-amine hydrochloride (38 mg, 331 μmol) and 2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (80 mg, 277 μmol) in 5 ml of DMF under nitrogen, DIPEA (241 μl, 1.38 mmol) is added followed by HATU (126 mg, 331 μmol). The resulting mixture is stirred at rt for 20 h. EtOAc is added to the mixture and the solution is washed twice with water, then with an aqueous solution of HCl (1M) and twice with brine. The organic layer is dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue is purified by reverse-phase chromatography using a Gilson GX271 system, a CSH 50×250 mm, 5 μm column (Waters™), water / formic acid (0.1% v / v) with a gradient of 18-50% ACN / FA (0.1% v / v) for 25 min to provide the title compound as a white solid (6 mg, 5.2% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 0.99-1.06(m,2H),1.10-1.25(m,3H),1.46(br d,J=7Hz,1H),1.65(br d,J=9Hz,2H),1.83(br t,J=10Hz,1H),1.95(br t,J=10Hz,1H),2.16(s,3H),2.30-2.42(m,1H),2.50(d,J=2Hz,1H),2.62-2.72(m,1H) ,3.70-3.78(m,1H),4.46-4.54(m,2H),7.29-7.34(m,2H),7.57(d,J=6Hz,1H),7.86(br d, J=8Hz, 1H) LCMS[M+H] + =386;Rt=0.56;Method A

[0086] The following examples were synthesized similarly to the previous procedure using the appropriate amine.

[0087] [Table 17]

[0088] Example 13: (R)-2-(2-chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide [ka] Int 5: 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] To a solution of methyl 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate (3.0 g, 13.91 mmol) in 60 ml of EtOH, a solution of hydrazine hydrate (35% in water) (7.78 ml, 55.65 mmol) is added and the mixture is heated under reflux overnight. After cooling the solution, the precipitate formed is filtered off, washed with ether and dried under vacuum. The title compound is obtained as a yellow solid (3 g, 100% yield). LCMS (Method F): Rt=1.15 min; MS m / z[M+H] + 216.0

[0089] Int 16: 2-Chloro-8-cyclopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] To a solution of 2-chloro-6H-thieno[2,3-b]pyrrole-5-carbohydrazide (500 mg, 2.32 mmol) in 10 ml of DMF under nitrogen, add methylcyclopropanecarboximidate hydrochloride (1.10 g, 7.73 mmol). The mixture is stirred at rt for 1 h.

[0090] Solid tBuOK (531 mg, 4.64 mmol) is then added and the resulting mixture is stirred for 18 h in a Dry-syn preheated to 90° C. After cooling to 0° C., the solution is acidified to pH 5 with a solution of HCl (1 M) and the formed precipitate is filtered off, rinsed with water then DCM and dried under reduced pressure in the presence of P2O5 to give the title compound as a brown solid (250 mg, 40% yield). LCMS (Method F): Rt=1.70 min; MS m / z[M+H] + 266.0

[0091] Int 17: Ethyl 2-(2-chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 2-chloro-8-cyclopropylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (650 mg, 2.45 mmol) in 15 ml of DMF under nitrogen, K2CO3 (406 mg, 2.94 mmol) is added, followed by dropwise addition of ethyl iodoacetate (641 mg, 2.94 mmol). The mixture is stirred at rt for 20 h. The reaction mixture is diluted with water and extracted twice with EtOAc. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.

[0092] The residue is purified by flash chromatography on silica gel using cyclohexane / EtOAc (5%-50%) to give the title compound as a pale yellow solid (250 mg, 29% yield). LCMS (Method F): Rt=2.04 min; MS m / z[M+H] + 352.1

[0093] Int 18: 2-(2-chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(2-chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (220 mg, 0.625 mmol) in 10 ml of dioxane / MeOH (1 / 1) is added a solution of (1 M) NaOH (1.88 ml, 1.88 mmol) and the resulting solution is stirred at rt for 20 h. The mixture is acidified with (1 M) HCl and extracted with CHCl. ​​The organic layer is washed with brine, dried over NaSO, filtered and concentrated under reduced pressure to provide the title compound as a white solid (202 mg, 74% yield). LCMS (Method F): Rt=1.72 min; MS m / z[M+H] + 324.0

[0094] Example 13: (R)-2-(2-chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide [ka] To a suspension of (R)-1-cyclopropylpiperidin-3-amine hydrochloride (33 mg, 185 μmol) and 2-(2 chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (50 mg, 154 μmol) in 3 ml of DMF under nitrogen, DIPEA (134 μl, 772 μmol) is added followed by HATU (71 mg, 185 μmol). The resulting mixture is stirred at rt for 20 h.

[0095] The reaction mixture is diluted with water and extracted twice with EtOAc. The organic extracts are washed with a solution of HCl (1M) then with brine, dried over Na2SO4, filtered and concentrated under reduced pressure.

[0096] The residue is purified by reverse-phase chromatography using a Gilson GX271 system, a CSH 50×250 mm, 5 μm column (Waters™), water / formic acid (0.1% v / v) with a gradient of 18-50% ACN / FA (0.1% v / v) for 25 min to provide the title compound as a white solid (30 mg, 44% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 0.21-0.32(m,2H),0.35-0.42(m,2H),0.98-1.05(m,2H),1.11-1.27(m,3H),1.33-1.44(m,1H),1.56-1.70(m,3H),2.02(br t,J=10Hz,1H),2.15(br t,J=10Hz,1H),2.24-2.39(m,1H),2.67-2.74(m,1H),2.84(br dd,J=10,3Hz,1H),3.60-3.69(m,1H),4.50(s,2H),7.31(s,1H),7.49(s,1H),7.78(br d,J=8Hz,1H) LCMS[M+H] + =446;Rt=0.73;Method A

[0097] Example 33: (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide [ka] Int 1: 6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] To a solution of methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (4 g, 22.07 mmol) in 100 ml of EtOH, a hydrazine solution (35% in water) (24.7 ml, 176.59 mmol) is added and the mixture is heated under reflux overnight. After cooling the solution, the precipitate formed is filtered off, washed with ether and dried under vacuum. The title compound is obtained as a white solid (3.4 g, 85% yield). LCMS (Method F): Rt=1.15 min; MS m / z[M+H] + 181.2

[0098] Int 19: 8-(Methoxymethyl)thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] Ethyl 2-methoxyethanimidate hydrochloride (524 mg, 3.31 mmol) is added to a solution of 6H-thieno[2,3-b]pyrrole-5-carbohydrazide (500 mg, 2.76 mmol) in 20 ml of DMF under nitrogen. The mixture is stirred at rt for 30 min. Solid tBuOK (632 mg, 5.52 mmol) is then added and the resulting mixture is stirred for 1 h in a preheated Dry-syn at 90° C. After cooling to 0° C., water is added and the mixture is acidified to pH 5 with HCl (1M). The precipitate formed is filtered off, washed with water and dried under reduced pressure in the presence of P2O5 to provide the title product as a soft yellow solid (303 mg, 46% yield). LCMS (Method F): Rt=1.27 min; MS m / z[M+H] + 236.0

[0099] Int 20: Ethyl 2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 8-(methoxymethyl)thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (300 mg, 1.28 mmol) in 10 ml of DMF under nitrogen, K2CO3 (267 mg, 1.91 mmol) is added, followed by dropwise addition of ethyl iodoacetate (238 μl, 1.91 mmol). The mixture is stirred at RT for 20 h. The reaction mixture is diluted with water and then extracted twice with EtOAc. The combined organic layers are washed with water, then with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure to give 450 mg of an oil, which is directly involved in the next step. LCMS (Method F): Rt=1.64 min; MS m / z[M+H] + 322.3

[0100] Int 21: 2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (450 mg, 1.40 mmol) in 20 ml of dioxane and 20 ml of MeOH is added a solution of NaOH (1 M) (4.2 ml, 4.2 mmol). The resulting solution is stirred at rt overnight. The mixture is acidified with HCl (1 M). The precipitate formed is filtered off and washed with water and pentane. After drying overnight under vacuum in the presence of P2O5, the title compound is obtained as a white solid (270 mg, 65% yield). LCMS (Method F): Rt=1.33 min; MS m / z[M+H] + 294.0

[0101] Example 33: (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide [ka] To a suspension of (R)-1-cyclopropylpiperidin-3-amine hydrochloride (65 mg, 368 μmol) and 2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (90 mg, 307 μmol) in 5 ml of DMF under nitrogen, DIPEA (268 μl, 1.53 mmol) is added followed by HATU (140 mg, 368 μmol). The resulting mixture is stirred at rt for 12 h. A few drops of TFA are added and the residue is purified by reverse phase chromatography using a Gilson GX271 system, a CSH 50×250 mm, 5 μm column (Waters™), water / formic acid (0.1% v / v) with a gradient of 18-50% ACN / FA (0.1% v / v) for 25 min to provide the title compound as a white powder (20 mg, 12% yield) after lyophilization. 1H NMR(400MHz,DMSO-d6)δppm 0.69-0.97(m,4H),1.35-2.04(m,4H),2.82-3.15(m,3H),3.44(s,5H),3.81-4.01(m, 1H),4.53-4.75(m,4H),7.27(d,J=6Hz,1H),7.39(s,1H),7.56(d,J=6Hz,1H),8.36(br d,J=4Hz,1H) LCMS[M+H] + =416;Rt=0.52;Method A

[0102] The following examples were synthesized similarly to the previous procedure using the appropriate amine.

[0103] [Table 18]

[0104] Starting from 2-chloro-6H-thieno[2,3-b]pyrrole-5-carbohydrazide, the following examples were synthesized analogously to the previous procedure.

[0105] [Table 19]

[0106] Example 60: (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-(ethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide [ka] Int 1: 6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] To a solution of methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (4 g, 22.07 mmol) in 100 ml of EtOH, a hydrazine solution (35% in water) (24.7 ml, 176.59 mmol) is added and the mixture is heated under reflux. After cooling the solution, the precipitate formed is filtered off, washed with ether and dried under vacuum. The title compound is obtained as a white solid (3.4 g, 85% yield). LCMS (Method F): Rt=1.15 min; MS m / z[M+H] + 181.2

[0107] Int 22: 8-(Ethyl)thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] Ethylpropanecarboximidate hydrochloride (1.08 g, 7.83 mmol) is added to a solution of 6H-thieno[2,3-b]pyrrole-5-carbohydrazide (1.0 g, 6.53 mmol) in 15 ml of DMF under nitrogen. The mixture is stirred at rt for 1 h. Solid tBuOK (1.50 g, 13.05 mmol) is then added and the resulting mixture is stirred for 1 h 30 min in a Dry-syn preheated at 90° C. After cooling to 0° C., water is added and the mixture is acidified to pH 5 with HCl (1M). The precipitate formed is filtered off, washed with water and dried under reduced pressure in the presence of P2O5 to provide the title product as a soft yellow solid (1.2 g, 84% yield). LCMS (Method F): Rt=1.38 min; MS m / z[M+H] + 220.1

[0108] Int 23: Ethyl 2-(8-(ethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 8-(ethyl)thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (1.2 g, 5.5 mmol) in 15 ml of DMF under nitrogen, Cs2CO3 (7.1 g, 22 mmol) is added, followed by dropwise addition of ethyl iodoacetate (780 μl, 6.6 mmol). The mixture is stirred at RT for 20 h.

[0109] The reaction mixture is diluted with water and then extracted twice with EtOAc. The combined organic layers are washed with water, then with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure to give 900 mg of an oil which is used in the next step without further purification. LCMS (Method F): Rt=1.78 min; MS m / z[M+H] + 306.2

[0110] Int 24: 2-(8-(ethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(8-(ethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (900 mg, 2.95 mmol) in 6 ml of THF is added a solution of NaOH (1 M) (3 ml, 3 mmol). The resulting solution is stirred at rt overnight. The mixture is acidified with HCl (1 M). The organic layer is extracted with DCM, concentrated under reduced pressure and the residue is triturated with Et2O and then filtered. After drying overnight under vacuum in the presence of P2O5, the title compound is obtained as a yellow solid (830 mg, 100% yield). LCMS (Method F): Rt=1.42 min; MS m / z[M+H] + 278.0

[0111] Example 60: (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-(ethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide [ka] To a suspension of (R)-1-cyclopropylpiperidin-3-amine hydrochloride (46 mg, 216 μmol) and 2-(8-(ethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (50 mg, 180 μmol) in 5 ml of ACN under nitrogen, DIPEA (157 μl, 0.900 mmol) is added followed by HATU (82 mg, 216 μmol). The resulting mixture is stirred at rt for 1 h 30 min. After evaporation under reduced pressure, the residue is purified by reverse phase chromatography using a Gilson GX271 system, a CSH 50×250 mm, 5 μm column (Waters™), water / formic acid (0.1% v / v) with a 14-45% gradient of ACN / FA (0.1% v / v) for 20 min to provide the title compound as a white powder (10 mg, 14% yield) after lyophilization. 1H NMR(400MHz,DMSO-d6)δ ppm 0.20-0.29(m,2H),0.34-0.42(m,2H),1.19-1.43(m,5H),1.55-1.71(m,3H),2.04(br t,J=10Hz,1H),2.11-2.21(m,1H),2.61-2.73(m,1H),2.84(br d,J=7Hz,1H),3.05(q,J=7Hz,2H),3.65(br d,J=9Hz,1H),4.54(s,2H),7.31(d,J=5Hz,1H),7.34(s,1H),7.57(d,J=5Hz,1H),7.81(br d,J=8Hz,1H) LCMS[M+H] + =400;Rt=0.57;Method A

[0112] The following examples were synthesized similarly to the previous procedure using the appropriate amine.

[0113] [Table 20]

[0114] The following examples were synthesized similarly to the previous procedure using the appropriate imidates.

[0115] [Table 21]

[0116] Examples 44 and 51: N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide [ka] Int 1: 6H-thieno[2,3-b]pyrrole-5-carbohydrazide [ka] To a solution of methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (4 g, 22.07 mmol) in 100 ml of EtOH, add hydrazine solution (35% in water) (24.7 ml, 176.59 mmol) and heat the solution under reflux overnight. After cooling the solution, the precipitate formed is filtered off, washed with ether and dried under vacuum. The title compound is obtained as a white solid (3.4 g, 85% yield). LCMS (Method F): Rt=1.15 min; MS m / z[M+H] + 181.2

[0117] Int 25: 8-(1-hydroxyethyl)-thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] To a solution of 6H-thieno[2,3-b]pyrrole-5-carbohydrazide (2.5 g, 13.80 mmol) in 50 ml of DMF under nitrogen, add ethyl 2-hydroxypropanimidate hydrochloride (2.74 g, 16.97 mmol). The mixture is stirred at rt for 1 h 30 min. Then solid tBuOK (3.16 g, 27.59 mmol) is added and the resulting mixture is stirred in a preheated Dry-syn at 90° C. for 1 h 30 min.

[0118] After cooling to 0° C., the mixture is acidified with HCl (1M). The formed precipitate is filtered off, washed with water and dried under reduced pressure in the presence of P2O5 to give the title compound as a soft yellow solid (800 mg, 25% yield). LCMS (Method F): Rt=1.25 min; MS m / z[M+H] + 236.1

[0119] Int 26: Ethyl 2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate [ka] To a solution of 8-(1-hydroxyethyl)-thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (350 mg, 1.49 mmol) in 6 ml of DMF, Cs2CO3 (581 mg, 1.79 mmol) is added, followed by dropwise addition of ethyl iodoacetate (222 μl, 1.79 mmol). The resulting mixture is stirred at rt for 20 h. The mixture is then diluted with water and extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, filtered off and concentrated under reduced pressure to give the title compound as a pale maroon powder (400 mg, 83% yield). LCMS (Method F): Rt=1.54 min; MS m / z[M+H] + 322.1

[0120] Int 27: 2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid [ka] To a solution of ethyl 2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetate (250 mg, 778 μmol) in 10 ml of THF and 3 ml of MeOH is added a solution of NaOH (1M) (3.89 ml, 3.89 mmol). The resulting solution is stirred at rt overnight. The mixture is acidified with HCl (1M) and extracted with CHCl. ​​The organic layer is washed with brine, dried over NaSO, filtered and evaporated to provide the title compound as a brown oil (230 mg, 100% yield). LCMS (Method F): Rt=1.20 min; MS m / z[M+H] + 294.1

[0121] Example 44: N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide (Dia 1) Example 51: N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide (Dia 2) [ka] To a suspension of (R)-1-cyclopropylpiperidin-3-amine hydrochloride (60 mg, 341 μmol) and 2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (100 mg, 341 μmol) in 5 ml of DMF under nitrogen, DIPEA (298 μl, 1.70 mmol) is added followed by HATU (1565 mg, 409 μmol). The resulting mixture is stirred at rt for 20 h. After concentration under reduced pressure, the residue is purified by reverse phase chromatography using a Gilson GX271 system, CSH 50×250 mm, 5 μm column (Waters™), water / formic acid (0.1% v / v) with a gradient of 18-50% ACN / FA (0.1% v / v) for 25 min to give two diastereomers: Dia 1 as a yellow powder (15 mg, 10% yield) and Dia 2 as an orange powder (12 mg, 8% yield). First diastereomer (Dia 1): 1H NMR(400MHz,DMSO-d6)δ ppm 0.71-0.96(m,4H),1.38-1.71(m,5H),1.75-2.02(m,2H),2.84-3.14(m,3H),3.37-3.54(m,2H),3.88(br s,1H),4.94-5.01(m,1H),5.16-5.30(m,2H),6.01(br s,1H),7.07-7.13(m,2H),7.19(d,J=5Hz,1H),8.58(br s,1H) LCMS[M+H] + =416;Rt=0.46;Method A Second diastereomer (Dia 2): 1H NMR(400MHz,DMSO-d6)δppm 0.71-0.95(m,4H),1.53(d,J=7Hz,5H),1.75-2.01(m,2H),2.81-2.99(m,2H),3.01-3.16(m,1H),3.37-3.56(m,2H),3.88(br s,1H),4.94-5.01(m,1H),5.16-5.30(m,2H),6.01(br s,1H),7.07-7.13(m,2H),7.19(d,J=5Hz,1H),8.58(br s,1H) LCMS[M+H] + =416;Rt=0.49;Method A

[0122] The following examples were synthesized similarly to the previous procedure using the appropriate amine.

[0123] [Table 22]

[0124] Example 52: N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-(2-hydroxypropan-2-yl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide [ka] Int 28: 8-Acetylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] To a solution of 8-(1-hydroxyethyl)-thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (Int 28) (400 mg, 1.70 mmol) in 15 ml of DMF, Dess-Martin periodinane (1.14 g, 2.55 mmol) is added and the mixture is stirred at rt for 30 min. Then a saturated aqueous solution of NaHCO3 is added and the formed precipitate is filtered off and rinsed with DCM to provide the title compound as a maroon solid (395 mg, 100% yield). LCMS (Method F): Rt=1.36 min; MS m / z[M+H] + 234

[0125] Int 29: 8-(2-hydroxypropan-2-yl)thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one [ka] Under nitrogen, a solution of lanthanum(III) chloride bis(lithium chloride) complex (in THF, 0.6 M) (11.43 ml, 6.86 mmol) is added to a solution of 8-acetylthieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (400 mg, 1.71 mmol) in 8 ml of anhydrous THF. The temperature is lowered to 0 °C and then a solution of methylmagnesium chloride (in THF, 3 M) is added dropwise, controlling the temperature between 5 °C and 8 °C. After the total addition, the mixture is stirred at RT for 1 h. Then an aqueous solution of NH4Cl (10%) is added, acidified with HCl (1 M) and the resulting mixture is extracted with DCM (3 times). The combined organic layers are dried over Na2SO4, filtered off and concentrated under reduced pressure to give the title compound as a brown solid (220 mg, 51% yield). LCMS (Method F): Rt=1.42 min; MS m / z[M+H] + 250.1

[0126] Int 30: 2-(8-(2-hydroxypropan-2-yl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid [ka] To a solution of 8-(2-hydroxypropan-2-yl)thieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-5(6H)-one (220 mg, 0.882 mmol) in 10 ml of DMF, Cs2CO3 (345 mg, 1.06 mmol) is added, followed by dropwise addition of ethyl iodoacetate (128 μl, 1.06 mmol). The resulting mixture is stirred at rt for 20 h and at 60° C. for 3 h. After cooling to rt, the mixture is diluted with water and extracted twice with EtOAc. The combined organic layers are dried over Na2SO4, filtered off and concentrated under reduced pressure to give the title compound as a pale maroon wax (290 mg, 64% pure), which is used in the next step without further purification. LCMS (Method F): Rt=1.32 min; MS m / z[M+H] + 308

[0127] Example 52: N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-(2-hydroxypropan-2-yl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide [ka] To a suspension of (R)-1-cyclopropylpiperidin-3-amine hydrochloride (44 mg, 246 μmol) and 2-(8-(2-hydroxypropan-2-yl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetic acid (63 mg, 205 μmol) in 2 ml of DMF under nitrogen, DIPEA (179 μl, 1.02 mmol) is added followed by HATU (94 mg, 246 μmol). The resulting mixture is stirred at rt for 20 h. After evaporation under reduced pressure, the residue is purified by reverse phase chromatography using a Gilson GX271 system, a CSH 50×250 mm, 5 μm column (Waters™), water / formic acid (0.1% v / v) with a 2-30% gradient of ACN / FA (0.1% v / v) for 40 min to provide the title compound as a white powder (3 mg, 3.5% yield) after lyophilization. 1H NMR(500MHz,DMSO-d6)δ ppm 0.15-0.48(m,4H),1.20-1.43(m,3H),1.58(d,J=11Hz,9H),1.95-2.89(m,3H),3.58-3.73(m,1H), 4.54(s,2H),6.33(s,1H),7.22(d,J=6Hz,1H),7.39(s,1H),7.45(d,J=6Hz,1H),7.79-8.06(m,1H) LCMS[M+H] + =430;Rt=1.98-2.00;Method C

[0128] Example 79: N-[(3R)-1-(1-hydroxy-2-methylpropan-2-yl)piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide [ka] At 0° C., a solution of LAH (in THF, 2M) (0.2 ml, 0.4 mmol) is added dropwise to a solution of ethyl-2-methyl-2-[3-[[2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetyl]amino]piperidin-1-yl]propanoate-(Example 80, 130 mg, 0.27 mmol) in 20 ml of THF, and the resulting mixture is stirred at RT for 2 h. The reaction mixture is quenched at 0° C. by adding a saturated aqueous solution of NH4Cl. After the addition of EtOAc, the organic layer is washed with NaCl (3 times), dried over MgSO4, filtered and concentrated under reduced pressure.

[0129] The residue is purified by reverse phase chromatography Waters SunFire Prep C18 OBD 30×100 mm column in water containing 0.1% HCO2H with a gradient of 10-60% acetonitrile in 15 min.

[0130] After concentration in vacuo and drying overnight, the title compound is obtained as a white solid (95 mg, 80% yield). 1H NMR (400MHz, DMSO-d6) δ ppm 0.92(s,6H), 1.24(m,1H), 1.35(d,J=7Hz,6H), 1.45(m,1H), 1.65(d,J=9Hz,2H), 2.17(br dd,J=11,9Hz,1H), 2.26-2.34(m,1H), 2.71(m,1H), 2.85(m,1H), 3.31-3.42(partially hidden m,3H), 3.71-3.78(m,2H), 4.47-4.63(m,2H), 7.32(d,J=6Hz,1H), 7.37(s,1H), 7.58(d,J=6Hz,1H), 7.83(d,J=8Hz,1H) LCMS[M+H] + =446;Rt=2.55;Method A

[0131] Example 88: N-[(1S,4R)-2-azabicyclo[2.2.1]heptan-6-yl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide hydrochloride [ka] A solution of tert-butyl (1R,4R)-6-[[2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetyl]amino]-2-azabicyclo[2.2.1]heptane-2-carboxylate (676 mg, 1.39 mmol) in 10 ml of DCM, obtained according to the process described in Example 1 and using the appropriate amine (1,1-dimethylethyl 6-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate), is treated with 4 M hydrochloric acid in dioxane (1.5 ml, 6 mmol) and stirred at rt overnight. The reaction mixture is concentrated under reduced pressure. The precipitate formed is filtered off to give 830 mg of the title compound as a brown solid.

[0132] 200 mg of this solid is purified by reverse phase chromatography Waters SunFire Prep C18 OBD 30×100 mm column in water containing 0.1% HCO2H with a gradient of 10-60% acetonitrile in 15 min.

[0133] After concentration in vacuo and drying overnight, 80 mg of the title compound is obtained as a beige solid. 1H NMR(400MHz,DMSO-d6)δ ppm 1.09(br d,J=13Hz,1H),1.35(dd,J=7,2Hz,6H),1.48-1.56(m,1H),1.59-1.66(m,1H),1.97-2.07(m,1H),2.39-2.43(m,1H),2.64-2.74(m,1H),2.92(br d,J=9Hz,1H),3.29-3.41(m,1H),3.53(br s,1H),4.03(br dd,J=7,4Hz,1H),4.54-4.68(m,2H),7.32(d,J=5Hz,1H),7.37(s,1H),7.59(d,J=6Hz,1H),8.25(s,2H) LCMS[M+H] + =386;Rt=0.62;Method A

[0134] Example 82: 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(1S,4S)-2-methyl-2-azabicyclo[2.2.1]heptan-6-yl]acetamide [ka] To a solution of N-[(1R,4S)-2-azabicyclo[2.2.1]heptan-6-yl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide - Example 88 (150 mg, 0.39 mmol) in 15 ml of MeOH, formaldehyde solution (0.22 mL, 2.14 mmol), sodium cyanoborohydride (97.8 mg, 1.56 mmol) and acetic acid (0.018 ml, 0.32 mmol) are added successively and the mixture is stirred at 45° C. overnight.

[0135] The reaction mixture is concentrated under reduced pressure and the residue is diluted with AcOEt. The organic layer is washed with saturated NaHCO3 solution, water, dried over MgSO4, filtered and concentrated under reduced pressure.

[0136] The residue is purified by reverse phase chromatography Waters SunFire Prep C18 OBD 30×100 mm column in water containing 0.1% HCO2H with a gradient of 10-60% acetonitrile in 15 min.

[0137] After concentration in vacuo and drying overnight, the title compound is obtained as a white solid (62 mg, 40% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 0.82(dt,J=12,3Hz,1H),1.28(br d,J=10Hz,1H),1.37(d,J=7Hz,6H),1.58(br d,J=10Hz,1H),1.85-1.93(m,1H),2.18-2.25(m,4H),2.30-2.36(m,1H),2.67-2.72(m,1H),2.90(br s,1H),3.37-3.41(m,1H),3.91-3.98(m,1H),4.53-4.66(m,2H),7.32(d,J=6Hz,1H),7.39(s,1H),7.59(d,J=6Hz,1H),7.73(br d,J=8Hz,1H) LCMS[M+H] + =400;Rt=0.62;Method A

[0138] Synthesis of amine building blocks Intermediate 31: (3R)-1-(1-methylcyclopentyl)piperidin-3-amine hydrochloride [ka] Int 32: tert-Butyl N-[(3R)-1-(1-cyanocyclopentyl)-3-piperidyl]carbamate [ka] To a solution of tert-butyl N-[(3R)-3-piperidyl]carbamate (2 g, 9.98 mmol) and cyclopentanone (0.88 ml, 9.98 mmol) in 20 mL of DCM, titanium(IV) isopropoxide (3.0 ml, 9.98 mmol) was added and the mixture was stirred at room temperature for 40 h. Diethylaluminum cyanide (1 M in toluene) (11.98 ml, 11.98 mmol) was added and the solution was stirred for another 20 h. After dilution with DCM, water was added and the resulting mixture was filtered and washed with DCM and water. The aqueous layer was extracted with DCM. The organic layers were pooled, dried over MgSO4, filtered and concentrated under reduced pressure.

[0139] The residue is purified by flash chromatography on silica gel using heptane / AcOEt (0% to 50%) to give the title compound (994 mg, 33% yield) as a yellow oil. LCMS (Method A): Rt=1.17 min; MS m / z[M+H]+294

[0140] Int 33: tert-Butyl N-[(3R)-1-(1-methylcyclopentyl)-3-piperidyl]carbamate [ka] Under N2, a solution of tert-butyl N-[(3R)-1-(1-cyanocyclopentyl)-3-piperidyl]carbamate (300 mg, 1.02 mmol) in 5 mL of THF is cooled to 0° C. and methylmagnesium bromide 3M in Et2O (1.70 ml, 5.11 mmol) is added dropwise. The mixture is stirred at 0° C. for 1 h and at rt overnight. The reaction is quenched with saturated aqueous NH4Cl solution and the aqueous layer is extracted with AcOEt. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure.

[0141] The residue is purified by flash chromatography on silica gel using DCM / MeOH (0%-10%) to give the title compound (85 mg, 30% yield) as a yellow oil. LCMS (Method A): Rt=0.54 min; MS m / z[M+H]283

[0142] Int 31: (3R)-1-(1-methylcyclopentyl)piperidin-3-amine hydrochloride [ka] A solution of tert-butyl N-[(3R)-1-(1-methylcyclopentyl)-3-piperidyl]carbamate (85 mg, 0.30 mmol) in 5 mL of DCM was treated with 4 M hydrochloric acid in dioxane (0.15 mL, 0.60 mmol) and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure. The precipitate formed was filtered off to give 68 mg of an orange oil, which was directly taken into the next step.

[0143] Intermediate 34: Ethyl 2-[(3R)-3-amino-1-piperidyl]-2-methyl-propanoate; hydrochloride [ka] Int 35: Ethyl 2-[(3R)-3-(tert-butoxycarbonylamino)-1-piperidyl]-2-methyl-propanoate [ka] To a solution of tert-butyl N-[(3R)-3-piperidyl]carbamate (4 g, 20 mmol) in 80 ml of acetonitrile, K2CO3 (6.8 g, 49.5 mmol) and ethyl 2-bromoisobutyrate (5.76 g, 29.56 mmol) are added. The mixture is stirred at 80° C. for 72 h. After cooling to rt, the mixture is diluted with water and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered off and concentrated under reduced pressure.

[0144] The residue is purified by flash chromatography on silica gel using heptane / EtOAc (0% to 30%) to give the title compound as a colorless oil (4.2 g, 66% yield). LCMS (Method D): Rt=1.71 min; MS m / z[M+H] + 315

[0145] Int 34: Ethyl 2-[(3R)-3-amino-1-piperidyl]-2-methyl-propanoate; hydrochloride [ka] To a solution of ethyl 2-[(3R)-3-(tert-butoxycarbonylamino)-1-piperidyl]-2-methyl-propanoate (Int 35) (4.2 g, 13.4 mmol) in 40 ml of dioxane, a 4 M solution of hydrochloric acid in dioxane (34 ml, 136 mmol) is added and the mixture is stirred at room temperature for 20 hours. The mixture is then concentrated under reduced pressure and the residue is triturated in Et2O. After drying overnight under vacuum in the presence of P2O5, the title compound is obtained as a white solid (3.5 g, 98% yield). LCMS (Method B): Rt=0.16 min; MS m / z[M+H] + 215

[0146] Intermediate 36: N-[(3-amino-1-bicyclo[1.1.1]pentanyl)methyl]-N-acetamide; hydrochloride [ka] Int 37: tert-Butyl N-[3-(acetamidomethyl)-1-bicyclo[1.1.1]pentanyl]carbamate [ka] To a solution of tert-butyl N-[3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl]carbamate (300 mg, 1.41 mmol) and DIPEA (1.23 ml, 7.07 mmol) in 10 ml of DCM, acetyl chloride (80 μl, 1.13 mmol) is added dropwise. The mixture is stirred at RT for 20 h. The mixture is neutralized with a saturated aqueous solution of NH4Cl and then extracted with DCM. The organic layer is dried over Na2SO4, filtered off and concentrated under reduced pressure. After drying overnight under vacuum in the presence of P2O5, the title compound is obtained as a white solid (300 mg, 83% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 1.37(s,9H),1.73(s,6H),1.80(s,3H),3.17(d,J=6Hz,2H),7.40(br m,1H),7.70(m,1H)

[0147] Int 36: N-[(3-amino-1-bicyclo[1.1.1]pentanyl)methyl]-N-acetamide; hydrochloride [ka] To a solution of tert-butyl N-[3-(acetamidomethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (200 mg, 0.79 mmol) in 5 ml of dioxane, a 4 M solution of hydrochloric acid in dioxane (2 ml, 8 mmol) is added and the mixture is stirred at room temperature for 20 h. The mixture is then concentrated under reduced pressure and the residue is triturated in Et2O. After drying overnight under vacuum in the presence of P2O5, the title compound is obtained as a white solid (160 mg, 98% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 1.81(s,3H),1.83(s,6H),3.23(d,J=6Hz,2H),7.86(br m,1H),8.56(m,3H)

[0148] The compounds of formula (I) were subjected to biochemical studies to assess their activity using the following in vitro methods:

[0149] IL-1β secretion assay Monocytic THP-1 cells (DSMZ) were maintained in RPMI medium (RPMI 1640 medium (1x) + 10% FBS, Eurobio CVFSVFOO-OU). Cells were then plated at 16,000 cells per well in 96-well round-bottom cell culture plates (TPP, ref 92097) and maintained in RPMI and 0.1% bovine serum albumin solution. Activation of the NLRP3 inflammasome requires both an NF-kB-dependent priming step and the addition of an NLRP3 activator. The priming step was induced by LPS (10 ng / mL, Sigma, ref: L4391) for 3 h at 37 °C, then compounds at 1:100 in DMSO (1:3.10 serial dilutions) and the activator nigericin (Sigma Aldrich, ref: SML1779), 10 μM (final concentration), were added to the cells and co-incubated for 2 h. 50 μL of supernatant was removed and IL-1β levels were monitored using the MSD assay (electrochemiluminescence immunoassay (ECLI)) according to the manufacturer's instructions.

[0150] TNF-α secretion assay Monocytic THP-1 cells (DSMZ) were maintained in RPMI medium (RPMI 1640 medium (1x) + 10% FBS, biowest S181H). They were then differentiated overnight at 37°C in 96-well flat-bottom cell culture plates at 160,000 cells per well with RPMI + 0.1% bovine serum albumin solution and 0.5 μM phorbol 12-myristate 13-acetate (PMA; Sigma, ref: P8139). Experimental compounds were prepared and added as described above. TNF-α secretion was induced by the addition of 0.5 μg / mL LPS (invivoGen, tlrl-3pelps) and cells were incubated for 24 hours. 2.5 μL of supernatant was removed and TNF-α levels were monitored using the MSD assay (Mesoscale, K15049) according to the manufacturer's instructions.

[0151] Interpretation of data I C 50 The value is y=A2+(A1-A2) / (1+(x / IC 50The inhibition coefficient was calculated from a plot of the percentage of inhibition against inhibitor concentration by a logistic fit according to: A1^p), where y is the percent inhibition at inhibitor concentration x. A1 is the minimum inhibition value, i.e., 0%, and A2 is the maximum inhibition value, i.e., 100%. The exponent p is the Hill coefficient. Curve fitting was performed using in-house developed software.

[0152] Brain to plasma ratio assessment A solution of 3 mg of compound in a common vehicle (glucofurol / solutol / dextrose 5%:10% / 5% / 85%, adjusted to pH 3) at a final concentration of 0.2 mg / ml is stirred overnight at ambient temperature protected from light.

[0153] 8-12 week old female C57Bl6 mice are administered the prepared solution in the tail vein as a single intravenous dose of 1 mg / kg at a dose of 5 ml / kg. A total of 3 animal replicates are evaluated for each compound utilizing an endpoint sampling method. 0.25 hours after dosing, under anesthesia, 400 μL of blood and whole brain are collected. Blood samples are centrifuged at 1500 g for 10 minutes at 4°C, and brains are weighed and homogenized using deionized water to obtain a final ratio of (1 / 2:w / v). Plasma and brain concentrations are measured by an exploratory LC-MS / MS method.

[0154] Individual brain to plasma concentration ratios were calculated for each animal and geometric mean values ​​are reported.

[0155] IC for the compounds disclosed herein 50 Values ​​were generally below 10 μM, more specifically below 1 μM, as shown in the table below.

[0156] [Table 23]

[0157] [Table 24]

[0158] [Table 25]

[0159] Thus, the compounds of formula (I) have inhibitory activity against the NOD-like receptor protein 3 (NLRP3) inflammasome.

[0160] Thus, the compounds of formula (I) may be used as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway.

[0161] Thus, the compounds of formula (I) may be used as medicines, in particular as medicines that are inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway.

[0162] Thus, according to another of its aspects, a subject of the disclosure is a medicinal product comprising a compound of formula (I) or an addition salt thereof with a pharma- ceutically acceptable acid.

[0163] These medicines are of therapeutic use in the treatment of neurodegenerative diseases, in particular Parkinson's disease, multiple system atrophy, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or brain injury.

[0164] According to another embodiment, the present disclosure relates to pharmaceutical compositions comprising, as an active ingredient, a compound of formula (I). These pharmaceutical compositions contain an effective dose of at least one compound of formula (I), or a pharma- ceutically acceptable salt of said compound.

[0165] These pharmaceutical compositions may also contain at least one pharma- ceutically acceptable excipient.

[0166] Said excipients are chosen according to the pharmaceutical form and the desired mode of administration from the usual excipients known to those skilled in the art.

[0167] The compounds of formula (I) may be used in the treatment of pathologies involving the NOD-like receptor protein 3 (NLRP3) inflammasome pathway.

[0168] According to another of its aspects, the present disclosure also provides a method of treating the above-indicated pathologies.

[0169] Thus, also described is a method for treating Parkinson's disease, multiple system atrophy, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharma- ceutically acceptable salt thereof.

Claims

1. A compound of formula (I) 【Chemistry 1】 During the ceremony: R1 is a hydrogen atom, a halogen atom, or -(C 1 ~C 2 )-alkyl group, R2 is unsubstituted or is a hydroxy group or -(C 1 ~C 3 )-substituted with 1 to 3 substituents independently selected from alkoxy groups -(C 1 ~C 3 ) alkyl group, or -(C 3 ~C 4 ) represents a cycloalkyl group; R3 is, - one -(C) which is unsubstituted or unsubstituted or substituted with one or two -NH(CO)Me groups 1 ~C 3 ) alkyl group substituted with -(C 5 ~C 8 ) a bicycloalkyl group, - unsubstituted, or - halogen atoms, oxo group, unsubstituted or hydroxy group, -(C 1 ~C 2 )-alkyl group, halogen atom, -(C 1 ~C 2 )-alkoxy group, nitrile group, —C(O)O(C 1 ~C 3 ) group or a —(C ) group that is unsubstituted or substituted by one or more halogen groups; 3 ~C 8 )-substituted with 1 to 3 substituents independently selected from cycloalkyl groups -(C 1 ~C 4 )-alkyl group, unsubstituted or one or more (C 1 ~C 2 ) alkyl group substituted with -(C 3 ~C 6 )-cycloalkyl group, -(CO)-(C 1 ~C 2 )-alkyl group, a heterocycloalkyl group, or unsubstituted or one or more -(C 1 ~C 4 ) a heteroaryl group substituted with an alkyl group -(C) having nitrogen as a heteroatom, substituted with one or more substituents independently selected from 4 ~C 7 ) heterocycloalkyl groups, - optionally, ・-(C 3 ~C 4 ) a cycloalkyl group, or ・-(C 1 ~C 3 ) alkyl group Hetero (C) having nitrogen as the heteroatom, substituted with one or more substituents independently selected from 6 ~C 9 ) a bicycloalkyl group, or - unsubstituted, or ・-(C 1 ~C 4 ) alkyl groups, ・-(C 1 ~C 4 ) an alkoxy group, or - Halogen atoms a mono- or bicycloheteroaryl group substituted with one or more substituents independently selected from a compound selected from or a pharmaceutically acceptable salt thereof.

2. During the ceremony, R1 represents a hydrogen atom, a halogen atom selected from among bromine and chlorine atoms, or a methyl group, and R2 is selected from among methyl, ethyl, propyl, and isopropyl groups, which are unsubstituted or substituted with one substituent independently selected from a hydroxy group or a methoxy group -(C 1 ~C 3 ) represents an alkyl group or a cyclopropyl group; R3 is, - one -(C) which is unsubstituted or substituted with one -NH(CO)Me group 1 ~C 3 ) a bicyclopentyl group substituted with an alkyl group; - unsubstituted, or fluorine atoms, oxo group, - unsubstituted or substituted with a hydroxy group, a methyl group, a fluorine atom, a methoxy group, a nitrile group, -C(O)O(C 1 ~C 2 ) group or a —(C 3 ~C 6 )-cycloalkyl groups, substituted by 1 to 3 substituents independently selected from -(C 1 ~C 4 )-alkyl group, - unsubstituted or substituted with one or more methyl groups - (C 3 ~C 5 )-cycloalkyl group, -(CO)-methyl group, a heterocyclopropyl group, or an imidazole group that is unsubstituted or substituted with one methyl group; -(C) having nitrogen as a heteroatom, substituted with one or more substituents independently selected from 4 ~C 6 ) heterocycloalkyl groups, - optionally, ・-(C 3 ~C 4 ) a cycloalkyl group, or ・Methyl group -hetero(C) having nitrogen as the heteroatom, substituted with one or more substituents independently selected from 6 ~C 9 ) a bicycloalkyl group, or - unsubstituted, or methyl group, a methoxy group, or ・Fluorine atom a mono- or bicycloaryl group substituted with one or two substituents independently selected from The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

3. During the ceremony, R1 represents a hydrogen atom or a halogen atom selected from among bromine and chlorine atoms; R2 is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy groups -(C 1 ~C 3 ) alkyl group, or -(C 3 ~C 4 ) represents a cycloalkyl group; R3 is, - one -(C) which is unsubstituted or unsubstituted or substituted with one or two -NH(CO)Me groups 1 ~C 3 ) alkyl group substituted with -(C 5 ~C 8 ) a bicycloalkyl group, - unsubstituted, or - unsubstituted or substituted with a hydroxy group, a methyl group, a fluorine atom, a methoxy group, a nitrile group, -C(O)O(C 1 ~C 3 ) group or a —(C 3 ~C 5 )-substituted with 1 to 3 substituents independently selected from cycloalkyl groups -(C 1 ~C 4 )-alkyl group, unsubstituted or one or more -(C 1 ~C 2 )-substituted by alkyl group -(C 3 ~C 6 )-cycloalkyl group, or Heterocycloalkyl groups -(C) having nitrogen as a heteroatom, substituted with one or more substituents independently selected from 4 ~C 7 ) heterocycloalkyl groups, - optionally one or more -(C 3 ~C 4 -hetero(C) having nitrogen as a heteroatom, substituted with a cycloalkyl group 6 ~C 8 ) a bicycloalkyl group, or a mono- or bicycloheteroaryl group which is unsubstituted or substituted by one fluorine atom; The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

4. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents a hydrogen atom.

5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents a bromine atom.

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents a chlorine atom.

7. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 represents a -iPr group.

8. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 represents a cyclopropyl group.

9. wherein R3 is unsubstituted, or unsubstituted or hydroxy group, -(C 1 ~C 2 )-alkyl group, a fluorine atom, -(C 1 ~C 2 )-alkoxy group, nitrile group, —C(O)O(C 1 ~C 3 ) group or a —(C 3 ~C 5 )-substituted with 1 to 3 substituents independently selected from cycloalkyl groups -(C 1 ~C 4 )-alkyl group, unsubstituted or one or more (C 1 ~C 2 ) substituted by an alkyl group -(C 3 ~C 6 )-cycloalkyl group, or Heterocyclopropyl group -(C) having nitrogen as a heteroatom, substituted with one or more substituents independently selected from 4 ~C 7 ) a heterocycloalkyl group, or a pharmaceutically acceptable salt thereof.

10. The list below: 1 (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2. 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(thiazol-5-yl)acetamide 3 N-((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 4 (R)—N-(1-cyclopropylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 5 (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 6 (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 7. 2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(thiazol-5-yl)acetamide 8 (R)-2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 9 (R)-2-(8-isopropyl-2-methyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 10 (R)-2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)-N-(1-cyclobutylpiperidin-3-yl)acetamide formate 11 (R)—N-(1-cyclobutylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 12 N-(benzo[d]thiazol-6-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 13 (R)-2-(2-chloro-8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide 14 (R)—N-(1-isobutylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 15 N-(benzo[d]thiazol-5-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 16 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(6-methoxypyridin-3-yl)acetamide 17 (R)—N-(1-(cyclopentylmethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 18. N-((3R)-1-((2,2-difluorocyclopropyl)methyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formulated with formaldehyde 19. (R)-N-(1-(2-hydroxyethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formulated with formaldehyde 20 (R)—N-(1-cyclobutylpiperidin-3-yl)-2-(8-cyclopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 21 (R)-2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide 22 2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)acetamide 23 (R)—N-(1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 24 (R)-2-(8-cyclopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methylpiperidin-3-yl)acetamide formate 25 N-((R)-1-cyclobutylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)propanamide formate 26 N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)propanamide formate 27 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methyl-1H-indazol-6-yl)acetamide formate 28 (R)—N-(1-(cyclopropylmethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 29 (R)-2-(2-chloro-8-(methoxymethyl)-5-oxothieno[3′, 2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclobutylpiperidin-3-yl)acetamide formate 30 (R)-2-(2-chloro-8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)-N-(1-cyclopropylpiperidin-3-yl)acetamide formate 31 (R)-2-(2-bromo-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-cyclobutylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 32 (R)—N-(1-cyclobutylpiperidin-3-yl)-2-(8-(methoxymethyl)-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 33 (R)-N-(1-cyclopropylpiperidin-3-yl)-2-(8-(methoxymethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)acetamide 2,2,2-trifluoroacetate 34 2-(2-chloro-8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(5,5-difluoro-1-methylpiperidin-3-yl)acetamide 2,2,2-trifluoroacetate 35 N-(5,5-difluoro-1-methylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 36 (R)—N-(1-(2-fluoroethyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 37 N-(1-(tert-butyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 38 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)acetamide 2,2,2-trifluoroacetate 39 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(quinuclidin-3-yl)acetamide 40 (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-(oxetan-3-yl)piperidin-3-yl)acetamide 41 (R)—N-(1-(3-fluoropropyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 42 (R)—N-(1-acetylpiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 43 (R)—N-(1-((3,3-difluorocyclobutyl)methyl)piperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide formate 44 N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 45 (R)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-(1-methyl-1H-imidazol-2-yl)piperidin-3-yl)acetamide 46 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methyl-2-oxopiperidin-4-yl)acetamide 47 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(1-methyl-6-oxopiperidin-3-yl)acetamide 48 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-isopropyl-3-piperidyl]acetamide 49 N-[(3R)-1-Cyclopentyl-3-piperidyl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 50 N-((R)-1-cyclobutylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 51 N-((R)-1-cyclopropylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2d][1,2,4]triazin-6(5H)-yl)acetamide 52 (R)—N-(1-cyclopropylpiperidin-3-yl)-2-(8-(2-hydroxypropan-2-yl)-5-oxothieno[3′,2′:4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 53 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(2-methylpyrazol-3-yl)acetamide 54 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(1-methylpyrazol-3-yl)acetamide 55 N-[(1-tert-butyl-5-oxo-pyrrolidin-3-yl)methyl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 56 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),3,7,11-tetraen-10-yl)-N-(4-pyridyl)acetamide 57 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[rac-(3R)-1-(2,2-dimethylcyclobutyl)-3-piperidyl]acetamide 58 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),2,7,11-tetraen-10-yl)-N-(4-pyridyl)acetamide 59 2-(4-bromo-12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(1-tert-butyl-3-piperidyl)acetamide 60 N-[(3R)-1-cyclopropyl-3-piperidyl]-2-(12-ethyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 61 N-[(3R)-1-cyclopropylazepan-3-yl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 62 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-methylazepan-3-yl]acetamide 63 N-(1-cyclopropyl-5,5-difluoropiperidin-3-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 2,2,2-trifluoroacetate 64 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-((3R)-1-(1-methoxypropan-2-yl)piperidin-3-yl)acetamide 65 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-(2-methoxypyridin-4-yl)acetamide 66 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-pyrimidin-4-yl-acetamide 67 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(4-pyridyl)acetamide 68 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(6-methyl-3-pyridyl)acetamide 69 2-(12-ethyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-[(2S)-2-hydroxypropyl]-3-piperidyl]acetamide 70 N-(5-fluoropyrimidin-4-yl)-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 71 2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-(1-methylcyclopentyl)-3-piperidyl]acetamide 72 N-[(3R)-1-cyclopropylpiperidin-3-yl]-2-(9-oxo-12-propyl-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 73 2-(12-ethyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[(3R)-1-methyl-3-piperidyl]acetamide 74 N-[3-(acetamidomethyl)bicyclo[1.1.1]pentan-1-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 75 N-[(3R)-1-(cyanomethyl)piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 76 N-[(3R)-1-methylpyrrolidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine acetamide 77 N-[(3R)-1-(2-cyanoethyl)piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 78 N-[(3R)-1-[(2R)-2-hydroxypropyl]piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 79 N-[(3R)-1-(1-hydroxy-2-methylpropan-2-yl)piperidin-3-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 80 Ethyl 2-methyl-2-[3-[[2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetyl]amino]piperidin-1-yl]propanoate 81 N-((R)-1-cyclobutylpiperidin-3-yl)-2-(8-(1-hydroxyethyl)-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 82 N-[(1R,4R)-2-methyl-2-azabicyclo[2.2.1]heptan-6-yl]-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 83 N-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazin-6(5H)-yl)acetamide 84 2-(8-isopropyl-5-oxothieno[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(5H)-yl)-N-pyrimidin-5-ylacetamide 85 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-(2-oxo-4-piperidyl)acetamide 86 N-(1-cyclopropylpyrrolidin-3-yl)-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide 87 2-(12-Isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)-N-[rac-(3R)-1-tert-butylpyrrolidin-3-yl]acetamide 88 N-[(1S,4R)-2-azabicyclo[2.2.1]heptan-6-yl]-2-(12-isopropyl-9-oxo-3-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),4,7,11-tetraen-10-yl)acetamide hydrochloride 2. The compound of formula (I) according to claim 1, selected from:

11. A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10.

13. A compound of formula (I) according to any one of claims 1 to 10 for use as an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome.

14. A compound of formula (I) according to any one of claims 1 to 10 for use in the treatment of Parkinson's disease, multiple system atrophy, Alzheimer's disease, frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis or brain injury.

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