Cyclopentathiophene carboxamide derivatives as platelet-activating factor receptor antagonists

Abstract

To provide novel platelet activating factor receptor antagonists.SOLUTION: Cyclopentathiophene carboxamides of formula (I.0) and pharmaceutically acceptable salts thereof can be used in methods for the treatment of diseases which can be influenced by antagonizing the activity mediated by the platelet activating factor receptor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel cyclopentathiophene carboxamide derivatives and pharmaceutically acceptable salts thereof, which are platelet-activating factor receptor antagonists. Furthermore, the present invention relates to pharmaceutical compositions and combinations containing the compounds, and their use in methods for treating diseases that can 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 ophthalmic diseases, allergy- and inflammation-related conditions and diseases, particularly dry and wet 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 (PAFLLs), and some oxidized phospholipids are structurally defined ligands of the PAF receptor (PAFR), a G protein-coupled receptor. PAFR expression is restricted to specific target cells in the immune, hemostatic, and inflammatory systems. The signaling functions of PAF are largely involved in acute and chronic inflammation in virtually all organs. PAF is believed to play a role in some inflammatory disorders, and may have significant relevance in ophthalmology, cardiovascular disease, cancer, neurological and neurodegenerative disorders, kidney disorders, liver diseases and allergies.Therefore, for example, the inhibition of PAFR activation by PAFR antagonists and / or inverse agonists is believed to be useful for treating a wide range of disorders that can be affected by antagonizing and / or inversely activating PAFR, for example, as mentioned hereinbefore and hereinbelow.In particular, PAFR antagonists and / or inverse agonists should be useful for preventing or treating ophthalmology, such as dry or wet age-related macular degeneration, and geographic atrophy or allergy, and inflammation-related disorders, such as urticaria and non-alcoholic steatohepatitis (NASH). Suitable PAFR antagonists and / or inverse agonists for therapeutic use should bind to PAFR potently and with high selectivity. PAFR antagonists and / or inverse agonists should be well absorbed from the gastrointestinal tract, have sufficient metabolic stability, and have favorable pharmacokinetic properties. They should also be non-toxic and have demonstrated no or few side effects.

[0003] For example, low molecular weight PAFR antagonists are known in the art, and 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).The thienotriazolodiazepine class compounds disclosed therein have been reported to undergo hydrolysis in acidic solution (for example, 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 isolation of the above and related compounds are disclosed in DE 4132763, EP 0388789, EP 0450504, U.S. Pat. No. 7015213, WO 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). Summary of the Invention

[0005] In a first aspect, the present invention provides a compound of formula (I.0) [ka] (In the formula, R 1 is C 1-4 -alkyl (optionally substituted with 1 to 3 F) and C 3-4 -R consisting of cycloalkyl 1 - selected from group G1, R 2 is R 2 - selected from the G1 group, R 2 -G1 group is F, Cl, Br, I, C 1-4 -alkyl (optionally substituted by 1 to 3 F or one -CN, one -OH or one -OC) 1-4 -alkyl), and 3-4 -Cycloalkyl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl)2, -COOH, -COO-C 1-4 -Alkyl, OH, -OC 1-4 -alkyl (optionally substituted with 1 to 3 F), -S(O) r -C 1-4 - alkyl (r=0, 1 or 2), n is selected from the group n-G1 consisting of 0, 1, 2, and 3; R 3 is H, and C optionally substituted by 1 to 5 F 1-4 -R consisting of alkyl 3 - selected from group G1, R 4 is C 1-6 -R consisting of alkyl 4 - selected from the group G1a, 1-6 -Alkyl is optionally substituted with 1 to 3 F; -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 -alkyl (optionally substituted with 1 to 3 F); or R 4 -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 may be substituted with 1 to 2 substituents selected from F and CH3. two H atoms of one >CH2 group of said alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems, The heterocyclyl may be N, NH, >N(C 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(=O)2(C 1-4 -alkyl) and O, and contains 1 to 2 ring members independently selected from >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain any heteroatom-heteroatom bonds other than The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with Cl, —CN, —CONH, —CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl)2, -COOH, -COO-C 1-4 -Alkyl, OH, -OC 1-3 -alkyl (optionally substituted with 1 to 3 F), and C1-4 -Alkyl (with 1 to 3 F, or -CN, OH, -OC 1-4 -alkyl), or R 4 -C 0-3 -alkylene-phenyl and -C 0-3 -alkylene-heteroaryl 4 - selected from the G1c group, The alkylene may be substituted with 1 to 2 substituents selected from F and CH3. two H atoms of one >CH2 group of said alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally containing 1 to 2 additional N ring members, or a 6-membered monocyclic ring containing 1 to 2 N ring members; The phenyl and heteroaryl are selected from the group consisting of F, Cl, Br, 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 (optionally substituted with 1 to 3 F), and C 1-4 -Alkyl (with 1 to 3 F, or -CN, OH and -OC 1-4 -alkyl), or R 3and R 4 is R 3 and R 4 R, taken together with the amide N atom to which they are attached, form a 3- to 8-membered saturated monocyclic heterocyclyl 3 / 4 -3- to 8-membered saturated monocyclic heterocyclyl selected from the G1a group is >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O; >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain any heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 4 F. 1 to 4 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by 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 -Alkylene-, C 1-3 -Alkyl-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O)2-NH-, OH and C 1-3 -alkyl-O- (optionally substituted by 1 to 3 F), or R 3 and R 4 is R 3 and R 4together with the amide N atom to which they are attached form a 5- to 12-membered saturated bicyclic heterocyclyl; R 3 / 4 -G1b Group, wherein the 5- to 12-membered saturated bicyclic heterocyclyl is >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O; >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain any heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 6 F; 1 to 4 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by 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 -Alkylene-, C 1-3 -Alkyl-OC 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 R 3 and R 4 is 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, R 3 / 4 - selected from the G1c group, the 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 -alkyl) and O, and may further contain 1 to 2 ring members independently selected from >C=O and >S(=O) r (r=0, 1 or 2), provided that there are no restrictions between members of said non-aromatic ring: NN, NO and NS(=O). r=1,2 There are no heteroatom-heteroatom bonds other than the aromatic ring is selected from a 5-membered monocyclic ring containing one ring member selected from NH, N, O, and S, which may further contain 1 to 2 N ring members, and a 6-membered monocyclic ring containing 0, 1, or 2 N ring members; the bicyclic ring system is optionally substituted by 1 to 4 F; 1 to 4 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by 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 -Alkylene-, C 1-3 -Alkyl-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O)2-NH-, OH and C 1-3 -alkyl-O- (optionally substituted by 1 to 3 F), Unless otherwise specified in any definitions referred to herein earlier, any alkyl or alkylene group may be straight-chained or branched. Isomers, stereoisomers, tautomers, metabolites, prodrugs, solvates, hydrates, cocrystals, and salts thereof, particularly 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 hereinbefore or hereinafter, or a pharmaceutically acceptable salt thereof, optionally together with 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 hereinbefore or hereinafter, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, together with optionally one or more inert carriers and / or diluents.

[0008] In a fourth aspect, the present invention relates to a compound of formula (I.0) as defined hereinbefore or hereinafter, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0009] In a fifth aspect, the present invention relates to a method for the treatment of a disease or condition that can be affected by antagonizing platelet-activating factor receptors in a patient in need thereof, comprising the step of administering to the patient one or more compounds of formula (I.0) as defined hereinbefore or hereinafter, 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 hereinbefore or hereinafter, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition that can be affected by antagonizing the platelet-activating factor receptor. Furthermore, the present invention relates to a compound of formula (I.0), as defined hereinbefore or hereinafter, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition that can be affected by antagonizing platelet-activating factor receptors in a patient in need thereof. Further aspects of the present invention will be apparent to those skilled in the art from what has been said above and below, as well as directly from the examples.

[0010] General Terms and Definitions Terms not specifically defined herein should be given the meanings that would be given those terms by one of ordinary skill in the art in light of this disclosure and the context. However, as used herein, unless specified to the contrary, the following terms have the indicated meanings and are subject to the following conventions: The terms "compound according to the invention", "compound of Formula (I.0)", "compound of the invention" and the like mean compounds of Formula (I.0) according to the invention, including their tautomers, stereoisomers and mixtures thereof, and salts thereof, particularly pharmaceutically acceptable salts thereof, as well as solvates, hydrates and co-crystals of such compounds, including solvates, hydrates and co-crystals of such tautomers, stereoisomers and salts thereof. Similarly, unless specifically indicated otherwise, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and 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 unequal 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), and solvates thereof (e.g., solvates of the free compounds or hydrates, including solvates of salts of the compounds). The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. 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-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains 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 the appropriate base or acid in water or an organic diluent such as ether, EtOAc, EtOH, isopropanol, or MeCN, or a mixture thereof. For example, salts of acids other than those mentioned above (eg, trifluoroacetates) that are useful for purifying or isolating the compounds of this invention also form part of this invention. When a compound of the invention is depicted in the form of a chemical name and as a formula, in the event of any discrepancy, the formula shall prevail.

[0011] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified before the group, e.g., C 1-6 -Alkyl means an alkyl group or radical having 1 to 6 carbon atoms. An asterisk can be used in a sub-formula to indicate a bond that is attached to a defined core molecule; for example, if there is more than one point of attachment, i.e., more than one asterisk, in a sub-formula, these asterisks can be further specified by a parenthetical indication of the attachment point of the core molecule. The naming of the atoms of a substituent begins with the atom closest to the core or group to which the substituent is attached.

[0012] For example, the term "3-carboxypropyl group" represents the following substituent: [ka] where the carboxy group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" represents the following group:

[0013] [ka]

[0014] The term "substituted," as used herein, means that any one or more hydrogens on the designated atom, radical, or moiety have been replaced with one selected from the indicated group, provided that the normal valence of the atom is not exceeded and that the substitution results in an acceptably stable compound. In the definitions of groups, terms such as "each of the X, Y and Z groups may be optionally substituted" means that each of the X groups, each of the Y groups and each of the Z groups may be optionally substituted as defined, either as an individual group or as part of the group of which each is composed. ex is H, C 1-3 -Alkyl, C 3-6 -cycloalkyl, C 1-3 -Alkyl-C 3-6 -cycloalkylene- or C 1-3-alkyl-O-, each alkyl group being one or more L ex " and the like in each of the above groups containing the term alkyl, i.e. the group C 1-3 -Alkyl, C 1-3 -Alkyl-C 3-6 -cycloalkylene- and C 1-3 In each of the -alkyl-O-, the alkyl moiety is ex It means that it may be substituted by:

[0015] The term “C 1-n "-alkyl" (n is an integer greater than 1), either alone or in combination with another radical, means a linear or branched acyclic saturated hydrocarbon radical having 1 to n carbon atoms. 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" (n is an integer greater than 1), either alone or in combination with another radical, means a divalent linear or branched acyclic alkyl radical having 1 to n carbon atoms. For example, the term C 1-4-Alkylene includes -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)-, -CH2-CH(CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3))2- and -C(CH3)(CH2CH3)-.

[0017] The term “C 3-n "-cycloalkyl" (n is an integer greater than 3), either alone or in combination with another radical, means an unbranched, cyclic saturated hydrocarbon radical having 3 to n carbon atoms. The cyclic group can be monocyclic, bicyclic, tricyclic, or spirocyclic, and is 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, norbornyl, norcaryl, adamantyl, and the like.

[0018] The term "heterocyclyl" refers to N, O, or S(O) r (r=0, 1, or 2), and optionally an aromatic ring of 3 to 14 ring atoms, wherein none of the heteroatoms are part of an aromatic ring. The term "heterocyclyl" is intended to include all possible isomers.

[0019] Thus, the term "heterocyclyl" includes the following exemplary structures, which are not depicted as radicals because each form may be attached via a covalent bond to any atom as long as appropriate valence is maintained: [ka] JPEG0007810743000005.jpg193169

[0020] The term "heteroaryl" refers to any group selected from N, O, or S(O) r (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] Thus, the term "heteroaryl" includes the following exemplary structures, which are not depicted as radicals, because each form may be attached via a covalent bond to any atom as long as appropriate valence is maintained: [ka]

[0022] The term "bicyclic ring system" means a group consisting of two joined cyclic moieties, including spirocyclic, fused and bridged ring systems. Many of the terms presented above may be used repeatedly in the definitions of formulae or groups and in each case have, independently of one another, one of the meanings presented above. The terms "treatment" and "treating" as used herein include both therapeutic, i.e., curative and / or palliative, and prophylactic, i.e., preventative, treatment.

[0023] Therapeutic treatment refers to the treatment of patients who have already developed one or more of the above conditions in their initial, acute or chronic form.Therapeutic treatment can be a symptomatic treatment to alleviate the symptoms of a particular symptom, or a causal treatment to reverse or partially reverse the symptom state or to stop or slow down the progression of the disease. Prophylactic treatment ("prophylaxis") refers to treating a patient at risk of developing one or more of the above conditions prior to the clinical onset of the disease, in order to reduce said risk.

[0024] The terms "treatment" and "treating" include the administration of one or more active compounds to prevent or delay the onset of symptoms or complications, and to prevent or delay the onset of a disease, condition or disorder and / or to eliminate or control the disease, condition or disorder, and to alleviate the symptoms or complications associated with a disease, condition or disorder. When the present invention refers to a patient in need of treatment, the invention is primarily concerned with treatment in mammals, particularly humans.

[0025] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a particular disease or condition, (ii) attenuates, ameliorates, 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 described herein. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention discloses novel cyclopentathiophene carboxamide derivatives that are effective platelet-activating receptor (PAFR) antagonists and have favorable pharmacological and pharmacokinetic properties for their use as medicaments to prevent or treat diseases and / or conditions that can be affected by PAFR antagonism, including, but not limited to, ocular diseases and inflammation-related conditions and diseases, particularly geographic atrophy, wet age-related macular degeneration, and allergies. The compounds of the present invention may realize several advantages, such as increased potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, increased solubility, increased permeability, desirable plasma protein binding, enhanced bioavailability, improved pharmacokinetic profile, and the potential to form stable salts.

[0027] Compounds of the Invention In a first aspect of the present invention, a compound of formula (I.0) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 It has been found that the compounds (where n is defined hereinbefore and hereinafter) are potent antagonists of PAFR and can exhibit advantageous 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 possibility of forming stable salts. In particular, they exhibit high in vitro potency as PAFR antagonists, and they show good in vivo efficacy in animal models of choroidal neovascularization. Furthermore, they have also been found to act as PAFR inverse agonists in in vitro models, which may further contribute to their beneficial pharmacological effects. Furthermore, the compounds according to the present invention exhibit advantageous chemical stability, especially at low pH values, and advantageous solubility at various pH values, i.e., in acidic media, while their renal clearance remains reasonably low.

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

[0029] Thus, according to one aspect of the present invention, a compound of formula (I.0) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and n are defined hereinbefore and hereinafter). As well as isomers, stereoisomers, tautomers, metabolites, prodrugs, solvates, hydrates, co-crystals, and salts thereof, particularly pharmaceutically acceptable salts thereof, are provided.

[0030] Unless otherwise stated, groups, residues and substituents, in particular R 1 , R 2 , R 3 , R 4 and n are defined hereinbefore and hereinafter. The substituent R 1 , R 2 , R 3 , R 4 Some preferred meanings of and n, and phenyl substitution patterns and stereochemistry are presented hereinafter 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 (optionally substituted with 1 to 3 F) 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 is R consisting of CH3 1 - selected from the group G4. According to another embodiment, R 1 is R selected from CH2CH3, CH2CH2CH3 and cyclopropyl 1 - selected from the group G5.

[0032] R 2 : More than one substituent R 2 is present in compounds of formula (I.0), i.e., n=2 or 3, R 2 are each an embodiment defined hereinafter and R 2 -G1 group~R 2 - selected independently from the group G8. According to one embodiment, R 2 is R 2 - selected from the G1 group, R 2 -G1 group is F, Cl, Br, I, C 1-4 -alkyl (optionally substituted by 1 to 3 F or one -CN, one -OH or one -OC) 1-4 -alkyl), and 3-4 -Cycloalkyl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl)2, -COOH, -COO-C 1-4-Alkyl, OH, -OC 1-4 -alkyl (optionally substituted with 1 to 3 F), -S(O) r -C 1-4 - alkyl (r=0, 1 or 2). According to another embodiment, R 2 is R 2 - selected from group G2, R 2 -G2 group: F, Cl, Br, C 1-3 -alkyl (optionally substituted by 2 or 3 F), cyclopropyl, -CN, -C 1-3 -Alkylene-OH, -C 1-2 -Alkylene-OC 1-2 -Alkyl, OH, -OC 1-3 -alkyl (optionally substituted by 2 or 3 F), 1-3 - consisting of alkyl. 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 is R consisting of F, Cl and Br, preferably Cl 2 - selected from the group G4. According to another embodiment, R 2 is R consisting of CH3 and CH2CH3 2 - selected from the group G5. According to another embodiment, R 2 is an R consisting of cyclopropyl and CF 2 - selected from the group G6. According to another embodiment, R 2 is an R consisting of CHOH and OH 2 - selected from the group G7. According to another embodiment, R 2 is an R consisting of OCH3 and S-CH3 2 - selected from the group G8.

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

[0034] Phenyl Substitution Pattern: In describing the substitution pattern of the phenyl ring shown in formula (I.0), the following carbon atom numbering is used: [ka]

[0035] In general, n substituents R 2 can each be attached to any of the carbon atoms C-2 to C-6, and any combination thereof. When n=1, according to one embodiment, R 2 is attached to carbon atom 2. According to another embodiment, R 2 is attached to carbon atom 4. When n=2, according to one embodiment, R 2 One of the R 2 is attached to carbon atom 5. According to another embodiment, R 2 One of the R 2 is attached to carbon atom 5.

[0036] R 2 , n and phenyl substitution patterns: According to one embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] The nucleotide sequence is selected so as to be selected from the Ph-G1 group consisting of:

[0037] According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] Preferably,

[0038] [ka] The compound is selected from the Ph-G2 group consisting of

[0039] According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] The nucleotide sequence is selected so as to be selected from the Ph-G3 group consisting of:

[0040] According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] The nucleotide sequence is selected from the group Ph-G4 consisting of:

[0041] According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] The nucleotide sequence is selected so as to be selected from the Ph-G5 group consisting of:

[0042] According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] The nucleotide sequence is selected from the group Ph-G6 consisting of:

[0043] According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] The nucleotide sequence is selected from the group Ph-G7 consisting of:

[0044] According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I.0) is [ka] The amine is selected so as to be selected from the group Ph-G8 consisting of:

[0045] R 3 and R 4 : According to one embodiment, R 3 teeth, H, and C optionally substituted with 1 to 5 F 1-4 -Alkyl R consisting of 3 - selected from Group G1. According to another embodiment, R 3 teeth, H, and C optionally substituted with 1 to 3 F 1-3 -Alkyl R consisting of 3 - selected from Group G2. According to another embodiment, R 3 is an R consisting of H, CH3 and CH2CH2CH33 - selected from Group G3. According to one embodiment, R 4 is C 1-6 -R consisting of alkyl 4 - selected from the group G1a, 1-6 -Alkyl is optionally substituted with 1 to 3 F; -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 -alkyl (optionally substituted with 1 to 3 F).

[0046] According to another embodiment, R 4 is C 1-6 -R consisting of alkyl 4 - selected from the G2a group, 1-6 -Alkyl is optionally substituted with 1 to 3 F; -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 -alkyl (optionally substituted with 1 to 3 F).

[0047] According to another embodiment, R 4 is C 1-4 -R consisting of alkyl 4 - selected from the G3a group, 1-4 -Alkyl is optionally substituted with 1 to 3 F; -CN, -CONH2, -COOH, OH and -OC 1-2 -alkyl (optionally substituted with 1 to 3 F). According to another embodiment, R 4 is C 1-4 -R consisting of alkyl 4 -G4a group, 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 the group G5a.

[0049] According to one embodiment, R 4 -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 may be substituted with 1 to 2 substituents selected from F and CH3. two H atoms of one >CH2 group of said alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems, The heterocyclyl may be N, NH, >N(C 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(=O)2(C 1-4 -alkyl) and O, and further containing 1 to 2 ring members independently selected from >C=O and >S(=O) r(r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain any heteroatom-heteroatom bonds other than The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with Cl, —CN, —CONH, —CONH(C 1-4 -alkyl), -CON(C 1-4 -Alkyl)2, -COOH, -COO-C 1-4 -Alkyl, OH, -OC 1-3 -alkyl (optionally substituted with 1 to 3 F), and C 1-4 -Alkyl (with 1 to 3 F, or -CN, OH, -OC 1-4 -alkyl).

[0050] According to another embodiment, R 4 -C 0-2 -Alkylene-C 3-8 -cycloalkyl and -C 0-2 -Alkylene-C 3-8 -R consisting of heterocyclyl 4 - selected from the G2b group, The cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems, said heterocyclyl contains one ring member selected from N, NH and O; The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with 1 to 2 substituents independently selected from Cl, —CN, —OCH 3 , CH 3 and CH 2 CH 3 .

[0051] According to another embodiment, R 4 -C 0-1 -Alkylene-C 3-6 -R consisting of cycloalkyl 4 - selected from the group G3b; said cycloalkyl is a saturated monocyclic or bicyclic ring system; The cycloalkyl may be substituted with 1 to 2 F, and may be substituted with one CH3 or CH2CH3.

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

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

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

[0055] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G7b group. According to one embodiment, R 4 -C 0-3 -alkylene-phenyl and -C 0-3 -alkylene-heteroaryl 4 - selected from the G1c group, The alkylene may be substituted with 1 to 2 substituents selected from F and CH3. two H atoms of one >CH2 group of said alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally containing 1 to 2 additional N ring members, or a 6-membered monocyclic ring containing 1 to 2 N ring members; The phenyl and heteroaryl are selected from the group consisting of F, Cl, Br, 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 (optionally substituted with 1 to 3 F), and C 1-4 -Alkyl (with 1 to 3 F, or -CN, OH and -OC 1-4 -alkyl).

[0056] According to another embodiment, R 4 -C 0-2 -alkylene-phenyl and -C 0-2 -alkylene-heteroaryl 4 - selected from the G2c group, The alkylene may be substituted with 1 to 2 CH3. two H atoms of one >CH2 group of said alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally containing one further N ring member, or a 6-membered monocyclic ring containing one to two N ring members; The phenyl and heteroaryl are F, Cl, Br, —CN, —OC 1-3 -alkyl (optionally substituted with 1 to 3 F), and C 1-3 -Alkyl (with 1 to 3 F) , or -CN and -OC 1-2 -alkyl and 1 to 3 substituents independently selected from Place It may be replaced.

[0057] According to another embodiment, R 4 -C 0-1 -alkylene-phenyl and -C 0-1 -alkylene-heteroaryl 4 - selected from the G3c group, two H atoms of one >CH2 group of said alkylene may be replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C(-CH2-CH2-), The heteroaryl is a 5- to 6-membered monocyclic ring containing one ring member =N-, and optionally containing one ring member selected from =N-, >NH, S, and O; The phenyl and heteroaryl may be substituted with 1 to 3 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 TIFF0007810743000025.tif112170 4 -G4c group.

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

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

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

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

[0063] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form a 3- to 8-membered saturated monocyclic heterocyclyl; R 3 / 4 -3- to 8-membered saturated monocyclic heterocyclyl selected from the G1a group is >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O; >C=O and >S(=O)r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain any heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 4 F. 1 to 4 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by 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 -Alkylene-, C 1-3 -Alkyl-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O)2-NH-, OH and C 1-3 -alkyl-O- (optionally substituted with 1 to 3 F).

[0064] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form a 3- to 8-membered saturated monocyclic heterocyclyl; R 3 / 4 -G2a group, and the 3- to 8-membered saturated monocyclic heterocyclyl is >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O, and may further contain one ring member selected from >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl does not have NS(=O) between ring members.r=1,2 does not contain any heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 2 F. 1 to 4 C optionally substituted with 2 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CON(C 1-4 -alkyl)2, -COO-C 1-4 -Alkyl, C 1-3 -Alkyl-OC 1-3 -Alkylene- and C 1-3 -alkyl-O-.

[0065] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form a 4- to 6-membered saturated monocyclic heterocyclyl; Not adjacent to the amide N atom, >N(C 1-4 -alkyl) and O, R forms a 4- to 6-membered saturated monocyclic heterocyclyl 3 / 4 - selected from the group G3a, The heterocyclyl is optionally substituted by 1 to 2 F. 1 to 4 C optionally substituted with 2 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CON(C 1-4 -alkyl)2, -COO-C 1-4 -Alkyl, C 1-3 -Alkyl-OC 1-3 -Alkylene- and C 1-3 -alkyl-O-.

[0066] According to one embodiment, R 3 and R 4 is R 3and R 4 together with the amide N atom to which they are attached form a 4- to 6-membered saturated monocyclic heterocyclyl; may contain one ring member O that is not adjacent to the amide N atom, R forms a 4- to 6-membered saturated monocyclic heterocyclyl 3 / 4 - selected from the group G4a, The heterocyclyl may be substituted by two F groups, and may be substituted by one to two CH3 groups.

[0067] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached, are heterocyclyl; [ka] R is selected from the group consisting of 3 / 4 - selected from the group G5a.

[0068] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached, are heterocyclyl; [ka] R is selected from the group consisting of 3 / 4 - selected from the group G6a.

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

[0070] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached, are heterocyclyl; [ka] R is selected from the group consisting of 3 / 4 - selected from group G8a.

[0071] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form a 5- to 12-membered saturated bicyclic heterocyclyl; R 3 / 4 -G1b Group, wherein the 5- to 12-membered saturated bicyclic heterocyclyl is >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O; >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain any heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 6 F; 1 to 4 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by 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 -Alkylene-, C 1-3 -Alkyl-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O)2-NH-, OH and C 1-3 -alkyl-O-.

[0072] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form a 6- to 11-membered saturated bicyclic heterocyclyl; R 3 / 4 -G2b group, and the 6- to 11-membered saturated bicyclic heterocyclyl is >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O; >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain any heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 6 F; 1 to 4 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by 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 -Alkylene-, C 1-3-Alkyl-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O)2-NH-, OH and C 1-3 -alkyl-O-.

[0073] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form a 6- to 11-membered saturated bridged bicyclic heterocyclyl or spiro bicyclic heterocyclyl; Not adjacent to the amide N atom, >N-, >NH, >N(C 1-4 -alkyl) and O, R forms a 6- to 11-membered saturated bridged bicyclic heterocyclyl or spiro bicyclic heterocyclyl. 3 / 4 - selected from the group G3b; provided that said heterocyclyl does not contain any O-O bonds between ring members; The heterocyclyl is optionally substituted by 1 to 4 F. 1 to 2 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CON(C 1-4 -alkyl)2, -COO-C 1-4 -Alkyl, C 1-3 -Alkyl-OC 1-3 -Alkylene- and C 1-3 -alkyl-O-.

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

[0075] According to one embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached, are heterocyclyl; [ka] R is selected from the group consisting of 3 / 4 - selected from the group G5b.

[0076] According to one embodiment, R 3 and R 4 is 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, R 3 / 4 - selected from the G1c group, the 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 -alkyl) and O, and may further contain 1 to 2 ring members independently selected from >C=O and >S(=O) r (r=0, 1 or 2), provided that there are no restrictions between members of said non-aromatic ring: NN, NO and NS(=O). r=1,2 There are no heteroatom-heteroatom bonds other than the aromatic ring is selected from a 5-membered monocyclic ring containing one ring member selected from NH, N, O, and S, which may further contain 1 to 2 N ring members, and a 6-membered monocyclic ring containing 0, 1, or 2 N ring members; the bicyclic ring system is optionally substituted by 1 to 4 F; 1 to 4 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by 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 -Alkylene-, C 1-3 -Alkyl-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O)2-NH-, OH and C 1-3 -alkyl-O- (optionally substituted with 1 to 3 F).

[0077] According to another embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form an 8- to 10-membered fused bicyclic ring system, R 3 / 4 - selected from the G2c group, the bicyclic ring system is a heterocyclyl or heteroaryl consisting of one non-aromatic ring and one aromatic ring, and phenyl and pyridine; the non-aromatic ring contains the amide N atom and optionally contains one ring member selected from =N-, >N- and O; the aromatic ring is selected from five-membered monocyclic rings containing one ring member selected from N, NH, O, and S, and optionally containing one further ring member N; the bicyclic ring system is optionally substituted by 1-2 F; 1 to 2 C optionally substituted by 1 to 3 F 1-2 - optionally substituted by alkyl, Cl and C 1-2 -alkyl-O- (optionally substituted with 1 to 3 F).

[0078] According to another embodiment, R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form an 8-9 membered fused bicyclic heteroaryl, R 3 / 4 - selected from the G3c group, The heteroaryl may be one non-aromatic ring containing the amide N atom, and may optionally contain one ring member >N- that is not adjacent to the amide N atom. and one pyrazolo or imidazolo ring It consists of The heteroaryl may be substituted with 1 to 2 CH3.

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

[0080] Stereochemistry: According to one embodiment, the stereochemistry of the compound of formula (I.0) is that of formula (I.1) [ka] This is due to the following.

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

[0082] Further preferred subembodiments of compounds of formula (I.0) are set forth as embodiments (Ia) to (Iz) in Table 1 below, where the above substituent definitions are used. For example, in column R 1 and item R in row (Ia) 1 -G1 in embodiment (Ia) is a substituent R 1 But R 1 -G1 means selected from the definitions indicated. The same applies to other variables incorporated in the general formula as well.

[0083] [Table 1]

[0084] R 1 , R 2 , R 3 , R 4 With regard to the definitions of and n, the subembodiments (Ia) to (Iz), in particular (Iw) to (Iz), which correspond to the subembodiments (Ia) to (Iz) of Table 1, are particularly preferred, the stereochemistry of these compounds being according to formula (I.1), i.e. the 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: [Table 2] JPEG0007810743000040.jpg232170 JPEG0007810743000041.jpg222163 JPEG0007810743000042.jpg229163 JPEG0007810743000043.jpg229163 JPEG0007810743000044.jpg180163

[0086] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of: [Table 3] JPEG0007810743000046.jpg188166

[0087] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of: [Table 4] JPEG0007810743000048.jpg228165 JPEG0007810743000049.jpg92165

[0088] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of: [Table 5] JPEG0007810743000051.jpg232165

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

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

[0091] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of: [Table 8] JPEG0007810743000055.jpg185165

[0092] According to another embodiment, the compound of formula (I.0) and / or (I.1) is: [Table 9]

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

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

[0095] preparation The compounds according to the present invention and intermediates thereto can be obtained using synthetic methods known to those skilled in the art and described in the organic chemistry literature, for example, in standard textbooks, monographs, and reviews covering the basic, applied, and specialized subjects of organic chemistry, especially organic synthesis. Preferably, the compounds are obtained similarly to the preparation methods described more fully hereinafter, particularly in the experimental section. In some cases, the order adopted in carrying out the reaction schemes may vary. Variations of these reactions known to those skilled in the art but not described in detail herein may also be used. General methods for preparing compounds according to the present invention will be apparent to those skilled in the art upon review of the schemes that follow. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared by analogous or similar methods. Prior to 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 described in the literature covering 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 compounds of formula (IV) can be reacted with a suitable coupling agent (e.g., O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), ... The respective acids of formula (II) and formula (V) (free acids, or Li) can be prepared by using (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-1-yloxy)tri-pyrrolidinophosphonium hexafluorophosphate (PyBOP), carbodiimide reagents, and the like, and a base (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, and the like). + , Na + , K. + R in Scheme 1 can be prepared from a suitable amine of formula (III) (either as the free amine or as a salt such as the hydrochloride or hydrobromide). 1 , R 2 , R 3 , R 4 and n has the meaning defined earlier in the specification. Alternatively, the respective carboxylic acid is converted to the carboxylic acid chloride (e.g., using oxalyl chloride or thionyl chloride in DCM) and coupled in situ with amine (III) in the presence of a suitable base (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.).

[0097] Compounds of formula (IV) have been reported in the literature and may also be obtained in enantiomerically enriched or pure form (see, for example, DE-A-4132763, EP-A-0388789, EP-A-0254245, EP-A-0450504, and Med. Res. Rev. 1989, 9, 181-218).

[0098] Scheme 2: [ka] Scheme 2: Imines (R 1 , R 2 , R 3 , R 4 and n has the meaning defined earlier in this specification) can be reduced to the corresponding amines (II) and (I), respectively, by using hydrogen in the presence of a transition metal catalyst or a suitable hydride source. Suitable hydride sources include NaBH4, KBH4, Na(NC)BH3, NaHB(OAc)3, Me4NBH4, and HCl, used in the presence of a Lewis or Bronsted acid, or a transition metal, at low to high temperatures (-70 °C to 100 °C) in a suitable solvent (e.g., toluene, DCM, THF, MeCN, HO, etc., or mixtures thereof, depending on the hydride source). n Boron hydrides such as Bu4NBH4, alanates such as LiAlH4, L-selectride, HAl i Selectrides such as Bu2, pinacolborane, H3B *The catalyst may be THF, boranes such as 9-BBN-H and EtBH, or silanes such as EtSiH and ClSiH. A more specific experimental protocol, which may be more generally applicable here, involves NaBH 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. Reduction of imines in the presence of one of these transition metal catalysts, optionally in the presence of transition metal-coordinating ligands and other additives, may be carried out using hydrogen (1 to 200 bar) in a suitable solvent (e.g., DCM, EtOAc, EtOH, THF, etc.) at 0°C to 150°C. Compounds (I) and (II) obtained by this procedure, depending on the reducing agent and conditions applied, are mixtures of diastereomers or pure diastereomers, which can be separated into the individual stereoisomers by methods known to those skilled in the art to give pure stereoisomers, e.g., (I.1) or (I.2).

[0099] The reduction of imines (IV) or (V) can also be carried out stereoselectively by using either chiral hydrides or hydrogen in the presence of a chiral catalyst to give compounds (I) or (II) as enriched or pure stereoisomers, depending on the enantiomeric purity of the starting imine, (IV) or (V), and the conditions used. For example, n The chiral hydride (→ n BuNHB((S) or (R)-N-Cbz-proline)3) can be a suitable reagent for the reduction of imines (IV) and (V) with high stereochemical selectivity. The 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] Reduction of the imine can also be carried out using ester (VI) under some of the conditions described above (Scheme 3) to give 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: Acids of formula (V) (R 1 , R 2 and n has the meaning defined earlier in this specification) are preferably prepared from the corresponding ester (VI) by hydrolysis or hydrogenolysis, depending on the nature 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 mixtures thereof) at ambient or elevated temperature. The acid can be isolated either as a salt with a metal cation or as the 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 mixtures thereof). Benzyl esters are preferably cleaved by hydrogenolysis over a suitable catalyst (for example palladium on carbon) in a suitable solvent (for example EtOH, MeOH, THF, DCM or EtOAc) under a hydrogen atmosphere (preferably 1-5 bar).

[0102] Compounds of formula (V) have been reported in the literature and may also be obtained in enantiomerically enriched or pure form (see, for example, EP-A-0 388 789, EP-A-0 254 245 and DE-A-4 132 763). Scheme 4

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

[0104] Scheme 4: Esters of formula (VI) (R 1 , R 2 and n has the meaning defined earlier in this specification) may be prepared from amide (VII) using a variety of synthetic strategies. A more preferred procedure involves converting the amide group in (VII) to the corresponding imidoyl chloride or phosphate 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, etc.) at moderate temperatures (preferably between 0°C and 40°C). Subsequently, the thus-modified acylhydrazine (R 1 Addition of -CO-NHNH2) to such activated amides gives N-acylaminoamidine derivatives, which can be converted to triazoles by heating (sometimes up to 140°C).

[0105] Alternatively, triazoles (VI) can be obtained by applying a three-step procedure via the thioamide of amide (VII), which is subsequently treated with hydrazine to give the corresponding N-aminoamidine, which is then converted to the appropriate orthoester (R 1 -C(OC 1-2-alkyl)3) to the triazole. This procedure, its variations, and alternative synthetic routes are reported in the organic chemistry literature and known to those skilled in the art (see, for example, EP 0 388 789 and EP 0 254 245).

[0106] Compounds of formula (VI) have been reported in the literature and may be obtained in enantiomerically enriched or enantiomerically pure form (see, for example, EP 0388789). Scheme 5 [ka] R'=C 1-4 -Alkyl or benzyl

[0107] Scheme 5: Esters of formula (VII) (R 2 and n has the meaning defined earlier in this specification) may be prepared from ketone (VIII) in one, two, or three separate synthetic steps. A well-established synthesis of compound (VII) is via the 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., NaHCO) in a suitable solvent (e.g., toluene and water) at 0°C to 80°C. This intermediate is then treated with an ammonia source (e.g., aqueous ammonia or ammonia in THF) to displace the bromine and provide the corresponding N-aminoacetyl derivative. The amino group then reacts with the keto group in a suitable solvent (e.g., silica gel in toluene, pyridine in HOAc, or methanesulfonic acid in 1,4-dioxane) at elevated temperatures (preferably between 30°C and 130°C) with the aid of suitable additives to form a seven-membered ring to give compound (VII).

[0108] This procedure has also been reported in the literature and applied to the synthesis of enantiomerically enriched or pure compounds (see, for example, EP 0254245 and EP 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: Compounds of formula (VIII) can be prepared from cyanoketones (IX) and ketones (X) according to the reported protocol for the so-called Gewald reaction; R in Scheme 6 2 and n have the meanings defined earlier in this specification. Thus, compounds (IX) and (X) are combined 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 conversion may be carried out in two separate steps, forming a condensation product from compounds (IX) and (X) in the first step (Knoevenagel reaction), and product (VIII) upon treatment with elemental sulfur and a base in the second step. Variations on these procedures have been reported in the organic chemistry literature. Compound (IX) is a known compound or can be prepared in the same manner as the former. The main and specific access routes to enantiomerically enriched or pure compound (X) are also reported in organic chemistry literature (see, for example, European Patent Application Publication No. EP0388789, Archive 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: Cyanoketones (R 2 and n have the meanings defined earlier in this specification) can be reacted with 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. - The deprotonated acetonitrile species is preferably prepared from a suitable base (e.g., NaH, LiN) in one solvent used for the subsequent reaction with ester (XI) at a temperature between -78°C and 40°C, depending on the base used. i Pr2, LiN(SiMe3)2, KO t It is prepared from acetonitrile by deprotonation with (e.g., Bu). Further synthetic routes and procedures for preparing compounds of formula (IX) are 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: Compounds of formula (I) can also be obtained by following the route outlined in Scheme 8; R 2 , R 3 , R 4and n have the meanings defined earlier in this specification. The synthetic sequence begins with the Gewald reaction of ketone (X) with cyanoester (XII) to give aminothiophene (XIII) (see the experimental section and WO 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 give compound (XIV). The methoxy group serves as a masked leaving group, which is intended to be displaced by ammonia to introduce the amino at a later stage of the synthesis. Therefore, many 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 Lawesson's reagent (or diphosphorus pentasulfide) in a solvent such as 1,4-dioxane or toluene at elevated temperatures (60-120°C). Triazoles (XVI) can be formed by treating thioamides (XV) with hydrazine in a solvent such as THF or 1,4-dioxane at ambient temperature to give N-aminoamidine intermediates, which are then reacted with trialkyl orthoacetates (e.g., MeC(OMe)3) or acetamide dialkyl acetals (e.g., MeC(OMe)2(NMe2)) at elevated temperatures (approximately 60-120°C), optionally in the presence of an acid (e.g., p-TsOH or MeCOOH). Alternatively, Under similar conditions, acetylhydrazine can be used instead to obtain the triazole. Bromide (XVIII) can be generated from compound (XVI) by direct displacement of the methoxy group with bromide or via the alcohol derivative (XVII), depending on the conditions applied. The alcohol route requires cleavage of the methoxy ether (e.g., with BBr3 in DCM) followed by transfer of the hydroxyl group with Br (e.g., MeSO2Br and NEt3 in DCM).Compound (XIX) can then be obtained by treating bromide (XVIII) with ammonia (e.g., in methanol at ambient temperature) and heating the displacement product, optionally in the presence of additional base (e.g., NEt), to achieve simultaneous cyclization and amide formation. The thioamide in (XX) can be introduced by treating the amide (XIX) with Lawesson's reagent or P2S5 in an inert solvent (e.g., toluene or 1,4-dioxane) at elevated temperatures (preferably between 60°C and 120°C). The key steps, ester hydrolysis, described in Scheme 3, and amide formation in Scheme 1, are followed to convert the ester functionality in (XX) to the corresponding amide, yielding compound (XXII); ester hydrolysis can be achieved using NaOH in a mixture of water and methanol at ambient temperature, while amide formation can be achieved by reacting the desired amine (R) in DMF at room temperature. 3 R 4 Methylation of the sulfur in thioamide (XXII) can be accomplished with methyl iodide or methyl trifluoromethanesulfonate in a solvent (e.g., acetone or MeCN) at ambient temperature, optionally in the presence of a base (e.g., KOtBu), to give compound (XXIII), which contains a functional group (-N=C(SMe)-) suitable for coupling an aromatic residue via a transition metal-catalyzed coupling reaction with an aromatic nucleophile, such as a boronic acid or a zinc halide. Coupling of compound (XXIII) with aromatic boronic acids (RB(OH)2) can be carried out in a solvent (e.g., NMP or 1,4-dioxane) at ambient or elevated temperatures (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 give compound (I'), i.e., compound (I) (where R 1 is a methyl group). The synthesis scheme outlined in Scheme 8 can be used to obtain 1 The compounds are not limited to compounds having methyl groups with R as defined earlier in this specification. 1This can in principle be extended to any other residue encompassed by the meaning of

[0115] The compounds of formula (I) may be resolved into their enantiomers and / or diastereomers, as specified below: for example, cis / trans mixtures may be resolved into their cis and trans isomers, diastereomeric mixtures may be separated into their diastereomers, and racemates may be separated into their enantiomers.

[0116] Cis / trans mixtures can be resolved into their cis and trans isomers, for example, by chromatography. Compounds of formula (I) that occur as racemates can be separated into their optical antipodes by methods known per se, and diastereomeric mixtures of compounds of general formula (I) can be resolved into their diastereomers by taking advantage of their different physicochemical properties using methods known per se, for example, chromatography and / or fractional crystallization; if the compounds obtained thereafter are racemic, they can be resolved into their enantiomers as described below.

[0117] Racemates are preferably resolved by column chromatography on chiral phases, by crystallization from optically active solvents, or by reaction with optically active substances that form salts or derivatives such as esters or amides with the racemate. Salts can be formed with enantiomerically pure acids in the case of basic compounds and with enantiomerically pure bases in the case of acidic compounds. Diastereomeric derivatives can be formed with enantiomerically pure auxiliary compounds, such as acids, their activated derivatives, or alcohols. Separation of diastereomeric mixtures of the salts or derivatives thus obtained can be achieved by taking advantage of their various physicochemical properties, such as differences in solubility. The free enantiomers can be liberated from the pure diastereomeric 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 noted above, compounds of formula (I), such as (I.0), can be converted into salts, particularly pharmaceutically acceptable salts, for use in medicines. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. The compounds according to the invention can also be advantageously obtained using the methods described in the examples that follow, which 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 use The activity of the compounds of the present invention and their suitability for pharmaceutical use can be demonstrated using the following assays: biological methods

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

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

[0121] IC of compounds according to the present invention 50The values ​​are shown in the table below. The compound numbers correspond to the example numbers in the experimental section. When a mixture of isomers with respect to the configuration at C-13 is used in the test, the observed activity can be attributed mainly 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] Evaluating Inverse Agonist Mode of Action Using Endpoint Assays Due to the constitutive activity of PAFR, the basal HTRF IP1 signal is higher in HEK293 cells overexpressing human PAFR compared to untransfected HEK293 cells. The ability of test compounds to act as inverse agonists at the PAF receptor can be determined using a modified protocol of the cellular HTRF IP1 assay described above. Various concentrations of test compounds are added to assay plates containing HEK293 cells overexpressing human PAFR and incubated for 340 minutes at 37°C / 5% CO2 without the addition of RAF ligand. The inverse agonist effect of the test compound is demonstrated by a reduction in the HTRF IP1 signal to the level of untransfected HEK293 cells. Evaluation of in vivo efficacy in an animal model of laser-induced choroidal neovascularization in Brown Norway rats Male Brown Norway rats (BN / Crl) weighing between 160 and 180 g are obtained from Charles River Labs (Sulzfeld, Germany). Animals are maintained in group housing with a 12-hour / 12-hour light / dark cycle (lights on at 6 AM) and allowed to acclimate for one week before the start of the study. Animals have free access to standard chow (Provimi Kliba No. 3438) and tap water. Animals receive test compounds by oral gavage once daily for two weeks.

[0124] On day 1, under anesthesia, the animal was placed in front of a fundus camera, with the optic nerve positioned at the center of the image. Laser treatment was performed using a Micron IV system (Phoenix Research Laboratories, Pleasanton, CA) with a green argon laser (Merilas) at 532 nm wavelength. The diameter of the laser beam was matched to the diameter of the optic nerve, and four lesions were generated per eye using laser pulses with an energy of 400 mW and a duration of 150 ms. The lesions were placed between major blood vessels, approximately twice the diameter of the optic nerve. Successful disruption of Bruch's membrane was indicated by the formation of an air bubble immediately after the laser beam and confirmed by OCT scans.

[0125] Animals are sacrificed 14 days after laser treatment by cervical dislocation under anesthesia. Eyes are enucleated and incised along the ora serrata. The cornea, iris, lens, vitreous, and retina are removed, and the remaining eyecup (consisting of the PRE, choroid, and sclera) is fixed in PFA (4%) for 1 hour at 4°C and then transferred to PBS containing 0.1% Triton X-100 for 1 hour at 4°C. The eyecup is stained with FITC-labeled isolectin B4 (10 μg / ml in saline; obtained from Sigma Aldrich, catalog number L9381) overnight at room temperature in the dark and washed three times with PBS. The eyecup is transferred to a glass slide and incised four times to form a flattened cloverleaf structure. The tissue is covered with mounting medium (Vectashield H-1200 containing DAPI) and a coverslip is placed on top to obtain RPE / choroid / sclera flatmounts (RPE side up), which are stored in the dark at 4°C until analysis.

[0126] The samples were analyzed using an LSM700 confocal laser scanning microscope (Carl Zeiss, Jena; gain 650, laser intensity 2%) at a wavelength of 488 nm to obtain images of the lesions. Lesion size was measured using Zen Blue software. The efficacy readout was the size of the lesion stained with isolectin B4 in RPE-choroid flat mounts. Evaluation of compound binding to melanin

[0127] The ability of compounds to bind to melanin is determined using an in vitro assay using 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. Compounds are incubated in microtiter plates at a final compound concentration of 1 μM (compounds in DMSO:assay buffer (40:60) are added to the plate; the final DMSO concentration is 1%) with a 1 mg / mL melanin suspension in control buffer (to determine free compound concentration) and without melanin (to determine total compound concentration). The plates are incubated at 37°C for 2 hours on an orbital shaker at 900 rpm. After incubation, the plates are centrifuged to pellet the melanin and bound compounds. Supernatants from both melanin and control wells are sampled and concentrations are measured using LC-MS. Bound concentrations are calculated by subtracting free compound concentrations from total compound concentrations.

[0128] Chemical Stability Assessment Decomposition studies are used to mimic the chemical stability of compounds in the acidic part of the gastrointestinal tract. The compounds of the present invention have shown high chemical stability in acidic aqueous media (pH values ​​of about 1.2), which makes the application of the compounds of the present invention as pharmaceuticals for treating human diseases less restrictive and problematic.

[0129] The chemical stability of the compounds of the present invention at pH values ​​of about 1.2 is determined as follows: The compound is dissolved in a mixture of acetonitrile / 0.1 M aqueous HCl (ratio: 2:3; pH approx. 1.2) in an HPLC vial to obtain a concentration of approximately 0.25 mg / ml. The 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. An additional sample is injected after 24 hours. The amount of degraded compound is measured by determining the recovery [%] of the compound during the 24 hour injection using an HPLC standard gradient method: the peak area of ​​the main peak for the first injection (AUt0) is determined and set as 100%. The peak area of ​​the main peak is also determined for the 24 hour injection (AUt0). 24h ), (AU 24h ) / AU t0 ) [%]. The chemical stability of exemplary compounds according to the present invention was tested as described above, and for all of them, the amount of compound decomposed was found to be no more than 3%.

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

[0131] Permeability assessment Caco-2 cells (1~2×10 5 cells / 1cm 2 The cells (area of ​​100 cells / well) are seeded onto a filter insert (Costar transwell polycarbonate or PET filter, 0.4 μm pore size) and cultured (in DMEM) for 10 to 25 days. Compounds are dissolved in an appropriate solvent (such as DMSO, stock solution 1–20 mM). The stock solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO, 1.8 mM CaCl, 4.17 mM NaHCO, 1.19 mM NaHPO × 7H2O, 0.41 mM NaHPO × 7H2O, 15 mM HEPES, 20 mM glucose, pH 7.2) to prepare transport solution (0.1–300 μM compound, final DMSO <= 0.5%). Transport solution (TL) is applied to the apical or basolateral donor side to measure AB or BA permeability, respectively (three filter replicates). The receiver side contains HTP-4 buffer supplemented with 2% BSA. Samples are taken from the donor side as well as the receiver side at the beginning and end of the experiment and at various time intervals up to 2 hours for concentration determination by HPLC-MS / MS or scintillation counting. The sampled receiver volume is replaced with fresh receiver solution.

[0132] Evaluation of metabolic stability in human or rat liver microsomes Metabolic degradation of test compounds is assayed using pooled human or rat liver microsomes at 37° C. Final incubation volumes of 100 μl per time point contain TRIS buffer (pH 7.6) (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg / mL), and test compound at a final concentration of 1 μM at room temperature. After a short preincubation period 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 aliquots to solvent. Additionally, NADPH-independent degradation is monitored in NADPH-free incubations and terminated at the final time point. The quenched incubations are pelleted by centrifugation (10,000 g, 5 min). An aliquot of the supernatant is assayed for the amount of parent compound by LC-MS / MS. The half-life (t INVITRO) is determined by the slope of a semi-logarithmic plot of the concentration-time profile.

[0133] Assessment of metabolic stability in human or rat hepatocytes The metabolic degradation of test compounds is assayed in hepatocyte suspensions. Hepatocytes (usually cryopreserved) are incubated in an appropriate buffer system (e.g., Dulbecco's modified Eagle's medium, with 5% serum and 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, and 3.75 mg hydrocortisone / 500 mL). After 30 min (typically) of pre-incubation in an incubator (37 °C, 10% CO), add 5 µL of test compound solution (80 µM; from 2 mM in DMSO stock solution diluted 1:25 with culture medium) to 395 µL of hepatocyte suspension (cell density ranging from 0.25 to 5 myocytes / mL, typically 1 myocyte / mL; final test compound concentration 1 µM, final DMSO concentration 0.05%). Cells are incubated (incubator, orbital shaker) for 6 hours and samples (25 μL) are taken at 0, 0.5, 1, 2, 4, and 6 hours. Samples are transferred to ACN and pelleted by centrifugation (5 minutes). Supernatants are transferred to a new 96-deep-well plate, solvent evaporated under nitrogen, and resuspended. The loss of 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 the data [μM x h], clast: concentration of the last data point [μM], k: slope of the regression line for the loss of the parent compound [h-1].

[0134] Assessment of plasma protein binding This equilibrium dialysis (ED) technique is used to determine the approximate in vitro binding rate of test compounds to plasma proteins. Dianorm Teflon dialysis 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 stock solution of each test compound is prepared at 1 mM in 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 200 μL aliquot of dialysis buffer (100 mM potassium phosphate, pH 7.4) is dispensed into the buffer chamber. A 200 μL aliquot of the test compound dialyzed solution is dispensed into the plasma chamber. Incubation is performed at 37°C with rotation for 2 hours.

[0135] At the end of the dialysis period, the dialysate is transferred to a reaction tube. The tube for the buffer fraction contains 0.2 mL of ACN / water (80 / 20). A 25 μL aliquot of the plasma dialysate 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 carried out by adding 200 μL of ACN.

[0136] A 50 μL aliquot of the buffered dialysate 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. Samples are measured on an HPLC-MS / MS system and evaluated with Analyst software. The binding percentage is calculated using the following formula: % binding = (plasma concentration - buffer concentration / plasma concentration) x 10

[0137] Solubility evaluation The aqueous solubility of the test compound is determined by comparing the amount dissolved in the buffer with the amount in an ACN / water (1 / 1) solution. Starting with a 10 mM DMSO stock solution, an aliquot is diluted with ACN / water (1 / 1) or buffer, respectively. After 24 hours of shaking, the solution is filtered and analyzed by LC-UV. The amount dissolved in the 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 is more than 90% soluble in the buffer, this value is noted with a ">".

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

[0139] Evaluation of pharmacokinetic characteristics in rodents Test compounds are administered either intravenously to fed rats or orally to fasted rats. At several time points after administration of the test compound, blood samples are taken, anticoagulated, and centrifuged. Analyte concentrations, i.e., administered compound and / or metabolites, are quantified in plasma samples by LC-MS / MS. To determine renal clearance, urine samples are collected over 24 hours after intravenous administration and urinary concentrations of administered compound are quantified by LC-MS / MS. PK parameters are calculated using non-compartmental PK analysis (NCA) by applying the trapezoidal rule (lin up-log down) and plotting the area under 0-tz ) and calculate the area under the curve. 0-Inf is extrapolated to the end of the period, and the AUC tz-∞ AUC 0-tz The individual CL values ​​are calculated according to Equation 1.

[0140]

number

[0141] In the second step, the 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 properties that make them suitable for use in therapy, i.e., as pharmaceuticals. In particular, compounds of formula (I.0) or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing them, may be useful in treating diseases or conditions in a patient that can be affected by antagonizing the platelet-activating factor receptor (PAFR), e.g., diseases or conditions that are mediated by undesirable activity of PAFR or in which antagonism of PAFR is beneficial. Further benefits may result from the inverse agonism of PAFR. Diseases and conditions that can be affected by antagonizing and / or inverse agonizing PAFR, for example, those mediated by unwanted PAFR activity or for which antagonism and / or inverse agonism of PAFR activity would be beneficial, include ophthalmic diseases, cardiovascular diseases, cancer, neurological and neurodegenerative disorders, nephropathy, liver disease, and allergies. These disorders include, but are not limited to, retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathies, diabetic macular ischemia (DMI), geographic atrophy, Stargardt's disease, retinal degeneration in glaucoma, myopic macular degeneration, chronic panuveitis, retinitis pigmentosa, retinal vein occlusion (such as central, branch, or hemiretinal vein occlusion), diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), and retinal vein occlusion (RVOI). E), post-lens extraction CME, cryotherapy-induced CME, uveitis-induced CME, endophthalmitis, post-vascular occlusion CME (e.g., central retinal vein occlusion, branch retinal vein occlusion, or hemiretinal vein occlusion), retinal edema, cataract surgery-related complications in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and exudative age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), choroidal neovascularization (CNV;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, e.g., following tissue and / or organ transplantation, surgery-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-related 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-related (ACE inhibitor) edema, high altitude cerebral edema, cytotoxic cerebral edema, penetrating cerebral Edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, traumatic brain injury, hemorrhagic stroke (e.g., cerebral aneurysm or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, brain trauma related to injury or surgery, encephalomyelitis, amyotrophic lateral sclerosis, neuropathic pain, cerebral aneurysm, arteriovenous malformation, reduction of blood loss during surgery (e.g., cardiothoracic surgery such as cardiopulmonary bypass or coronary artery bypass graft), blood clotting disorders such as thrombosis, eczema, disorders with an inflammatory component (e.g., multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease, excessive daytime sleepiness, essential hypertension, diabetes or elevated blood pressure due to hyperlipidemia, renal failure, renal impairment (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 due to fibrinolytic treatment, angina pectoris, angioedema, sepsis, arthritis (e.g., rheumatoid arthritis, osteoarthritis, infectious arthritis), ulcerative colitis, pancreatitis, lupus, gout, psoriasis, inflammatory bowel disease, diabetes, diabetic complications, or due to metabolic syndrome Comorbidities include 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, astrocyte activation-related diseases (e.g., Alzheimer's disease or multiple sclerosis), Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, stroke, epilepsy, and trauma (e.g., brain trauma), allergic edema, e.g., airway obstruction in chronic allergic sinusitis or perennial rhinitis; airway obstruction in acute asthma;These include serositis associated with systemic lupus erythematosus (SLE), acute respiratory distress syndrome (ARDS), cancer (such as breast cancer, colon cancer, esophageal cancer, lung cancer, liver cancer, pancreatic cancer, skin cancer (including melanoma), and cervical cancer), and other diseases;

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

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

[0145] This compound and composition, including any combination with one or more additional therapeutic agents according to the present invention, can be administered by oral, intravitreal, transdermal, inhalation, parenteral or sublingual route.Among possible administration methods, oral administration and intravitreal administration are preferred, especially oral administration.For intravitreal injection, the preferred dose should not exceed 5mg per eye. The patient to be treated is preferably a mammal, most preferably a human patient. Thus, in another aspect, the present invention provides compounds of formula (I.0), including pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0146] In another aspect, the present invention provides a method of treating a disease or condition mediated by unwanted activity of platelet-activating factor receptor or in which antagonism of platelet-activating factor receptor is beneficial in a patient in need thereof. Similarly, the present invention provides a compound of formula (I.0) or a pharmaceutically acceptable salt thereof for use in a method of treating a disease or condition in a patient in need thereof that is mediated by undesired activity of the platelet-activating factor receptor, or in which antagonism of the platelet-activating factor receptor is beneficial. Similarly, the invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating, in a patient in need thereof, a disease or condition mediated by undesired activity of platelet-activating factor receptor, or in which antagonism of platelet-activating factor receptor is beneficial. 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 a patient in need thereof that is mediated by undesired activity of platelet-activating factor receptor, or in which antagonism of platelet-activating factor receptor is beneficial.

[0147] According to one embodiment, the method of treatment comprises administering to the patient one or more compounds of formula (I.0), or pharmaceutically acceptable salts thereof, preferably administering to the patient a therapeutically effective amount of one or more compounds of formula (I.0), or pharmaceutically acceptable salts thereof. According to another embodiment, the method of treatment comprises the step of administering to a patient a pharmaceutical composition according to the invention. According to one embodiment, the disease or condition mediated by undesired activity of platelet-activating factor receptor or in which antagonism of platelet-activating factor receptor is beneficial is selected from ocular indications such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, dry and exudative age-related macular degeneration (AMD), geographic atrophy, polypoidal choroidal vasculopathy (PCV), and choroidal neovascularization (CNV). According to another embodiment, the disease or condition mediated by unwanted activity of the platelet-activating factor receptor or in which antagonism of the platelet-activating factor receptor is beneficial is selected from allergy- and inflammation-related conditions and diseases, such as hives and NASH. According to another embodiment, the disease or condition mediated by undesired activity of platelet-activating factor receptor or in which antagonism of platelet-activating factor receptor 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 compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used as the active ingredient in pharmaceutical compositions. Suitable formulations for administering the compounds of the present invention, optionally in combination with one or more additional therapeutic agents, will be apparent 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(s) is advantageously in the range of 0.1 to 90% by weight, e.g., 1 to 70% by weight, 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 the desired preparation will be familiar to those skilled in the art based on their expert knowledge. Preference will be given to those suitable for the particular formulation and the desired method of administration. Preparations or formulations according to the invention can be prepared using methods known per se, with which those skilled in the art are familiar, such as by mixing or combining at least one compound of formula (I.0) according to the invention or a pharmaceutically acceptable salt of such a compound with one or more excipients, carriers, and / or diluents. Thus, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising one or more compounds of formula (I.0), or pharmaceutically acceptable salts thereof, optionally together with 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, optionally together with one or more inert carriers and / or diluents, are provided for use in methods of treating diseases or conditions mediated by undesirable activity of PAFR or in which antagonism of PAFR is beneficial in a patient in need thereof. In particular, the present invention provides pharmaceutical compositions according to the present invention for use in methods of treating ocular indications such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, dry and exudative age-related macular degeneration (AMD), geographic atrophy, polypoidal 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 a pharmaceutical composition according to the present invention for treating a disease or condition mediated by unwanted activity of PAFR in a patient, preferably a human. Similarly, the present invention relates to the use of a pharmaceutical composition according to the invention for treating a disease or condition in a patient, preferably a human, in which antagonism of PAFR is beneficial.

[0151] According to one embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula (I.0) or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, together with optionally one or more inert carriers and / or diluents. For example, the composition comprises one 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 further be combined with one or more, preferably one, additional therapeutic agent. According to one embodiment, the additional therapeutic agent is selected from the group of therapeutic agents useful for the treatment of diseases or conditions described herein earlier, particularly ocular diseases such as diabetic macular edema (DME), dry and wet age-related macular degeneration (AMD), geographic atrophy, nonexudative choroidal neovascularization (CNV), urticaria and NASH, allergy- and inflammation-related conditions and diseases, 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 which, for example, enhance the therapeutic effect of one or more active substances for one of the indications mentioned and / or allow for a reduction in the dosage of one or more active substances. Thus, 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 conditions and diseases related to allergy and inflammation.

[0153] Antidiabetic agents are, 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 analogues, GLP-1 and GLP-1 analogues, or amylin and amylin analogues, dual agonists containing GLP-1 activity together with glucagon or GIP activity, cycloset, 11β-HSD inhibitors. Other suitable combination partners are, for example, inhibitors of glucose-6-phosphatase or fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, glucagon receptor antagonists, and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinase activators, 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, such as, for example, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and their derivatives, cholesterol absorption inhibitors such as PPAR-(alpha, gamma or alpha / gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or bile acid-binding substances such as inhibitors of the ileal bile acid transporter, MTP inhibitors, or HDL-raising compounds such as CETP inhibitors or ABC1 modulators.

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

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

[0156] Therapeutic agents for the treatment of ocular diseases can include, for example, intravitreally administered corticosteroids, intravitreally administered anti-VEGF therapy, 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, PKK inhibitors. Additional treatments for eye diseases can include laser coagulation therapy. Therapeutic agents for treating hives can include, for example, antihistamines, steroids such as cortisone, epinephrine, antibodies to immunoglobulin E, immunosuppressants such as cyclosporin A, and leukotriene receptor antagonists.

[0157] Therapeutic agents for treating 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. The therapeutic agents may include, for example, an anti-inflammatory drug, an anti-inflammatory drug (AID), an anti-inflammatory drug (AAC3) inhibitor, an anti-inflammatory drug (JNK1) inhibitor, a CCR2 / 5 inhibitor, an ACC inhibitor, a DGAT inhibitor, a KHK inhibitor, a PPARα / δ agonist, an FGF19 agonist, a β-Klotho / FGFR1c agonist, a PNPLA3 inhibitor, an NLRP3 inhibitor, a THR-β agonist, an HSD17β13 inhibitor, a galectin-3 inhibitor, an SCD1 inhibitor, an ASK1 inhibitor, an endothelin receptor A antagonist, a FASN inhibitor, a calpain inhibitor, an autotaxin inhibitor, a TREM2 agonist, a sGC inhibitor, a PKK inhibitor, a RORc inhibitor, a TLR4 inhibitor, and an IL11 inhibitor.

[0158] The compounds of the invention and / or pharmaceutical compositions comprising the compounds of the invention, optionally 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 usually from 1 / 5 of the lowest recommended dose to 1 / 1 of the normally recommended dose. The use of the compounds according to the present invention in combination with an additional therapeutic agent may be simultaneous or at staggered times.

[0159] Both the compound according to the invention and the one or more additional therapeutic agents may be present together in one formulation, e.g., a tablet or capsule, or separately in two identical or different formulations, e.g., as a so-called kit of parts. Thus, according to another aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds according to the invention and one or more additional therapeutic agents as described hereinbefore and hereinafter, together with optionally one or more inert carriers and / or diluents. According to another aspect, the present invention provides a method of treating a disease or condition mediated by undesired activity of the platelet-activating factor receptor or in which antagonism of PAFR is beneficial in a patient in need thereof, comprising the steps of administering to the patient one or more compounds of formula (I.0), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents as described hereinbefore and hereinafter; Preferably, methods are provided which comprise 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 a therapeutically effective amount of one or more additional therapeutic agents as described hereinbefore and hereinafter. Similarly, the present invention provides a compound of formula (I.0) or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents described hereinbefore or hereinafter, for use in a method of treating, in a patient in need thereof, a disease or condition mediated by undesirable activity of PAFR, or in which antagonism of PAFR is beneficial. Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating, in a patient in need thereof, a disease or condition mediated by undesirable activity of PAFR, or in which antagonism of PAFR is beneficial, in combination with one or more additional therapeutic agents described hereinbefore or hereinafter. 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 hereinbefore or hereinafter in a method of treating a disease or condition in a patient in need thereof that is mediated by undesirable activity of PAFR or in which antagonism of PAFR is beneficial.

[0160] According to one embodiment, the method of treatment comprises administering to a patient one or more compounds of formula (I.0), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents described hereinbefore and hereinafter; Preferably, the method comprises 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 hereinbefore and hereinafter.

[0161] According to another embodiment, the method of treatment comprises administering to a patient a pharmaceutical composition comprising one or more compounds according to the invention and one or more additional therapeutic agents as described hereinbefore and hereinafter, together with one or more inert carriers and / or diluents. According to one embodiment, the 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, the disease or condition mediated by undesirable activity of PAFR or in which antagonism of PAFR is beneficial is selected from ocular indications such as diabetic retinopathy, proliferative and non-proliferative retinopathies, diabetic macular edema (DME), dry and exudative age-related macular degeneration (AMD), geographic atrophy, polypoidal 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 from the following more detailed examples which illustrate, by way of example, the principles of the invention.

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

[0165] Abbreviation Ac 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]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DMEM Dulbecco's Modified Eagle's Medium DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDTA Ethylenediaminetetraacetate EtOAc ethyl acetate EtOH ethanol h time HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate HPLC High-Performance Liquid Chromatography HPLC-MS High-Performance Liquid Chromatography-Mass Spectrometry IPA Isopropanol LC liquid chromatography LC-MS 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 (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate R f Retention Factor 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'-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid THF tetrahydrofuran UV ultraviolet light

[0166] The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20°C, e.g., 15-25°C. in general, 1 H-NMR and / or mass spectra are obtained for the compounds prepared. Unless otherwise specified, compounds containing chiral centers possess the stereochemistry shown. The assignment of stereochemistry is made either by the use of chiral starting materials of 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 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 at 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 / DCM 50:50) and then recrystallized from MeOH to give the title compound.

[0178] Step 2: Methyl 3-(2-chlorobenzoyl)-2-(2-bromoacetamido)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate To a stirred mixture 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) is added bromoacetyl bromide (41.9 g) at 0 °C. The cooling bath is removed, and the mixture is stirred at 60 °C for 4 h. After cooling to room temperature, water is added, and the resulting mixture is extracted with EtOAc (2x). The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (petroleum ether / EtOAc 70:30) to give the title compound.

[0179] Step 3: Methyl 2-(2-aminoacetamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate To a flask equipped with a stir bar, methyl 3-(2-chlorobenzoyl)-2-(2-bromoacetamido)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (10.0 g) and ammonia (0.5 mol / L in THF; 70.0 mL) are added at room temperature. The flask is sealed, and the mixture is stirred overnight. The mixture is concentrated to remove excess ammonia and most of the THF, and EtOAc is added. The resulting mixture is washed with water, dried (Na2SO4), and concentrated to give 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-aminoacetamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (8.00 g) in toluene (80.0 mL) is added silica gel (3.05 g). To the resulting mixture is added 4 Å molecular sieves (1.00 g). The reaction mixture is stirred at 110 °C for 24 h. After cooling to room temperature, the mixture is filtered and concentrated, and the residue is chromatographed on silica gel (petroleum ether / EtOAc 70:30) to give 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 5.05 g of ]trideca-1(8),2(6),12-triene-4-carboxylate in 50.0 mL of THF was added ClPO(OEt) (3.01 mL) and DBU (3.02 mL) at room temperature. The mixture was stirred for 10 minutes, and then 1.56 g of acetic acid hydrazide was added. The mixture was stirred for another 30 minutes at room temperature and then at 60 °C for 4 hours. After cooling to room temperature, EtOAc was added, and the resulting mixture was washed with water, aqueous NaHCO and brine. The organic phase was dried (MgSO) and concentrated. The residue was chromatographed on silica gel (DCM / MeOH 99:1->95:5) to give 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) is added NaOH (4 mol / L in water; 35.0 mL) at room temperature. The mixture is stirred at room temperature for 16 hours. The mixture is diluted with water, and HCl (4 mol / L in water) is added to adjust the pH of the mixture to about 4.5, and then the mixture is extracted with DCM (5x). The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated to give 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 11,15] Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (racemic mixture, 10.0 g) is dissolved (50 mg / mL in EtOH / DCM 2:1) and then resolved 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 afford the isolated title compounds.

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

[0188] [ka] (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15] 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) was added HATU (10.0 mg) at room temperature. After stirring for 5 minutes, morpholine (5.00 mg) was added, and the resulting mixture was stirred for 1 hour. The reaction mixture was diluted with DMF and purified by reverse-phase chromatography (HPLC; ACN / water / aqueous ammonia) to give 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)-pentaene

[0190] [ka] The title compound was prepared from 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetra-cyclo[8.6.0.0] following a procedure similar to that described for Intermediate 5. 2,6 .0 11,15 ] 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)-pentaene

[0192] [ka] The title compound was prepared from (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetra-cyclo[8.6.0.0] following a procedure similar to that described for Intermediate 5. 2,6 .0 11,15 ] 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) at 0° C., tetrabutylammonium borohydride (16.6 g) is added in small portions. After hydrogen evolution has ceased, the mixture is stirred at room temperature for an additional hour. The resulting solution is added to a solution of (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] cooled to −10° C. 2,6 .0 11,15 ] is added dropwise to a solution of hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid (8.6 g) in DCM (120 mL), and the reaction mixture is stirred at -10°C for 1 hour and at room temperature for another hour. Aqueous HCl (1 M) is added to adjust the pH of the mixture to 1, and the mixture is extracted with aqueous HCl (1 M, 3x). The pH of the combined aqueous layer is carefully adjusted with aqueous NaOH (4 M) until a pH of 4.5 is reached and a white precipitate appears. The mixture is extracted with DCM (3x). The combined organic extracts are dried (MgSO4) and concentrated. The crude product is purified by reverse phase chromatography (HPLC; ACN / water / TFA) to give the title compound. LC (Method 2):tR = 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 from (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 8. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid. LC (Method 2): 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), followed by the addition of aqueous HCl (4 M, 1.25 mL) and sodium borohydride (379 mg). 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 evolution ceases, 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 additional MeTHF. The crude product, consisting of a diastereomeric mixture of intermediate 8 and the title compound, is purified by reverse-phase chromatography (HPLC; ACN / water / TFA) to give 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 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-bromoacetamido)-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 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-aminoacetamido)-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(4-chlorobenzoyl)-2-(2-bromoacetamido)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate following a procedure similar to that described in Step 3 of Intermediate 1. LC (Method 2):t R = 0.82 min; 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-aminoacetamido)-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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 was prepared by the synthesis of methyl 13-(4-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] following a procedure similar to that described in Step 5 of Intermediate 1. 2,6 ]-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 the synthesis of methyl 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] following a procedure similar to that described for Intermediate 2. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): 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)-pentaene The title compound was prepared from 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] following a procedure similar to that described for Intermediate 5. 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 = 0.78 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 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-bromoacetamido)-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 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-aminoacetamido)-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-ethylbenzoyl)-2-(2-bromoacetamido)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate following a procedure similar to that described in Step 3 of Intermediate 1. LC (Method 2):t R = 0.82 min; 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-aminoacetamido)-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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 was prepared by the synthesis of methyl 13-(2-ethylphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] following a procedure similar to that described in Step 5 of Intermediate 1. 2,6 ]-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 cleaving methyl 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 2. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): 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)-pentaene The title compound was prepared from 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 5. 2,6 .0 11,15 ]-Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and morpholine. LC (Method 2): 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)-pentaene

[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 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-bromoacetamido)-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 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-aminoacetamido)-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-methoxybenzoyl)-2-(2-bromoacetamido)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate following a procedure similar to that described in Step 3 of Intermediate 1. LC (Method 2):t R = 0.92 min; 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-aminoacetamido)-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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 was prepared by the synthesis of methyl 13-(2-methoxyphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] following a procedure similar to that described in Step 5 of Intermediate 1. 2,6 ]-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 the synthesis of methyl 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 2. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): 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)-pentaene The title compound was prepared from 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] following a procedure similar to that described for Intermediate 5. 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 = 0.66 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)-pentaene

[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 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-bromoacetamido)-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 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-aminoacetamido)-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-fluorobenzoyl)-2-(2-bromoacetamido)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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-aminoacetamido)-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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 was prepared by the synthesis of methyl 13-(2-fluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] following a procedure similar to that described in Step 5 of Intermediate 1. 2,6 ]-trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R = 0.82 min; 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 cleaving methyl 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 2. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): 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)-pentaene The title compound was prepared from 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] following a procedure similar to that described for Intermediate 5. 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 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-bromoacetamido)-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 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-aminoacetamido)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 2-(2-bromoacetamido)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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-aminoacetamido)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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 was prepared by the synthesis of methyl 10-oxo-13-[2-(trifluoromethyl)phenyl]-7-thia-9,12-diazatricyclo-[6.5.0.0] following a procedure similar to that described in Step 5 of Intermediate 1. 2,6 ] prepared from trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2): 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 cleaving methyl 3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 2. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): 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 from 3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] following a procedure similar to that described for Intermediate 5. 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 min; 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)-pentaene

[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 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-bromoacetamido)-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 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-aminoacetamido)-3-(2-bromobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate The title compound is prepared from methyl 3-(2-bromobenzoyl)-2-(2-bromoacetamido)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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-aminoacetamido)-3-(2-bromobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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 was prepared by the synthesis of methyl 13-(2-bromophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] following a procedure similar to that described in Step 5 of Intermediate 1. 2,6 ]-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 the synthesis of methyl 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 2. 2,6 .0 11,15] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): 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)-pentaene The title compound was prepared from 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] following a procedure similar to that described for Intermediate 5. 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 = 0.79 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 was prepared from 3-(3,5-difluorophenyl)-3-oxopropanenitrile and methyl 3-oxocyclopentane-1-carboxylate following a procedure similar to that described in Step 1 of Intermediate 1. Prepared from LC (Method 2):t R = 1.04 min; Mass spectrum (ESI + ): m / z=338[M+H] + . Step 2: Methyl 2-(2-bromoacetamido)-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 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-bromoacetamido)-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate 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 11,15]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate The title compound was prepared by the reaction of methyl 13-(3,5-difluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo-[6.5.0.0] following a procedure similar to that described in Step 5 of Intermediate 1. 2,6 ] prepared from trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2): 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 cleaving methyl 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 2. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate. LC (Method 2): 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 from 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] following a procedure similar to that described for Intermediate 5. 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 = 0.81 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 following a procedure similar to that described in Step 1 of Intermediate 1. LC (Method 2):t R = 1.93 min; Mass spectrum (ESI + ): m / z=256[M+H] + . Step 2: 3,5-dimethyl 2-(2-methoxyacetamido)-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-Dimethyl 2-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 the organic phase is then separated, dried (Na2SO4), and concentrated to dryness to give the title compound. LC (Method 2):t R = 1.01 min; Mass spectrum (ESI+): m / z = 328 [M+H] + . Step 3: 3,5-dimethyl 2-(2-methoxyethanethioamido)-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-Dimethyl 2-(2-methoxyacetamido)-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (36.0 g) is dissolved in 1,4-dioxane (150 mL) and Lawesson's reagent (48.9 g) is added. The reaction is stirred at 80° C. for 6 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness. The residue is triturated with methanol to give the title compound. LC (Method 2): R = 1.16 min; Mass spectrum (ESI+): m / z = 344 [M+H] + . Step 4: 3,5-dimethyl 2-[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-methoxyethanethioamido)-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 h. N,N-Dimethylacetamide dimethyl acetal (5.1 mL) is added and the reaction is stirred at room temperature for an additional 1.5 h. 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 EtOAc, made basic with NaHCO3, and extracted with EtOAc (3×). The combined organic extracts are dried (MgSO4) and concentrated to dryness. The residue is chromatographed on silica gel (petroleum ether / EtOAc / methanol 80:16:4 to 20:64:16) to give the title compound. LC (Method 1):t R = 0.82 min; Mass spectrum (ESI+): m / z = 366 [M+H] + . Step 5: 3,5-dimethyl 2-[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-triazol-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (2.79 g) is dissolved in DCM (40 mL), and then boron tribromide (1 M in DCM, 15.3 mL) is added. The reaction mixture is stirred at room temperature for 1.75 hours. The reaction mixture is diluted with DCM and saturated aqueous NaHCO3, stirred for 15 minutes, and then extracted with DCM (2x). The combined organic extracts are dried (MgSO4) and concentrated to give the title compound. LC (Method 2):t R = 0.75 min; Mass spectrum (ESI+): m / z = 352 [M+H] + . Step 6: 3,5-dimethyl 2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate 3,5-Dimethyl 2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopenta[b]thiophene-3,5-dicarboxylate (2.47 g) is dissolved in DCM (30 mL), and then EtN (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 NaHCO and extracted with DCM (2x). The combined organic extracts are dried (MgSO) and concentrated to give the title compound, which is used immediately 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 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) is dissolved in a solution of ammonia in methanol (7 M, 30 mL). The reaction mixture is stirred at room temperature for 3.75 hours, after which the mixture is concentrated to dryness. The resulting crude intermediate is dissolved in methanol (40 mL), and EtN (1.0 mL) is added. The reaction mixture is stirred at 80° C. for 7 hours, after which the mixture is concentrated to dryness. The residue is chromatographed on silica gel (petroleum ether / EtOAc / methanol 95:4:1 to 0:80:20) to give the title compound. LC (Method 2): R = 0.71 min; Mass spectrum (ESI+): m / z = 319 [M+H] + . Step 8: Methyl 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-carboxylate Methyl 3-methyl-9-oxo-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 (1.00 g) and Lawesson's reagent (3.00 g) are dissolved in 1,4-dioxane (20 mL). The reaction mixture is stirred at 65° C. for 16 h. An additional portion of Lawesson's reagent (1.00 g) is added and stirring is continued at 65° C. for 10 h. The reaction mixture is diluted with aqueous NaHCO and extracted with DCM (2×). The combined organic extracts are washed with brine, dried (MgSO), and concentrated to give 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 ]Hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylate (1.70 g) 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 to near dryness. The reaction mixture is acidified with TFA, and the resulting precipitate is collected by filtration to give 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)-tetraene-9-thione 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 (1.65 g) and 1,1'-carbonyldiimidazole (0.92 g) are dissolved in DMF (30 mL). The solution is stirred at 50°C for 1 hour. Morpholine (0.68 mL) is added and the solution is stirred at room temperature for 1 hour. The reaction mixture is diluted with water / brine (1:1) and extracted with EtOAc (3x). The combined organic extracts are washed with brine, dried (MgSO4), and concentrated to dryness. The residue is purified by reverse phase chromatography (HPLC; ACN / water / TFA) to give the title compound. LC (Method 2):tR = 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 ]Hexadeca-1(10),3,5,11(15)-tetraene-9-thione (0.60 g) and potassium tert-butoxide (0.175 g) are dissolved in acetone (10 mL), and then methyl iodide (0.77 mL) is added. The solution is stirred at room temperature for 1 hour. The reaction mixture is diluted with water and extracted with DCM (2x). The combined organic extracts are washed with brine, dried (MgSO4), and concentrated to dryness to give 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)-pentaene

[0224] [ka] 3-Methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15]Hexadeca-1(10),3,5,8,11(15)-pentaene (100 mg) and copper(I) 3-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 h. If the conversion is incomplete, additional (2-cyclopropylphenyl)boronic acid (50 mg) and tetrakis(triphenylphosphine)palladium(0) (30 mg) are added, and stirring is continued at 50 °C for 2 h. Upon completion, the reaction mixture is diluted with aqueous NaHCO (1 M) and extracted with EtOAc (3x). The combined organic extracts are dried (MgSO) and concentrated. The crude product is purified by reverse phase chromatography (HPLC; ACN / water / NH3) to give the title compound. 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 from 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for intermediate 19. 2,6 .0 11,15 ] 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 from 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for intermediate 19. 2,6 .0 11,15 ] 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 from 3-methyl-9-(methylsulfanyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for intermediate 19.2,6 .0 11,15 ] 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)-pentaene

[0232] [ka] Stir 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 A vial containing hexa-deca-1(10),3,5,8,11(15)-pentaene (50 mg), methylboronic acid (13 mg), KPO (71 mg), Pd(OAc) (1.2 mg), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.4 mg) was purged with Ar for 5 minutes. Water (25 μL) and toluene (0.25 mL) were added, the vial was sealed, and the mixture was stirred in a microwave oven at 140 °C for 30 minutes. An additional portion of methylboronic acid (13 mg), Pd(OAc) (1.2 mg), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.4 mg) was added at room temperature, and the mixture was stirred 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 chromatographed on reverse phase (HPLC; ACN / water / TFA) to give the title compound. LC (Method 2):tR = 0.72 min; 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 can be obtained by the synthesis of methyl 3-methyl-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] by applying a two-step procedure involving hydrolysis of the 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). 2,6 .0 11,15 ] can be obtained from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylate (for synthesis, see EP 0 254 245). LC (Method 2): R = 0.69 min; Mass spectrum (ESI+): m / z = 434 [M+H] + .

[0235] The intermediates summarized in the table below were (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 11,15] are obtained by following a procedure similar to that described for intermediate 5 using hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid and the respective amine.

[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] [ka] The title compound can be obtained by following a procedure similar to that described in Step 5 of Intermediate 1 to obtain methyl 13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2,6 ] can be obtained from trideca-1(8),2(6),12-triene-4-carboxylate and propanohydrazide, and methyl 9-(2-chlorophenyl)-3-ethyl-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. The ester is then saponified by following a procedure similar to that described for Intermediate 2, and the resulting carboxylic acid is converted to the title compound by following a procedure similar to that described for Intermediate 5. Alternatively, methyl 9-(2-chlorophenyl)-3-ethyl-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 from methyl 13-(2-chlorophenyl)-10-sulfanylidene-7-thia-9,12-diazatricyclo[6.5.0.0] according to a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or U.S. Pat. No. 7,015,213. 2,6 ] can be obtained from trideca-1(8),2(6),12-triene-4-carboxylate. LC (Method 2):t R = 0.82 min; Mass spectrum (ESI+): m / z = 482 [M+H] + .

[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)-pentaene

[0240] [ka] The title compound can be obtained by following a procedure similar to that described in Step 5 of Intermediate 1 to obtain methyl 13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2,6 ] can be obtained from trideca-1(8),2(6),12-triene-4-carboxylate and butyric acid hydrazide, and 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 is obtained. The ester is then saponified by following a procedure similar to that described for Intermediate 2, and the resulting carboxylic acid is converted to the title compound by following 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 from methyl 13-(2-chlorophenyl)-10-sulfanylidene-7-thia-9,12-diazatricyclo[6.5.0.0] according to a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or U.S. Pat. No. 7,015,213. 2,6 ] 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)-pentaene

[0242] [ka] The title compound can be obtained by following a procedure similar to that described in Step 5 of Intermediate 1 to obtain 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 and cyclopropanecarbohydrazide, and methyl 9-(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. The ester is then saponified by following a procedure similar to that described for Intermediate 2, and the resulting carboxylic acid is converted to the title compound by following a procedure similar to that described for Intermediate 5. Alternatively, methyl 9-(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 from methyl 13-(2-chlorophenyl)-10-sulfanylidene-7-thia-9,12-diazatricyclo[6.5.0.0] according to a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or U.S. Pat. No. 7,015,213. 2,6 ] 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)-pentaene

[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 ]-Hexadeca-1(10),3,5,8,11(15)-pentaene (135 mg), copper(I) iodide (50 mg), and DABCO (59 mg) are dissolved in anhydrous DMSO (2.0 mL). The reaction mixture is stirred under argon at 130° C. for 16 hours. The mixture is diluted with acetonitrile and purified by reverse-phase chromatography (HPLC; ACN / water / TFA) to give the title compound. LC (Method 2): R = 0.74 min; Mass spectrum (ESI + ): m / z=480[M+H] + .

[0245] Example Synthesis: 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 11,15] To a solution of hexadeca-1(10),3,5,8,11(15)-pentaene (200 mg) in DCE (1 mL) is added sequentially at room temperature NaBH4 (32 mg) and HCl (4 M in water; 0.26 mL). The mixture is stirred for 2 hours, after which an additional portion of NaBH4 (16 mg) and HCl (4 mol / L in water; 0.26 mL) are added. The reaction is further stirred at room temperature until complete. If the reaction is not complete, additional NaBH4 and HCl are added. Aqueous NaHCO3 is added, and the resulting mixture is extracted with DCM (3x). The combined organic extracts are dried (Na2SO4) and concentrated. The residue is purified by reverse-phase chromatography (HPLC; ACN / water / aqueous ammonia) to give the title compound as a racemic mixture of two diastereomers (approximately 60 / 40). LC (Method 2):t R = 0.72 min; 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 solution of hexadeca-1(10),3,5,8,11(15)-pentaene (1.00 g) in DCM (25 mL) was added HCl (4 M in water, 1.07 mL) and NaBH4 (323 mg) sequentially at room temperature. The mixture was stirred for 1 h until complete. The mixture was diluted with water and aqueous HCl (1 M) until a pH of 8-9 was achieved, and extracted with DCM (2x). The combined organic extracts were dried (Na2SO4) and concentrated. Repeated purification of the residue by reverse-phase chromatography (HPLC; ACN / water / aqueous TFA) afforded the completely separated diastereomeric TFA salts. These diastereomers could be liberated from their salt forms by adding aqueous NaHCO3, extracting the resulting mixture with DCM, and concentrating the organic extract to give the title compound. Example 2: LC (Method 2): R = 0.72 min; Mass spectrum (ESI + ): m / z=470[M+H] + ; Example 3: LC (Method 2): 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 from (9R,13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described for Intermediate 5. 2,6 .0 11,15 ] prepared from hexadeca-1(10),3,5,11(15)-tetraene-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 (Ex.) summarized in the table below are 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15 ] by using the individual stereoisomers or mixtures of stereoisomers of hexadeca-1(10),3,5,11(15)-tetraene-13-carboxylic acid and the respective amines and following procedures similar to those described for intermediate 5. SFC separation is used to obtain Examples 11 and 12 [Column: Chiral Art® Amylose-SA (10 mm x 250 mm, 5 μm); Column temperature: 40° C.; Flow rate: 10 mL / min; BPR: 150 bar; Injection volume: 250 μL (2.5 mg); Isocratic conditions: 70:30 CO:MeOH (20 mM NH)], and Examples 13 and 14 [Column: Chiralpak® IA (10 mm x 250 mm, 5 μm); Column temperature: 40° C.; Flow rate: 10 mL / min; BPR: 150 bar; Injection volume: 200 μL (2 mg); Isocratic conditions: 65:35 CO:EtOH (20 mM NH)].

[0252] [Table 25] JPEG0007810743000113.jpg227169 JPEG0007810743000114.jpg220169 JPEG0007810743000115.jpg226169 JPEG0007810743000116.jpg230169 JPEG0007810743000117.jpg227169 JPEG0007810743000118.jpg224169 JPEG0007810743000119.jpg226169 JPEG0007810743000120.jpg231169 JPEG0007810743000121.jpg233169 JPEG0007810743000122.jpg229169 JPEG0007810743000123.jpg234169 JPEG0007810743000124.jpg167169 JPEG0007810743000125.jpg239169 JPEG0007810743000126.jpg152169 JPEG0007810743000127.jpg166169 JPEG0007810743000128.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 .0 11 , 15 ]Hexadeca-1(10),3,5,11(15)-tetraene

[0254] [ka] The title compound was prepared from 9-(4-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2 , 6 .0 11 , 15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): R = 0.72 min; 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 from 9-(2-ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2 , 6 .0 11 , 15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): R= 0.72 / 0.74 min (diastereomers); 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 from 9-(2-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2 , 6 .0 11 , 15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): 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 from 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): R = 0.78 / 0.79 min (diastereomers); 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 from 3-methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): 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 from 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2,6 .0 11,15 ] prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2):t R = 0.71 / 0.72 min (diastereomers); 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 from 9-(3,5-difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): R = 0.72 min; 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 from 9-(2-cyclopropylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): R = 0.73 / 0.75 min (diastereomers); 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 the procedure similar to that described in Example 1 using {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. LC (Method 2): R = 0.64 / 0.65 min (diastereomers); 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 the procedure similar to that described in Example 1, using 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. LC (Method 1): R = 0.74 / 0.75 min (diastereomers); 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 from 9-(2-chloro-5-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2,6 .0 11,15 ] Prepared from hexadeca-1(10),3,5,8,11(15)-pentaene. LC (Method 2): R = 0.73 min; Mass spectrum (ESI+): m / z = 500 [M+H] + .

[0275] (Example 63 and Example 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 the procedure similar to that described in Example 1 using (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),3,5,8,11(15)-pentaene. The diastereomers are purified by reverse phase chromatography (HPLC; ACN / water / TFA) to give the title compound. Example 63: LC (Method 2): R = 0.71 min; Mass spectrum (ESI+): m / z = 450 [M+H] + ; Example 64: LC (Method 2): 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)-tetraene-13-carboxamide

[0278] [ka] The title compound was prepared by the procedure similar to that described in Example 1 using (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 ] prepared from hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxamide. LC (Method 2):t R = 0.72 min; 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 the procedure similar to that described in Example 1 from 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): R = 0.99 min; Mass spectrum (ESI+): m / z = 494 [M+H] + .

[0281] The examples summarized in the table below were prepared by following a procedure similar to that described in Example 1, to obtain 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] prepared from hexadeca-1(10),3,5,11(15)-pentaene. The individual stereoisomers are obtained by chiral SFC: a first separation to give Examples 68 and 69 [Column: Chiralpak® IA (20 mm x 250 mm, 5 μm); Column temperature: 40°C; Flow rate: 60 mL / min; BPR: 150 bar; Injection volume: 250 μL (2.5 mg); Isocratic conditions: 70:30 CO2:EtOH (20 mM NH3)], followed by a second separation of the mixed fractions to give Reference Examples 70 and 71 [Column: Chiral Art® Amylose-SA (10 mm x 250 mm, 5 μm); Column temperature: 40°C; Flow rate: 10 mL / min; BPR: 150 bar; Injection volume: 200 μL (4 mg); Isocratic conditions: 80:20 CO2:MeOH (20 mM NH3)].

[0282] [Table 26] JPEG0007810743000144.jpg149166 (Example 72 and Example 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)-tetraene-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)-tetraene-13-carboxamide (Example 73)

[0283] [ka] The title compound was prepared by the procedure similar to that described in Example 1 using (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 ] is prepared from hexadeca-1(10),3,5,11(15)-tetraene-13-carboxamide. The diastereomers are separated by chiral SFC [Column: Chiral Art® Amylose-SA (10 mm x 250 mm, 5 μm); Column temperature: 40 °C; Flow rate: 10 mL / min; BPR: 150 bar; Injection volume: 100 μL (2 mg); Isocratic conditions: 75:25 CO2:MeOH (20 mM NH3)]. Example 72: LC (Method 7): R = 2.10 min; Mass spectrum (ESI+): m / z = 484 [M+H] + ; Example 73: LC (Method 7): R = 3.02 min; Mass spectrum (ESI+): m / z = 484 [M+H] + .

[0284] The examples summarized in the table below were prepared by following a procedure similar to that described in Example 1, to obtain 3-methyl-13-(morpholine-4-carbonyl)-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0 2,6 .0 11,15] from hexadeca-1(10),3,5,8,11(15)-pentaene. The trans and cis diastereomers are separated by reversed-phase chromatography (HPLC; ACN / water / TFA). The separated diastereomeric racemates can be further separated into their individual enantiomers by chiral SFC to give Examples 75 and 76 [Column: Chiralpak IA (20 mm x 250 mm, 5 μm); Column temperature: 40° C.; Flow rate: 10 mL / min; BPR: 150 bar; Injection volume: 200 μL (3 mg); Isocratic conditions: 70:30 scCO:MeOH (20 mM NH)] and Reference Example 77 and Example 78 [Column: CHIRAL ART® Cellulose-SB (10 x 250 mm, 5 μm); Column temperature: 40° C.; Flow rate: 10 mL / min; BPR: 150 bar; Injection volume: 200 μL (2 mg); Isocratic conditions: 70:30 CO:iPrOH (20 mM NH)].

[0285] [Table 27] JPEG0007810743000147.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 a procedure similar to that described in Example 1 using (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 ] prepared from hexadeca-1(10),3,5,11(15)-pentaene. LC (Method 2):t R = 0.70 / 0.71 min (diastereomers); 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 from 9-(2-chlorophenyl)-13-(morpholine-4-carbonyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2 , 6 .0 11 , 15 ] Prepared from hexadeca-1(10),3,5,11(15)-pentaene. LC (Method 2): R = 0.77 / 0.78 min (diastereomers); 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 from 9-(2-chlorophenyl)-3-cyclopropyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] following a procedure similar to that described in Example 1. 2 , 6 .0 11 , 15 ] Prepared from hexadeca-1(10),3,5,11(15)-pentaene. LC (Method 2): R = 0.75 min; Mass spectrum (ESI+): m / z = 496 [M+H] + . Preferred embodiments of the present invention are as follows. [1] Compound of formula (I.0) JPEG0007810743000151.jpg5659 (In the formula, R 1 is C 1-4 -alkyl (optionally substituted with 1 to 3 F) and C 3-4 -R consisting of cycloalkyl 1 - selected from group G1, R 2 is R 2 - selected from the G1 group, R 2 -G1 group is F, Cl, Br, I, C 1-4 -alkyl (optionally substituted by 1 to 3 F or one -CN, one -OH or one -OC) 1-4 -alkyl), and 3-4 -Cycloalkyl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, OH, -OC 1-4 -alkyl (optionally substituted with 1 to 3 F), and -S(O) r -C 1-4 - alkyl (r=0, 1 or 2), n is selected from the group n-G1 consisting of 0, 1, 2, and 3; R 3 H, and C 1-4 -R consisting of alkyl (optionally substituted with 1 to 5 F) 3 - selected from group G1, R 4 is C 1-6 -R consisting of alkyl 4 - selected from the group G1a, 1-6 -Alkyl is optionally substituted with 1 to 3 F; -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 -OC 1-3 -alkyl (optionally substituted with 1 to 3 F), or R 4 -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 selected from F and CH 3 may be substituted with 1 to 2 substituents selected from One of the alkylene groups >CH 2 The two H atoms in the group are ethylene (-CH 2 -CH 2 -) bridge, the cyclopropylene moiety >C(-CH 2 -CH 2 -), The cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems, The heterocyclyl may be N, NH, >N(C 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(=O) 2 (C 1-4 -alkyl) and O, and contains 1 to 2 ring members independently selected from >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain heteroatom-heteroatom bonds other than The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with Cl, —CN, —CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, OH, -OC 1-3 -alkyl (optionally substituted with 1 to 3 F), and C 1-4 -Alkyl (with 1 to 3 F, or -CN, OH, -OC 1-4 -alkyl), or R 4 -C 0-3 -alkylene-phenyl and -C 0-3 -alkylene-heteroaryl 4 - selected from the G1c group, The alkylene is selected from F and CH 3 may be substituted with 1 to 2 substituents selected from One of the alkylene groups >CH 2 The two H atoms in the group are ethylene (-CH 2 -CH 2 -) bridge, the cyclopropylene moiety >C(-CH 2 -CH 2 -), the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally containing 1 to 2 additional N ring members, or a 6-membered monocyclic ring containing 1 to 2 N ring members; The phenyl and heteroaryl are selected from the group consisting of F, Cl, Br, 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), -OC 1-4 -alkyl (optionally substituted with 1 to 3 F), and C 1-4 -Alkyl (with 1 to 3 F, or -CN, OH and -OC 1-4 -alkyl), or R 3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached form a 3- to 8-membered saturated monocyclic heterocyclyl; R 3 / 4 -3- to 8-membered saturated monocyclic heterocyclyl selected from the G1a group is >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 -alkyl) and O; >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 4 F. 1 to 4 C's 1-3 -alkyl (optionally substituted with 1 to 3 F); 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-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O) 2 -NH-, OH and C 1-3 -alkyl-O- (optionally substituted by 1 to 3 F), or R 3 and R 4 is R 3 and R4 together with the amide N atom to which they are attached form a 5- to 12-membered saturated bicyclic heterocyclyl; R 3 / 4 -G1b Group, wherein the 5- to 12-membered saturated bicyclic heterocyclyl is >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 -alkyl) and O; >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 6 F; 1 to 4 C's 1-3 -alkyl (optionally substituted with 1 to 3 F); 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-OC 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 R 3 and R 4 is 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, R 3 / 4 - selected from the G1c group, the 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 -alkyl) and O, and may further contain 1 to 2 ring members independently selected from >C=O and >S(=O) r (r=0, 1 or 2), provided that NN, NO and NS(=O) are not included between the ring members of said non-aromatic ring. r=1,2 There are no heteroatom-heteroatom bonds other than the aromatic ring is selected from a 5-membered monocyclic ring containing one ring member selected from NH, N, O, and S, which may further contain 1 to 2 N ring members, and a 6-membered monocyclic ring containing 0, 1, or 2 N ring members; the bicyclic ring system is optionally substituted by 1 to 4 F; 1 to 4 C's 1-3 -alkyl (optionally substituted with 1 to 3 F); 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-OC 1-3 -Alkylene-, C 1-3 -Alkyl-CO-NH-, C 1-3 -Alkyl-S(=O) 2 -NH-, OH and C 1-3 -alkyl-O- (optionally substituted by 1 to 3 F) Or its salt. 〔2〕R 1 But CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CHF 2 , CF 3 and R consisting of cyclopropyl 1 The compound or salt thereof according to [1] above, selected from Group G2. 〔3〕R 2 But R 2 - selected from group G2, R 2 -G2 group is F, Cl, Br, C 1-3 -alkyl (optionally substituted by 2 or 3 F), cyclopropyl, -CN, -C 1-3 -Alkylene-OH, -C 1-2 -Alkylene-OC 1-2 -Alkyl, OH, -OC 1-3 -alkyl (optionally substituted by 2 or 3 F), and -SC 1-3 The compound or salt thereof according to one or more of the above [1] to [2], wherein the compound is a substituted or unsubstituted alkyl. 〔4〕R 3 But, H, and C 1-3 -R consisting of alkyl (optionally substituted with 1 to 3 F)3 - selected from group G2, R 4 But C 1-6 -R consisting of alkyl 4 - selected from the G2a group, 1-6 -Alkyl is optionally substituted with 1 to 3 F; -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 -OC 1-2 -alkyl (optionally substituted with 1 to 3 F), or R 4 But -C 0-2 -Alkylene-C 3-8 -cycloalkyl and -C 0-2 -Alkylene-C 3-8 -R consisting of heterocyclyl 4 - selected from the G2b group, wherein the cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems; the heterocyclyl contains one ring member selected from N, NH, and O; The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with Cl, —CN, OCH 3 , C.H. 3 and C.H. 2 CH 3 or may be substituted by 1 to 2 substituents independently selected from or R 4 But -C 0-2 -alkylene-phenyl and -C 0-2 -alkylene-heteroaryl 4 - selected from the G2c group, The alkylene is 1 to 2 CH 3 and optionally substituted by One of the alkylene groups >CH 2 The two H atoms in the group are ethylene (-CH 2 -CH 2 -) bridge, the cyclopropylene moiety >C(-CH 2 -CH 2 -), the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally containing an additional N ring member, or a 6-membered monocyclic ring containing one to two N ring members; The phenyl and heteroaryl are F, Cl, Br, —CN, —OC 1-3 -alkyl (optionally substituted with 1 to 3 F), and C 1-3 -Alkyl (with 1 to 3 F, or -CN and -OC 1-2 -alkyl), or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached form a 3- to 8-membered saturated monocyclic heterocyclyl; R 3 / 4 -G2a group, and the 3- to 8-membered saturated monocyclic heterocyclyl is >NH, >N(C 1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 -alkyl) and O, and may further contain one ring member selected from >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl does not have NS(=O) between ring members. r=1,2 does not contain heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 2 F. 1 to 4 C's 1-3 -alkyl (optionally substituted with 2 to 3 F); Cl, -CN, -CON(C 1-4 -alkyl) 2 , -COO-C 1-4 -Alkyl, C 1-3 -Alkyl-OC 1-3 -Alkylene- and C 1-3 -alkyl-O-, or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached form a 6- to 11-membered saturated bicyclic heterocyclyl; R 3 / 4 -G2b group, and the 6- to 11-membered saturated bicyclic heterocyclyl is >N-, >NH, >N(C1-4 -alkyl), >N(CO-C 1-3 -alkyl), >N(S(=O) 2 -C 1-3 -alkyl) and O; >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have NN, NO, and NS(=O) between the ring members. r=1,2 does not contain heteroatom-heteroatom bonds other than The heterocyclyl is optionally substituted by 1 to 6 F; 1 to 4 C's 1-3 -alkyl (optionally substituted with 1 to 3 F); 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-OC 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 R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached form an 8- to 10-membered fused bicyclic ring system, R 3 / 4 - selected from the G2c group, the bicyclic ring system is a heterocyclyl or heteroaryl consisting of one non-aromatic ring and one aromatic ring, and phenyl and pyridine; the non-aromatic ring contains the amide N atom and optionally contains one ring member selected from =N-, >N- and O; the aromatic ring is selected from five-membered monocyclic rings containing one ring member selected from N, NH, O, and S, and optionally containing one further ring member N; the bicyclic ring system is optionally substituted by 1-2 F; 1-2 C's 1-2 -alkyl (optionally substituted with 1 to 3 F); Cl and C 1-2 -alkyl-O-(optionally substituted by 1 to 3 F), The compound or salt thereof according to one or more of the above [1] to [3]. 〔5〕R 3 But, H, and C 1-3 -R consisting of alkyl (optionally substituted with 1 to 3 F) 3 - selected from group G2, R 4 But C 1-4 -R consisting of alkyl 4 - selected from the G3a group, 1-4 -Alkyl is optionally substituted with 1 to 3 F; -CN, -CONH 2 , -COOH, OH and -OC 1-2 -alkyl (optionally substituted with 1 to 3 F), or R 4 But -C 0-1 -Alkylene-C 3-6 -R consisting of cycloalkyl 4 - selected from the group G3b; said cycloalkyl is a saturated monocyclic or bicyclic ring system; The cycloalkyl may be substituted with 1 to 2 F and 1 CH 3 or CH 2 CH 3 or may be substituted by or R 4 But -C 0-1 -alkylene-phenyl and -C 0-1 -alkylene-heteroaryl 4 - selected from the G3c group, One of the alkylene groups >CH 2 The two H atoms in the group are ethylene (-CH 2 -CH 2 -) bridge, the cyclopropylene moiety >C(-CH 2 -CH 2 -), the heteroaryl is a 5- to 6-membered monocyclic ring containing one ring member =N-, optionally containing one ring member selected from =N-, >NH, S, and O; The phenyl and heteroaryl are selected from the group consisting of F, Cl, —CN, OCH 3 , O.C.H.F. 2 , OCF 3 , C.H. 3 , CHF 2 and CF 3 or may be substituted by 1 to 3 substituents independently selected from or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached form a 4- to 6-membered saturated monocyclic heterocyclyl which may contain one ring member O that is not adjacent to the amide N atom; R 3 / 4 - selected from the group G4a, The heterocyclyl may be substituted by two F and one to two CH 3 or may be substituted by or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached form a 6- to 10-membered saturated bridged bicyclic or spiro bicyclic heterocyclyl which may contain one ring member O that is not adjacent to the amide N atom; R 3 / 4 - selected from the G4b group; or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached form an 8-9 membered fused bicyclic heteroaryl, R 3 / 4 - selected from the G3c group, the heteroaryl consists of one non-aromatic ring containing the amide N atom, which optionally contains one ring member >N- that is not adjacent to the amide N atom, and one pyrazolo or imidazolo ring; The heteroaryl is selected from the group consisting of 1 to 2 CH 3 optionally substituted by The compound or salt thereof according to one or more of the above [1] to [4]. 〔6〕R 3 But, H, CH 3 and C.H. 2 CH 2 CH 3 R consisting of 3 - selected from the G3 group, R 4 but, JPEG0007810743000152.jpg26150 R consisting of 4 - selected from the group G5a or R 4 but, JPEG0007810743000153.jpg48170 R consisting of 4 - selected from the group G4b or R 4 but, JPEG0007810743000154.jpg180170 R consisting of 4 - selected from the group G4c; or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached, JPEG0007810743000155.jpg59170 R forms a heterocyclyl selected from the group consisting of 3 / 4 - selected from group G5a; or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached, JPEG0007810743000156.jpg27170 R forms a heterocyclyl selected from the group consisting of 3 / 4 - selected from the G5b group; or R 3 and R 4 But R 3 and R 4 together with the amide N atom to which they are attached to form the following heteroaryl JPEG0007810743000157.jpg33170 Forming R 3 / 4 - selected from the group G4c The compound or salt thereof according to one or more of the above [1] to [5]. [7] The stereochemistry of the compound is represented by the formula (I.1) JPEG0007810743000158.jpg54170 The compound or salt thereof according to any one of the above [1] to [6]. [8] A pharmaceutically acceptable salt of the compound according to one or more of the above [1] to [7]. [9] A pharmaceutical composition comprising one or more compounds according to any one or more of the above [1] to [7], or a pharmaceutically acceptable salt thereof, which may also contain one or more inert carriers and / or diluents.

[10] A pharmaceutical composition comprising one or more compounds according to any one or more of [1] to [7] above or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, which may also contain one or more inert carriers and / or diluents.

[11] The pharmaceutical composition of

[10] , wherein the 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] The compound according to any one or more of the above [1] to [7] or a pharmaceutically acceptable salt thereof for use as a medicine.

[13] A method for treating ocular diseases, preferably diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy and nonexudative choroidal neovascularization, and for treating conditions and diseases related to allergies and inflammation, preferably urticaria and NASH, in a patient in need of such treatment, comprising administering to the patient one or more compounds described in any one or more of [1] to [7] above, or a pharmaceutically acceptable salt thereof.

[14] The compound according to any one or more of [1] to [7] above, or a pharmaceutically acceptable salt thereof, for use in a method for treating ocular diseases, preferably diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy and nonexudative choroidal neovascularization, and for treating conditions and diseases associated with allergy and inflammation, preferably urticaria and NASH, wherein the method comprises administering to a patient one or more compounds according to any one or more of [1] to [7] above, or a pharmaceutically acceptable salt thereof.

[15] Use of the compound according to any one or more of [1] to [7] above or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an ocular disease, preferably diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy and nonexudative choroidal neovascularization, and for treating conditions and diseases associated with allergy and inflammation, preferably urticaria and NASH, wherein the method comprises administering to a patient one or more compounds according to any one or more of [1] to [7] above or a pharmaceutically acceptable salt thereof.

Claims

1. Compound of formula (I.0) (In the formula, R 1 is C 1-4 - alkyl (optionally substituted by 1 to 3 F) and C 3-4 -cycloalkyl, R 2 are F, Cl, Br, I, 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, and -S(O) r -C 1-4 - alkyl (r=0, 1 or 2), C as R2 group 1-4 -Alkyl may be substituted by 1 to 3 F or by one CN, one OH or one -O-C 1-4 - optionally substituted by alkyl, -O-C as R 2 group 1-4 - alkyl is optionally substituted by 1 to 3 F; n is selected from the group consisting of 0, 1, 2 and 3; R 3 is H, and C 1-4 - alkyl (optionally substituted with 1 to 5 F), R 4 is C 1-6 - alkyl, C 1-6 -Alkyl is optionally substituted by 1 to 3 F; -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 -alkyl (optionally substituted by 1 to 3 F); or R 4 is -C 0-3 -Alkylene-C 3-10 -cycloalkyl and -C 0-3 -Alkylene-C 3-10 -heterocyclyl, The alkylene is selected from F and CH 3 may be substituted by 1 to 2 substituents selected from One of the alkylene groups >CH 2 The two H atoms in the group are ethylene (-CH 2 -CH 2 -) bridge, and the cyclopropylene moiety > C(-CH 2 -CH 2 -), The cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems, The heterocyclyl may be N, NH, >N(C 1-4 -alkyl), >NCO(C 1-4 -alkyl), >NS(=O) 2 (C 1-4 -alkyl) and O, and contains 1 to 2 ring members independently selected from >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may have N-N, N-O and N-S(=O) between ring members. r=1,2 does not contain heteroatom-heteroatom bonds other than The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with Cl, —CN, —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 (optionally substituted by 1 to 3 F), and C 1-4 - alkyl (with 1 to 3 F or -CN, OH, -O-C 1-4 -alkyl), or R 4 is -C 0-3 -alkylene-phenyl and -C 0-3 -alkylene-heteroaryl; The alkylene is selected from F and CH 3 may be substituted by 1 to 2 substituents selected from One of the alkylene groups >CH 2 The two H atoms in the group are ethylene (-CH 2 -CH 2 -) bridge, and the cyclopropylene moiety > C(-CH 2 -CH 2 -), the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally containing 1 to 2 additional N ring members, or a 6-membered monocyclic ring containing 1 to 2 N ring members; The phenyl and heteroaryl are F, Cl, Br, 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 (optionally substituted by 1 to 3 F), and C 1-4 - alkyl (with 1 to 3 F or -CN, OH and -O-C 1-4 -alkyl) or a pharmaceutically acceptable salt thereof.

2. R 1 But CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CHF 2 , C.F. 3 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: and cyclopropyl.

3. R 1 But CH 3 2. The compound of claim 1, wherein:

4. R 2 is F, Cl, Br, CH 3 , C.H. 2 CH 3 , cyclopropyl, CF 3 , C.H. 2 OH, OH, OCH 3 , and S-CH 3 is selected from the group consisting of n is selected from the group consisting of 0, 1 and 2; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. R 2 is selected from the group consisting of F, Cl and Br; n is 1; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. R 2 is Cl, n is 1; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. R 1 But CH 3 and R 2 , n, and the phenyl substitution pattern such that the resulting substituted phenyl ring shown in formula (I.0) is selected so that 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. R 3 But H, CH 3 and C.H. 2 CH 2 CH 3 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

9. R 4 But C 1-4 - alkyl, C 1-4 -Alkyl may be substituted with 1 to 3 F, -CN, -CONH 2 , —COOH, OH and —O—C 1-2 - alkyl (optionally substituted by 1 to 3 F), 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. R 4 But C 1-4 - alkyl, C 1-4 -Alkyl is F, OH and OCF 3 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, optionally substituted with one substituent selected from:

11. R 4 but, 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

12. R 4 But, -C 0-1 -Alkylene-C 3-6 -cycloalkyl, said cycloalkyl is a saturated monocyclic or bicyclic ring system; The cycloalkyl may be substituted with 1 to 2 F and one CH 3 or CH 2 CH 3 optionally substituted by 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. R 4 but, 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

14. R 4 But, -C 0-2 -alkylene-phenyl and -C 0-2 -alkylene-heteroaryl; The alkylene is a group having 1 to 2 CH 3 and optionally substituted by One of the alkylene groups >CH 2 The two H atoms in the group are ethylene (-CH 2 -CH 2 -) bridge, and the cyclopropylene moiety > C(-CH 2 -CH 2 -), the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally containing one additional N ring member, or a 6-membered monocyclic ring containing 1 to 2 N ring members; The phenyl and heteroaryl are F, Cl, Br, —CN, —O—C 1-3 - alkyl (optionally substituted by 1 to 3 F), and C 1-3 -alkyl (optionally substituted by 1 to 3 F or by one substituent selected from -CN and -O-Ci_2-alkyl), 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. R 4 but, 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

16. The stereochemistry of the compound is 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof,

17. 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. A pharmaceutically acceptable salt of the compound of any one of claims 1 to 16.

19. The compound described in claim 17, which is:

20. The compound described in claim 17, which is:

21. The compound described in claim 17, which is:

22. The compound described in claim 17, which is

23. The compound described in claim 17, which is

24. The compound described in claim 17, which is:

25. The compound described in claim 17, which is:

26. 18. A pharmaceutically acceptable salt of the compound of claim 17, wherein the compound is A pharmaceutically acceptable salt thereof.

27. 18. A pharmaceutically acceptable salt of the compound of claim 17, wherein the compound is A pharmaceutically acceptable salt thereof.

28. 18. A pharmaceutically acceptable salt of the compound of claim 17, wherein the compound is A pharmaceutically acceptable salt thereof.

29. 18. A pharmaceutically acceptable salt of the compound of claim 17, wherein the compound is A pharmaceutically acceptable salt thereof.

30. 18. A pharmaceutically acceptable salt of the compound of claim 17, wherein the compound is A pharmaceutically acceptable salt thereof.

31. 18. A pharmaceutically acceptable salt of the compound of claim 17, wherein the compound is A pharmaceutically acceptable salt thereof.

32. 18. A pharmaceutically acceptable salt of the compound of claim 17, wherein the compound is A pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 17 or 19 to 25, and / or one or more pharmaceutically acceptable salts according to any one of claims 18 or 26 to 32, optionally together with one or more inert carriers and / or diluents.

34. 32. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 17 or 19 to 25, and / or one or more pharmaceutically acceptable salts according to any one of claims 18 or 26 to 32, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

35. 35. The pharmaceutical composition of claim 34, wherein the 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 allergy- and inflammation-related conditions and diseases.

36. The pharmaceutical composition according to any one of claims 33 to 35, for preventing or treating an eye disease.

37. 37. The pharmaceutical composition of claim 36, wherein the ocular disease to be prevented or treated is selected from the group consisting of diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy, and nonexudative choroidal neovascularization.

38. A pharmaceutical composition according to any one of claims 33 to 35 for preventing or treating conditions and diseases associated with allergies and inflammation.

39. 39. The pharmaceutical composition of claim 38, wherein the allergy- and inflammation-related condition and disease to be prevented or treated is hives or NASH.

40. Use of a compound according to any one of claims 1 to 17 or 19 to 25 or a pharmaceutically acceptable salt according to any one of claims 18 or 26 to 32 in the preparation of a medicament for preventing or treating an eye disease.

41. 41. The use of claim 40, wherein the ocular disease to be prevented or treated is selected from the group consisting of diabetic macular edema, dry and exudative age-related macular degeneration, geographic atrophy, and nonexudative choroidal neovascularization.

42. 36. Use of a compound according to any one of claims 1 to 17 or 19 to 25 or a pharmaceutically acceptable salt according to any one of claims 18 or 26 to 32 in the preparation of a medicament for the prevention or treatment of conditions and diseases associated with allergy and inflammation.

43. 43. The use of claim 42, wherein the allergy and inflammation related condition and disease to be prevented or treated is urticaria or NASH.

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