Cyclopentathiofen carboxamide derivatives as platelet-activating factor receptor antagonists

Abstract

The present invention provides compounds, pharmaceutical compositions, and their uses that are suitable for the prevention and / or treatment of eye diseases, allergies, and conditions and diseases related to inflammation, particularly atrophic and exudative age-related macular degeneration, geographic atrophy, urticaria, and NASH. [Solution] Cyclopentathiofen carboxamide of formula (I.0) and pharmaceutically acceptable salts thereof can be used in methods to treat diseases that may be affected by antagonizing platelet-activating factor receptor-mediated activity. JPEG2026090284000159.jpg5255

Description

[Technical Field]

[0001] The present invention relates to novel cyclopentathiofen carboxamide derivatives and pharmaceutically acceptable salts thereof that are platelet-activating factor receptor antagonists. Furthermore, the present invention relates to pharmaceutical compositions and combinations comprising the said compounds, and their use in methods for treating diseases that may be affected by antagonizing platelet-activating factor receptors. In particular, the pharmaceutical compositions of the present invention are suitable for the prevention and / or treatment of eye diseases, allergy and inflammation-related conditions and diseases, especially atrophic and exudative age-related macular degeneration, geographic atrophy, urticaria, and NASH. [Background technology]

[0002] Platelet-activating factor (PAF) is an ether phospholipid and the most potent lipid mediator known. PAF is synthesized constitutively or under specific stimuli by a variety of cells, including platelets, macrophages, monocytes, neutrophils, basophils, eosinophils, mast cells, and endothelial cells. PAF, PAF-like lipids (PAFLL), and some oxidized phospholipids are G protein-coupled receptors, with the PAF receptor (PAFR) having a clearly defined structure as its ligand. PAFR expression is limited in certain target cells of the immune, hemostatic, and inflammatory systems. The signaling function of PAF is largely involved in acute and chronic inflammation in virtually all organs. PAFR is thought to play a role in several inflammatory disorders and can be highly relevant in eye diseases, cardiovascular diseases, cancer, neurological and neurodegenerative disorders, renal disorders, liver diseases, and allergies. Therefore, for example, suppression of PAFR activation by PAFR antagonists and / or inverse agonists is considered useful in treating a wide range of disorders that may be affected by antagonizing and / or acting in the opposite way, as referred to earlier and later in this specification. In particular, PAFR antagonists and / or inverse agonists should be useful in the prevention or treatment of eye diseases, such as atrophic or exudative age-related macular degeneration, and geographic atrophy or allergies, and inflammation-related disorders, such as urticaria and non-alcoholic steatohepatitis (NASH). PAFR antagonists and / or inverse agonists suitable for therapeutic use should bind to PAFR with potent and high selectivity. PAFR antagonists and / or inverse agonists should be well absorbed from the gastrointestinal tract, have sufficient metabolic stability, and possess favorable pharmacokinetic properties. They should be non-toxic and demonstrated to have little to no side effects.

[0003] For example, low molecular weight PAFR antagonists, which are compounds described in European Patent Application Publication No. 0194416 and European Patent Application Publication No. 0254245 by Weber et al. (Med. Res. Rev. 1989, 9, 181-218) and Summers et al. (Curr. Pharm. Des. 1995, 1, 161-190), are known in the art. Compounds of the class of thienotriazolodiazepines disclosed therein have been reported to undergo hydrolysis in acidic solutions (e.g., Gallo et al. (J. Heterocyclic Chem. 1988, 25, 867-869), Legouin et al. (J. Heterocyclic Chem. 2000, 37, 127-129)). Some of these compounds have also been identified as inverse agonists of PAFR (Dupre et al. (J. Pharm. Exp. Ther. 2001, 299, 1, 358-365), Cellai et al. (Exp. Hematol. 2009, 37, 1176-1185)).

[0004] Further methods useful for the synthesis and separation of the aforementioned compounds and related compounds are disclosed in German Patent Publication No. 4132763, European Patent Publication No. 0388789, European Patent Publication No. 0450504, U.S. Patent No. 7015213, International Publication No. 2008 / 063667, Tahara et al. (Arzneimittel-forschung 1978, 28, 1153-1158), Sung et al. (Archiv der Pharmazie 1996, 329, 291-300), Fier et al. (Org. Lett. 2017, 19, 1454-1457), and Brenna et al. (Green Chem. 2017, 19, 5122-5130). [Overview of the Initiative]

[0005] In the first aspect, the present invention relates to a compound of formula (I.0) [Chemical formula] (wherein, R 1 is selected from the group of R 1-4 -alkyl (which may be substituted by 1 to 3 Fs) and C 3-4 -cycloalkyl, and is selected from the R 1 -G1 group; R 2 is selected from the R 2 -G1 group, and the R 2 -G1 group consists of F, Cl, Br, I, C 1-4 -alkyl (which may be substituted by 1 to 3 Fs, or may be substituted by one -CN, one OH or one -O-C 1-4 -alkyl), and further consists of C 3-4 -cycloalkyl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, OH, -O-C 1-4 -alkyl (which may be substituted by 1 to 3 Fs), and further consists of -S(O) r -C 1-4 -alkyl (r = 0, 1 or 2); n is selected from the group of n-G1 consisting of 0, 1, 2 and 3; R 3 is selected from the group of R 1-4 -alkyl which may be substituted by H and 1 to 5 Fs; 3 -G1 group; R 4 is selected from the group of R 1-6 -alkyl consisting of C 4 -G1a group, and the C 1-6 -alkyl may be substituted by 1 to 3 Fs, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, C1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-,OH and -OC 1-3 -It may be substituted with one or two substituents independently selected from alkyl (which may be substituted with one to three F atoms), or R 4 is -C 0-3 -Alkilen-C 3-10 -Cycloalkyl and -C 0-3 -Alkilen-C 3-10 - R consisting of heterocyclyl 4 -Selected from group G1b, The alkylene may be substituted with one or two substituents selected from F and CH3. The two H atoms of one >CH2 group of the alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The cycloalkyl and heterocyclyl compounds are saturated monocyclic or bicyclic systems. The aforementioned heterocyclyl is N, NH, >N(C 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(=O)2(C 1-4 It contains one or two ring members independently selected from -alkyl and O, and >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), However, the heterocyclyl has NN, NO, and NS(=O) between its ring members. r=1,2 It contains no heteroatom-heteroatom bonds other than those mentioned above. The cycloalkyl and heterocyclyl may be substituted with 1-2 F atoms, such as Cl, -CN, -CONH2, and -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, OH, -OC 1-3 -alkyl (may be substituted with 1-3 F atoms), and C1-4 -alkyl (with 1-3 F, or -CN, OH, -OC) 1-4 -May be substituted with one substituent selected from alkyl) or may be substituted with one or two substituents independently selected from alkyl, or R 4 is -C 0-3 - Alkylene-phenyl and -C 0-3 - R consisting of alkylene heteroaryl 4 -Selected from group G1c, The alkylene may be substituted with one or two substituents selected from F and CH3. The two H atoms of one >CH2 group of the alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The heteroaryl is a five-membered monoring containing one ring member selected from N, NH, O, and S, which may further contain one or two ring members N, or a six-membered monoring containing one or two ring members N. The phenyl and heteroaryl compounds are F, Cl, Br, and C. 3-4 -Cycloalkyl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, -NHCO-C 1-4 -alkyl, -NHS(=O)2-C 1-4 -alkyl, -S (=O) r -C 1-4 -alkyl (r=0, 1, or 2), -OC 1-4 -alkyl (may be substituted with 1-3 F atoms), and C 1-4 -alkyl (with 1-3 F, or -CN, OH and -OC) 1-4 -May be substituted with 1 to 3 substituents independently selected from alkyl groups, or R 3and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a saturated monocyclic heterocycline with 3 to 8 members. 3 / 4 -Selected from group G1a, saturated monocyclic heterocyclines with 3 to 8 members are, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 It may further contain one or two ring members independently selected from -alkyl and O, >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), However, the heterocyclyl has NN, NO, and NS(=O) between its ring members. r=1,2 It contains no heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 4 F molecules. 1 to 4 C which may be substituted by 1 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, HO-C 1-3 -Alkilen-, C 1-3 -alkyl-OC 1-3 -Alkilen-, C 1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O- (which may be substituted with one to three F atoms), or R 3 and R 4 R 3 and R 4R, together with the amide N atom to which they are attached, forms a 5- to 12-membered saturated bicyclic heterocyclyl, 3 / 4 selected from the -G1b group, and the 5- to 12-membered saturated bicyclic heterocyclyl contains 1 to 3 ring members independently selected from >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O, and may contain 1 ring member selected from >C=O and >S(=O) r (r = 0, 1 or 2), provided that the heterocyclyl contains no heteroatom-heteroatom bonds other than N-N, N-O and N-S(=O) r=1,2 between the ring members, the heterocyclyl may be substituted by 1 to 6 F, 1 to 4 C 1-3 -alkyl, which may be substituted by 1 to 3 F, may also be substituted by 1 to 2 substituents selected from Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-O-C 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 -alkyl-O-, or or R 3 and R 4 are selected from the -G1c group, where R 3 and R 4 together with the amide N atom to which they are attached form a 7- to 12-membered fused bicyclic ring system, 3 / 4 ​The aforementioned bicyclic ring system is a heterocyclyl or heteroaryl consisting of one non-aromatic ring and one aromatic ring. The non-aromatic ring contains the amide N atom, and is =N-, >N-, >NH, >N(C) 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 It may further contain one or two ring members independently selected from -alkyl) and O, such as >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), provided that NN, NO, and NS(=O) are present between the members of the non-aromatic ring. r=1,2 No other heteroatom-heteroatom bonds exist. The aromatic ring is selected from a 5-membered monoring containing one ring member selected from NH, N, O, and S, which may further contain 1 to 2 ring members N, and a 6-membered monoring containing O, 1 or 2 ring members N. The aforementioned biring ring system may be substituted with 1 to 4 F molecules. 1 to 4 C which may be substituted by 1 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, HO-C 1-3 -Alkilen-, C 1-3 -alkyl-OC 1-3 -Alkilen-, C 1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O- (which may be substituted with one to three F atoms), In any definitions referred to herein prior to this, unless otherwise specified, any alkyl or alkylene group may be linear or branched. Isomers, stereoisomers, tautomers, metabolites, prodrugs, solvates, hydrates, cocrystals, and salts thereof, in particular pharmaceutically acceptable salts thereof or combinations thereof. Regarding.

[0006] In a second aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I.0) as defined earlier or later in this specification, or pharmaceutically acceptable salts thereof, which may together comprise one or more inert carriers and / or diluents.

[0007] In a third aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I.0) as defined earlier or later in this specification, or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, which may together comprise one or more inert carriers and / or diluents.

[0008] In a fourth aspect, the present invention relates to compounds of formula (I.0) as defined earlier or later in this specification, or pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0009] In a fifth aspect, the present invention relates to a method for treating a disease or condition that may be affected by antagonizing platelet-activating factor receptors in a patient in need thereof, the method comprising the step of administering to the patient one or more compounds of formula (I.0) as defined earlier or later in this specification, or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to the use of one or more compounds of formula (I.0) as defined earlier or later in this specification, or pharmaceutically acceptable salts thereof, in the manufacture of a pharmacopoeia for treating a disease or condition that may be affected by antagonizing platelet-activating factor receptors. Furthermore, the present invention relates to compounds of formula (I.0) as defined earlier or later herein, or pharmaceutically acceptable salts thereof, for use in methods of treating diseases or conditions that may be affected by antagonizing platelet-activating factor receptors in patients who require such treatment. Further aspects of the present invention will become apparent to those skilled in the art directly from the above and below, as well as from the examples.

[0010] General terms and definitions Terms not specifically defined herein should be given the meanings that a person skilled in the art would expect to be given in light of this disclosure and the context. However, where used herein, unless otherwise specified, the following terms have the meanings indicated and the following conventions apply. The terms "compound according to the present invention," "compound of formula (I.0)," and "compound of the present invention" refer to compounds of formula (I.0) according to the present invention, including their tautomers, stereoisomers and mixtures thereof, and salts thereof, in particular pharmaceutically acceptable salts thereof, as well as solvates, hydrates and cocrystals of such compounds, and include solvates, hydrates and cocrystals of such tautomers, stereoisomers and salts thereof. Similarly, unless otherwise specifically indicated, throughout this specification and the accompanying claims, a given chemical formula or name shall encompass tautomers, as well as all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.), as well as racemates thereof, as well as mixtures of different proportions of individual enantiomers, mixtures of diastereomers, or mixtures of any of the above-mentioned forms in which such isomers and enantiomers exist, as well as salts (including pharmaceutically acceptable salts thereof), as well as solvates thereof (e.g., hydrates including solvates of the free compound or solvates of salts of the compound, etc.). The phrase "pharmaceutically acceptable" is used herein to mean a compound, substance, composition and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, given a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment. As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound in which the parent compound is modified by producing an acid salt or basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of a suitable base or acid in water or in an organic diluent such as ether, ¼, EtOH, isopropanol, or MeCN, or a mixture thereof. For example, salts of acids other than those mentioned above (e.g., trifluoroacetates) that are useful for purifying or isolating the compounds of the present invention also constitute part of the present invention. In the event of any difference between the chemical name and the formula used to illustrate the compounds of the present invention, the formula shall prevail.

[0011] In the groups, radicals, or parts defined below, the number of carbon atoms is often specified before the group, for example, C 1-6 -Alkyl refers to an alkyl group or radical having 1 to 6 carbon atoms. Asterisks can be used in subformulas to indicate bonds attached to the core molecule being defined. For example, if a subformula contains more than one bond point, i.e., more than one asterisk, these asterisks may be further specified by the parenthetical notation of the bond portion of the core molecule. The naming of substituent atoms begins with the atom closest to the core or group to which the substituent is attached.

[0012] For example, the term "3-carboxypropyl group" refers to the following substituents: [ka] (In the formula, the carboxyl group is bonded to the third carbon atom of the propyl group). The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" group refer to the following groups:

[0013] [ka]

[0014] As used herein, the term "substituted" means that one or more hydrogen atoms on a specified atom, radical, or part are replaced by a group selected from those indicated, provided that the substitution does not exceed the normal valency of the atom and that the substitution results in a compound that is reasonably stable. In the definition of a group, terms such as "each of the X, Y, and Z groups may be substituted by ~" mean that each of the X groups, each of the Y groups, and each of the Z groups may be substituted as defined, either as a separate group or as part of the group from which they constitute. For example, definition "R ex H, C 1-3 -alkyl, C 3-6 -Cycloalkyl, C 1-3 -alkyl-C 3-6 -Cycloalkylene- or C 1-3-Alkyl-O- means that each alkyl group is one or more L ex The phrase "may be substituted by" means that in each of the above-mentioned groups including alkyl, i.e., group C 1-3 -alkyl, C 1-3 -alkyl-C 3-6 -Cycloalkylene- and C 1-3 In each of the -alkyl-O- groups, the alkyl portion is defined as L ex This means that it may be replaced by [another term].

[0015] The term “C 1-n The term "-alkyl" (where n is an integer greater than 1) refers to a linear or branched acyclic saturated hydrocarbon radical having 1 to n carbon atoms, either alone or in combination with another radical. For example, the term C 1-5 -Alkyl is H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-C Includes H2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0016] The term “C 1-n -Alkylene (where n is an integer greater than 1) refers to a divalent linear or branched acyclic alkyl radical having 1 to n carbon atoms, either alone or in combination with another radical. For example, term C 1-4Alkylenes include -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -CH2-CH(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH(CH3))2-, and -C(CH3)(CH2CH3)-.

[0017] The term “C 3-n A cycloalkyl group (where n is an integer greater than 3) refers to an unbranched, cyclic saturated hydrocarbon radical having 3 to n carbon atoms, either alone or in combination with another radical. The cyclic group may be monocyclic, bicyclic, tricyclic, or spirocyclic, most preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcarel, and adamantyl.

[0018] The term "heterocyclyl" refers to N, O, or S(O) r A saturated or unsaturated monocyclic or polycyclic ring system containing one or more heteroatoms selected from (r=0, 1, or 2), and which may contain an aromatic ring consisting of 3 to 14 ring atoms, wherein none of the heteroatoms are part of the aromatic ring. The term "heterocyclyl" is intended to include all possible isomers.

[0019] Therefore, the term “heterocyclyl” includes the following exemplary structures, which are not illustrated as radicals, as each form may be bonded via covalent bonds to any atom, provided that the appropriate valency is maintained: [ka] JPEG2026090284000005.jpg193169

[0020] The term "heteroaryl" refers to N, O, or S(O) r A monocyclic or polycyclic aromatic ring system consisting of 5 to 14 ring atoms and containing one or more heteroatoms selected from (r=0, 1, or 2), wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all possible isomers.

[0021] Therefore, the term “heteroaryl” includes the following exemplary structures, which are not illustrated as radicals, as each form may be bonded via covalent bonds to any atom, provided that the appropriate valency is maintained: [ka]

[0022] The term "bicyclic ring system" refers to a group consisting of two cyclic substructures, including spirocyclic ring systems, fused ring systems, and bridging ring systems. Many of the terms presented above may be used repeatedly in the definitions of formulas or bases, and in each case, they have one of the meanings presented above independently of each other. The terms “treatment” and “to treat” as used herein encompass both therapeutic, i.e., curative and / or palliative treatments, and preventive, i.e., protective treatments.

[0023] Therapeutic treatment refers to treatment of a patient who has already developed one or more of the aforementioned conditions in their onset, acute, or chronic form. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a particular sign, or causal treatment to reverse or partially reverse the state of the sign, or to halt or slow the progression of the disease. Preventive measures ("prevention") refer to treating patients at risk of developing one or more of the aforementioned conditions before the clinical onset of the disease, in order to reduce the risk.

[0024] The terms “treatment” and “to treat” include administering one or more active compounds to prevent or delay the onset of symptoms or complications, to prevent or delay the onset of a disease, condition or disorder, and / or to eliminate or control a disease, condition or disorder, and to alleviate symptoms or complications associated with a disease, condition or disorder. When the present invention refers to a patient requiring treatment, the present invention primarily relates to treatment in mammals, particularly humans.

[0025] The term “therapeutic dose” means the amount of the compound of the present invention that (i) treats or prevents a particular disease or condition, (ii) reduces, improves or eliminates one or more symptoms of a particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease or condition as described herein. [Modes for carrying out the invention]

[0026] The present invention discloses novel cyclopentathiophene carboxamide derivatives that are effective platelet-activating receptor (PAFR) antagonists and possess suitable pharmacological and pharmacokinetic properties for use as pharmaceuticals to prevent or treat diseases and / or conditions that may be affected by PAFR antagonism, including, but are not limited to, eye diseases and inflammation-related conditions and diseases, particularly geographic atrophy, exudative age-related macular degeneration, and allergies. The compounds of the present invention can achieve several advantages, including increased potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, increased solubility, increased permeability, desired plasma protein binding, improved bioavailability, improved pharmacokinetic profile, and the possibility of forming stable salts.

[0027] The compound of the present invention In a first aspect of the present invention, the compound of formula (I.0) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 The compounds (and n as defined prior to and hereafter in this specification) are potent antagonists of PAFR and have been found to exhibit favorable properties in terms of selectivity, safety and tolerability, metabolic and / or chemical stability, pharmacokinetic and physicochemical characteristics, solubility, permeability, plasma protein binding, bioavailability, and the potential to form stable salts. In particular, they exhibit high efficacy in vitro as PAFR antagonists and show good efficacy in vivo in animal models of choroidal angiogenesis. Furthermore, they have also been found to act as PAFR inverse agonists in in vitro models, which may contribute to further beneficial pharmacological effects. Moreover, the compounds according to the present invention exhibit favorable chemical stability, even at low pH values, and favorable solubility at a variety of pH values, i.e., even in acidic media, while simultaneously maintaining a moderately low renal clearance.

[0028] Therefore, compounds of formula (I.0) as defined earlier or later in this specification, or pharmaceutically acceptable salts thereof, are expected to be useful in treating diseases and / or conditions that may be affected by PAFR antagonism. Surprisingly, the compound of formula (I.0) can also be shown to exclusively bind to melanin, which affects the biodistribution and pharmacokinetic properties of the compound; in particular, this leads to the accumulation of the compound in the eye, resulting in prolonged drug retention. Therefore, the compounds of the present invention are expected to be particularly suitable for the treatment of eye diseases.

[0029] Therefore, according to one aspect of the present invention, the compound of formula (I.0) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 (and n are defined in the preceding and subsequent parts of this Specification) Also provided are isomers, stereoisomers, tautomers, metabolites, prodrugs, solvates, hydrates, cocrystals, and salts thereof, in particular pharmaceutically acceptable salts thereof.

[0030] Unless otherwise specified, groups, residues and substituents, especially R 1 , R 2 , R 3 , R 4 and n are defined prior to and hereafter in this Spec. Substituent R of the compound of formula (I.0) 1 , R 2 , R 3 , R 4 Some of the preferred meanings of n and phenyl substitution patterns and stereochemistry are presented later in this specification as embodiments of the present invention. Any of these definitions and embodiments may be combined with each other.

[0031] R 1 : According to one embodiment, R 1 teeth, C 1-4 -alkyl (may be substituted with 1-3 F atoms) and C 3-4 -cycloalkyl R consisting of1 - Selected from group G1. According to another embodiment, R 1 teeth, CH3, CH2CH3, CH2CH2CH3, CHF2, CF3 and cyclopropyl R consisting of 1 - Selected from group G2. According to another embodiment, R 1 teeth, CH3, CH2CH3, CH2CH2CH3 and cyclopropyl R consisting of 1 - Selected from group G3. According to another embodiment, R 1 R consists of CH3 1 - Selected from group G4. According to another embodiment, R 1 R is selected from CH2CH3, CH2CH2CH3, and cyclopropyl. 1 - Selected from group G5.

[0032] R 2 : More than one substituent R 2 If R is present in the compound of formula (I.0), i.e., when n=2 or 3, 2 Each of these is defined in the embodiments and gG1 group ~ R as defined herein. 2 -Selected independently from group G8. According to one embodiment, R 2 R 2 -Selected from group G1, R 2 -Group G1 is, F, Cl, Br, I, C 1-4 -alkyl (may be substituted with 1-3 F atoms, or one -CN, one OH, or one -OC) 1-4 -May be substituted with alkyl) and C 3-4 -Cycloalkyl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, OH, -OC1-4 -Alkyl (may be substituted with 1-3 F) and -S(O) r -C 1-4 - Consists of alkyl (r=0, 1, or 2). According to another embodiment, R 2 R 2 -Selected from group G2, R 2 -Group G2 is, F, Cl, Br, C 1-3 - Consists of alkyl (may be substituted with 2 or 3 F atoms), cyclopropyl, -CN, -C 1-3 -alkylene-OH, -C 1-2 -Alkilen-OC 1-2 -alkyl, OH, -OC 1-3 -Alternatively, alkyl (which may be substituted with two or three F atoms), -SC 1-3 - Consists of alkyl groups. According to another embodiment, R 2 teeth, F, Cl, Br, CH3, CH2CH3, cyclopropyl, CF3, CH2OH, OH, OCH3 and S-CH3 R consisting of 2 - Selected from group G3. According to another embodiment, R 2 R consists of F, Cl, and Br, preferably Cl. 2 - Selected from group G4. According to another embodiment, R 2 R consists of CH3 and CH2CH3. 2 - Selected from group G5. According to another embodiment, R 2 R consists of cyclopropyl and CF3. 2 - Selected from group G6. According to another embodiment, R 2 R consists of CH2OH and OH. 2 - Selected from group G7. According to another embodiment, R 2 R consists of OCH3 and S-CH3. 2 - Selected from group G8.

[0033] n: According to one embodiment, n is selected from the n-G1 group consisting of 0, 1, 2, and 3. According to another embodiment, n is selected from the n-G2 group consisting of 0, 1, and 2. In another embodiment, n is the n-G3 group consisting of 0. In another embodiment, n is an n-G4 group consisting of 1. In another embodiment, n is an n-G5 group consisting of 2.

[0034] Phenyl substitution pattern: When describing the substitution pattern of the phenyl ring shown in formula (I.0), use the following carbon atom numbering: [ka]

[0035] Generally, n substituents R 2 Each of these can bond to any carbon atom from C-2 to C-6, and any combination thereof. When n=1, according to one embodiment, R 2 It is bonded to carbon atom 2. According to another embodiment, R 2 It is bonded to carbon atom 4. In the case of n=2, according to one embodiment, R 2 One of them is bonded to carbon atom 2, and the other R 2 It is bonded to carbon atom 5. According to another embodiment, R 2 One of them is bonded to carbon atom 3, and the other R 2 It is bonded to carbon atom 5.

[0036] R 2 , n and phenyl substitution patterns: According to one embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] The selection is made from the Ph-G1 group, which consists of the following.

[0037] According to another embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] Preferably,

[0038] [ka] Selected from the Ph-G2 group consisting of

[0039] According to another embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] The selection is made from the Ph-G3 group, which consists of the following:

[0040] According to another embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] The selection is made from the Ph-G4 group, which consists of the following:

[0041] According to another embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] The selection is made from the Ph-G5 group, which consists of the following.

[0042] According to another embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] The selection is made from the Ph-G6 group, which consists of the following:

[0043] According to another embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] The selection is made from the Ph-G7 group, which consists of the following:

[0044] According to another embodiment, R 2 The phenyl substitution pattern is as follows: The resulting substituted phenyl ring is shown in formula (I.0). [ka] The selection is made from the Ph-G8 group, which consists of the above.

[0045] R 3 and R 4 : According to one embodiment, R 3 teeth, C may be substituted with H and 1 to 5 F. 1-4 -alkyl R consisting of 3 - Selected from group G1. According to another embodiment, R 3 teeth, C may be substituted with H and 1 to 3 F. 1-3 -alkyl R consisting of 3 - Selected from group G2. According to another embodiment, R 3 R consists of H, CH3, and CH2CH2CH3. 3- Selected from group G3. According to one embodiment, R 4 C 1-6 R consisting of -alkyl 4 -Selected from group G1a, C 1-6 -Alkyl is, It may be substituted with 1 to 3 Fs. -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, C 1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-,OH and -OC 1-3 -It may be substituted with one or two substituents independently selected from alkyl (which may be substituted with one to three F atoms).

[0046] According to another embodiment, R 4 C 1-6 R consisting of -alkyl 4 -Selected from group G2a, C 1-6 -Alkyl is, It may be substituted with 1 to 3 Fs. -CN, -CONH2, -CONH(C 1-2 -alkyl), -CON(C 1-2 -alkyl)2,-COOH,-COO-C 1-2 -alkyl, C 1-2 -alkyl-CO-NH-,C 1-2 -alkyl-S(=O)2-NH-,OH and -OC 1-2 -It may be substituted with one substituent selected from alkyl (which may be substituted with 1 to 3 F atoms).

[0047] According to another embodiment, R 4 C 1-4 R consisting of -alkyl 4 -Selected from group G3a, C 1-4 -Alkyl is, It may be substituted with 1 to 3 Fs. -CN, -CONH2, -COOH, OH, and -OC 1-2 -It may be substituted with one substituent selected from alkyl (which may be substituted with 1 to 3 F atoms). According to another embodiment, R 4 C 1-4 R consisting of -alkyl 4 -Selected from group G4a, C 1-4 -Alkyl is, It may be substituted with one substituent selected from F, OH, and OCF3.

[0048] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G5a.

[0049] According to one embodiment, R 4 is -C 0-3 -Alkilen-C 3-10 -Cycloalkyl and -C 0-3 -Alkilen-C 3-10 - R consisting of heterocyclyl 4 -Selected from group G1b, The alkylene may be substituted with one or two substituents selected from F and CH3. The two H atoms of one >CH2 group of the alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The cycloalkyl and heterocyclyl compounds are saturated monocyclic or bicyclic systems. The aforementioned heterocyclyl is N, NH, >N(C 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(=O)2(C 1-4 It contains one or two ring members independently selected from -alkyl) and O, and further >C=O and >S(=O) rIt may contain one ring member selected from (r=0, 1, or 2), However, the heterocyclyl has NN, NO, and NS(=O) between its ring members. r=1,2 It contains no heteroatom-heteroatom bonds other than those mentioned above. The cycloalkyl and heterocyclyl may be substituted with 1-2 F atoms, such as Cl, -CN, -CONH2, and -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, OH, -OC 1-3 -alkyl (may be substituted with 1-3 F atoms), and C 1-4 -alkyl (with 1-3 F, or -CN, OH, -OC) 1-4 -May be substituted with one or two substituents independently selected from alkyl groups.

[0050] According to another embodiment, R 4 is -C 0-2 -Alkilen-C 3-8 -Cycloalkyl and -C 0-2 -Alkilen-C 3-8 - R consisting of heterocyclyl 4 -Selected from group G2b, The cycloalkyl and heterocyclyl compounds are saturated monocyclic or bicyclic systems. The heterocyclyl contains one ring member selected from N, NH, and O. The cycloalkyl and heterocyclyl may be substituted with 1-2 F atoms, or with 1-2 substituents independently selected from Cl, -CN, OCH3, CH3, and CH2CH3.

[0051] According to another embodiment, R 4 is -C 0-1 -Alkilen-C 3-6 -Cycloalkyl R 4 -Selected from group G3b, The aforementioned cycloalkyl is a saturated monocyclic or bicyclic ring system. The cycloalkyl group may be substituted with 1 to 2 F atoms, or with 1 CH3 or CH2CH3 group.

[0052] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G4b.

[0053] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G5b.

[0054] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G6b.

[0055] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G7b. According to one embodiment, R 4 is -C 0-3 - Alkylene-phenyl and -C 0-3 - R consisting of alkylene heteroaryl 4 -Selected from group G1c, The alkylene may be substituted with one or two substituents selected from F and CH3. The two H atoms of one >CH2 group of the alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The heteroaryl is a five-membered monoring containing one ring member selected from N, NH, O, and S, which may further contain one or two ring members N, or a six-membered monoring containing one or two ring members N. The phenyl and heteroaryl compounds are F, Cl, Br, and C. 3-4 -Cycloalkyl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, -NHCO-C 1-4 -alkyl, -NHS(=O)2-C 1-4 -alkyl, -S (=O) r -C 1-4 -alkyl (r=0, 1, or 2), -OC 1-4 -alkyl (may be substituted with 1-3 F atoms), and C 1-4 -alkyl (with 1-3 F, or -CN, OH and -OC) 1-4 -May be substituted with 1 to 3 substituents independently selected from alkyl groups (which may be substituted with one substituent selected from alkyl groups).

[0056] According to another embodiment, R 4 is -C 0-2 - Alkylene-phenyl and -C 0-2 - R consisting of alkylene heteroaryl 4 -Selected from group G2c, The alkylene may be substituted with 1 or 2 CH3 groups. The two H atoms of one >CH2 group of the alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The heteroaryl is a five-membered monoring containing one ring member selected from N, NH, O, and S, which may further contain one ring member N, or a six-membered monoring containing one or two ring members N. The phenyl and heteroaryl compounds are F, Cl, Br, -CN, -OC 1-3 -alkyl (may be substituted with 1-3 F atoms), and C 1-3 -alkyl (with 1-3 F, or -CN and -OC) 1-2 -May be substituted with 1 to 3 substituents independently selected from alkyl groups (which may be substituted with one substituent selected from alkyl groups).

[0057] According to another embodiment, R 4 is -C 0-1 - Alkylene-phenyl and -C 0-1 - R consisting of alkylene heteroaryl 4 - Selected from group G3c, The two H atoms of one >CH2 group of the alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The heteroaryl is a 5-6 member monoring containing one ring member =N-, and may contain one ring member selected from =N-, >NH, S, and O. The phenyl and heteroaryl compounds may be substituted with one to three substituents independently selected from F, Cl, -CN, OCH3, OCHF2, OCF3, CH3, CHF2, and CF3.

[0058] According to another embodiment, R 4 teeth, [ka] R consisting of TIFF2026090284000025.tif112170 4 - Selected from group G4c.

[0059] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G5c.

[0060] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G6c.

[0061] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G7c.

[0062] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - Selected from group G8c.

[0063] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a 3- to 8-membered saturated monocyclic heterocycline, R 3 / 4 -Selected from group G1a, saturated monocyclic heterocyclines with 3 to 8 members are, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 It may further contain one or two ring members independently selected from -alkyl and O, >C=O and >S(=O)r It may contain one ring member selected from (r=0, 1, or 2), However, the heterocyclyl has NN, NO, and NS(=O) between its ring members. r=1,2 It contains no heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 4 F molecules. 1 to 4 C which may be substituted by 1 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, HO-C 1-3 -Alkilen-, C 1-3 -alkyl-OC 1-3 -Alkilen-, C 1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O- (which may be substituted with one to three F atoms).

[0064] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a 3- to 8-membered saturated monocyclic heterocycline, R 3 / 4 -Selected from group G2a, saturated monocyclic heterocyclines with 3 to 8 members are, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 It may further contain one ring member selected from -alkyl and O, such as >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), However, the heterocyclyl has NS(=O) between its ring members.r=1,2 It contains no heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 2 F molecules. 1 to 4 C which may be substituted by 2 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CON(C 1-4 -alkyl)2,-COO-C 1-4 -alkyl, C 1-3 -alkyl-OC 1-3 -Alkilen- and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-.

[0065] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atoms to which they are bonded, they form a 4- to 6-membered saturated monocyclic heterocycline. >N(C) 1-4 It may further contain one ring member selected from -alkyl and O, R forms saturated monocyclic heterocyclines with 4 to 6 members. 3 / 4 -Selected from group G3a, The heterocyclyl may be substituted with 1 to 2 F molecules. 1 to 4 C which may be substituted by 2 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CON(C 1-4 -alkyl)2,-COO-C 1-4 -alkyl, C 1-3 -alkyl-OC 1-3 -Alkilen- and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-.

[0066] According to one embodiment, R 3 and R 4 R 3and R 4 However, together with the amide N atoms to which they are bonded, they form a 4- to 6-membered saturated monocyclic heterocycline. The amide may contain one ring member O that is not adjacent to the N atom. R forms saturated monocyclic heterocyclines with 4 to 6 members. 3 / 4 -Selected from group G4a, The heterocycline may be substituted with two F groups, or with one or two CH3 groups.

[0067] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a heterocycline. [ka] R, which is selected from the group consisting of the following, forms a heterocycline. 3 / 4 - Selected from group G5a.

[0068] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a heterocycline. [ka] R, which is selected from the group consisting of the following, forms a heterocycline. 3 / 4 - Selected from group G6a.

[0069] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a heterocycline. [ka] Forming R3 / 4 - Selected from group G7a.

[0070] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a heterocycline. [ka] R, which is selected from the group consisting of the following, forms a heterocycline. 3 / 4 - Selected from group G8a.

[0071] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a saturated bicyclic heterocycline with 5 to 12 members, R 3 / 4 -Selected from group G1b, saturated bicyclic heterocyclines with 5 to 12 members are, >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 It may further contain 1 to 3 ring members independently selected from -alkyl and O, >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), However, the heterocyclyl has NN, NO, and NS(=O) between its ring members. r=1,2 It contains no heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 6 F molecules. 1 to 4 C which may be substituted by 1 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4-alkyl)2,-COOH,-COO-C 1-4 -alkyl, HO-C 1-3 -Alkilen-, C 1-3 -alkyl-OC 1-3 -Alkilen-, C 1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-.

[0072] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a saturated bicyclic heterocycline with 6 to 11 members, R 3 / 4 -Selected from group G2b, saturated bicyclic heterocyclines with 6 to 11 members are, >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 It may further contain one or two ring members independently selected from -alkyl and O, >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), However, the heterocyclyl has NN, NO, and NS(=O) between its ring members. r=1,2 It contains no heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 6 F molecules. 1 to 4 C which may be substituted by 1 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, HO-C 1-3 -Alkilen-, C 1-3-alkyl-OC 1-3 -Alkilen-, C 1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-.

[0073] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atoms to which they are bonded, they form a saturated 6- to 11-membered bridging bicyclic heterocycline or spiro-bicyclic heterocycline. Amides that are not adjacent to the N atom, >N-, >NH, >N(C) 1-4 It may further contain one or two ring members independently selected from -alkyl and O, R forms saturated cross-linked bicyclic heterocyclines or spiro-bicyclic heterocyclines with 6 to 11 members. 3 / 4 -Selected from group G3b, However, the heterocyclyl is provided that it does not contain any OO bonds between its ring members. The heterocyclyl may be substituted with 1 to 4 F molecules. 1 to 2 C which may be substituted by 1 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CON(C 1-4 -alkyl)2,-COO-C 1-4 -alkyl, C 1-3 -alkyl-OC 1-3 -Alkilen- and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-.

[0074] According to one embodiment, R 3 and R 4 R 3 and R 4However, together with the amide N atom to which they are bonded, they may form a 6- to 10-membered saturated bridging bicyclic or spiro-dicyclic heterocycline, which may contain one ring member O that is not adjacent to the amide N atom. 3 / 4 - Selected from group G4b.

[0075] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a heterocycline. [ka] R, which is selected from the group consisting of the following, forms a heterocycline. 3 / 4 - Selected from group G5b.

[0076] According to one embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atoms to which they are bonded, they form a 7- to 12-membered fused bicyclic ring system, R 3 / 4 -Selected from group G1c, The aforementioned bicyclic ring system is a heterocyclyl or heteroaryl consisting of one non-aromatic ring and one aromatic ring. The non-aromatic ring contains the amide N atom, and is =N-, >N-, >NH, >N(C) 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 It may further contain one or two ring members independently selected from -alkyl) and O, such as >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), provided that NN, NO, and NS(=O) are present between the members of the non-aromatic ring. r=1,2 No other heteroatom-heteroatom bonds exist. The aromatic ring is selected from a 5-membered monoring containing one ring member selected from NH, N, O, and S, which may further contain 1 to 2 ring members N, and a 6-membered monoring containing O, 1 or 2 ring members N. The aforementioned biring ring system may be substituted with 1 to 4 F molecules. 1 to 4 C which may be substituted by 1 to 3 F 1-3 - May be substituted with alkyl, Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl)2,-COOH,-COO-C 1-4 -alkyl, HO-C 1-3 -Alkilen-, C 1-3 -alkyl-OC 1-3 -Alkilen-, C 1-3 -alkyl-CO-NH-,C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O- (which may be substituted with one to three F atoms).

[0077] According to another embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atoms to which they are bonded, they form an 8- to 10-membered fused bicyclic ring system, R 3 / 4 -Selected from group G2c, The aforementioned bicyclic ring system is a heterocyclyl or heteroaryl consisting of one non-aromatic ring and one aromatic ring, as well as phenyl and pyridine. The non-aromatic ring contains the amide N atom and may contain one ring member selected from =N-, >N-, and O. The aromatic ring is a five-membered monoring containing one ring member selected from N, NH, O, and S, and may further contain one ring member N, selected from five-membered monorings. The aforementioned bicyclic ring system may be substituted with 1 to 2 F molecules. 1 to 2 C which may be substituted by 1 to 3 F 1-2 - May be substituted with alkyl, Cl and C 1-2 It may be substituted with one or two substituents selected from -alkyl-O- (which may be substituted with one to three F atoms).

[0078] According to another embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form an 8-9 member condensed bicyclic heteroaryl, R 3 / 4 - Selected from group G3c, The heteroaryl is a non-aromatic ring containing the amide N atom, which may contain one ring member >N- that is not adjacent to the amide N atom. and one pyrazolo ring or imidazolo ring It consists of, The heteroaryl group may be substituted with one or two CH3 groups.

[0079] According to another embodiment, R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a heteroaryl compound. [ka] Forming R 3 / 4 - Selected from group G4c.

[0080] Stereochemistry: According to one embodiment, the stereochemistry of the compound of formula (I.0) is as follows: [ka] This is due to...

[0081] According to another embodiment, the stereochemistry of the compound of formula (I.0) is given by formula (I.2). [ka] This is due to...

[0082] Further preferred lower embodiments of the compound of formula (I.0) are described as embodiments (Ia) to (Iz) in Table 1 below, in which the above substituent definitions are used. For example, column R 1 and item R in row (Ia) 1 -G1 is a substituent R in embodiment (Ia). 1 However, R 1 -G1 indicates that the variable is selected from the definitions displayed. The same applies to other variables incorporated into the general formula.

[0083] [Table 1]

[0084] R 1 , R 2 , R 3 , R 4 With regard to the definition of n, the lower embodiments (Ia) to (Iz), particularly (Iw) to (Iz), which correspond to the lower embodiments (Ia) to (Iz) in Table 1, are particularly preferred, and the stereochemistry of these compounds is according to formula (I.1), i.e., embodiments (I.1-w), (I.1-x), (I.1-y), and (I.1-z). Particularly preferred compounds, their salts, or any solvates or hydrates thereof are those described in the Examples section and experimental data.

[0085] According to one embodiment, the compound of formula (I.0) is selected from the group consisting of the following. [Table 2] JPEG2026090284000040.jpg232170 JPEG2026090284000041.jpg222163 JPEG2026090284000042.jpg229163 JPEG2026090284000043.jpg229163 JPEG2026090284000044.jpg180163

[0086] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 3] JPEG2026090284000046.jpg188166

[0087] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 4] JPEG2026090284000048.jpg228165 JPEG2026090284000049.jpg92165

[0088] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 5] JPEG2026090284000051.jpg232165

[0089] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 6]

[0090] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 7]

[0091] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 8] JPEG2026090284000055.jpg185165

[0092] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are as follows: [Table 9]

[0093] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 10]

[0094] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of the following: [Table 11]

[0095] preparation The compounds and intermediates of the present invention can be obtained using synthetic methods known to those skilled in the art, and synthetic methods described in the literature of organic chemistry, e.g., standard textbooks, monographs, and general overviews covering fundamental, applied, and specialized subjects of organic chemistry, particularly organic synthesis. Preferably, the compounds can be obtained in the same manner as the preparation methods described in the experimental section, which are described more fully later in this specification. In some cases, the order in which the reaction scheme is carried out can vary. Variations of these reactions, known to those skilled in the art but not described in detail herein, may also be used. The general method for preparing the compounds of the present invention will become apparent to those skilled in the art when considering the scheme that follows. The starting compounds can be commercially available or can be prepared by methods described in the literature or herein, or by similar or equivalent methods. Before carrying out the reaction, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage in the reaction sequence using methods familiar to those skilled in the art and methods described in the literature on the use of protecting groups in organic synthesis.

[0096] Scheme 1: [ka] Scheme 1: Compounds of formula (I), e.g., (I.0), (I.1), or (I.2), and compound of formula (IV) are heated in a suitable solvent (e.g., DCM, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidinone) at -20°C to 100°C with a suitable coupling agent (e.g., O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyllonium-hexafluorophosphate (HATU), O- By using (benzotriazol-1-yl)-N,N,N',N'-tetramethylronium tetrafluoroborate (TBTU), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), carbodiimide reagents, etc.), and a base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, etc.), the respective acids of formulas (II) and (V) (free acid, or Li) can be obtained. + kaNa + , K + It can be prepared from either a carboxylate salt with a suitable metal cation such as, and a suitable amine of formula (III) (either a free amine or a salt such as a hydrochloride or hydrobromide). R in Scheme 1 1 , R 2 , R 3 , R 4 and n have the meanings previously defined herein. Alternatively, individual carboxylic acids are converted to carboxylic acid chlorides (e.g., using oxalyl chloride or thionyl chloride in DCM), which are then coupled with amine(III) in the presence of a suitable base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, etc.).

[0097] Compounds of formula (IV) have been reported in the literature and can be obtained in enantiomer-rich or pure forms (see, for example, German Patent Application Publication No. 4132763, European Patent Application Publication No. 0388789, European Patent Application Publication No. 0254245, European Patent Application Publication No. 0450504, and Med. Res. Rev. 1989, 9, 181-218).

[0098] Scheme 2: [ka] Scheme 2: Imine (R) of equations (IV) and (V) 1 , R 2 , R 3 , R 4 (wherein n has the meaning defined herein earlier) can be reduced to the corresponding amines (II) and (I) by hydrogen in the presence of a transition metal catalyst or by using a suitable hydride source. Suitable hydride sources are, depending on the hydride source, NaBH4, KBH4, Na(NC)BH3, NaHB(OAc)3, Me4NBH4 and (N) used in the presence of a transition metal, a Lewis acid or a Brønsted acid, or a suitable solvent (e.g., toluene, DCM, THF, MeCN, H2O, etc., or a mixture thereof depending on the hydride used and conditions), at temperatures from low to high (-70°C to 100°C), NaBH4, KBH4, Na(NC)BH3, NaHB(OAc)3, Me4NBH4 and n Boron hydride such as Bu4NBH4, aranates such as LiAlH4, L-selectride, HAl i Selectride models such as Bu2, Pinacole Volan, H3B *Boranes such as THF, 9-BBN-H, and Et2BH, and silanes such as Et3SiH and Cl3SiH can be used. A more specific experimental protocol, which may be more generally applicable, involves NaBH4 and an acid, such as aqueous HCl or acetic acid, in 1,2-dichloroethane at 0°C to 40°C. Active catalysts, which may be used in combination with molecular hydrogen, are preferably derived from, for example, Co, Ni, Pd, Pt, Rh, Ru, and Ir. The reduction of the imine, in the presence of one of these transition metal catalysts, and possibly ligands coordinating to the transition metal and other additives, may be carried out using hydrogen (1 to 200 bar) in a suitable solvent (e.g., DCM, HCl, EtOH, THF, etc.) at 0°C to 150°C. Compounds (I) and (II) obtained by this procedure may be a mixture of diastereomers or pure diastereomers, depending on the reducing agent and conditions applied, and can be separated into individual stereoisomers by methods known to those skilled in the art to obtain pure stereoisomers, for example, (I.1) or (I.2).

[0099] The reduction of imine (IV) or (V) can also be carried out stereoselectively by using either a chiral hydride or hydrogen in the presence of a chiral catalyst, yielding compound (I) or (II) as a stereoisomer-rich or pure stereoisomer, depending on the enantiopurity of the starting imine, (IV) or (V), and the conditions used. For example, n A chiral hydride is formed by the reaction of Bu4NBH4 with (S)- or (R)-N-benzyloxycarbonyl (Cbz)-proline (→ n Bu4NHB((S) or (R)-N-Cbz-proline)3) exhibits high stereochemical selectivity and can be a suitable reagent for reducing imines (IV) and (V). This reaction is preferably carried out in DCM at -78°C to 40°C using a chiral hydride formed in a separate step or in situ before the addition of the imine.

[0100] The reduction of the imine can also be carried out using ester (VI) under some of the above conditions (Scheme 3) to obtain the corresponding amine, which can be converted to compound (II) by hydrolysis of the ester group as described below (Scheme 3), and then to compound (I) by coupling with amine (III) as further described above (Scheme 1).

[0101] Scheme 3 [ka] R'=C 1-4 -alkyl or benzyl Scheme 3: Acid (R) of formula (V) 1 , R 2 (wherein n has the meaning defined herein) are preferably prepared from the corresponding ester (VI) by hydrolysis or hydrocracking, depending on the properties of R'. Esters of lower alkyl groups, such as ethyl or methyl esters, are preferably cleaved by hydrolysis with hydroxide salts such as NaOH, LiOH, or KOH in a mixture of water and a suitable miscible solvent (e.g., THF, MeOH, EtOH, 1,4-dioxane, or a mixture thereof) at ambient temperature or high temperature. Acids can be isolated either as a salt with a metal cation or as a carboxylic acid. Tert-butyl esters are preferably cleaved by treatment with an acid (e.g., hydrochloric acid or TFA) in a suitable solvent (e.g., DCM, 1,4-dioxane, MeOH, EtOH, THF, water, or a mixture thereof). The benzyl ester is preferably cleaved by hydrogenolysis with a suitable catalyst (e.g., carbon-supported palladium) in a suitable solvent (e.g., EtOH, MeOH, THF, DCM, or toluene) under a hydrogen atmosphere (preferably 1 to 5 bar).

[0102] Compounds of formula (V) have been reported in the literature and can be obtained in enantiomer-rich or pure forms (see, for example, European Patent Application Publication No. 0388789, European Patent Application Publication No. 0254245 and German Patent Application Publication No. 4132763). Scheme 4

[0103] [ka] R'=C 1-4 -alkyl or benzyl

[0104] Scheme 4: Ester(R) of formula (VI) 1 , R 2 (wherein n has the meaning defined herein earlier) may be prepared from amide (VII) using various synthetic strategies. A more preferred procedure involves converting the amide group in (VII) to the corresponding chloride imidoyl or phosphate ester anhydride using diethyl chlorophosphate in the presence of a base (e.g., 1,8-diazabicyclo[5.4.0]undecene (DBU)) in a suitable solvent (e.g., THF, 1,4-dioxane) at a moderate temperature (preferably between 0°C and 40°C). Subsequently, the thus modified acylhydrazine (R 1 By adding (-CO-NHNH2) to such an activated amide, an N-acylaminoamidine derivative can be obtained, which can then be converted to a triazole by heating (in some cases, up to 140°C).

[0105] Alternatively, triazole(VI) can be obtained by applying a three-step procedure via the thioamide of amide(VII), which is then treated with hydrazine to give the corresponding N-aminoamidine, which is then converted to a suitable orthoester(R) 1 -C(OC 1-2It is converted to triazole by treatment with (-alkyl)3). This procedure, its variations, and alternative synthetic routes are reported in the organic chemistry literature and literature known to those skilled in the art (see, for example, European Patent Application Publication No. 0388789 and European Patent Application Publication No. 0254245).

[0106] Compounds of formula (VI) have been reported in the literature and can be obtained in enantiomer-rich or pure forms (see, for example, European Patent Application Publication No. 0388789). Scheme 5 [ka] R'=C 1-4 -alkyl or benzyl

[0107] Scheme 5: Ester(R) of formula (VII) 2 Compound (VII) (where n has the meaning defined herein) may be prepared from ketone (VIII) in one, two, or three separate synthesis steps. A well-established synthesis of compound (VII) is carried out via an N-bromoacetyl derivative of compound (VIII), which can be obtained by treating compound (VIII) with bromoacetyl bromide in the presence of a base (e.g., NaHCO3) at 0°C to 80°C in a suitable solvent (e.g., toluene and water). Next, this intermediate is treated with an ammonia source (e.g., ammonia in aqueous ammonia or THF) to replace the bromine and obtain the corresponding N-aminoacetyl derivative. Then, compound (VII) is obtained by reacting the amino group with the keto group to form a seven-membered ring in a suitable solvent (e.g., silica gel in toluene, pyridine in HOAc or methanesulfonic acid in 1,4-dioxane) at a high temperature (preferably between 30°C and 130°C) with the help of a suitable additive, thereby forming a seven-membered ring.

[0108] This procedure has also been reported in the literature and is applicable to the synthesis of enantiomer-rich or pure compounds (see, for example, European Patent Application Publication No. 0254245 and European Patent Application Publication No. 0388789). Compound (VII) can also be obtained from compound (VIII) in just one reaction step, as reported in Org. Lett. 2017, 19, 1454-1457.

[0109] Scheme 6 [ka] R'=C 1-4 -alkyl or benzyl Scheme 6: The compound of formula (VIII) can be prepared from cyanoketone (IX) and ketone (X) according to the protocol reported for the so-called Gewald reaction; R in Scheme 6 2 And n have the meanings defined herein earlier. Thus, compounds (IX) and (X) are brought together and treated with a base (e.g., NEt3, HNEt2, morpholine, piperidine, pyridine, etc.) in the presence of elemental sulfur in a solvent (e.g., MeOH, EtOH, DMF, 1,4-dioxane, etc.) at 0°C to 120°C.

[0110] Alternatively, this transformation may be carried out in two separate steps: a condensation product from compounds (IX) and (X) in the first step (Knoevenagel reaction), and product (VIII) formed during treatment with elemental sulfur and a base in the second step. Variations of these procedures have been reported in the organic chemistry literature. Compound (IX) is either a known compound or can be prepared in the same manner as the former. Major and specific sources of enantiomer-rich or pure compound (X) are also reported in the organic chemistry literature (see, for example, European Patent Application Publication EP0388789, Archiv der Pharmazie 1996, 329, 291-300 and Green Chem. 2017, 19, 5122-5130).

[0111] Scheme 7 [ka] R"=C 1-4 -alkyl or benzyl

[0112] Scheme 7: Cyanoketone (R) of Equation (IX) 2 (and n have the meanings defined herein earlier) are used to prepare the corresponding ester (XI) and deprotonated acetonitrile (NCCH2) in a suitable solvent (e.g., THF, toluene, MeCN, DMF, DMSO, 1,4-dioxane, etc.) at -78°C to 100°C. - ) are preferably prepared from the species. The deprotonated acetonitrile species is preferably prepared at -78°C to 40°C in one of the solvents used for the subsequent reaction with ester (XI) at a suitable base (e.g., NaH, LiN) i Pr2, LiN(SiMe3)2, KO t It is prepared from acetonitrile by deprotonation with a compound (such as Bu). Further synthetic routes and procedures for preparing the compound of formula (IX) have been reported in the organic chemistry literature.

[0113] Scheme 8 [ka] R'=C 1-4 -alkyl or benzyl; R"=C 1-4 -alkyl or benzyl

[0114] Scheme 8: The compound of formula (I) can also follow the pathway outlined in Scheme 8; R 2 , R 3 , R 4and n have the meanings defined herein prior to this. The synthesis sequence begins with a Gewald reaction of the ketone (X) and the cyanoester (XII) to obtain aminothiophene (XIII) (see the experimental section and International Publication No. 2008 / 063667 for specific reaction conditions). Aminothiophene (XIII) can be acetylated at N with methoxyacetyl chloride in the presence of a base (e.g., pyridine) in an inert solvent (e.g., DCM) at ambient temperature to obtain compound (XIV). The methoxy group acts as a masked leaving group, which is to be replaced by ammonia in a later step of the synthesis to introduce an amino. A number of other masked or protected amino equivalents, such as phenoxy instead of methoxy, can be considered for this purpose. Compound (XIV) can then be converted to triazole (XVI) via thioamide (XV). The latter compound can be obtained by treating (XIV) with Lawson's reagent (or phosphorus pentasulfide) in a solvent (e.g., 1,4-dioxane or toluene) at a high temperature (60°C to 120°C). Triazole (XVI) can be formed by treating thioamide (XV) with hydrazine in a solvent (e.g., THF or 1,4-dioxane) at ambient temperature to obtain an N-aminoamidine intermediate, which is then reacted with trialkyl orthoacetate (e.g., MeC(OMe)3) or acetamide dialkyl acetal (e.g., MeC(OMe)2(NMe2)) at a high temperature (about 60°C to 120°C) in the presence of an acid (e.g., p-TsOH or MeCOOH). Alternatively, Under similar conditions, triazoles can be obtained by using acetylhydrazine instead. Bromides (XVIII) can be produced from compound (XVI) by directly substituting the methoxy group with the bromide, or via an alcohol derivative (XVII), depending on the conditions applied. The procedure via alcohols requires cleavage of the methoxy ether (e.g., using BBr3 in DCM), followed by the transfer of the hydroxyl group by Br (e.g., MeSO2Br and NEt3 in DCM).Next, compound (XIX) can be obtained by treating bromide (XVIII) with ammonia (e.g., in methanol at ambient temperature), and heating the substitution product in the presence of an optional additional base (e.g., NEt3) to simultaneously achieve cyclization and amide formation. The thioamide in (XX) can be introduced by treating the amide (XIX) with Lawson's reagent or P2S5 in an inert solvent (e.g., toluene or 1,4-dioxane) at a high temperature (preferably between 60°C and 120°C). The main procedure described in Scheme 3, ester hydrolysis, and amide formation in Scheme 1, are followed to convert the ester functional group in (XX) to the corresponding amide and obtain compound (XXII); ester hydrolysis can be achieved at ambient temperature in a mixture of water and methanol using NaOH, while amide formation can be achieved in DMF at room temperature with the desired amine (R 3 R 4 This can be done using NH) and carbonyl diimidazole. Methylation of sulfur in thioamide (XXII) can be achieved in a solvent (e.g., acetone or MeCN) at ambient temperature, optionally in the presence of a base (e.g., KOtBu), using methyl iodide or methyl trifluoromethanesulfonate to obtain compound (XXIII), which has a functional group (-N=C(SMe)-) suitable for coupling aromatic residues in a transition metal-catalyzed coupling reaction with an aromatic nucleophile such as a boronic acid or zinc halide. Coupling of compound (XXIII) with an aromatic boronic acid (RB(OH)2) can be carried out in a solvent (e.g., NMP or 1,4-dioxane) at ambient temperature or high temperature (preferably between 20°C and 120°C), using a transition metal catalyst based on Pd (e.g., Pd(PPh3)4) and a Cu-based additive (e.g., copper(I) thiophene-2-carboxylate) to obtain compound (I'), i.e., compound (I) (wherein R 1 (where is a methyl group) can be obtained. The synthesis scheme outlined in Scheme 8 is R 1 This specification is not limited to compounds having methyl in relation to, but R as defined earlier herein 1This can, in principle, be extended to any other residue that is encompassed by its meaning.

[0115] Compounds of formula (I) can be separated into their enantiomers and / or diastereomers as specified below. For example, a cis / trans mixture may be separated into its cis and trans isomers, a diastereomer mixture may be separated into its diastereomers, and a racemic compound may be separated into its enantiomers.

[0116] A cis / trans mixture can be separated into its cis and trans isomers, for example, by chromatography. Compounds of formula (I) that result as racemates can be separated into their optical isomers by methods known to the extent of the matter, and diastereomer mixtures of compounds of general formula (I) can be separated into their diastereomers by methods known to the extent of the matter, for example, by using chromatography and / or fractional crystallization, by taking advantage of their different physicochemical properties; if the compounds obtained thereafter are racemates, they may be separated into enantiomers as described below.

[0117] Racemates are preferably separated by column chromatography on a chiral phase, by crystallization from an optically active solvent, or by reaction with an optically active substance that forms a salt or derivative such as an ester or amide with the racemic compound. Salts can be formed with pure acid as enantiomers in the case of basic compounds, and with pure base as enantiomers in the case of acidic compounds. Diastereomer derivatives are formed with pure auxiliary compounds, such as acids, their activated derivatives, or alcohols, as enantiomers. Separation of diastereomer mixtures of the thus obtained salts or derivatives can be achieved by utilizing their various physicochemical properties, such as differences in solubility. Free adipocytes can be released from pure diastereomer salts or derivatives by the action of a suitable agent. Optically active acids commonly used for such purposes, and optically active alcohols applicable as auxiliary residues, are known to those skilled in the art. As described above, compounds of formula (I), such as (I.0), can be converted to salts, particularly pharmaceutically acceptable salts for use in pharmaceuticals. As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound, wherein the parent compound is modified by the preparation of its acid salt or base salt. The compounds according to the present invention can also be advantageously obtained using the methods described in the following examples, and the examples can also be combined for this purpose using methods known to those skilled in the art from the literature.

[0118] Pharmacological activity and suitability for pharmaceutical applications The activity of the compound of the present invention and its suitability for pharmaceutical applications can be demonstrated using the following assay: biological methods

[0119] The ability of the compound of formula (I.0) to inhibit the activation of the PAF receptor (PAFR) by PAF C-16 ligand (PAF) is determined using the following cellular HTRF IP1 assay (CisbioI IP1 Gq assay kit, catalog number: 62IP1APEJ) in assay buffer (1×HBSS, 20 mM Hepes, pH 7.4, 50 mM LiCl, and containing 0.1% (w / v) BSA). Evaluation of PAFR activation inhibition using endpoint assays

[0120] HEK293 cells (generated in-house) overexpressing human PAFR are seeded into a lidded 384-well white cell culture microtiter assay plate coated with poly-D-lysine (15,000 cells per well). The plate is then incubated overnight at 37°C / 5%CO2. The following day, the cells are washed, and then various concentrations of the test compound (compound in 100% DMSO; the final DMSO concentration in the wells is 1%) are added to the assay plate using an Echo555 acoustic liquid handler. The plate is then incubated with the lid on at 37°C / 5%CO2 for 90 minutes. After this, PAF ligand (Cayman Chemical Company, item number: 60900) is added to a final concentration of 11 nM. The plate is then incubated with the lid on at 37°C / 5%CO2 for 60 minutes. Next, add 5 μl of anti-IP1 antibody-cryptate solution and 5 μl of IP1-d2 solution per well to all wells of the plate, and incubate the plate at room temperature, protected from light, for a further 60 minutes. Measure the emission at 620 nm and 665 nm (excitation wavelength: 320 nm) using an Envision reader (PerkinElmer).

[0121] IC of the compound according to the present invention 50The values ​​are shown in the table below. The compound numbers correspond to the example numbers in the experimental items. When a mixture of isomers relating to the stereochemistry at C-13 is used in the test, the observed activity can be attributed primarily to the (13S)-isomer, which is the isomer according to the present invention. This is evident from a direct comparison of (reference) Examples 67-71 and 74-78.

[0122] [Table 12]

[0123] Evaluation of inverse agonist mechanisms using endpoint assays Due to the constitutive activity of PAFR, basal HTRF IP1 signaling is significantly higher in HEK293 cells overexpressing human PAFR compared to untransfected HEK293 cells. The ability of the test compound to act as an inverse agonist at the PAF receptor can be determined using a modified protocol of the cell HTRF IP1 assay described above. Various concentrations of the test compound are added to assay plates containing HEK293 cells overexpressing human PAFR, and incubated at 37°C / 5% CO2 for 340 minutes without the addition of the RAF ligand. The inverse agonizing effect of the test compound is demonstrated by a reduction in HTRF IP1 signaling to the level of untransfected HEK293 cells. Evaluation of in vivo efficacy of laser-induced choroidal angiogenesis in an animal model in Brown Norway rats. Male Brown Norway rats (BN / Crl) weighing between 160g and 180g were obtained from Charles River Labs (Sulzfeld, Germany). The animals were kept in a group housing with a 12-hour / 12-hour light / dark cycle (lights on at 6 AM) and acclimatized for one week prior to the start of the study. The animals were given ad libitum access to standard feed (Provimi Kliba number 3438) and tap water. The animals were administered the test compound once daily by forced oral administration for two weeks.

[0124] Under anesthesia, on day 1, the animal is positioned in front of the fundus camera so that the optic nerve is centered in the image. Laser treatment is performed using a Micron IV system (Phoenix Research Laboratories, Pleasanton, CA) with a 532 nm wavelength green argon laser (Merilas). The diameter of the laser beam is matched to the diameter of the optic nerve, and four lesions are generated per eye using a laser pulse with an energy of 400 mW and a duration of 150 milliseconds. The lesions are placed between large blood vessels located approximately twice the diameter of the optic nerve. Successful destruction of the Bruch membrane is recognized by the formation of bubbles immediately after the laser beam and confirmed by OCT scan.

[0125] The animals are sacrificed 14 days after laser treatment by cervical dislocation under anesthesia. The eyes are extracted and cut along the serrated edges. The cornea, iris, lens, vitreous humor, and retina are removed, and the remaining optic cup (consisting of PRE, choroid, and sclera) is fixed in PFA (4%) at 4°C for 1 hour, then transferred to PBS containing 0.1% Triton X-100 at 4°C for 1 hour. The optic cup is stained with FITC-labeled isolectin B4 (10 μg / ml in physiological saline; obtained from Sigma Aldrich, catalog number L9381) in the dark overnight at room temperature, and washed three times with PBS. The optic cup is transferred to a glass slide and cut four times to create a flat clover leaf-like structure. Cover the tissue with a mounting medium (Vectashield H-1200 containing DAPI), place a coverslip on top, and obtain a flat mount of the RPE / choroid / sclera (RPE side up). Store the flat mount in the dark at 4°C until analysis.

[0126] This sample is analyzed using an LSM700 confocal laser scanning microscope (Carl Zeiss, Jena; gain650, laser intensity 2%) at a wavelength of 488 nm to obtain images of the lesion. Lesion size is measured using Zen Blue software. Efficacy is read out as the lesion size stained with isolectin B4 in a flat mount of the RPE choroid. Evaluation of the binding of compounds to melanin

[0127] The ability of the compound to bind to melanin is determined using an in vitro assay with melanin from Sepia officinalis (Sigma-Aldrich, catalog number: M2649) in assay buffer (phosphate buffer, pH 6.5, 0.9% (w / v) NaCl). To measure binding, a 1 mg / mL (w / v) melanin suspension and a 0.1% (w / v) BSA solution (control buffer) are prepared in assay buffer. The compound is incubated in a microtiter plate at a final compound concentration of 1 μM (DMSO: add the compound from assay buffer (40:60) to the plate; the final DMSO concentration is 1%) in control buffer, with a 1 mg / mL melanin suspension (to determine the free compound concentration), and without melanin (to determine the total compound concentration). This plate is incubated at 37°C for 2 hours using a 900 rpm orbital shaker. After incubation, the plate is centrifuged to pelletize the melanin and bound compound. Supernatant samples are taken from both the melanin and control wells, and their concentrations are measured using LC-MS. The bound concentration is calculated by subtracting the free compound concentration from the total compound concentration.

[0128] Evaluation of chemical stability Decomposition studies are used to mimic the chemical stability of compounds in the acidic regions of the gastrointestinal tract. The compounds of the present invention demonstrate high chemical stability in acidic aqueous media (pH value of approximately 1.2), which does not significantly limit or pose a problem for their application as pharmaceuticals to treat human diseases.

[0129] The chemical stability of the compound of the present invention with a pH of approximately 1.2 is determined as follows: The compound is dissolved in a mixture of acetonitrile / 0.1M aqueous HCl (ratio: 2:3; pH approximately 1.2) in an HPLC vial to obtain a concentration of approximately 0.25 mg / ml. This vial is then transferred to an HPLC autosampler system and maintained at a temperature of 37°C. The first sample is taken and immediately injected into a standard HPLC system equipped with a UV DAD detector. Further samples are injected after 24 hours. The amount of degraded compound is measured by determining the recovery rate [%] of the compound during the 24-hour injection using the standard HPLC gradient method. Specifically, the peak area of ​​the major peak for the first injection (AUt0) is calculated and set to 100%. The peak area of ​​the major peak is also calculated for the 24-hour injection (AUt0). 24h ), (AU 24h ) / AU t0 Expressed as a percentage. The chemical stability of the exemplary compounds according to the present invention was tested as described above. For all of them, it was found that the amount of decomposed compound was at most 3% or less.

[0130] The table below shows the degree of decomposition of typical compounds of the present invention. The number of each compound corresponds to the number of the example in the experimental procedure. [Table 13]

[0131] Evaluation of permeability Caco-2 cells (1~2×10 5 individual cells / 1cm 2 Seeds (in area) are seeded onto a filter insert (Costar transwell polycarbonate or PET filter, pore size 0.4 μm) and cultured for 10-25 days (DMEM). The compound is dissolved in a suitable solvent (such as DMSO, a 1-20 mM storage solution). The storage solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4×7H2O, 0.41 mM NaH2PO4×H2O, 15 mM HEPES, 20 mM glucose, pH 7.2) to prepare the transport solution (0.1-300 μM of the compound, final DMSO <= 0.5%). The transport solution (TL) is applied to the apical or basal donor side to measure AB or BA permeability (3 filter repeats), respectively. The receiver side contains HTP-4 buffer supplemented with 2% BSA. To perform concentration measurements by HPLC-MS / MS or scintillation counting, samples are collected from both the donor and receiver at the start and end of the experiment, and at various time intervals of up to 2 hours. The sampled receiver volume is replaced with fresh receiver solution.

[0132] Evaluation of metabolic stability in human or rat liver microsomes Metabolic degradation of the test compound is assayed at 37°C using pooled human or rat liver microsomes. The final incubation volume, which is 100 μl per time point, contains TRIS buffer (pH 7.6) (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg / mL), and the test compound at a final concentration of 1 μM at room temperature. After a short pre-incubation at 37°C, the reaction is initiated by adding reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM), and terminated at various time points by transferring a fixed amount to the solvent. Furthermore, NADPH-independent degradation is monitored in an NADPH-free incubation and terminated at the final time point. The incubated material after quenching is pelletized by centrifugation (10000 g, 5 minutes). The amount of the parent compound is assayed by LC-MS / MS on a fixed amount of the supernatant. The half-life (t1 / 2 INVITRO) is determined by the slope of the semi-logarithmic plot of the concentration-time profile.

[0133] Evaluation of metabolic stability in human or rat hepatocytes The metabolic degradation of the test compound is assayed in a hepatocyte suspension. Hepatocytes (usually stored cryopreserved) are incubated in a suitable buffer system containing 5% serum species (e.g., Dulbecco's Modified Eagle Medium, and 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, and 3.75 mg hydrocortisone / 500 mL). After pre-incubation for 30 minutes (usually) in an incubator (37°C, 10% CO2), 5 μL of the test compound solution (80 μM; from 2 mM in DMSO storage solution diluted 1:25 with culture medium) is added to 395 μL of hepatocyte suspension (cell density ranging from 0.25 to 5 myo cells / mL, typically in the range of 1 myo cell / mL; final concentration of test compound 1 μM, final DMSO concentration 0.05%). Incubate the cells for 6 hours (incubator, orbital shaker), and collect samples (25 μL) at 0, 0.5, 1, 2, 4, and 6 hours. Transfer the samples to ACN and pelletize by centrifugation (5 minutes). Transfer the supernatant to a new 96-deep-well plate, evaporate the solvent under nitrogen, and resuspend. The decrease in the parent compound is analyzed by HPLC-MS / MS. CLint is calculated as follows: CL_INTRINSIC = dose / AUC = (C0 / CD) / (AUD+clast / k) × 10 / 60. C0: initial concentration in incubation [μM], CD: cell density of viable cells [10e6 cells / mL], AUD: area under data [μMx], clath: concentration at the last data point [μM], k: slope of the regression line for the decrease in the parent compound [h-1].

[0134] Evaluation of protein binding in plasma This equilibrium dialysis (ED) technique is used to determine the approximate in vitro binding rate of the test compound to plasma proteins. Dianorm Teflon-dialyzed cells (micro 0.2) are used. Each cell consists of a donor chamber and an acceptor chamber separated by an ultrathin semipermeable membrane with a molecular weight cutoff of 5 kDa. A storage solution for each test compound is prepared in 1 mM DMSO and diluted to a final concentration of 1.0 μM. The following dialysis solutions are prepared in pooled human or rat plasma (containing NaEDTA) from male and female donors. A fixed volume of dialysis buffer (100 mM potassium phosphate, pH 7.4) totaling 200 μL is dispensed into the buffer chamber. A fixed volume of dialysis solution of the test compound totaling 200 μL is dispensed into the plasma chamber. Incubation is performed at 37°C under rotation for 2 hours.

[0135] At the end of the dialysis period, the dialysate is transferred to the reaction tube. The tube for the buffer fraction contains 0.2 mL of ACN / water (80 / 20). A fixed volume of plasma dialysate totaling 25 μL is transferred to a deep well plate and mixed with 25 μL of ACN / water (80 / 20), 25 μL of buffer, 25 μL of calibration solution, and 25 μL of internal standard solution. Protein precipitation is performed by adding 200 μL of ACN.

[0136] A fixed volume of buffered dialysate totaling 50 μL is transferred to a deep-well plate and mixed with 25 μL of blank plasma, 25 μL of internal standard solution, and 200 μL of ACN. The samples are measured using an HPLC-MS / MS system and evaluated with Analyst software. The binding rate is calculated using the following formula: Binding % = (Plasma concentration - Buffer concentration / Plasma concentration) × 10

[0137] Evaluation of solubility The water solubility of the test compound is determined by comparing the amount dissolved in buffer with the amount in an ACN / water (1 / 1) solution. Starting with a 10 mM DMSO storage solution, a fixed amount is diluted with either ACN / water (1 / 1) or buffer. After shaking for 24 hours, the solution is filtered and analyzed by LC-UV. The amount dissolved in buffer is compared with the amount in the ACN solution. Solubility is typically measured as 0.001–0.125 mg / mL at a 2.5% DMSO concentration. If the compound dissolves more than 90% in the buffer, this value is indicated by ">".

[0138] The compounds of the present invention exhibit favorable solubility even at low pH values ​​(pH 2.2 mimics the acidic region of the gastrointestinal tract), a desirable characteristic for drug development and administration purposes. The following table shows data relating to the selected compounds of the present invention. [Table 14]

[0139] Evaluation of pharmacokinetic characteristics in rodents The test compound is administered intravenously to fed rats or orally to fasted rats. Blood samples are collected at several time points after administration of the test compound, treated with anticoagulants, and centrifuged. The concentration of the analyte, i.e., the administered compound and / or metabolite, is quantified in plasma samples by LC-MS / MS. To determine renal clearance, urine samples are collected over 24 hours after intravenous administration, and the urine concentration of the administered compound is quantified by LC-MS / MS. PK parameters are calculated using non-compartmental PK analysis (NCA). The trapezoidal rule is applied (linear up - log down), and the AUC is calculated from time 0 to the final measured concentration. 0-tz Find the area under each curve up to ). AUC 0-Inf This extrapolates the end-of-life stage and AUC tz-∞ AUC 0-tz The calculation is performed by adding the values. Each CL value is calculated according to Equation 1.

[0140]

number

[0141] In the second step, drug-specific renal clearance for each animal is calculated using Equation 2.

number

[0142] Treatment method In another aspect of the present invention, the compounds of formula (I.0) or pharmaceutically acceptable salts thereof have suitable properties for therapeutic use, i.e., for use as pharmaceuticals. In particular, the compounds of formula (I.0) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, may be useful in treating diseases or conditions in patients that may be affected by antagonizing platelet-activating factor receptors (PAFRs), for example, those mediated by undesirable PAFR activity or for which the antagonism of PAFRs is beneficial. Further benefits may be brought about by the inverse action of PAFR. Diseases and conditions that can be affected by antagonizing PAFR and / or inversely activating it, for example, those mediated by undesirable PAFR activity, or for which antagonism and / or inverse activation of PAFR activity are beneficial, include eye diseases, cardiovascular diseases, cancer, neurological and neurodegenerative disorders, renal disorders, hepatic diseases, and allergies. These disorders include, but are not limited to, retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular ischemia (DMI), geographic atrophy, Stargardt disease, retinal degeneration in glaucoma, myopic macular degeneration, chronic panuveitis, retinitis pigmentosa, retinal vein occlusion (such as central, bifurcation, or hemiretinal vein occlusion), diabetic macular edema (DME), clinically significant macular edema (CSME), and cystic macular edema (CM). E) Post-cataract CME, cryotherapy-induced CME, uveitis-induced CME, endophthalmitis, post-vascular occlusion CME (e.g., central retinal vein occlusion, branch retinal vein occlusion, or hemi-retinal vein occlusion), retinal edema, cataract surgery-related complications in diabetic retinopathy, hypertensive retinopathy, retinal trauma, atrophic and exudative age-related macular degeneration (AMD), polypoid choroidal vasculopathy (PCV), choroidal neovascularization (CNV);For example, non-exudative choroidal neovascularization, subretinal fibrosis (e.g., associated with non-exudative or exudative choroidal neovascularization), posterior vitreous detachment (PVD), ischemia-reperfusion injury in all kinds of situations associated with tissue and / or organ transplantation, surgery-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-associated edema, spinal cord injury, pain, ischemia, focal cerebral ischemia, neurological deficits and agnosia, deep vein thrombosis, stroke, myocardial infarction, atherosclerosis, acquired angioedema, hereditary angioedema (HAE), drug-associated (ACE inhibitor) edema, altitude edema, cytotoxic cerebral edema, osmotic brain Edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, traumatic brain injury, hemorrhagic stroke (e.g., stroke or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic changes in ischemic stroke, traumatic brain injury associated with injury or surgery, encephalomyelitis, amyotrophic lateral sclerosis, neuropathic pain, cerebral aneurysm, arteriovenous malformation, reduction of blood loss during surgery (e.g., cardiac and thoracic surgery such as cardiopulmonary bypass or coronary artery bypass grafting), blood coagulation disorders such as thrombosis, tinea, disorders due to inflammatory components (e.g., multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease, excessive daytime sleepiness, essential hypertension, diabetes Alternatively, it can be caused by hyperlipidemia-related hypertension, renal failure, kidney damage (including chronic kidney disease), interstitial cystitis / bladder pain syndrome, heart failure, microalbuminuria, albuminuria, proteinuria, disorders associated with increased vascular permeability (e.g., increased retinal vascular permeability, increased vascular permeability of the legs, feet, and ankles), intracerebral hemorrhage, deep vein thrombosis, coagulation resulting from fibrinolytic treatment, angina pectoris, angioedema, sepsis, arthritis (e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis), ulcerative colitis, pancreatitis, lupus, gout, psoriasis, inflammatory bowel disease, diabetes mellitus, diabetic complications, or metabolic syndrome. Complications, non-alcoholic steatohepatitis (NASH), allergies, bacterial and viral infections (including HIV infection), anaphylaxis, sepsis, chronic obstructive pulmonary disease (COPD), asthma, periodontitis, psoriasis, urticaria, UVB-induced dermatitis, astrocytosis-related disorders (e.g., Alzheimer's disease or multiple sclerosis), Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, stroke, epilepsy and trauma (e.g., traumatic brain injury), allergic edema, airway obstruction in chronic allergic sinusitis or perennial rhinitis, etc.; airway obstruction in acute asthma;This includes serositis associated with systemic lupus erythematosus (SLE), acute respiratory distress syndrome (ARDS), cancer (such as breast cancer, colorectal cancer, esophageal cancer, lung cancer, liver cancer, pancreatic cancer, skin cancer (including melanoma), and cervical cancer), and other diseases.

[0143] Therefore, the compounds and pharmaceutical compositions according to the present invention are particularly suitable for the treatment of ocular diseases, including diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, atrophic and exudative age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vasculopathy (PCV), and choroidal neovascularization (CNV; for example, non-exudative choroidal neovascularization). Furthermore, the compounds and pharmaceutical compositions according to the present invention are particularly suitable for treating allergy- and inflammation-related conditions and diseases such as urticaria and NASH.

[0144] The compounds and pharmaceutical compositions according to the present invention are most particularly suitable for the treatment of diabetic macular edema (DME), atrophic and exudative age-related macular degeneration (AMD), geographic atrophy, non-exudative choroidal neovascularization (CNV), urticaria, and NASH. The applicable daily dose range for the compound of formula (I.0) is typically 0.01 mg to 10 mg per kg of body weight. The actual therapeutically effective dose or dosage naturally depends on factors known to those skilled in the art, such as the patient's age and weight, the route of administration, and the severity of the disease. In any case, the compound or composition is administered in a dosage and manner that is capable of delivering a therapeutically effective dose based on the patient's specific condition.

[0145] The compound and composition may be administered orally, intravitreal, transdermally, by inhalation, parenterally, or sublingually, including in any combination with one or more additional therapeutic agents according to the present invention. Of the possible methods of administration, oral administration and intravitreal administration are preferred, with oral administration being particularly preferred. In the case of intravitreal injection, the preferred dose should not exceed 5 mg per eye. The patients to be treated are preferably mammals, most preferably human patients. Therefore, in another embodiment, the present invention provides compounds of formula (I.0), including pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0146] In another embodiment, the present invention provides a method for treating a disease or condition in a patient for which undesirable activity of platelet-activating factor receptors is mediated or antagonism of platelet-activating factor receptors is beneficial. Similarly, the present invention provides compounds of formula (I.0) or pharmaceutically acceptable salts thereof for use in methods of treating diseases or conditions in patients for which undesirable activity of platelet-activating factor receptors is mediated or antagonism of platelet-activating factor receptors is beneficial. Similarly, the present invention provides for the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for use in a method of treating a disease or condition in which the undesirable activity of platelet-activating factor receptors is mediated by or the antagonistic effect of platelet-activating factor receptors is beneficial in patients who require it. Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in a method for treating a disease or condition in which undesirable activity of platelet-activating factor receptors is mediated by or antagonism of platelet-activating factor receptors is beneficial in patients who require it.

[0147] According to one embodiment, the treatment method includes the step of administering to a patient one or more compounds of formula (I.0) or a pharmaceutically acceptable salt thereof, preferably the step of administering to a patient a therapeutically effective amount of one or more compounds of formula (I.0) or a pharmaceutically acceptable salt thereof. According to another embodiment, the treatment method includes the step of administering a pharmaceutical composition according to the present invention to a patient. According to one embodiment, diseases or conditions mediated by undesirable activity of platelet-activating factor receptors, or for which antagonism of platelet-activating factor receptors is beneficial, are selected from ocular indications such as diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, atrophic and exudative age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vasculopathy (PCV), and choroidal neovascularization (CNV). According to another embodiment, diseases or conditions mediated by undesirable activity of platelet-activating factor receptors, or for which antagonism of platelet-activating factor receptors is beneficial, are selected from allergy and inflammation-related conditions and diseases such as urticaria and NASH. According to another embodiment, a disease or condition mediated by undesirable activity of platelet-activating factor receptors, or in which antagonism of platelet-activating factor receptors is beneficial, is selected from diabetic complications associated with diabetic retinopathy, such as diabetic macular edema, diabetic macular ischemia, and proliferative diabetic retinopathy. According to one embodiment, the patient is a human patient.

[0148] Pharmaceutical composition In another aspect of the present invention, it is stated that the compound of the present invention or a pharmaceutically acceptable salt thereof may be used as an active ingredient in a pharmaceutical composition. Suitable preparations for administering the compounds of the present invention, which may be combined with one or more additional therapeutic agents, will be obvious to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants, and powders. Oral formulations, particularly solid forms such as tablets or capsules, are preferred. For intravitreal injection, solutions are preferred. The content of the pharmaceutically active compound is advantageous to be in the range of 0.1 to 90% by mass, for example, 1 to 70% by mass, of the composition as a whole.

[0149] Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula (I.0) with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants. Tablets may also consist of several layers. Specific excipients, carriers, and / or diluents suitable for a desired preparation will be familiar to those skilled in the art, based on expert knowledge. Preferred ones are those suitable for a particular formulation and a desired method of administration. Preparations or formulations according to the present invention can be prepared using methods known to those skilled in the art, such as by mixing or combining, for example, one or more excipients, carriers, and / or diluents, with at least one compound of formula (I.0) according to the present invention or a pharmaceutically acceptable salt of such a compound. Accordingly, according to another aspect of the present invention, there is a pharmaceutical composition comprising one or more compounds of formula (I.0) or pharmaceutically acceptable salts thereof, which may together comprise one or more inert carriers and / or diluents.

[0150] Similarly, pharmaceutical compositions comprising one or more of the above compounds, or pharmaceutically acceptable salts thereof, which may together comprise one or more inert carriers and / or diluents, are provided for use in patients in need of a method of treating a disease or condition mediated by undesirable activity of PAFR or in which the antagonistic effect of PAFR is beneficial. In particular, the present invention provides pharmaceutical compositions for use in methods of treating ocular indications such as diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, atrophic and exudative age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vasculopathy (PCV), and choroidal neovascularization (CNV; e.g., non-exudative choroidal neovascularization), as well as allergy and inflammation-related conditions and diseases such as urticaria and NASH. Furthermore, the present invention relates to the use of pharmaceutical compositions according to the present invention for treating diseases or conditions mediated by undesirable PAFR activity in patients, preferably humans. Similarly, the present invention relates to the use of pharmaceutical compositions according to the present invention for treating diseases or conditions in patients, preferably humans, where the antagonistic effect of PAFR is beneficial.

[0151] According to one embodiment, a pharmaceutical composition is provided comprising one or more compounds of formula (I.0) or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, which may together comprise one or more inert carriers and / or diluents. For example, this composition comprises a compound of formula (I.0) or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0152] Combination therapy The compounds of the present invention may be further combined with one or more, preferably one, additional therapeutic agents. According to one embodiment, additional therapeutic agents are selected from a group of therapeutic agents useful for treating diseases or conditions previously described herein, in particular eye diseases such as diabetic macular edema (DME), atrophic and exudative age-related macular degeneration (AMD), geographic atrophy, non-exudative choroidal neovascularization (CNV), urticaria and NASH, conditions and diseases related to allergies and inflammation, or metabolic diseases or conditions such as diabetes, obesity, diabetic complications, hypertension and hyperlipidemia. Suitable additional therapeutic agents for such combinations include, in particular, those that activate, for example, the therapeutic effect of one or more active substances with respect to one of the indicated indications, and / or those that enable a reduction in the dosage of one or more active substances. Accordingly, the compounds of the present invention may be combined with one or more additional therapeutic agents selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and / or obesity, agents for the treatment of hypertension, heart failure and / or atherosclerosis, agents for the treatment of eye diseases, and agents for the treatment of allergy and inflammation-related conditions and diseases.

[0153] Antidiabetic agents include, for example, metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma, or alpha / gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2 inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs, or amylin and amylin analogs, dual agonists containing both GLP-1 activity and glucagon or GIP activity, cycloset, and 11β-HSD inhibitors. Other suitable combination partners include, for example, inhibitors of glucose-6-phosphatase or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists, and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, alpha-2 antagonists, CCR-2 antagonists or glucokinase activators, as well as inhibitors of protein tyrosine phosphatase 1, which are substances that affect the deregulation of glucose production in the liver. One or more lipid-lowering agents are also suitable as combination partners for cholesterol absorption inhibitors such as HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and their derivatives, PPAR-(alpha, gamma, or alpha / gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors, or bile acid-binding substances such as inhibitors of ileal bile acid transporters, MTP inhibitors, or CETP inhibitors, or HDL-raising compounds such as ABC1 regulators.

[0154] Therapeutic agents for treating overweight and / or obesity include, for example, cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3 agonists, leptin or leptin mimetic, 5HT2c receptor agonists, and dual agonists of GLP-1 and glucagon receptors.

[0155] Therapeutic agents for the treatment of hypertension, chronic heart failure, and / or atherosclerosis include, for example, A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, centrally acting antihypertensives, alpha-2-adrenergic receptor antagonists, neutral endopeptidase inhibitors, platelet activity inhibitors, or combinations thereof. Angiotensin II receptor antagonists are used to treat or prevent hypertension and complications of diabetes, often in combination with diuretics such as hydrochlorothiazide.

[0156] Therapeutic agents for the treatment of eye diseases may include, for example, intravitreal corticosteroids, intravitreal anti-VEGF therapies, anti-Ang2 inhibitors, dual anti-VEGF / anti-Ang2 inhibitors, anti-PDGF, dual anti-VEGF / anti-PDGF, VAP-1 (AOC3) inhibitors, complement inhibitors (e.g., complement factor 3, 5, B, and D inhibitors), bradykinin receptor 1 antagonists, CCR-2 antagonists, and PKK inhibitors. Additional treatments for eye diseases may include laser coagulation therapy. Therapeutic agents for treating urticaria may include, for example, antihistamines, steroids such as cortisone, epinephrine, antibodies against immunoglobulin E, immunosuppressants such as cyclosporine A, and leukotriene receptor antagonists.

[0157] Therapies used to treat NASH include, for example, FXR agonists, FXR / TGR5 agonists, THR-β agonists, ACC inhibitors, TGF-β1 antagonists, LTA4 hydrolase inhibitors, SGLT inhibitors, activin type 2 receptor antagonists, NLRP3 inhibitors, avβ1 integrin inhibitors, cGAS / STING inhibitors, GLP-1R agonists, FGF21 agonists, GLP-1 / glucagon receptor dual agonists, GLP-1 / GIP receptor dual agonists, GLP-1 / FGF21 receptor dual agonists, and GLP-1 / GIP / glucagon receptor triple agonists. This may include AOC3 inhibitors, JNK1 inhibitors, CCR2 / 5 inhibitors, ACC inhibitors, DGAT inhibitors, KHK inhibitors, PPARα / δ agonists, FGF19 agonists, β-cloto / FGFR1c agonists, PNPLA3 inhibitors, NLRP3 inhibitors, THR-β agonists, HSD17β13 inhibitors, galectin-3 inhibitors, SCD1 inhibitors, ASK1 inhibitors, endothelin receptor A antagonists, FASN inhibitors, calpain inhibitors, autotaxin inhibitors, TREM2 agonists, sGC inhibitors, PKK inhibitors, RORc inhibitors, TLR4 inhibitors, and IL11 inhibitors.

[0158] A compound of the present invention, and / or a pharmaceutical composition comprising a compound of the present invention, which may be included in combination with one or more additional therapeutic agents, may be administered in conjunction with exercise and / or diet. The dosage for the above combination partners is typically between 1 / 5 of the recommended minimum dose and 1 / 1 of the recommended dose. The use of the compounds according to the present invention, in combination with additional therapeutic agents, may be carried out simultaneously or with a time delay.

[0159] The compounds according to the present invention, and one or more additional therapeutic agents, may exist together in a single formulation, for example, a tablet or a capsule, or individually in two identical or different formulations, for example, as a so-called kit of parts. Accordingly, in another aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds according to the present invention and one or more additional therapeutic agents described earlier and later in this specification, which may together comprise one or more inert carriers and / or diluents. In another embodiment, the present invention relates to a method for treating a disease or condition in a patient for which undesirable activity of platelet-activating factor receptors (PAFRs) is mediated or for which antagonism of PAFRs is beneficial, comprising the steps of administering to the patient one or more compounds of formula (I.0), or pharmaceutically acceptable salts thereof, in combination with one or more additional therapeutic agents described earlier and later in this specification. Preferably, the present invention provides a method comprising the step of administering to a patient a therapeutically effective amount of one or more compounds of formula (I.0), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents described earlier and later in this specification. Similarly, the present invention provides compounds of formula (I.0) or pharmaceutically acceptable salts thereof, in combination with one or more additional therapeutic agents described earlier or later in this specification, for use in methods of treating diseases or conditions mediated by undesirable activity of PAFR or in which the antagonistic effect of PAFR is beneficial in patients in need thereof. Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents described earlier or later in this specification, in the manufacture of a pharmaceutical for use in a method of treating a disease or condition in which the undesirable activity of PAFR or the antagonistic effect of PAFR is beneficial in a patient who requires it. Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents described earlier or later in this specification, in a method of treating a disease or condition in which the undesirable activity of PAFR or the antagonistic effect of PAFR is beneficial in a patient who requires it.

[0160] According to one embodiment, the treatment method involves administering to a patient one or more compounds of formula (I.0), or pharmaceutically acceptable salts thereof, in combination with one or more additional therapeutic agents described earlier and later in this specification. Preferably, the procedure includes administering to the patient a therapeutically effective amount of one or more compounds of formula (I.0), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents described earlier and later in this specification.

[0161] According to another embodiment, the treatment method includes administering to a patient a pharmaceutical composition comprising one or more compounds according to the present invention, and one or more additional therapeutic agents described earlier and later in this specification, which may together comprise one or more inert carriers and / or diluents. According to one embodiment, one or more additional therapeutic agents are selected from antidiabetic agents, agents for the treatment of overweight and / or obesity, agents for the treatment of hypertension, heart failure and / or atherosclerosis, and agents for the treatment of eye diseases, particularly from such agents specifically mentioned above.

[0162] According to one embodiment, diseases or conditions mediated by undesirable activity of PAFR, or for which the antagonistic effect of PAFR is beneficial, are selected from ocular indications such as diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), atrophic and exudative age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vasculopathy (PCV), and choroidal neovascularization (CNV), from allergy and inflammation-related conditions and diseases such as urticaria or NASH, and from diabetic complications associated with diabetic retinopathy such as diabetic macular edema, diabetic macular ischemia, and proliferative diabetic retinopathy.

[0163] According to one embodiment, the patient is a human patient. Other features and advantages of the present invention will become apparent, for example, from the following more detailed embodiments illustrating the principles of the present invention.

[0164] Examples and experimental data The following embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0165] abbreviation Acetyl ACN Acetonitrile BPR back pressure regulator BSA (Bovine Serum Albumin) CBZ Benzyloxycarbonyl d Number of days DABCO 1,4-Diazabicyclo[2.2.2]octane DAD Diode Array Detector DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-Ene DCE 1,2-Dichloroethane DCM Dichloromethane DMEM Dulbecco's Modified Eagle Medium DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) EDTA (Ethylenediaminetetraacetate) HCl ethyl acetate EtOH Ethanol h time HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyllonium-hexafluorophosphate HPLC (High-Performance Liquid Chromatography) HPLC-MS coupled high-performance liquid chromatography-mass spectrometry IPA Isopropanol LC (Reset Chromatography) LC-MS coupled liquid chromatography-mass spectrometry M molar concentration (mol / L) MeTHF 2-methyltetrahydrofuran MeOH methanol min minutes MS mass spectrometry NADPH Nicotinamide adenine dinucleotide phosphate NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance PET (Polyethylene Terephthalate) pet. petroleum PyBop (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate R f Retention coefficient rt / RT room temperature t R Retention time (HPLC / LC) Sc supercritical SFC Supercritical Fluid Chromatography TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylronium tetrafluoroborate TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) UV ultraviolet light

[0166] The terms "ambient temperature" and "room temperature" are used interchangeably and refer to temperatures of approximately 20°C, for example, between 15 and 25°C. in general, 1 1H-NMR and / or mass spectra are obtained for the prepared compound. Unless otherwise specified, compounds containing a chiral center have the stereochemistry shown in the diagram. The stereochemistry is assigned by using chiral starting materials with known stereochemistry, by stereoselective synthesis of known stereochemistry, or by biological activity.

[0167] Analysis method: [Table 15]

[0168] [Table 16]

[0169] [Table 17]

[0170] [Table 18]

[0171] [Table 19]

[0172] [Table 20]

[0173] [Table 21]

[0174] [Table 22]

[0175] [Table 23]

[0176] Synthesis of intermediates: Intermediate 1 Methyl 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11-(15)-pentaene-13-carboxylate

[0177] [ka] Step 1: Methyl 2-amino-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate A mixture consisting of 3-(2-chlorophenyl)-3-oxopropanenitrile (126 g), methyl 3-oxocyclopentane-1-carboxylate (100 g), sulfur (22.5 g), morpholine (61.8 mL), and MeOH (800 mL) is stirred under reflux for 4 hours. After cooling to room temperature, the reaction mixture is concentrated. The crude product is purified by silica gel column chromatography (petroleum ether / DCM50:50), and then recrystallized from MeOH to obtain the title compound.

[0178] Step 2: Methyl 3-(2-chlorobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate To a stirred mixture consisting of methyl 2-amino-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (100 g), NaHCO3 (30.0 g), toluene (1200 mL), and water (100 mL), bromoacetyl bromide (41.9 g) is added at 0°C. The cooling bath is removed, and the mixture is stirred at 60°C for 4 hours. After cooling to room temperature, water is added, and the resulting mixture is extracted with ELISA (2×). The combined extract is dried (Na2SO4) and concentrated. The residue is subjected to chromatography (petroleum ether / ELISA 70:30) on silica gel to obtain the title compound.

[0179] Step 3: Methyl 2-(2-aminoacetamide)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate Add methyl 3-(2-chlorobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (10.0 g) and ammonia (0.5 mol / L in THF; 70.0 mL) to a flask containing a stirring bar at room temperature. Seal the flask and stir the mixture overnight. Concentrate the mixture to remove excess ammonia and most of the THF, and add RINKAN. Wash the resulting mixture with water, dry it (Na2SO4), and concentrate it to obtain the crude title compound, which is used in the next reaction step without further purification.

[0180] Step 4: Methyl-13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate To a solution of methyl 2-(2-aminoacetamide)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (8.00 g) in toluene (80.0 mL), silica gel (3.05 g) is added. To the resulting mixture, a 4 Å molecular sieve (1.00 g) is added. The reaction mixture is stirred at 110 °C for 24 hours. After cooling to room temperature, the mixture is filtered and concentrated, and the residue is subjected to chromatography (petroleum ether / siRNA 70:30) on silica gel to obtain the title compound.

[0181] Step 5: Methyl 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate Methyl-13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 To a solution of trideca-1(8),2(6),12-triene-4-carboxylate (5.05 g) in THF (50.0 mL), add ClPO(OEt)2 (3.01 mL) and DBU (3.02 mL) at room temperature. Stir the mixture for 10 minutes, then add hydrazide acetate (1.56 g). Stir the mixture for a further 30 minutes at room temperature, then stir at 60°C for 4 hours. After cooling to room temperature, add ethyl acetate, and wash the resulting mixture with water, aqueous NaHCO3 solution, and brine. Dry the organic phase (MgSO4) and concentrate. Chromatography (DCM / MeOH 99:1->95:5) of the residue on silica gel yields the title compound.

[0182] Intermediate 2 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid

[0183] [ka] Methyl 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 To a solution of hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate (20.0 g) in THF (150 mL), add NaOH (4 mol / L in water; 35.0 mL) at room temperature. Stir this mixture at room temperature for 16 hours. Dilute this mixture with water and add HCl (4 mol / L in water) to adjust the pH of the mixture to approximately 4.5. Then extract this mixture by DCM (5 ×). Wash the combined organic extract with brine, dry (Na₂SO₄), and concentrate to obtain the crude title compound, which is used directly in the next reaction step.

[0184] Intermediate 3 and reference intermediate 4 (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (intermediate 3) and (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (reference intermediate 4)

[0185] [ka] 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (racemic mixture, 10.0 g) was dissolved (50 mg / mL in EtOH / DCM2:1), and then separated by SFC on a chiral phase [column: Lux C4 (30 mm × 250 mm, 5 μm); column temperature: 40 °C; flow rate: 50 mL / min; BPR: 100 bar; injection volume: 500 μL (25 mg); isocratic conditions: 50:50 CO2:EtOH (0.2% v / v formic acid)] to obtain the title compound.

[0186] Intermediate 3:LC (Method 3):t R = 4.87 mins; mass spectrum (ESI + ):m / z=399 / 401(Cl)[M+H] + ; Reference intermediate 4:LC (Method 3):t R = 4.26 mins; mass spectrum (ESI + ):m / z=399 / 401(Cl)[M+H] + .

[0187] Intermediate 5 (13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0188] [ka] (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15HATU (10.0 mg) is added to a mixture of hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (10.0 mg), N,N-diisopropyl-ethylamine (0.010 mL), and DMF (1.00 mL) at room temperature. After stirring for 5 minutes, morpholine (5.00 mg) is added, and the resulting mixture is stirred for 1 hour. The reaction mixture is diluted with DMF and purified by reverse-phase chromatography (HPLC; ACN / water / ammonia water) to obtain the title compound.

[0189] Intermediate 6 9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexa-Deca-1(10),3,5,8,11(15)-Pentaen

[0190] [ka] The title compound was prepared by following the same procedure as described for intermediate 5: 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetra-cyclo[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine.

[0191] Reference Intermediate 7 (13R)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0192] [ka] The title compound was prepared by following the same procedure as described for intermediate 5: (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetra-cyclo[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine.

[0193] Intermediate 8 (9R,13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylic acid

[0194] [ka] To a stirred solution of N-Cbz-L-proline (48.1 g) in DCM (80 ml), tetrabutylammonium borohydride (16.6 g) is added in small portions at 0°C. After hydrogen generation ceases, the mixture is stirred for a further 1 hour at room temperature. The resulting solution is cooled to -10°C and (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Add hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (8.6 g) dropwise to a solution of DCM (120 mL), and stir the reaction mixture at -10°C for 1 hour and then at room temperature for another 1 hour. Add aqueous HCl (1 M) to adjust the pH of the mixture to 1, and extract the mixture with aqueous HCl (1 M, 3 ×). Carefully adjust the pH of the combined aqueous layer with aqueous NaOH (4 M) until the pH reaches 4.5 and a white precipitate appears. Extract the mixture with DCM (3 ×). Dry the combined organic extract (MgSO4) and concentrate. Purify the crude product by reverse-phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound. LC (Method 2):R =0.67 min; Mass spectrum (ESI+): m / z=401 [M+H] + .

[0195] Reference Intermediate 9 (9R,13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylic acid

[0196] [ka] The title compound was prepared by following the same procedure as described for intermediate 8: (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid. LC (Method 2): t R =0.70 min; Mass spectrum (ESI+): m / z=401 [M+H] + .

[0197] Intermediate 10 (9S,13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylic acid

[0198] [ka] (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (1.00 g) is dissolved in DCM (35 mL), and then aqueous HCl (4 M, 1.25 mL) and sodium borohydride (379 mg) are added. The reaction mixture is stirred at room temperature for 1.25 hours. Aqueous HCl (4 M) is added, and the mixture is stirred until gas release stops, then MeOH and THF are added. The resulting precipitate is filtered, and the filtrate is concentrated. The residue is dissolved in MeTHF and stirred at room temperature for 1 hour. The resulting precipitate is filtered and washed with further MeTHF. The crude product consisting of the diastereomer mixture of intermediate 8 and the title compound are purified by reverse-phase chromatography (HPLC; ACN / water / TFA) to obtain the isolated title compound. LC (Method 2):t R =0.71 min; Mass spectrum (ESI+): m / z=401 [M+H] + .

[0199] Intermediate 11 9-(4-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene

[0200] [ka]

[0201] Step 1: Methyl 2-amino-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from 3-(4-chlorophenyl)-3-oxopropanenitrile and methyl 3-oxocyclopentane-1-carboxylate by following a procedure similar to that described in step 1 of intermediate 1. LC (Method 2):t R = 1.04 min; mass spectrum (ESI+ ):m / z=336[M+H] + . Step 2: Methyl 3-(4-chlorobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-amino-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate and bromoacetyl bromide by following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2):t R = 1.14 min; mass spectrum (ESI + ):m / z=456 / 458(Br)[M+H] + . Step 3: Methyl 2-(2-aminoacetamide)-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(4-chlorobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 3 of intermediate 1. LC (Method 2):t R = 0.82 mins; mass spectrum (ESI + ):m / z=393[M+H] + . Step 4: Methyl-13-(4-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate The title compound is prepared from methyl 2-(2-aminoacetamide)-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 4 of intermediate 1. LC (Method 2):t R = 0.75 min; Mass spectrum (ESI + ):m / z=375[M+H] + . Step 5: Methyl 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound is prepared by following the same procedure as described in step 5 of intermediate 1: methyl-13-(4-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Prepared from ]-trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R = 0.88 min; mass spectrum (ESI + ):m / z=413[M+H] + . Step 6: 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid The title compound was prepared by following the same procedure as described for intermediate 2, using methyl9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): t R = 0.75 min; Mass spectrum (ESI + ):m / z=399[M+H] + . Step 7: 9-(4-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen The title compound was prepared by following the same procedure as described for intermediate 5: 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2):t R = 0.78 min (diastereomer); mass spectrum (ESI + ):m / z=468[M+H] + .

[0202] Intermediate 12 9-(2-ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene

[0203] [ka]

[0204] Step 1: Methyl 2-amino-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from 3-(2-ethylphenyl)-3-oxopropanenitrile and methyl 3-oxocyclopentane-1-carboxylate by following a procedure similar to that described in step 1 of intermediate 1. LC (Method 2):t R = 1.05 min; mass spectrum (ESI + ):m / z=330[M+H] + . Step 2: Methyl 3-(2-ethylbenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-amino-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate and bromoacetyl bromide by following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2):t R = 1.17 min; mass spectrum (ESI + ):m / z=450 / 452(Br)[M+H] + . Step 3: Methyl 2-(2-aminoacetamide)-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-ethylbenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 3 of intermediate 1. LC (Method 2):t R = 0.82 mins; mass spectrum (ESI + ):m / z=387[M+H] + . Step 4: Methyl-13-(2-ethylphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate The title compound is prepared from methyl 2-(2-aminoacetamide)-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 4 of intermediate 1. LC (Method 2):t R = 0.75 min; Mass spectrum (ESI + ):m / z=369[M+H] + . Step 5: Methyl 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound is prepared by following the same procedure as described in step 5 of intermediate 1: methyl-13-(2-ethylphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Prepared from ]-trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R = 0.84 min; mass spectrum (ESI + ):m / z=407[M+H] + . Step 6: 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid The title compound was prepared by following the same procedure as described for intermediate 2, using methyl9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): t R = 0.74 min; Mass spectrum (ESI + ):m / z=393[M+H] + . Step 7: 9-(2-ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen The title compound was prepared by following the same procedure as described for intermediate 5: 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from ]-Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2): t R= 0.75 min; Mass spectrum (ESI + ):m / z=462[M+H] + .

[0205] Intermediate 13 9-(2-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0206] [ka]

[0207] Step 1: Methyl 2-amino-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from 3-(2-methoxyphenyl)-3-oxopropanenitrile and methyl 3-oxocyclopentane-1-carboxylate by following a procedure similar to that described in step 1 of intermediate 1. LC (Method 2):t R = 0.95 min; Mass spectrum (ESI + ):m / z=332[M+H] + . Step 2: Methyl 3-(2-methoxybenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-amino-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate and bromoacetyl bromide by following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2):t R = 1.08 min; mass spectrum (ESI + ):m / z=452 / 454(Br)[M+H] + . Step 3: Methyl 2-(2-aminoacetamide)-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-methoxybenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 3 of intermediate 1. LC (Method 2):t R = 0.92 mins; mass spectrum (ESI + ):m / z=389[M+H] + . Step 4: Methyl-13-(2-methoxyphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate The title compound is prepared from methyl 2-(2-aminoacetamide)-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 4 of intermediate 1. LC (Method 2):t R = 0.70 min; mass spectrum (ESI + ):m / z=371[M+H] + . Step 5: Methyl 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound is prepared by following a procedure similar to that described in step 5 of intermediate 1: methyl-13-(2-methoxyphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Prepared from ]-trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R = 0.73 min; Mass spectrum (ESI +):m / z=409[M+H] + . Step 6: 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid The title compound was prepared by following the same procedure as described for intermediate 2, using methyl9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): t R = 0.64 min; mass spectrum (ESI + ):m / z=395[M+H] + . Step 7: 9-(2-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen The title compound was prepared by following the same procedure as described for intermediate 5: 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2):t R = 0.66 min (diastereomer); mass spectrum (ESI + ):m / z=464[M+H] + .

[0208] Intermediate 14 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.02 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0209] [ka]

[0210] Step 1: Methyl 2-amino-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from 3-(2-fluorophenyl)-3-oxopropanenitrile and methyl 3-oxocyclopentane-1-carboxylate by following a procedure similar to that described in step 1 of intermediate 1. LC (Method 2):t R = 0.98 min; mass spectrum (ESI + ):m / z=320[M+H] + . Step 2: Methyl 3-(2-fluorobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-amino-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate and bromoacetyl bromide by following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2):t R = 1.11 min; mass spectrum (ESI + ):m / z=440 / 442(Br)[M+H] + . Step 3: Methyl 2-(2-aminoacetamide)-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-fluorobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 3 of intermediate 1. LC (Method 2):t R = 0.76 min; mass spectrum (ESI + ):m / z=377[M+H] + . Step 4: Methyl-13-(2-fluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate The title compound is prepared from methyl 2-(2-aminoacetamide)-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 4 of intermediate 1. LC (Method 2):t R = 0.70 min; mass spectrum (ESI + ):m / z=359[M+H] + . Step 5: Methyl 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound is prepared by following the same procedure as described in step 5 of intermediate 1: methyl-13-(2-fluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Prepared from ]-trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R = 0.82 mins; mass spectrum (ESI + ):m / z=397[M+H] + . Step 6: 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid The title compound was prepared by following the same procedure as described for intermediate 2, using methyl9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): t R = 0.71 min; mass spectrum (ESI + ):m / z=383[M+H] + . Step 7: 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen The title compound was prepared by following the same procedure as described for intermediate 5: 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2): R = 0.73 min; Mass spectrum (ESI + ):m / z=452[M+H] + .

[0211] Intermediate 15 3-methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2 , 6 .0 11 , 15]Hexadeca-1(10),3,5,8,11(15)-pentaene

[0212] [ka]

[0213] Step 1: Methyl 2-amino-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from 2-(trifluoromethyl)benzoyl cyanide and methyl 3-oxocyclopentane-1-carboxylate by following a procedure similar to that described in step 1 of intermediate 1. Mass spectrum (ESI + ):m / z=370[M+H] + . Step 2: Methyl 2-(2-bromoacetamide)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-amino-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate and bromoacetyl bromide by following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2): R = 1.14 min; mass spectrum (ESI + ):m / z=490 / 492(Br)[M+H] + . Step 3: Methyl 2-(2-aminoacetamide)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-(2-bromoacetamide)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 3 of intermediate 1. LC (Method 2):t R = 0.80 min; mass spectrum (ESI +):m / z=427[M+H] + . Step 4: Methyl 10-oxo-13-[2-(trifluoromethyl)phenyl]-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate The title compound is prepared from methyl 2-(2-aminoacetamide)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 4 of intermediate 1. LC (Method 2):t R = 0.78 min; mass spectrum (ESI + ):m / z=409[M+H] + . Step 5: Methyl 3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound is prepared by following the same procedure as described in step 5 of intermediate 1, using methyl10-oxo-13-[2-(trifluoromethyl)phenyl]-7-thia-9,12-diazatricyclo-[6.5.0.0 2,6 Prepared from trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2): t R = 0.91 min; mass spectrum (ESI + ):m / z=447[M+H] + . Step 6: 3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid The title compound was prepared by following the same procedure as described for intermediate 2, using methyl3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): t R = 0.80 min; mass spectrum (ESI + ):m / z=433[M+H] + . Step 7: 3-methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene The title compound was prepared by following the same procedure as described for intermediate 5, and 3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2): R = 0.82 mins; mass spectrum (ESI + ):m / z=502[M+H] + .

[0214] Intermediate 16 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11, , 15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0215] [ka]

[0216] Step 1: Methyl 2-amino-3-(2-bromobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from 3-(2-bromophenyl)-3-oxopropanenitrile and methyl 3-oxocyclopentane-1-carboxylate by following a procedure similar to that described in step 1 of intermediate 1. LC (Method 2):t R = 0.99 min; Mass spectrum (ESI + ):m / z=380 / 382(Br)[M+H] + . Step 2: Methyl 3-(2-bromobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-amino-3-(2-bromobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate and bromoacetyl bromide by following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2):t R = 1.14 min; mass spectrum (ESI + ):m / z=500 / 502 / 504(2Br)[M+H] + . Step 3: Methyl 2-(2-aminoacetamide)-3-(2-bromobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-bromobenzoyl)-2-(2-bromoacetamide)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 3 of intermediate 1. LC (Method 2):t R = 0.79 min; Mass spectrum (ESI + ):m / z=437 / 439(Br)[M+H] + . Step 4: Methyl-13-(2-bromophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate The title compound is prepared from methyl 2-(2-aminoacetamide)-3-(2-bromobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 4 of intermediate 1. LC (Method 2):t R = 0.74 min; Mass spectrum (ESI + ):m / z=419 / 421(Br)[M+H] + . Step 5: Methyl 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound is prepared by following the same procedure as described in step 5 of intermediate 1: methyl-13-(2-bromophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Prepared from ]-trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R = 0.88 min; mass spectrum (ESI + ):m / z=457 / 459(Br)[M+H] + . Step 6: 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid The title compound was prepared by following the same procedure as described for intermediate 2, using methyl9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): t R = 0.78 min; mass spectrum (ESI + ):m / z=443 / 445(Br)[M+H] + . Step 7: 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen The title compound was prepared by following the same procedure as described for intermediate 5: 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2):t R = 0.79 min; Mass spectrum (ESI + ):m / z=512 / 514(Br)[M+H] + .

[0217] Intermediate 17 9-(3,5-difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene

[0218] [ka]

[0219] Step 1: Methyl 2-amino-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared by following a procedure similar to that described in step 1 of intermediate 1, using 3-(3,5-difluorophenyl)-3-oxopropanenitrile and methyl 3-oxocyclopentane-1-carboxylate. Prepare from this. LC (Method 2):t R = 1.04 min; mass spectrum (ESI + ):m / z=338[M+H] + . Step 2: Methyl 2-(2-bromoacetamide)-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-amino-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate and bromoacetyl bromide by following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2):t R = 1.14 min; mass spectrum (ESI + ):m / z=460[M+H] + . Step 3: Methyl-13-(3,5-difluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 Trideca-1(8),2(6),12-triene-4-carboxylate The title compound is prepared directly from methyl 2-(2-bromoacetamide)-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate by following a procedure similar to that described in step 3 of intermediate 1. LC (Method 2):t R = 0.77 min; Mass spectrum (ESI + ):m / z=377[M+H] + . Step 4: Methyl 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound is prepared by following the same procedure as described in step 5 of intermediate 1: methyl-13-(3,5-difluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo-[6.5.0.0 2,6 Prepared from trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2): t R = 0.91 min; mass spectrum (ESI + ):m / z=415[M+H] + . Step 5: 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid The title compound was prepared by following the same procedure as described for intermediate 2: methyl9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): t R = 0.79 min; Mass spectrum (ESI + ):m / z=401[M+H] + . Step 6: 9-(3,5-difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene The title compound was prepared by following the same procedure as described for intermediate 5: 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2): R = 0.81 min; mass spectrum (ESI + ):m / z=470[M+H] + .

[0220] Intermediate 18 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene

[0221] [ka]

[0222] Step 1: 3,5-dimethyl-2-amino-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate The title compound is prepared from methyl cyanoacetate and methyl 3-oxocyclopentane-1-carboxylate by following the same procedure as described in step 1 of intermediate 1. LC (Method 2):t R = 1.93 mins; mass spectrum (ESI + ):m / z=256[M+H] + . Step 2: 3,5-dimethyl-2-(2-methoxyacetamide)-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-dimethyl2-amino-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (26.8 g) and pyridine (12.7 mL) are dissolved in DCM (200 mL). Methoxyacetyl chloride (9.56 mL) is added, and the reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched by the addition of water, and then the organic phase is separated and dried (Na2SO4), and concentrated to dryness to obtain the title compound. LC (Method 2):t R =1.01 min; Mass spectrum (ESI+): m / z=328 [M+H] + . Step 3: 3,5-dimethyl2-(2-methoxyethanethioamide)-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-dimethyl-2-(2-methoxyacetamide)-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (36.0 g) is dissolved in 1,4-dioxane (150 mL), and Lawson's reagent (48.9 g) is added. The reaction mixture is stirred at 80°C for 6 hours. The reaction mixture is filtered, and the filtrate is concentrated to dryness. The residue is powdered with methanol to obtain the title compound. LC (Method 2): R =1.16 min; Mass spectrum (ESI+): m / z=344 [M+H] + . Step 4: 3,5-dimethyl2-[3-(methoxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-Dimethyl-2-(2-methoxyethanethioamide)-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (3.00 g) is dissolved in THF (45 mL), and hydrazine hydrate (0.849 mL) is added. The reaction mixture is stirred at room temperature for 0.75 hours. N,N-dimethylacetamidodimethylacetal (5.1 mL) is added, and the reaction mixture is stirred at room temperature for a further 1.5 hours. Acetic acid (15.3 mL) is added, and the reaction mixture is stirred at 100 °C for 3.5 days. The reaction mixture is diluted with water and ethyl acetate, made basic with NaHCO3, and extracted with ethyl acetate (3×). The combined organic extracts are dried (MgSO4) and concentrated to dryness. The residue is subjected to chromatography (petroleum ether / ethyl acetate / methanol 80:16:4 → 20:64:16) on silica gel to obtain the title compound. LC (Method 1):t R =0.82 mins; Mass spectrum (ESI+): m / z = 366 [M+H] + . Step 5: 3,5-dimethyl2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-dimethyl-2-[3-(methoxymethyl)-5-methyl-4H-1,2,4-triazole-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (2.79 g) is dissolved in DCM (40 mL), and then 15.3 mL of boron tribromide (1 M in DCM) is added. The reaction mixture is stirred at room temperature for 1.75 hours. The reaction mixture is diluted with DCM and saturated aqueous solution NaHCO3, stirred for 15 minutes, and then extracted with DCM (2×). The combined organic extract is dried (MgSO4) and concentrated to obtain the title compound. LC (Method 2):t R =0.75 min; Mass spectrum (ESI+): m / z=352 [M+H] + . Step 6: 3,5-dimethyl2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-dimethyl-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazole-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (2.47 g) is dissolved in DCM (30 mL), and then Et3N (2.2 mL) and methanesulfonyl bromide (1.3 mL) are added. The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with saturated aqueous solution NaHCO3 and extracted with DCM (2 ×). The combined organic extract is dried (MgSO4) and concentrated to obtain the title compound, which is immediately used in the next step. LC (Method 2):t R =0.88 min; Mass spectrum (ESI+): m / z = 414 / 416 (Br) [M+H] + . Step 7: Methyl 3-methyl-9-oxo-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.02,6 .0 11,15 Hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylate Dissolve 3,5-dimethyl 2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (3.20 g) in a methanol solution of ammonia (7 M, 30 mL). Stir this reaction mixture at room temperature for 3.75 h, and then concentrate the mixture to dryness. Dissolve the resulting crude intermediate in methanol (40 mL) and add Et3N (1.0 mL). Stir this reaction mixture at 80 °C for 7 h, and then concentrate the mixture to dryness. Subject the residue to chromatography on silica gel (petroleum ether / EtOAc / methanol 95:4:1 → 0:80:20) to obtain the title compound. LC (method 2): t R = 0.71 min; mass spectrum (ESI+): m / z = 319 [M+H] + . Step 8: Methyl 3-methyl-9-sulfanilidene-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylate Methyl 3-methyl-9-oxo-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Dissolve methyl 3-methyl-9-oxo-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylate (1.00 g) and Lawesson's reagent (3.00 g) in 1,4-dioxane (20 mL). Stir this reaction mixture at 65 °C for 16 h. Add an additional portion of Lawesson's reagent (1.00 g) and continue stirring at 65 °C for 10 h. Dilute this reaction mixture with aqueous NaHCO3 and extract with DCM (2×). Wash the combined organic extracts with brine, dry (MgSO4), and concentrate to obtain the title compound, which is used immediately in the next reaction. LC (method 2): t R = 0.79 min; mass spectrum (ESI+): m / z = 335 [M+H] +. Step 9: 3-methyl-9-sulfanylidene-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylic acid Methyl 3-methyl-9-sulfanylidene-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 1.70 g of hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylate is suspended in methanol (20 mL), and aqueous NaOH (4 M, 5.00 mL) is added. The reaction mixture is stirred at room temperature for 1 hour, after which the mixture is concentrated and allowed to almost dry. The reaction mixture is acidified with TFA, and the resulting precipitate is collected by filtration to obtain the title compound. LC (Method 2):t R =0.68 min; Mass spectrum (ESI+): m / z=321 [M+H] + . Step 10: 3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,11(15)-tetraen-9-thione 3-methyl-9-sulfanylidene-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Dissolve hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylic acid (1.65 g) and 1,1'-carbonyldiimidazole (0.92 g) in DMF (30 mL). Stir this solution at 50°C for 1 hour. Add morpholine (0.68 mL) and stir this solution at room temperature for 1 hour. Dilute the reaction mixture with water / brine (1:1) and extract with dimethylethanol (3×). Wash the combined organic extract with brine, dry (MgSO4), and concentrate to dryness. Purify the residue by reverse-phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound. LC (Method 2):R =0.71 min; Mass spectrum (ESI+): m / z = 390 [M+H] + . Step 11: 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene 3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 0.60 g of hexadeca-1(10),3,5,11(15)-tetraen-9-thion and 0.175 g of potassium tert-butoxide are dissolved in acetone (10 mL), and then methyl iodide (0.77 mL) is added. This solution is stirred at room temperature for 1 hour. The reaction mixture is diluted with water and extracted by DCM (2×). The combined organic extracts are washed with brine, dried (MgSO4), and concentrated to dryness to obtain the title compound. LC (Method 2):t R =0.70 min; Mass spectrum (ESI+): m / z=404 [M+H] + .

[0223] Intermediate 19 9-(2-cyclopropylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0224] [ka] 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15Hexadeca-1(10),3,5,8,11(15)-pentaene (100 mg) and copper(I) methylsalicylate (160 mg) are suspended in NMP (2.00 mL) under an argon atmosphere. (2-cyclopropylphenyl)boronic acid (100 mg) and tetrakis(triphenylphosphine)palladium (0) (30 mg) are added, and the reaction mixture is stirred at 50°C for 1 hour. If the conversion is incomplete, an additional amount of (2-cyclopropylphenyl)boronic acid (50 mg) and tetrakis(triphenylphosphine)palladium (0) (30 mg) is added, and stirring is continued at 50°C for 2 hours. Once complete, the reaction mixture is diluted with aqueous NaHCO3 (1 M) and extracted with ethyl(3 ×). The combined organic extract is dried (MgSO4) and concentrated. The title compound is obtained by purifying the crude product by reverse-phase chromatography (HPLC; ACN / water / NH3). LC (Method 2): R =0.75 min; Mass spectrum (ESI+): m / z = 474 [M+H] + .

[0225] Intermediate 20 {2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaen-9-yl]phenyl methanol

[0226] [ka] The title compound was prepared by following a procedure similar to that described for intermediate 19: 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene and 2-(hydroxymethyl)phenylboronic acid. LC (Method 2):t R=0.66 min; Mass spectrum (ESI+): m / z=464 [M+H] + .

[0227] Intermediate 21 2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaen-9-yl]phenol

[0228] [ka] The title compound was prepared by following a procedure similar to that described for intermediate 19: 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene and (2-hydroxyphenyl)boronic acid. LC (Method 2):t R =0.73 min; Mass spectrum (ESI+): m / z = 450 [M+H] + .

[0229] Intermediate 22 9-(2-chloro-5-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene

[0230] [ka] The title compound was prepared by following a procedure similar to that described for intermediate 19: 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.02,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene and (2-chloro-5-methoxyphenyl)boronic acid. LC (Method 2):t R =0.84 min; Mass spectrum (ESI+): m / z = 498 [M+H] + .

[0231] Intermediate 23 9-(2-methylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0232] [ka] Stirring bar, 9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Purge a vial containing hexa-deca-1(10),3,5,8,11(15)-pentaene (50 mg), methylboronic acid (13 mg), K3PO4 (71 mg), Pd(OAc)2 (1.2 mg), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.4 mg) with Ar for 5 minutes. Add water (25 μL) and toluene (0.25 mL), seal the vial, and stir the mixture in a microwave oven at 140°C for 30 minutes. Add the additional methylboronic acid (13 mg), Pd(OAc)2 (1.2 mg), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.4 mg) at room temperature, and stir the mixture in a microwave oven at 140°C for 30 minutes. After cooling to room temperature, MeOH is added, the resulting mixture is filtered, and the filtrate is subjected to reverse-phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound. LC (Method 2):tR =0.72 mins; Mass spectrum (ESI+): m / z = 448 [M+H] + .

[0233] Intermediate 24 3-methyl-13-(morpholine-4-carbonyl)-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene

[0234] [ka] The title compound is obtained by applying a two-step procedure comprising hydrolysis of a methyl ester (similar to that described for intermediate 2) and amide coupling of the resulting carboxylic acid with morpholine (similar to that described for intermediate 5), resulting in methyl 3-methyl-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 It can be obtained from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate (for synthesis, see European Patent Application Publication No. 0254245). LC (Method 2): t R =0.69 min; Mass spectrum (ESI+): m / z=434 [M+H] + .

[0235] The intermediates summarized in the table below are (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid or 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetra-azatetracyclo[8.6.0.0 2,6 .0 11,15It is obtained by following a procedure similar to the one described for Intermediate 5, using hexadeca-1(10),3,5,8,11(15)-pentaen-13-carboxylic acid and individual amines.

[0236]

Table 24

[0237] Intermediate 28 9-(2-Chlorophenyl)-3-ethyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 hexadeca-1(10),3,5,8,11(15)-pentaene

[0238]

Chemical formula

[0239] Intermediate 29 9-(2-chlorophenyl)-3-propyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0240] [ka] The title compound is obtained by following a procedure similar to that described in step 5 of intermediate 1: methyl-13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 [8.6.0.0] can be obtained from trideca-1(8),2(6),12-triene-4-carboxylate and butyrate hydrazide, methyl 9-(2-chlorophenyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate is obtained. Subsequently, the ester is saponified by a procedure similar to that described for intermediate 2, and the resulting carboxylic acid is converted to the title compound by a procedure similar to that described for intermediate 5. Alternatively, methyl 9-(2-chlorophenyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate was prepared by following a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or U.S. Patent No. 7015213, using methyl 13-(2-chlorophenyl)-10-sulfanylidene-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 It can be obtained from trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R =0.87 min; Mass spectrum (ESI+): m / z=496 [M+H] + .

[0241] Intermediate 30 9-(2-chlorophenyl)-3-cyclopropyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-Pentaen

[0242] [ka] The title compound is obtained by following a procedure similar to that described in step 5 of intermediate 1: methyl-13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0 2,6[8.6.0.0] can be obtained from trideca-1(8),2(6),12-triene-4-carboxylate and cyclopropanecarbohydrazide, methyl9-(2-chlorophenyl)-3-cyclopropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate is obtained. Subsequently, the ester is saponified by a procedure similar to that described for intermediate 2, and the resulting carboxylic acid is converted to the title compound by a procedure similar to that described for intermediate 5. Alternatively, methyl9-(2-chlorophenyl)-3-cyclopropyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate was prepared by following a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or U.S. Patent No. 7015213, using methyl 13-(2-chlorophenyl)-10-sulfanylidene-7-thia-9,12-diazatricyclo[6.5.0.0 2,6 It can be obtained from trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R =0.83 min; Mass spectrum (ESI+): m / z = 494 [M+H] + .

[0243] Intermediate 31 (3-methyl-9-[2-(methylsulfanyl)phenyl]-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-Pentaen

[0244] [ka] 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Dissolve 135 mg of hexadeca-1(10),3,5,8,11(15)-pentaene, 50 mg of copper(I) iodide, and 59 mg of DABCO in 2.0 mL of anhydrous DMSO. Stir this reaction mixture under argon at 130°C for 16 hours. Dilute the mixture with acetonitrile and purify by reverse-phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound. LC (Method 2): R = 0.74 min; Mass spectrum (ESI + ):m / z=480[M+H] + .

[0245] Synthesis of the example: (Example 1) 9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,11(15)-Tetraene

[0246] [ka] 9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15To a solution of hexadeca-1(10),3,5,8,11(15)-pentaene (200 mg) in DCE (1 mL), NaBH4 (32 mg) and HCl (4 M in water; 0.26 mL) were added sequentially at room temperature. After stirring the mixture for 2 hours, a further amount of NaBH4 (16 mg) and HCl (4 mol / L in water; 0.26 mL) were added. The mixture was stirred further at room temperature until the reaction was complete. If the reaction was not complete, additional NaBH4 and HCl were added. An aqueous solution of NaHCO3 was added, and the resulting mixture was extracted by DCM (3 ×). The combined organic extract was dried (Na2SO4) and concentrated. The residue was purified by reverse-phase chromatography (HPLC; ACN / water / ammonia water) to obtain the title compound as a racemic mixture (approximately 60 / 40) of the two diastereomers. LC (Method 2):t R = 0.72 mins; mass spectrum (ESI + ):m / z=470[M+H] + .

[0247] (Examples 2 and 3) (9R,13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-tetraene (Example 2) and (9S,13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-tetraene (Example 3)

[0248] [ka] (13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetra-cyclo[8.6.0.0 2,6 .0 11,15 To a 25 mL solution of hexadeca-1(10),3,5,8,11(15)-pentaene (1.00 g), add HCl (4 M in water, 1.07 mL) and NaBH4 (323 mg) sequentially at room temperature. Stir the mixture for 1 hour until complete. Dilute the mixture with water and aqueous HCl (1 M) until a pH of 8–9 is achieved, and extract by DCM (2×). Dry the combined organic extract (Na2SO4) and concentrate. Repeated purification of the residue by reverse-phase chromatography (HPLC; ACN / water / aqueous TFA) yields the TFA salts of the diastereomers, which are completely separated. These diastereomers can be liberated from their salt forms by adding aqueous NaHCO3, extracting the resulting mixture by DCM, and concentrating the organic extract to obtain the title compound. Example 2: LC (Method 2): t R = 0.72 mins; mass spectrum (ESI + ):m / z=470[M+H] + ; Example 3: LC (Method 2): t R = 0.73 min; Mass spectrum (ESI + ):m / z=470[M+H] + .

[0249] (Example 4) (9R,13S)-9-(2-chlorophenyl)-3-methyl-13-[(2S)-2-methylmorpholine-4-carbonyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0250] [ka] The title compound was prepared by following the same procedure as described for intermediate 5: (9R,13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,11(15)-tetraen-13-carboxylic acid and (2S)-2-methyl-morpholine hydrochloride. LC (method 4):t R = 0.50 min; mass spectrum (ESI + ):m / z=484[M+H] + .

[0251] The examples summarized in the table below (Ex.) are 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 This is obtained by using each stereoisomer or stereoisomer mixture of hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylic acid and individual amines, and following a procedure similar to that described for intermediate 5. Examples 11 and 12 [Column: Chiral Art® Amylose-SA (10mm x 250mm, 5μm); Column temperature: 40℃; Flow rate: 10mL / min; BPR: 150 bar; Injection volume: 250μL (2.5mg); Isocratic conditions: 70:30CO2:MeOH (20mM NH3)], and Examples 13 and 14 [Column: Chiralpak® IA (10mm x 250mm, 5μm); Column temperature: 40℃; Flow rate: 10mL / min; BPR: 150 bar; Injection volume: 200μL (2mg); Isocratic conditions: 65:35CO2:EtOH (20mM NH3)].

[0252] [Table 25] JPEG2026090284000113.jpg227169 JPEG2026090284000114.jpg220169 JPEG2026090284000115.jpg226169 JPEG2026090284000116.jpg230169 JPEG2026090284000117.jpg227169 JPEG2026090284000118.jpg224169 JPEG2026090284000119.jpg226169 JPEG2026090284000120.jpg231169 JPEG2026090284000121.jpg233169 JPEG2026090284000122.jpg229169 JPEG2026090284000123.jpg234169 JPEG2026090284000124.jpg167169 JPEG2026090284000125.jpg166169 JPEG2026090284000126.jpg229169 JPEG2026090284000127.jpg166169 JPEG2026090284000128.jpg229169

[0253] (Example 52) 9-(4-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .011 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0254] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(4-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.72 mins; Mass spectrum (ESI+): m / z = 470 [M+H] + .

[0255] (Example 53) 9-(2-ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0256] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(2-ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.72 / 0.74 mins (diastereomer); mass spectrum (ESI+): m / z=464 [M+H]+ .

[0257] (Example 54) 9-(2-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-Tetraene

[0258] [ka] The title compound was prepared by following a procedure similar to that described in Example 1: 9-(2-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.68 min; Mass spectrum (ESI+): m / z=466 [M+H] + .

[0259] (Example 55) 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0260] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.78 / 0.79 mins (diastereomer); mass spectrum (ESI+): m / z=454 [M+H] + .

[0261] (Example 56) 3-methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-Tetraene

[0262] [ka] The title compound was prepared by following the same procedure as described in Example 1: 3-methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.76 min; Mass spectrum (ESI+): m / z = 504 [M+H] + .

[0263] (Example 57) 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 ,15 Hexadeca-1(10),3,5,11(15)-tetraene

[0264] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2):t R =0.71 / 0.72 mins (diastereomer); mass spectrum (ESI+): m / z = 514 / 516 (Br) [M+H] + .

[0265] (Example 58) 9-(3,5-difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-Tetraene

[0266] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(3,5-difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.72 mins; Mass spectrum (ESI+): m / z = 472 [M+H] + .

[0267] (Example 59) 9-(2-cyclopropylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-Tetraene

[0268] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(2-cyclopropylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.73 / 0.75 min (diastereomer); mass spectrum (ESI+): m / z=476 [M+H] + .

[0269] (Example 60) {2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]Hexadeca-1(10),3,5,11(15)-tetraen-9-yl]phenyl}methanol

[0270] [ka] The title compound was prepared by following the same procedure as described in Example 1: {2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15Prepared from hexadeca-1(10),3,5,8,11(15)-pentaen-9-yl]phenylmethanol. LC (Method 2): t R =0.64 / 0.65 min (diastereomer); mass spectrum (ESI+): m / z=466 [M+H] + .

[0271] (Example 61) 2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]Hexadeca-1(10),3,5,11(15)-tetraen-9-yl]phenol

[0272] [ka] The title compound was prepared by following the same procedure as described in Example 1: 2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaen-9-yl]phenol. LC (Method 1): R =0.74 / 0.75 min (diastereomer); mass spectrum (ESI+): m / z=452 [M+H] + .

[0273] (Example 62) 9-(2-chloro-5-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0274] [ka] The title compound was prepared by following a procedure similar to that described in Example 1: 9-(2-chloro-5-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): t R =0.73 min; Mass spectrum (ESI+): m / z=500 [M+H] + .

[0275] (Examples 63 and 64) (9R,13S)-3-methyl-9-(2-methylphenyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-tetraene (Example 63) and (9S,13S)-3-methyl-9-(2-methylphenyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]-Hexadeca-1(10),3,5,11(15)-tetraene (Example 64)

[0276] [ka] The title compound was prepared by following the same procedure as described in Example 1: (13S)-3-methyl-9-(2-methylphenyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. The title compound is obtained by purifying the diastereomer by reverse-phase chromatography (HPLC; ACN / water / TFA). Example 63: LC (Method 2): t R =0.71 min; Mass spectrum (ESI+): m / z=450 [M+H] + ; Example 64: LC (Method 2): t R =0.69 min; Mass spectrum (ESI+): m / z=450 [M+H] + .

[0277] (Example 65) (13S)-9-(2-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraen-13-carboxamide

[0278] [ka] The title compound was prepared by following the same procedure as described in Example 1: (13S)-9-(2-chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 It is prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxamide. LC (Method 2):t R =0.72 mins; Mass spectrum (ESI+): m / z = 472 [M+H] + .

[0279] (Example 66) 13-{5-azaspiro[2.5]octane-5-carbonyl}-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0280] [ka] The title compound was prepared by following a procedure similar to that described in Example 1: 13-{5-azaspiro[2.5]octane-5-carbonyl}-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Prepared from hexadeca-1(10),3,5,11(15)-pentaene. LC (Method 1): t R =0.99 min; Mass spectrum (ESI+): m / z=494 [M+H] + .

[0281] The examples summarized in the table below were obtained by following the same procedure as described in Example 1: 9-(2-chlorophenyl)-3-ethyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15It is prepared from hexadeca-1(10),3,5,11(15)-pentaene. Individual stereoisomers are obtained by chiral SFC: first separation to obtain Examples 68 and 69 [column: Chiralpak® IA (20mm x 250mm, 5μm); column temperature: 40℃; flow rate: 60mL / min; BPR: 150bar; injection volume: 250μL (2.5mg); isocratic conditions: 70:30CO2:EtOH (20mM NH3)], then second separation of the mixed fraction to obtain Reference Examples 70 and 71 [column: Chiral Art® Amylose-SA (10mm x 250mm, 5μm); column temperature: 40℃; flow rate: 10mL / min; BPR: 150bar; injection volume: 200μL (4mg); isocratic conditions: 80:20CO2:MeOH (20mM NH3)].

[0282] [Table 26] JPEG2026090284000144.jpg149166 (Examples 72 and 73) (9S,13S)-9-(2-chlorophenyl)-3-methyl-N,N-dipropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 ]Hexadeca-1(10),3,5,11(15)-tetraen-13-carboxamide (Example 72) and (9R,13S)-9-(2-chlorophenyl)-3-methyl-N,N-dipropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraen-13-carboxamide (Example 73)

[0283] [ka] The title compound was prepared by following a procedure similar to that described in Example 1: (13S)-9-(2-chlorophenyl)-3-methyl-N,N-dipropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 Prepared from hexadeca-1(10),3,5,11(15)-tetraen-13-carboxamide. Diastereomers are separated by chiral SFC [Column: Chiral Art® Amylose-SA (10mm x 250mm, 5μm); Column temperature: 40℃; Flow rate: 10mL / min; BPR: 150bar; Injection volume: 100μL (2mg); Isocratic conditions: 75:25CO2:MeOH (20mM NH3)]. Example 72: LC (Method 7): t R =2.10 min; Mass spectrum (ESI+): m / z=484 [M+H] + ; Example 73: LC (Method 7): t R =3.02 mins; Mass spectrum (ESI+): m / z = 484 [M+H] + .

[0284] The examples summarized in the table below were obtained by following the same procedure as described in Example 1: 3-methyl-13-(morpholine-4-carbonyl)-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15It is obtained from hexadeca-1(10),3,5,8,11(15)-pentaene. The trans and cis diastereomers are separated by reverse-phase chromatography (HPLC; ACN / water / TFA). The racemic mixture of diastereomers after separation can be further separated into individual enantiomers by chiral SFC to obtain Examples 75 and 76 [Column: Chiralpak IA (20mm x 250mm, 5μm); Column temperature: 40℃; Flow rate: 10mL / min; BPR: 150bar; Injection volume: 200μL (3mg); Isocratic conditions: 70:30scCO2:MeOH (20mM NH3)], as well as Reference Example 77 and Example 78 [Column: CHIRAL ART® Cellulose-SB (10×250mm, 5μm); Column temperature: 40℃; Flow rate: 10mL / min; BPR: 150bar; Injection volume: 200μL (2mg); Isocratic conditions: 70:30CO2:iPrOH (20mM NH3)].

[0285] [Table 27] JPEG2026090284000147.jpg139168

[0286] (Example 79) 3-Methyl-9-[2-(methylsulfanyl)phenyl]-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0287] [ka] The title compound was prepared by following the same procedure as described in Example 1: (3-methyl-9-[2-(methylsulfanyl)phenyl]-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 It is prepared from hexadeca-1(10),3,5,11(15)-pentaene. LC (Method 2):t R =0.70 / 0.71 mins (diastereomer); mass spectrum (ESI+): m / z = 482 [M+H] + .

[0288] (Example 80) 9-(2-chlorophenyl)-13-(morpholine-4-carbonyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0289] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(2-chlorophenyl)-13-(morpholine-4-carbonyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Prepared from hexadeca-1(10),3,5,11(15)-pentaene. LC (Method 2): t R =0.77 / 0.78 mins (diastereomer); mass spectrum (ESI+): m / z = 498 [M+H] + .

[0290] (Example 81) 9-(2-chlorophenyl)-3-cyclopropyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Hexadeca-1(10),3,5,11(15)-tetraene

[0291] [ka] The title compound was prepared by following the same procedure as described in Example 1: 9-(2-chlorophenyl)-3-cyclopropyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2 , 6 .0 11 , 15 Prepared from hexadeca-1(10),3,5,11(15)-pentaene. LC (Method 2): t R =0.75 min; Mass spectrum (ESI+): m / z=496 [M+H] + .

Claims

1. Compound of formula (I.0) 【Chemistry 1】 (In the formula, R 1 C 1-4 - Alkyl (may be substituted with 1 to 3 F atoms) and C 3-4 - R consisting of cycloalkyl 1 - Selected from Group G1, R 2 is selected from the R 2 -G1 group, and the R 2 -G1 group consists of F, Cl, Br, I, C 1-4 -alkyl (which may be substituted by 1 to 3 Fs, or may be substituted by one -CN, one OH or one -O-C 1-4 -alkyl), C 3-4 -cycloalkyl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -alkyl, OH, -O-C 1-4 -alkyl (which may be substituted by 1 to 3 Fs), and further consists of -S(O) r -C 1-4 -alkyl (r = 0, 1 or 2), n is selected from the n-G1 group consisting of 0, 1, 2, and 3. R 3 H and C 1-4 - R consisting of alkyl (which may be substituted with 1 to 5 F atoms) 3 - Selected from Group G1, R 4 C 1-6 - R consisting of alkyl 4 - Selected from group G1a, C 1-6 - Alkyl is, It may be substituted with 1 to 3 Fs, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl) 2 , -COOH, -COO-C 1-4 - Alkyl, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S (=O) 2 -NH-, OH, and -O-C 1-3 - May be substituted with one or two substituents independently selected from alkyl groups (which may be substituted with one to three F atoms), or R 4 is, -C 0-3 -Alkylene-C 3-10 -Cycloalkyl and -C 0-3 -Alkylene-C 3-10 - R consisting of heterocyclyl 4 - Selected from group G1b, The alkylene is F and CH 3 It may be substituted with one or two substituents selected from the following: One of the alkylenes >CH 2 The two H atoms of the group are ethylene (-CH 2 -CH 2 -) Replaced by crosslinking, cyclopropylene portion > C(-CH 2 -CH 2 -) may be formed, The cycloalkyl and heterocyclyl compounds are saturated monocyclic or bicyclic systems. The aforementioned heterocyclyl is N, NH, >N(C) 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(=O) 2 (C 1-4 It contains one or two ring members independently selected from alkyl and O, and >C=O and >S(=O) r It may contain one ring member selected from (r = 0, 1, or 2), However, the heterocyclyl has N-N, N-O and N-S (=O) between its ring members. r=1,2 It does not contain any heteroatom-heteroatom bonds other than those mentioned above. The cycloalkyl and heterocyclyl may be substituted with one or two F atoms, such as Cl, -CN, and -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl) 2 , -COOH, -COO-C 1-4 -alkyl, OH, -O-C 1-3 - Alkyl (may be substituted with 1 to 3 F atoms), and C 1-4 -Alkyl (by 1 to 3 F atoms, or -CN, OH, -O-C) 1-4 - May be substituted with one or two substituents independently selected from alkyl groups, or R 4 is, -C 0-3 -alkylene-phenyl and -C 0-3 R consisting of -alkylene-heteroaryl 4 - Selected from group G1c, The alkylene is F and CH 3 It may be substituted with one or two substituents selected from the following: One of the alkylenes >CH 2 The two H atoms of the group are ethylene (-CH 2 -CH 2 -) Replaced by crosslinking, cyclopropylene portion > C(-CH 2 -CH 2 -) may be formed, The heteroaryl is a five-membered monoring containing one ring member selected from N, NH, O, and S, and may further contain one or two ring members N, or a six-membered monoring containing one or two ring members N. The phenyl and heteroaryl compounds are F, Cl, Br, and C. 3-4 -Cycloalkyl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, -NHCO-C 1-4 -alkyl, -NHS (=O) 2 -C 1-4 -alkyl, -S (=O) r -C 1-4 -Alkyl (r=0, 1, or 2), -O-C 1-4 - Alkyl (may be substituted with 1 to 3 F atoms), and C 1-4 -Alkyl (by 1 to 3 F atoms, or -CN, OH and -O-C) 1-4 - May be substituted with 1 to 3 substituents independently selected from (which may be substituted with one substituent selected from alkyl), or R 3 and R 4 R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a 3- to 8-membered saturated monocyclic heterocycline, R 3 / 4 - Selected from group G1a, saturated monocyclic heterocyclines with 3 to 8 members are, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 -alkyl) and O may further contain one or two ring members independently selected from >C=O and >S(=O) r It may contain one ring member selected from (r = 0, 1, or 2), However, the heterocyclyl has N-N, N-O and N-S (=O) between its ring members. r=1,2 It does not contain any heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 4 F molecules. 1 to 4 Cs 1-3 - It may be substituted with alkyl (which may be substituted with 1 to 3 F atoms), Cl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-O-C 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O) 2 -NH-, OH and C 1-3 -alkyl-O-(which may be substituted by 1 to 3 F), or may be substituted by 1 to 2 substituents selected from or R 3 and R 4 R 3 and R 4 However, together with the amide N atoms to which they are bonded, they form a saturated bicyclic heterocycline with 5 to 12 members, R 3 / 4 - Selected from group G1b, saturated bicyclic heterocyclines with 5 to 12 members are, >N-, >NH, >N(C 1-4 -Alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 It may further contain one to three ring members independently selected from (alkyl) and O, >C=O and >S(=O) r It may contain one ring member selected from (r = 0, 1, or 2), However, the heterocyclyl has N-N, N-O and N-S (=O) between its ring members. r=1,2 It does not contain any heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 6 F molecules. 1 to 4 Cs 1-3 - It may be substituted with alkyl (which may be substituted with 1 to 3 F atoms), Cl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, HO-C 1-3 -Alkylene-, C 1-3 -Alkyl-O-C 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S (=O) 2 -NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-, or R 3 and R 4 R 3 and R 4 However, together with the amide N atoms to which they are bonded, they form a 7- to 12-membered fused bicyclic ring system, R 3 / 4 - Selected from group G1c, The aforementioned bicyclic ring system is a heterocyclyl or heteroaryl consisting of one non-aromatic ring and one aromatic ring. The non-aromatic ring contains the amide N atom, and is =N-, >N-, >NH, >N(C) 1-4 -Alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 It may further contain one or two ring members independently selected from -alkyl) and O, such that >C=O and >S(=O) r It may contain one ring member selected from (r=0, 1, or 2), provided that N-N, N-O, and N-S (=O) are present between the ring members of the non-aromatic ring. r=1,2 No other heteroatom-heteroatom bonds exist. The aromatic ring is selected from a five-membered monoring containing one ring member selected from NH, N, O, and S, and which may further contain one or two ring members N, and a six-membered monoring containing O, one or two ring members N. The aforementioned bicyclic ring system may be substituted with 1 to 4 F molecules. 1 to 4 Cs 1-3 - It may be substituted with alkyl (which may be substituted with 1 to 3 F atoms), Cl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, HO-C 1-3 -Alkylene-, C 1-3 -Alkyl-O-C 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S (=O) 2 -NH-, OH and C 1-3 (May be substituted with one or two substituents selected from -alkyl-O- (which may be substituted with one to three fluorine atoms)) or its salt.

2. R 1 However, CH 3 ,CH 2 CH 3 ,CH 2 CH 2 CH 3 CHF 2 CF 3 and R consisting of cyclopropyl 1 - A compound or salt thereof according to claim 1, selected from group G2.

3. R 2 However, R 2 - Selected from group G2, R 2 - Group G2 consists of F, Cl, Br, and C 1-3 - Alkyl (may be substituted with two or three F atoms), cyclopropyl, -CN, -C 1-3 -Alkylene-OH, -C 1-2 -Alkylene-O-C 1-2 -alkyl, OH, -O-C 1-3 - Alkyl (which may be substituted with two or three F atoms), and -S-C 1-3 - A compound or salt thereof according to one or more claims 1 to 2, comprising an alkyl group.

4. R 3 However, H and C 1-3 - R consisting of alkyl (which may be substituted with 1 to 3 F atoms) 3 - Selected from group G2, R 4 However, C 1-6 - R consisting of alkyl 4 - Selected from group G2a, C 1-6 - Alkyl is, It may be substituted with 1 to 3 Fs, -CN, -CONH 2 , -CONH(C 1-2 -alkyl), -CON(C 1-2 -Alkyl) 2 , -COOH, -COO-C 1-2 - Alkyl, C 1-2 -Alkyl-CO-NH-, C 1-2 -Alkyl-S (=O) 2 -NH-, OH, and -O-C 1-2 - May be substituted with one substituent selected from alkyl groups (which may be substituted with 1 to 3 F atoms), or R 4 However, -C 0-2 -Alkylene-C 3-8 -Cycloalkyl and -C 0-2 -Alkylene-C 3-8 - R consisting of heterocyclyl 4 - Selected from group G2b, The cycloalkyl and heterocyclyl compounds are saturated monocyclic or bicyclic systems. The heterocycline contains one ring member selected from N, NH, and O. The cycloalkyl and heterocyclyl may be substituted with one or two fluorine atoms, such as Cl, -CN, and OCH. 3 ,CH 3 and CH 2 CH 3 It may be substituted with one or two substituents independently selected from the above, or R 4 However, -C 0-2 -alkylene-phenyl and -C 0-2 R consisting of -alkylene-heteroaryl 4 - Selected from group G2c, The alkylene comprises 1 to 2 CH 3 It may be replaced by, One of the alkylenes >CH 2 The two H atoms of the group are ethylene (-CH 2 -CH 2 -) Replaced by crosslinking, cyclopropylene portion > C(-CH 2 -CH 2 -) may be formed, The heteroaryl is a five-membered monoring containing one ring member selected from N, NH, O, and S, which may further contain one ring member N, or a six-membered monoring containing one or two ring members N. The phenyl and heteroaryl are F, Cl, Br, -CN, -O-C 1-3 - Alkyl (may be substituted with 1 to 3 F atoms), and C 1-3 -Alkyl (by 1 to 3 F atoms, or by -CN and -O-C) 1-2 - May be substituted with 1 to 3 substituents independently selected from (which may be substituted with one substituent selected from alkyl), or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a 3- to 8-membered saturated monocyclic heterocycline, R 3 / 4 - Selected from group G2a, saturated monocyclic heterocyclines with 3 to 8 members are, >NH, >N(C 1-4 -Alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 It may further contain one ring member selected from -alkyl) and O, such that >C=O and >S(=O) r It may contain one ring member selected from (r = 0, 1, or 2), However, the heterocyclyl has N-S (=O) between its ring members. r=1,2 It does not contain any heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with one or two F molecules. 1 to 4 Cs 1-3 - It may be substituted with alkyl (which may be substituted with 2 to 3 F atoms), Cl, -CN, -CON(C 1-4 -Alkyl) 2 , -COO-C 1-4 - Alkyl, C 1-3 -Alkyl-O-C 1-3 -Alkylene- and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, they form a 6- to 11-membered saturated bicyclic heterocycline, R 3 / 4 - Selected from group G2b, saturated bicyclic heterocyclines with 6 to 11 members are, >N-, >NH, >N(C 1-4 -Alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 It may further contain one or two ring members independently selected from (alkyl) and O, >C=O and >S(=O) r It may contain one ring member selected from (r = 0, 1, or 2), However, the heterocyclyl has N-N, N-O and N-S (=O) between its ring members. r=1,2 It does not contain any heteroatom-heteroatom bonds other than those mentioned above. The heterocyclyl may be substituted with 1 to 6 F molecules. 1 to 4 Cs 1-3 - It may be substituted with alkyl (which may be substituted with 1 to 3 F atoms), Cl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, HO-C 1-3 -Alkylene-, C 1-3 -Alkyl-O-C 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S (=O) 2 -NH-, OH and C 1-3 It may be substituted with one or two substituents selected from -alkyl-O-, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atoms to which they are bonded, they form an 8- to 10-membered fused bicyclic ring system, R 3 / 4 - Selected from group G2c, The aforementioned bicyclic ring system is a heterocyclyl or heteroaryl consisting of one non-aromatic ring and one aromatic ring, as well as phenyl and pyridine. The non-aromatic ring contains the amide N atom and may contain one ring member selected from =N-, >N-, and O. The aromatic ring is a five-membered monoring containing one ring member selected from N, NH, O, and S, and may further contain one ring member N, selected from a five-membered monoring. The aforementioned biring ring system may be substituted with one or two F molecules. 1-2 C 1-2 - It may be substituted with alkyl (which may be substituted with 1 to 3 F atoms), Cl and C 1-2 It may be substituted with one or two substituents selected from -alkyl-O- (which may be substituted with one to three F atoms), A compound or salt thereof as described in one or more of claims 1 to 3.

5. R 3 However, H and C 1-3 - R consisting of alkyl (which may be substituted with 1 to 3 F atoms) 3 - Selected from group G2, R 4 However, C 1-4 - R consisting of alkyl 4 - Selected from group G3a, C 1-4 - Alkyl is, It may be substituted with 1 to 3 Fs, -CN, -CONH 2 -COOH, OH and -O-C 1-2 - May be substituted with one substituent selected from alkyl groups (which may be substituted with 1 to 3 F atoms), or R 4 However, -C 0-1 -Alkylene-C 3-6 - R consisting of cycloalkyl 4 - Selected from group G3b, The cycloalkyl group is a saturated monocyclic or bicyclic ring system. The cycloalkyl group may be substituted with one or two F atoms, and one CH group may be substituted with one CH group. 3 or CH 2 CH 3 Is it acceptable for it to be replaced by, or R 4 However, -C 0-1 -alkylene-phenyl and -C 0-1 R consisting of -alkylene-heteroaryl 4 - Selected from group G3c, One of the alkylenes >CH 2 The two H atoms of the group are ethylene (-CH 2 -CH 2 -) Replaced by crosslinking, cyclopropylene portion > C(-CH 2 -CH 2 -) may be formed, The heteroaryl is a 5-6 member monoring containing one ring member =N-, and may contain one ring member selected from =N-, >NH, S, and O. The phenyl and heteroaryl compounds are F, Cl, -CN, OCH 3 , OCHF 2 OCF 3 ,CH 3 CHF 2 and CF 3 It may be substituted with one to three substituents independently selected from, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, they may form a 4- to 6-membered saturated monocyclic heterocycline containing one ring member O that is not adjacent to the amide N atom, R 3 / 4 - Selected from group G4a, The heterocyclyl may be substituted with two F molecules, and one to two CH molecules. 3 Is it acceptable for it to be replaced by, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, they may contain one ring member O that is not adjacent to the amide N atom, forming a 6- to 10-membered saturated bridging bicyclic or spiro-bicyclic heterocycline, R 3 / 4 - Selected from group G4b, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, they form an 8-9 member condensed bicyclic heteroaryl, R 3 / 4 - Selected from group G3c, The heteroaryl comprises one non-aromatic ring containing the amide N atom, which may contain one ring member >N- not adjacent to the amide N atom, and one pyrazolo ring or imidazolo ring. The aforementioned heteroaryl is composed of 1 to 2 CH 3 It may be replaced by A compound or salt thereof as described in one or more of claims 1 to 4.

6. R 3 However, H, CH 3 and CH 2 CH 2 CH 3 R consisting of 3 - Selected from group G3, R 4 but, 【Chemistry 2】 R consisting of 4 - Selected from group G5a, or R 4 but, 【Transformation 3】 R consisting of 4 - Selected from group G4b, or R 4 but, 【Chemistry 4】 R consisting of 4 - Selected from group G4c, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, 【Transformation 5】 R forms a heterocycline selected from the group consisting of 3 / 4 - Selected from group G5a, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, 【Transformation 6】 R forms a heterocycline selected from the group consisting of 3 / 4 - Selected from group G5b, or R 3 and R 4 However, R 3 and R 4 However, together with the amide N atom to which they are bonded, they form the following heteroaryl compounds. 【Transformation 7】 Forming, R 3 / 4 - Selected from group G4c, A compound or salt thereof as described in one or more of claims 1 to 5.

7. The stereochemistry of the compound is given by formula (I.1) 【Transformation 8】 A compound or salt thereof according to one or more of claims 1 to 6.

8. A pharmaceutically acceptable salt of one or more of the compounds described in claims 1 to 7.

9. A pharmaceutical composition comprising one or more compounds described in one or more claims 1 to 7, or a pharmaceutically acceptable salt thereof, which may together comprise one or more inert carriers and / or diluents.

10. A pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof as described in one or more claims 1 to 7, and one or more additional therapeutic agents, which may together comprise one or more inert carriers and / or diluents.

11. The pharmaceutical composition according to claim 10, wherein one or more additional therapeutic agents are selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and / or obesity, agents for the treatment of hypertension, heart failure and / or atherosclerosis, agents for the treatment of eye diseases, and agents for the treatment of conditions and diseases related to allergies and inflammation.

12. A compound according to one or more of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

13. A method for treating eye diseases, preferably diabetic macular edema, atrophic and exudative age-related macular degeneration, geographic atrophy and non-exudative choroidal neovascularization, and allergy and inflammation-related conditions and diseases, preferably urticaria and NASH, comprising the step of administering to a patient one or more compounds described in one or more of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

14. A compound or pharmaceutically acceptable salt thereof, for use in a method for treating eye diseases, preferably diabetic macular edema, atrophic and exudative age-related macular degeneration, geographic atrophy and non-exudative choroidal neovascularization, and conditions and diseases associated with allergies and inflammation, preferably urticaria and NASH, wherein the method comprises the step of administering to a patient one or more compounds or pharmaceutically acceptable salt thereof, according to one or more of claims 1 to 7.

15. Use of one or more compounds or pharmaceutically acceptable salts thereof according to claims 1 to 7 in the preparation of a medicament for treating eye diseases, preferably diabetic macular edema, atrophic and exudative age-related macular degeneration, geographic atrophy and non-exudative choroidal neovascularization, and for treating allergy and inflammation-related conditions and diseases, preferably urticaria and NASH, wherein the method comprises the step of administering to a patient one or more compounds or pharmaceutically acceptable salts thereof according to one or more compounds according to claims 1 to 7.

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