Cyclopentathiophene carboxamide derivatives as platelet-activating factor receptor antagonists

Abstract

Cyclopentathiophene carboxamide (R 1 , R 2 , R 3 , R 4 and n are as defined in the description and claims), and pharma- ceutically acceptable salts thereof, can be used in methods of treating diseases that can be affected by antagonizing activity mediated by the platelet-activating factor receptor. JPEG2025501761000185.jpg5053

Description

[Technical field]

[0001] The present invention relates to novel cyclopentathiophene carboxamide derivatives and pharma- ceutical acceptable salts thereof, which are platelet activating factor receptor antagonists.Furthermore, the present invention relates to pharmaceutical compositions and combinations comprising said 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 conditions and diseases related to ophthalmic diseases, allergies and inflammation, in particular 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, such as platelets, macrophages, monocytes, neutrophils, basophils, eosinophils, mast cells, and endothelial cells. PAF, PAF-like lipids (PAFLL), and some oxidized phospholipids are structurally well-defined ligands of the PAF receptor (PAFR), a G protein-coupled receptor. Expression of PAFR is restricted to certain target cells of 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 great relevance in ophthalmic diseases, cardiovascular diseases, cancer, neurological and neurodegenerative disorders, renal disorders, liver diseases and allergies.Therefore, for example, the inhibition of PAFR activation by PAFR antagonists is believed to be useful for treating a wide range of disorders that can be affected by antagonizing PAFR, for example, as mentioned hereinbefore and hereinafter.In particular, PAFR antagonists should be useful for preventing or treating ophthalmic diseases, such as atrophic or wet age-related macular degeneration, and geographic atrophy or allergy, and inflammation-related disorders, such as urticaria and non-alcoholic steatohepatitis (NASH). PAFR antagonists suitable for therapeutic use should bind to PAFR potently and with high selectivity. PAFR antagonists should be well absorbed from the gastrointestinal tract, have sufficient metabolic stability, and have favorable pharmacokinetic properties. They should be non-toxic and have demonstrated no or few side effects.

[0003] Low molecular weight PAFR antagonists are known in the art, for example the compounds described in European Patent Application Publication Nos. 0194416, 0254245, 0368175 and 0480455 by Weber et al. (Med. Res. Rev.1989, 9, 181-218), Miyazawa et al. (Chem. Pharm. Bull. 1991, 39, 3215-3220) and Summers et al. (Curr. Pharm. Des. 1995, 1, 161-190). The thienotriazolodiazepine class of compounds disclosed therein has been reported to undergo hydrolysis in acidic solutions (e.g., Gallo et al., J. Heterocyclic Chem. 1988, 25, 867-869; Legouin et al., J. Heterocyclic Chem. 2000, 37, 127-129).

[0004] Additional methods useful for the synthesis and characterization of the above and related compounds are disclosed in EP 0 388 789, Sung et al. (Archiv der Pharmazie 1996, 329, 291-300), Fier et al. (Org. Lett. 2017, 19, 1454-1457), Brenna et al. (Green Chem. 2017, 19, 5122-5130), Filippakopoulos et al. (Nature 2010, 468, 1067-1073), Syeda at al. (Tetrahedron Lett. 2015, 56, 3454-3457) and Yeo et al. (Br. J. Clin. Pharmacol. 2004, 57, 687-688). Summary of the Invention

[0005] In a first aspect, the present invention provides a compound of formula (I) [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, n is selected from the group n-G1 consisting of 0, 1, 2 and 3; R 2 is R 2 - independently selected from group G1, 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), 3-4 -Cycloalkyl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4-alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, NH 2 , OH, -OC 1-4 -alkyl (optionally substituted with 1 to 3 F), -S(O) r -C 1-4 -alkyl (r=0, 1 or 2), 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, -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 by 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 one or two substituents selected from One of the alkylene groups is >CH 2 The base is [ka] may be replaced by a part, 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), >NCOO(C 1-4 -alkyl), >NS(=O) 2 (C 1-4 -alkyl), >N-phenyl, >N-pyridinyl, >N-pyrimidinyl and O, and contains 1 to 2 ring members independently selected from >C=O, >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may not include NN, NO, or 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 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), >S(=O) 2 -C 1-4 -Alkyl 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 group G1c; The alkylene is selected from F and CH 3may be substituted with one or two substituents selected from One of the alkylene groups is >CH 2 The base is [ka] Part or [ka] may be replaced by a moiety, or One of the alkylene groups is -CH 2 -CH 2 The - group is [ka] Part or [ka] may be replaced by a part, the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing 1 to 2 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), -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 4 R is a 7- to 12-membered fused bicyclic aryl, heteroaryl, or heterocyclyl. 4 - selected from the group G1d, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I) 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), and one aromatic ring selected from phenyl, pyrrole, furan and thiophene, in each of which one to two CH ring members are optionally replaced by N; The bicyclic aryl, heteroaryl or heterocyclyl is optionally substituted by 1 to 4 F; 1 to 4 C optionally substituted by 1 to 4 F 1-3 - optionally substituted by alkyl, 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-, NH 2 , 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 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 -G1a group, 3-8 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, >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may not include NN, NO, or 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, -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 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 not include NN, NO, or 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, -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-, Unless otherwise specified in any definition referred to herein earlier, any alkyl or alkylene group may be linear or branched. Isomers, stereoisomers, tautomers, metabolites, prodrugs, solvates, hydrates, cocrystals, and salts thereof, particularly pharma- ceutically 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) as defined hereinbefore or hereinafter, or a pharma- ceutically 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) as defined hereinbefore or hereinafter, or a pharma- ceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

[0008] In a fourth aspect, the present invention relates to a compound of formula (I) as defined hereinbefore or hereinafter, or a pharma- ceutically 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 the platelet activating factor receptor, in a patient in need thereof, comprising the step of administering to the patient one or more compounds of formula (I) as defined hereinbefore or hereinafter, or a pharma- ceutically acceptable salt thereof. Furthermore, the invention relates to the use of one or more compounds of formula (I) as defined hereinbefore or hereinafter, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition that can be affected by antagonizing the platelet activating factor receptor. Furthermore, the invention relates to a compound of formula (I) as defined hereinbefore or hereinafter, or a pharma- ceutically acceptable salt thereof, for use in a method of treating a disease or condition that can be affected by antagonizing the platelet activating factor receptor in a patient in need thereof. Further aspects of the present invention will be apparent to those skilled in the art from the foregoing and following description as well as from the examples directly.

[0010] General Terms and Definitions Terms not specifically defined herein should be given the meanings that would be given to 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 meanings indicated and follow the following conventions: The terms "compound according to the invention", "compound of formula (I)", "compound of the invention" and the like mean compounds of formula (I) according to the invention, including their tautomers, stereoisomers and mixtures thereof, and salts thereof, in particular 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.

[0011] 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 different ratios of the 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 pharma- ceutically acceptable salts thereof, and solvates thereof (e.g., solvates of the free compounds or hydrates, including solvates of salts of the compounds). The phrase "pharmacologically 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, where 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.

[0012] 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 pharma- ceutically 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 in an organic diluent, such as ether, EtOAc, EtOH, isopropanol, or MeCN, or mixtures thereof. For example, salts of acids other than those mentioned above that are useful for purifying or isolating the compounds of the invention (eg, trifluoroacetates) also form part of the 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.

[0013] In the groups, radicals or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C 1-6 -Alkyl means an alkyl group or radical having 1 to 6 carbon atoms. An asterisk may be used in a subformula 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 subformula, these asterisks may be further specified by a parenthetical indication of the attachment portion 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.

[0014] 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 group: [ka] The term "substituted," as used herein, means that one or more hydrogens on the designated atom are replaced with a chemical group selected from the defined group of substituents, provided that the normal valence of the designated atom is not exceeded and that the substitution results in an acceptably stable compound. Similarly, the term "substituted" may be used in connection with chemical moieties in place of a single atom, such as "substituted alkyl," "substituted aryl," and the like.

[0015] In the definitions of groups, terms such as "X, Y and Z groups each may be optionally substituted" mean that each of the X groups, each of the Y groups and each of the Z groups may each be substituted as defined, either as an individual group or as part of the group of which each is composed. ex , 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 selected from one or more L ex " may be substituted with" 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 portion is as defined ex It means that it may be substituted by:

[0016] 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 H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH2 -, H 3 CC(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -CH 2 -, H 3 C-CH 2 -C(CH 3 ) 2 -, H 3 CC(CH 3 ) 2 -CH 2 -, H 3 C-CH(CH 3 )-CH(CH 3 )- and H 3 C-CH 2 -CH(CH 2 CH 3 )-Includes. 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 saturated alkyl radical having 1 to n carbon atoms. For example, the term C 1-4 -Alkylene includes -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -CH(CH 3 )-CH 2 -, -CH2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -, -CH(CH 3 )-CH(CH 3 )-, -CH 2 -CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )-CH 2 -, -CH(CH 2 CH 2 CH 3 )-, -CH(CH(CH 3 )) 2 - and -C(CH 3 )(CH 2 CH 3 )- is included.

[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 may 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 any heterocyclic group selected from N, O, and 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 the possible isomers. 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] [ka]

[0019] The term "aryl," as used herein, either alone or in combination with another radical, refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further fused to a second 5- or 6-membered carbocyclic group, which is aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, and dihydronaphthyl.

[0020] The term "heteroaryl" refers to any heteroaryl group selected from N, O, or S(O) r (r=0, 1 or 2) and at least one aromatic ring of 5-14 ring atoms, where at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all possible isomers. 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:

[0021] [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 formulas or groups and in each case have, independently of 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 a patient who already suffers from one or more of the above conditions in their initial, acute or chronic form. Therapeutic treatment can be symptomatic treatment to alleviate the symptoms of a particular indication, or causal treatment to reverse or partially reverse the indication 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, so as 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, as well as to alleviate the symptoms or complications associated with a disease, condition or disorder. Where the present invention refers to a patient in need of treatment, the invention is primarily concerned with treatment in mammals, particularly humans. 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 PREFERRED EMBODIMENTS

[0025] 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, allergies and NASH.

[0026] The compounds of the present invention may realize several advantages, such as increased potency, increased metabolic and / or chemical stability, increased selectivity, safety and tolerability, increased solubility, increased permeability, desirable plasma protein binding, enhanced bioavailability and improved pharmacokinetic profiles.

[0027] Compounds of the Invention In a first aspect of the present invention, a compound of formula (I) [ka] (In the formula, R 1 , R 2 , R 3 , R 4It has been found that the compounds according to the present invention (where n and n are 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, and bioavailability. In particular, they surprisingly provide high potency in vitro as PAFR antagonists, and they show good efficacy in vivo in animal models of choroidal neovascularization. Furthermore, the compounds according to the present invention show advantageous chemical stability, especially at low pH values. They advantageously show low cytotoxicity and balanced metabolism, i.e., their metabolism is not mainly mediated by one single cytochrome P450 (CYP) enzyme such as CYP3A4, and therefore the risk of associated drug-drug interactions is low. At the same time, their renal clearance remains reasonably low.

[0028] Accordingly, compounds of formula (I) as defined hereinbefore or hereinafter, or a pharma- ceutically acceptable salt thereof, are expected to be useful in the treatment of diseases and / or conditions which may be affected by PAFR antagonism. Surprisingly, the compound of formula (I) can also be shown to bind exclusively to melanin, which affects the biodistribution and pharmacokinetic properties of the compound; in particular, this leads to the accumulation of the compound in the eye, resulting in prolonged drug retention.Therefore, the compound of the present invention can be particularly suitable for treating eye diseases. Thus, according to one aspect of the invention, a compound of formula (I) [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 pharma- ceutically acceptable salts thereof, are provided.

[0029] 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 of the preferred meanings of and n, as well as the phenyl substitution patterns, are presented hereinafter as embodiments of the present invention. Any of these definitions and embodiments may be combined with each other.

[0030] 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 of 1 - selected from group G1. According to another embodiment, R 1 teeth, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CHF 2 , C.F. 3 and cyclopropyl R consisting of 1 - selected from group G2. According to another embodiment, R 1 teeth, CH 3 and C.H. 2 CH 3 R consisting of 1 - selected from the group G3. According to another embodiment, R1 is CH 3 R consisting of 1 - selected from the group G4. According to another embodiment, R 1 is CH 2 CH 3 R is selected from 1 - selected from the group G5.

[0031] 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.

[0032] R 2 : More than one substituent R 2 When is present in compounds of formula (I), i.e. when n=2 or 3, R 2 R 2 -G1 group~R 2 - selected independently from the group G6. According to one embodiment, R 2 is R 2 - independently selected from group G1, R 2 -G1 group: 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), 3-4 -Cycloalkyl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, NH2 , OH, -OC 1-4 -alkyl (optionally substituted with 1 to 3 F), -S(O) r -C 1-4 -alkyl (r=0, 1 or 2).

[0033] According to another embodiment, R 2 is R 2 - independently selected from group G2, 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, NH 2 , OH, -OC 1-3 -alkyl (optionally substituted by 2 or 3 F); 1-3 - alkyl. According to another embodiment, R 2 is R 2 - independently selected from group G3, R 2 -G3 group is Cl, Br, CH 3 , -CN,NH 2 , OH and OCH 3 It consists of: According to another embodiment, R 2 R is Cl, Br and -CN, preferably Cl. 2 - independently selected from the group G4.

[0034] According to another embodiment, R 2 is CH 3 and OCH 3 R consisting of 2 - independently selected from the group G5. According to another embodiment, R 2 NH 2 and R consisting of OH 2 - independently selected from the group G6.

[0035] Phenyl Substitution Pattern: In describing the substitution pattern of the phenyl ring shown in formula (I), the following carbon atom numbering is used: [ka] In general, n substituents R 2 can each be bonded to any of the carbon atoms C-2 to C-6, and any combination thereof. For n=1, according to one embodiment, R 2 is attached to carbon atom 2. For n=2, according to one 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) is [ka] The nucleotide sequence is selected from the Ph-G1 group consisting of: According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I) is [ka] The nucleotide sequence is selected from the Ph-G2 group consisting of: According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I) is [ka] Preferably [ka] The nucleotide sequence is selected from the Ph-G3 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) is [ka] The nucleotide sequence is selected from the group Ph-G4 consisting of: According to another embodiment, R 2 , n and the phenyl substitution pattern are such that the resulting substituted phenyl ring shown in formula (I) is [ka] The nucleotide sequence is selected from the group Ph-G5 consisting of:

[0038] 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 H, CH 3 , C.H. 2 CH 3 and C.H. 2 CH 2 CH 3 R consisting of 3 - selected from the group G3. According to another embodiment, R 3 is R consisting of H 3 - selected from the group G4. According to another embodiment, R 3 is CH 3 , C.H. 2 CH 3 and C.H. 2 CH 2 CH 3 R consisting of 3 - selected from the group G5. 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, -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 by 1 to 3 F).

[0039] According to another embodiment, R 4 is C 1-6 -R consisting of alkyl 4 - selected from the group G2a, 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). According to another embodiment, R 4 is C 1-4 -R consisting of alkyl 4 - selected from the group G3a, 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). According to another embodiment, R 4 is C 1-4 -R consisting of alkyl 4 -G4a group, 1-4 -Alkyl is F and OCF 3 may be substituted with one group selected from

[0040] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - selected from the group G5a.

[0041] 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 is selected from F and CH 3 may be substituted with one or two substituents selected from One of the alkylene groups is >CH 2 The base is [ka] may be replaced by a part, 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), >NCOO(C 1-4 -alkyl), >NS(=O) 2 (C 1-4 -alkyl), >N-phenyl, >N-pyridinyl, >N-pyrimidinyl and O, and contains 1 to 2 ring members independently selected from >C=O, >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may not include NN, NO, or 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 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), >S(=O) 2 -C 1-4 -Alkyl and C 1-4 -Alkyl (with 1 to 3 F or -CN, OH, -OC 1-4 -alkyl).

[0042] According to another embodiment, R 4 -C 0-2 -Alkylene-C 3-8 -cycloalkyl and -C 0-2 -Alkylene-C 3-9 -R consisting of heterocyclyl 4 - selected from group G2b; The cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems, The heterocyclyl is N, NH, >NCOCH 3 ,>NCOO(C 1-2 -alkyl), >NS(=O) 2 CH 3 , >N-pyrimidinyl, O and >S(=O) 2 and containing one ring member selected from The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with -CN, OH, -OCH 3 ,>S(=O) 2 CH 3 and C 1-3 -Alkyl (with 2-3 F or -CN, OH, -OC 1-4 -alkyl).

[0043] According to another embodiment, R 4 -C 0-1 -Alkylene-C 3-7 -Cycloalkyl and C 3-9 -R consisting of heterocyclyl 4 - selected from the group G3b; The cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems, The heterocyclyl is N, NH, >NCOCH 3 ,>NCOO(C 1-2 -alkyl), >NS(=O) 2 CH 3 , >N-pyrimidinyl, O and >S(=O) 2 and containing one ring member selected from

[0044] The cycloalkyl may be substituted by 1 to 2 F or 1 to 2 CH 3 may be substituted by a group or CH 2 CH 3 , -CN, CH 2 OH, C(CH 3 )2 OH, CHF 2 , C.F. 3 , OH, -OCH 3 and >S(=O) 2 CH 3 and optionally substituted with one substituent selected from The heterocyclyl may be substituted by 2 F or 1 to 2 CH 3 may be substituted by a group or CH 2 CH 3 and C(CH 3 ) 2 H. According to another embodiment, R 4 teeth,

[0045] [ka] [ka] R consisting of 4 -G4b group.

[0046] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G5b group.

[0047] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G6b group.

[0048] According to another embodiment, R 4 teeth, [ka] R consisting of4 -G7b group.

[0049] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G8b group.

[0050] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G9b group.

[0051] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - selected from the group G10b.

[0052] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G11b group.

[0053] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - selected from the group G12b.

[0054] According to another embodiment, R 4 teeth, [ka] R consisting of4 - selected from the group G13b.

[0055] According to another embodiment, R 4 teeth, [ka] R consisting of 4 - selected from the group G14b. According to one embodiment, R 4 -C 0-3 -alkylene-phenyl and -C 0-3 -alkylene-heteroaryl 4 - selected from the group G1c; The alkylene is selected from F and CH 3 may be substituted with one or two substituents selected from

[0056] One of the alkylene groups is >CH 2 The base is [ka] Part or [ka] may be replaced by a moiety, or

[0057] One of the alkylene groups is -CH 2 -CH 2 The - group is [ka] Part or [ka] may be replaced by a part, the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing 1 to 2 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), -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).

[0058] 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 is 1 to 2 CH 3 and optionally substituted by One of the alkylene groups is >CH 2 The base is [ka] Part or [ka] may be replaced by a moiety, or

[0059] One of the alkylene groups is -CH 2 -CH 2 The - group is [ka] Part or [ka] may be replaced by a part, The heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and may further contain one 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, -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).

[0060] According to another embodiment, R 4 -C 1-2 -alkylene-phenyl and C 0-1 -alkylene-heteroaryl 4 - selected from the group G3c, One of the alkylene groups is >CH 2 The base is [ka] Part or [ka] may be replaced by a moiety, or

[0061] One of the alkylene groups is -CH 2 -CH 2 The - group is [ka] Part or [ka] may be replaced by a part, The heteroaryl is a 5- to 6-membered monocyclic ring containing one ring member =N-, and optionally containing one ring member independently selected from =N- and O; The phenyl and heteroaryl are F, Cl, OCH 3 and C.H. 3 may be substituted with 1 to 2 substituents independently selected from:

[0062] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G4c group.

[0063] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G5c group.

[0064] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G6c group.

[0065] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G7c group.

[0066] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G8c group.

[0067] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G9c group.

[0068] According to one embodiment, R 4 R is a 7- to 12-membered fused bicyclic aryl, heteroaryl, or heterocyclyl. 4 - selected from the group G1d, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I) 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) and one aromatic ring selected from phenyl, pyrrole, furan and thiophene, in each of which one to two CH ring members are optionally replaced by N; The bicyclic aryl, heteroaryl or heterocyclyl is optionally substituted by 1 to 4 F; 1 to 4 C optionally substituted by 1 to 4 F 1-3 - optionally substituted by alkyl, 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-, NH 2 , 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) may be optionally substituted by 1 to 2 substituents selected from the group consisting of:

[0069] According to another embodiment, R 4 R is an 8- to 11-membered fused bicyclic aryl, heteroaryl, or heterocyclyl. 4 - selected from the G2d group, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I) is >N-, >NH, >NCH 3 , >NCOCH 3 ,>NS(=O) 2 CH 3 and O, C=O and S(=O) 2 one non-aromatic ring, which may contain one ring member selected from and one aromatic ring selected from phenyl, pyrrole, furan and thiophene, in each of which one CH ring member may be replaced by N; The bicyclic aryl, heteroaryl or heterocyclyl is optionally substituted by 1 to 2 F; 1 to 2 C optionally substituted by 1 to 2 F 1-2 - optionally substituted by alkyl, Cl, -CN, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2, -COOH, -COO-C 1-2 -Alkyl, HO-C 1-3 -Alkylene-, CH 3 -OC 1-3 -Alkylene-, NH 2 , C.H. 3 -CO-NH-, CH 3 -S(=O) 2 -NH-, OH and CH 3 -alkyl-O- (optionally substituted with 1 to 3 F).

[0070] According to another embodiment, R 4 R is a 9- to 10-membered fused bicyclic aryl, heteroaryl, or heterocyclyl. 4 -G3d group, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I), which may contain one ring member selected from >N- and O and consisting of one aromatic ring selected from phenyl, pyridine, pyrazole and thiazole; The bicyclic aryl, heteroaryl or heterocyclyl is selected from the group consisting of F, CH 3 , C.H. 2 CH 3 , -CN,NH 2 and OH.

[0071] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G4d group.

[0072] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G5d group.

[0073] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G6d group.

[0074] According to another embodiment, R 4 teeth, [ka] R consisting of 4 -G7d group.

[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 form a 3- to 8-membered saturated monocyclic heterocyclyl; R 3 / 4 -G1a group, 3-8 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, >C=O and >S(=O) r (r=0, 1 or 2), However, the heterocyclyl may not include NN, NO, or 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, -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 with 1 to 3 F).

[0076] According to one embodiment, R 3 and R 4 is R 3 and R 4 R, taken together with the amide N atom to which they are attached, form a 4- to 7-membered saturated monocyclic heterocyclyl 3 / 4 -G2a group, wherein the 4- to 7-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) 2 and may contain one ring member selected from However, the heterocyclyl does not have 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 2 F. 1 to 2 C optionally substituted by 2 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CON(C 1-3 -alkyl) 2 , -COO-C1-3 -Alkyl, C 1-3 -Alkyl-OC 1-3 -Alkylene- and C 1-3 -alkyl-O-.

[0077] According to one embodiment, R 3 and R 4 is R 3 and R 4 R, taken together with the amide N atom to which they are attached, form a 4- to 6-membered saturated monocyclic heterocyclyl 3 / 4 -G3a group, wherein the 4- to 6-membered saturated monocyclic heterocyclyl is may further contain one ring member O that is not adjacent to the amide N atom, The heterocyclyl may be substituted by 1 to 2 F or 1 to 2 CH 3 may be substituted by:

[0078] 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 to form a heterocyclyl R 3 / 4 -G4a group, heterocyclyl is [ka] is selected from the group consisting of:

[0079] 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] Form R 3 / 4 - selected from the group G5a.

[0080] According to one embodiment, R3 and R 4 is R 3 and R 4 together with the amide N atom to which they are attached, are heterocyclyl; [ka] R 3 / 4 - selected from the group G6a.

[0081] 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 to form a heterocyclyl R 3 / 4 -G7a group, heterocyclyl is [ka] is selected from the group consisting of:

[0082] 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 not include NN, NO, or 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, -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-.

[0083] According to one embodiment, R 3 and R 4 is R 3 and R 4 R, taken together with the amide N atom to which they are attached, form a 6- to 11-membered saturated bicyclic heterocyclyl 3 / 4 -G2b group, wherein 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), with the proviso that said heterocyclyl does not contain any O-S bonds between ring members, The heterocyclyl is optionally substituted by 1 to 4 F. 1 to 3 C optionally substituted by 1 to 3 F 1-3- optionally substituted by alkyl, 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-.

[0084] According to one embodiment, R 3 and R 4 is R 3 and R 4 R, taken 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. 3 / 4 -G3b group, 6- to 11-membered saturated bridged bicyclic heterocyclyl or spiro bicyclic heterocyclyl is Not adjacent to the amide N atom, >N-, >NH, >N(C 1-4 -alkyl) and O, The heterocyclyl is optionally substituted by 1 to 2 F. 1 to 2 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CON(C 1-3 -alkyl) 2 , -COO-C 1-3 -Alkyl, C 1-3 -Alkyl-OC 1-3 -Alkylene- and C 1-3 -alkyl-O-.

[0085] 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 8-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 -G4b group.

[0086] 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 3 / 4 -G5b group.

[0087] Further preferred subembodiments of the compounds of formula (I) are set forth as embodiments (Ia) to (Iz) in Table 1 below, where the above definitions of the substituents 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.

[0088] [Table 1]

[0089] In particular, embodiments (Is) to (Iz) are preferred. Particularly preferred compounds, their salts, or any solvates or hydrates thereof, are those described in the Examples section and in the Experimental Data.

[0090] preparation The compounds according to the invention and intermediates thereof 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 technical subjects of organic chemistry, especially organic synthesis. Preferably, the compounds are obtained similarly to the preparation methods described more fully hereafter in the present specification, in particular in the experimental section. In some cases, the sequence adopted in carrying out the reaction schemes can be varied. Variants of these reactions known to those skilled in the art but not described in detail herein may also be used. General methods for preparing the compounds according to the invention will be clear to those skilled in the art upon examination 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 in a similar or similar manner. Before carrying out the reaction, any corresponding functional groups in the starting compounds can be protected using conventional protecting groups. These protecting groups can 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.

[0091] Advantageously, the compounds according to the invention contain a seven-membered ring that is not asymmetrically substituted, thus avoiding the more cumbersome synthesis resulting from racemization of this moiety during synthesis, as observed in the case of asymmetrically monosubstituted seven-membered rings in structurally related compounds (Filippakopoulos et al. (Nature 2010, 468, 1067-1073); Syeda at al. (Tetrahedron Lett. 2015, 56, 3454-3457)).

[0092] Scheme 1: [ka] Scheme 1: Compounds of formula (I) can be prepared by coupling the respective acids of formula (II) (free acids or Li) with suitable coupling agents (e.g., O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-1-yloxy)tri-pyrrolidinophosphonium hexafluorophosphate (PyBOP), carbodiimide reagents, etc.) and bases (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.) in suitable solvents (e.g., DCM, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidinone) at -20°C to 100°C. + , 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 salt). 1 , R 2 , R 3 , R 4 and n have the meanings defined earlier in the specification. Alternatively, the respective carboxylic acids are converted to carboxylic acid chlorides (e.g., using oxalyl chloride or thionyl chloride in DCM) and coupled directly with amine (III) in the presence of a suitable base (e.g., triethylamine, N,N-diisopropyl-ethylamine, pyridine, etc.).

[0093] Compounds of formula (I) can also be obtained from a mixture of compounds (II) and their enantiomers by separating the two enantiomeric products according to the procedures described above by methods known to those skilled in the art, such as chromatography on chiral phases, crystallization and enzymatic derivatization.

[0094] Scheme 2 [ka] Scheme 2: Acid of formula (II) (R 1 , R 2 and n have the meanings defined hereinbefore) are preferably prepared from the corresponding esters (III) 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, such as THF, MeOH, EtOH, 1,4-dioxane, or mixtures thereof, at ambient or elevated temperature. The acids can be isolated either as salts with metal cations or as carboxylic acids. tert-Butyl esters are preferably cleaved by treatment with an acid, such as hydrochloric acid or TFA, in a suitable solvent, such as DCM, 1,4-dioxane, MeOH, EtOH, THF, water, or mixtures thereof. Benzyl esters are preferably cleaved by hydrogenolysis under a hydrogen atmosphere (preferably 1-5 bar) in a suitable solvent (eg EtOH, MeOH, THF, DCM or EtOAc) with a suitable catalyst (eg palladium on carbon).

[0095] Compounds of formula (II) can also be obtained from a mixture of compounds (III) and their enantiomers by separating the two enantiomeric products according to the procedures described above by methods known to those skilled in the art, such as chromatography on chiral phases, crystallization and enzymatic derivatization.

[0096] Scheme 3 [ka]

[0097] Scheme 3: Esters of formula (III) (R 1 , R 2and n has the meaning defined earlier in this specification) may be prepared from amides (IV) using various synthetic strategies. A more preferred procedure involves converting the amide group in (IV) 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.). The thus modified acylhydrazine (R 1 -CO-NHNH 2 ) can be added to such activated amides to give N-acylaminoamidine derivatives, which can be converted to triazoles by heating (optionally up to 140° C.).

[0098] Alternatively, the triazoles (III) can be obtained by applying a three-step procedure via the thioamide of the amide (IV), 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 This procedure, variations thereof, and alternative synthetic routes are reported in the organic chemistry literature and are known to those skilled in the art (see, for example, EP-A-0388789 and EP-A-0254245). Compounds of formula (III) can also be obtained from mixtures of compounds (IV) and their enantiomers by separating the two enantiomeric products according to the various procedures described above and by methods known to those skilled in the art, such as chromatography on chiral phases, crystallization and enzymatic derivatization.

[0099] Scheme 4 [ka]

[0100] Scheme 4: Esters of formula (IV) (R 2 and n has the meaning defined earlier in this specification) may be prepared from ketone (V) in one, two or three separate synthetic steps. A well-established synthesis of compound (IV) is via the N-(1-aminocyclopropyl)carbonyl derivative of compound (V), which can be obtained by treating compound (V) with the hydrochloride salt of 1-aminocyclopropane-1-carbonyl chloride in a suitable solvent (e.g., 1,4-dioxane) at 0° C. to 80° C. Then, a seven-membered ring is formed by reacting the amino group with the keto group with the aid of suitable additives (e.g., silica gel in toluene, pyridine in HOAc, pyridine in 1,4-dioxane and methanesulfonic acid or triluoromethanesulfonic acid) in a suitable solvent at temperatures between 0° C. and 130° C. to give compound (IV).

[0101] Compound (IV) can also be obtained from compound (V) in just one reaction step, as reported in Org. Lett. 2017, 19, 1454-1457. Compounds of formula (IV) can also be obtained from mixtures of compounds (V) and their enantiomers by separating the two enantiomeric products according to the various procedures described above and by methods known to those skilled in the art, such as chromatography on chiral phases, crystallization and enzymatic derivatization.

[0102] Scheme 5 [ka] Scheme 5: Compounds of formula (V) can be prepared from cyanoketones (VI) and ketones (VII) according to the reported protocol for the so-called Gewald reaction; R in Scheme 6 2and n have the meanings defined earlier in the specification. Thus, compounds (VI) and (VII) are combined and reacted with a base (e.g., NEt) in a solvent (e.g., MeOH, EtOH, DMF, 1,4-dioxane, etc.) at 0° C. to 120° C. in the presence of elemental sulfur. 3 , HNEt 2 , morpholine, piperidine, pyridine, etc.

[0103] Alternatively, this conversion may be carried out in two separate steps, forming a condensation product from compounds (VI) and (VII) in the first step (Knoevenagel reaction) and product (V) 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 (VI) is a known compound or can be prepared analogously to the former. The main and specific access routes to racemic compound (VII) or enantiomerically enriched or pure compound (VII) are reported in the organic chemistry literature (see, for example, EP 0388789, Archiv der Pharmazie 1996, 329, 291-300 and Green Chem. 2017, 19, 5122-5130). Racemic mixtures can be resolved into their pure enantiomers using procedures known to those skilled in the art, such as crystallization or chromatography on chiral phases.

[0104] Scheme 6 [ka]

[0105] Scheme 6: Cyanoketones of formula (VI) (R 2 and n have the meanings defined earlier in this specification) can be reacted with the corresponding ester (VIII) and deprotonated acetonitrile (NCCH) in a suitable solvent (e.g., THF, toluene, MeCN, DMF, DMSO, 1,4-dioxane, etc.) at −78° C. to 100° C. 2 -The deprotonated acetonitrile species is preferably prepared from the ester (VIII) in a solvent, preferably at −78° C. to 40° C., depending on the base used, in a suitable base (e.g., NaH, LiN i Pr 2 , LiN(SiMe 3 ) 2 , K.O. t Further synthetic routes and procedures for the preparation of compounds of formula (VI) are reported in the organic chemistry literature. The compounds of formula (I) may be resolved into their stereoisomers, as mentioned 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.

[0106] Cis / trans mixtures can be resolved into their cis and trans isomers, for example, by chromatography. Compounds of formula (I) occurring as stereoisomers can be resolved into the pure stereoisomers of general formula (I) by methods known per se, i.e. by taking advantage of the different physicochemical properties of the stereoisomers, using methods known per se, for example, chromatography and / or fractional crystallization.

[0107] The racemates are preferably resolved by column chromatography on chiral phases or by crystallization from optically active solvents or by reaction with optically active substances forming salts or derivatives such as esters or amides with the racemates. 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 are formed with enantiomerically pure auxiliary compounds, such as acids, their activated derivatives or alcohols. Separation of the diastereomeric mixtures of salts or derivatives thus obtained can be achieved by taking advantage of their various physicochemical properties, such as differences in solubility. The free antipodes can be liberated from the pure diastereomeric salts or derivatives by the action of suitable agents. The optically active acids commonly used for such purposes and the optically active alcohols applicable as auxiliary residues are known to those skilled in the art. As noted above, the compounds of formula (I) can be converted into salts, particularly pharma- ceutically acceptable salts, for use in medicines. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds where 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 the skilled person from the literature.

[0108] Pharmacological activity and suitability for pharmaceutical use The activity of the compounds of the invention, and their suitability for pharmaceutical use, can be demonstrated using the following assays: biological methods The ability of compounds of formula (I) 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

[0109] 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 at 37° C. / 5% CO for 24 h at 4° C. for 1 h at 4° C. 2 The following day, the cells are washed and then various concentrations of test compounds (compounds in 100% DMSO; final concentration of DMSO in the wells is 1%) are added to the assay plate using an Echo555 acoustic liquid handler. The plate is then incubated at 37° C. / 5% CO 2 The plates are then incubated, covered, for 90 minutes at 37°C / 5% CO. After this, PAF ligand (Cayman Chemical Company, Part Number: 60900) is added to a final concentration of 11 nM. The plates are then incubated at 37°C / 5% CO 2 Cover and incubate at 4°C for 60 min. Then add 5 μl of anti-IP1-antibody-cryptate solution per well and 5 μl of IP1-d2 solution per well to all wells of the plate and incubate the plate for another 60 min at room temperature protected from light. Measure emission at 620 nm and 665 nm (excitation wavelength: 320 nm) using an Envision reader (PerkinElmer). IC of the compounds according to the invention 50 The values ​​are shown in the table below, where the compound numbers correspond to the example numbers in the experimental section.

[0110] [Table 2]

[0111] The overall high efficacy of the compounds according to the invention is particularly surprising in view of the teachings offered by the prior art. For example, European Patent Application Publication No. 0368175 discloses a seven-membered ring >CH 2 R 5 The present invention discloses hetrazepines which are monosubstituted by R 5 It has surprisingly been found that the (-)-enantiomer of general formula Ia, where = methyl, exhibits significantly higher pharmacological potency than the (+)-enantiomer.

[0112] Specifically, in the case of Example 1, a methyl-substituted derivative of WEB2086 (apafant), the (-)-enantiomer (1B) is observed to bind 35 times more strongly to PAFR than the (+)-enantiomer (1A). This is consistent with the finding in EP 0480455 (compound B therein) that the S-configured enantiomer has several times more potent RAF antagonist activity than the racemate. Of note, the PAFR affinity of Example 1 as a racemate is reported in EP 0368175 as 16 nM, which is in the same range as the affinity of unsubstituted WEB2086 (15 nM; see Weber et al. (Med. Res. Rev.1989, 9, 181-218)). From these findings it can be concluded that one enantiomer of methylated apafant has a higher affinity than unsubstituted apafant, whereas the other enantiomer has a lower affinity than unsubstituted apafant.

[0113] [Table 3]

[0114] Similarly, European Patent Application Publication No. 0368175 discloses, as Example 9d, WEB2170 (bepafant) and its four diastereomers (-)9dA, (+)9dA, (-)9dB and (+)9dB, which are reported to have PAFR binding affinities of 70nM, 400nM, 8nM and 3000nM, respectively. For the enantiomers of bepafant, affinities of 14nM and 660nM, respectively, are described in the literature (Weber et al. (Med. Res. Rev.1989, 9, 181-218)). Similarly, in this example, it can be derived from literature data that the affinity of the isomer with only one methyl substitution is improved, while the other has a lower affinity compared to the unsubstituted parent compound.

[0115] [Table 4] Indeed, this conclusion could be demonstrated in the case of S-bepafant and its eutomers of methylated derivatives with the aid of the above-mentioned assays: one methyl-substituted isomer showed improved activity compared to S-bepafant, whereas the other methyl-substituted isomer showed significantly less activity.

[0116] [Table 5]

[0117] Similar results were reported for a related class of compounds in Miyazawa et al. (Chem. Pharm. Bull. 1991, 39, 3215-3220), who also showed that the singly methyl-substituted isomers showed stronger PAFR binding, while the other isomers showed weaker PAFR binding than the unsubstituted parent compound:

[0118] [Table 6]

[0119] As a consequence of these findings, the dimethyl- and diethyl-substituted compounds have also been described to exhibit significantly weaker binding than the unsubstituted parent compounds: [Table 7]

[0120] In summary, the prior art has 2 It is taught that monomethyl substitution of one of the H atoms of the group can provide a higher PAFR binding affinity for the hetrazepine compound, and in contrast, monomethyl substitution of the other H atom reduces the binding affinity. 2 When the group is disubstituted, weaker binding affinity is also expected.

[0121] Against this background, it is surprising that the cyclopropylene-substituted compounds according to the present invention show superior potency. In this regard, the exceptional properties of the cyclopropylene substituent are further supported by the observation that the dimethyl and cyclobutylene analogs of S-bepafant show lower potency than the cyclopropylene analog (Example 114).

[0122] [Table 8] Further pairwise comparisons of cyclopropylene and dimethylmethylene derivatives.

[0123] [Table 9-1] [Table 9-2]

[0124] EVALUATION OF THE IN VIVO EFFICACY OF AN ANIMAL MODEL OF LASER-INDUCED CHOROIDAL NEOVASCULARIZATION IN BROWN NORWAY RATS Male Brown Norway rats (BN / Crl) weighing between 160g and 180g are obtained from Charles River Labs (Sulzfeld, Germany). Animals are maintained in group housing with a 12h / 12h light / dark cycle (lights on at 6AM) and allowed to acclimate for one week before the start of the study. Animals have free access to standard chow (Provimi Kliba #3438) and tap water. Animals receive test compounds by oral gavage once daily for two weeks.

[0125] Under anesthesia, on day 1, the animal is placed in front of the fundus camera to position the optic nerve in the center of the image. Laser treatment is performed with a green argon laser (Merilas) at a wavelength of 532 nm using a Micron IV system (Phoenix Research Laboratories, Pleasanton, CA). The diameter of the laser beam is matched to the diameter of the optic nerve, and laser pulses with an energy of 400 mW and a duration of 150 ms are used to generate four lesions per eye. The lesions are placed between the large blood vessels at a distance of approximately twice the diameter of the optic nerve. Successful disruption of Bruch's membrane is recognized by the formation of an air bubble immediately after the laser beam and confirmed by OCT (optical coherence tomography) scanning.

[0126] The animals are sacrificed 14 days after the laser treatment by cervical dislocation under anesthesia. The eyes are enucleated and cut along the ora serrata. The cornea, iris, lens, vitreous and retina are removed and the remaining eye cup (consisting of PRE, choroid and sclera) is fixed in PFA (4%) for 1 h at 4° C. and then transferred to PBS containing 0.1% Triton X-100 for 1 h at 4° C. The eye cup is stained with FITC-labeled isolectin B4 (10 μg / ml in saline; obtained from Sigma Aldrich, Cat. No. L9381) overnight at room temperature in the dark and washed three times with PBS. The eye cup is transferred to a glass slide and incised four times to form a flattened cloverleaf-like 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). Flatmounts are stored at 4°C in the dark until analysis.

[0127] The samples are analyzed using a 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 measurements are performed using Zen Blue software. The efficacy readout is the lesion size stained by isolectin B4 in RPE-choroid flat mounts.

[0128] Evaluation of compound binding to melanin The ability of compounds to bind to melanin is determined using an in vitro assay using melanin from Sepia officinalis (Sigma-Aldrich, Cat. No. 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: final DMSO concentration is 1%) with a 1 mg / mL melanin suspension (to determine free compound concentration) and without melanin (to determine total compound concentration) in control buffer. The plate is incubated for 2 hours at 37° C. on an orbital shaker at 900 rpm. After incubation, the plate is 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.

[0129] Chemical stability evaluation Within the scope of solution-state stability studies, the effects of temperature, pH and light exposure are analyzed. Stress conditions are applied to obtain rapid signals of possible chemical degradation via hydrolytic, oxidative or photolytic pathways.

[0130] Typical conditions are: - in aqueous 0.1N HCl at 40°C or 60°C for 3 days - in aqueous buffer (pH 2.2) at 40°C or 60°C for 3 days - in aqueous buffer (pH 4.0) at 40°C or 60°C for 3 days - in aqueous buffer (pH 6.0) at 40°C or 60°C for 3 days - in aqueous buffer (pH 7.4) at 40°C or 60°C for 3 days - in aqueous buffer (pH 10.0) at 40°C or 60°C for 3 days - 0.1N NaOH solution at 40℃ or 60℃ for 3 days - 0.3%H 2 O 2 In solution (at its own pH) at room temperature for 3 days - 24 hours of UV irradiation of the solution in water (at its own pH) using an Atlas Suntest CPS+ system (wavelength: 300-800 nm, power: 200 W / m 2 )

[0131] For compounds that are poorly soluble in aqueous media, the addition of an organic co-solvent (usually up to 50% by volume of acetonitrile) is possible. Stressed / stored samples are analyzed by a stability-indicating chiral or achiral HPLC method, as appropriate. 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 show high chemical stability in acidic aqueous media (pH value of about 1.2), which makes the application of the compounds of the present invention as medicines for treating human diseases less restrictive and problematic.

[0132] 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 the desired temperature, for example 40° 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. That is, the recovery [%] of the compound during the first injection (AUt 0 The peak area of ​​the main peak is determined for the 24 hour injection (AU 24h ), (AU 24h ) / (AU t0) [%]. Similarly, the amount of compound decomposed when a stability test is carried out for more than one day, for example, three days, is calculated. Following the same procedure as above, the chemical stability of the exemplary compounds according to the present invention under acidic conditions was tested. For all of them, the amount of decomposed compound was found to be at most 5% or less.

[0133] The following table shows the degree of decomposition of representative compounds of the present invention. The numbers of each compound correspond to the numbers of the examples in the experimental section. [Table 10] Moreover, analogs of the compounds according to the invention that contain an asymmetrically monosubstituted seven-membered ring instead of a cyclopropylene substitution are observed to undergo some degree of epimerization at the asymmetric carbon atom of the seven-membered ring under basic storage conditions (0.1N aqueous NaOH at 40°C for 3 days). However, such isomerization is not only undesirable from a general quality standpoint, but is also associated with a significant decrease in binding affinity in particular (see efficacy findings above).

[0134] In contrast, the compounds according to the present invention contain a seven-membered ring that is not asymmetrically substituted, and thus epimerization of this moiety cannot occur, thus avoiding the deleterious effects of such epimerization.

[0135] Permeability assessment Caco-2 cells (1~2×10 5 Cells / 1cm 2 The cells (area) are seeded onto filter inserts (Costar transwell polycarbonate or PET filters, 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). Stock solution is diluted in HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO). 4 , 1.8 mM CaCl2 , 4.17 mM NaHCO 3 , 1.19mM Na 2 HPO 4 x7H 2 0.41 mM NaHCO 2 PO 4 ×H 2 Transport solutions (0.1-300 μM compound, final DMSO <=0.5%) are prepared by dilution in 10 mM HO, 15 mM HEPES, 20 mM glucose, pH 7.2). Transport solutions (TL) are 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 from the receiver side at the beginning and end of the experiment and at various time intervals up to 2 h for concentration measurements by HPLC-MS / MS or scintillation counting. The sampled receiver aliquots are replaced with fresh receiver solution.

[0136] Evaluation of metabolic stability in human or rat liver microsomes The 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 the addition of reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM) and terminated after various time points by transferring aliquots to solvent. In addition, NADPH-independent degradation is monitored in NADPH-free incubations and terminated at the final time point. The quenched incubations are pelleted by centrifugation (10000g, 5 min). An aliquot of the supernatant is assayed by LC-MS / MS for the amount of parent compound. The half-life (t1 / 2 INVITRO) is determined by the slope of a semi-log plot of the concentration-time profile.

[0137] Assessment of metabolic stability in human or rat hepatocytes The metabolic degradation of the test compound is assayed in a hepatocyte suspension. Hepatocytes (usually cryopreserved) are incubated in an appropriate buffer system (e.g., Dulbecco's modified Eagle's medium, with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, and 3.75 mg hydrocortisone / 500 mL) containing 5% serum species. Incubate in a cool, dark place at 37 °C and 10% CO 2 After a 30 min (typically) pre-incubation in DMSO, add 5 µL of test compound solution (80 µM; from 2 mM in DMSO stock solution diluted 1:25 with medium) to 395 µL of hepatocyte suspension (cell density ranging from 0.25 to 5 myocytes / mL, typically 1 myocyte / mL; final concentration of test compound 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 min). Supernatants are transferred to a new 96 deep-well plate, solvent evaporated under nitrogen and resuspended. The loss of parent compound is analyzed by HPLC-MS / MS. CLint is calculated as follows: CL_INTRINSIC=dose / AUC=(C0 / CD) / (AUD+clast / k)×10 / 60. C0: initial concentration in incubation [μM], CD: cell density of viable cells [10e6 cells / mL], AUD: area under data [μM×h], clast: concentration of last data point [μM], k: slope of regression line for loss of parent [h-1].

[0138] Response phenotype assay Phenotypic assays are performed to identify the metabolic enzymes responsible for the metabolic conversion of the test compound. The metabolic degradation of the test compounds and the formation of metabolites are evaluated using Supersome (human CYP expressed in baculovirus-infected insect cells). The substrate affinity of the compounds for CYP isoenzymes 1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2, 3A4, 3A5 and FMO3 are tested. Incubations in TRIS buffer (0.1 M, pH 7.6, supplemented with 5 mM magnesium chloride) consisted of 200 pmol / mL of each Supersomal protein and 10 μM of test compound.

[0139] After a short preincubation period of 15 min at 37° C., the reaction is initiated by the addition of reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM). The incubation is terminated by transferring an aliquot of the sample into acetonitrile after 60 min at 37° C. Samples are analyzed for metabolite formation by HPLC-MS / MS. In parallel, evaluation of the metabolic degradation of the test compounds and the formation of metabolites is performed using human hepatocytes. After recovery from cryopreservation, human hepatocytes are diluted in Dulbecco's modified Eagle's medium (supplemented with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, 3.75 mg hydrocortisone / 500 mL and 5% human serum) to obtain a final cell density of 1.0 × 106 cells / mL or 4.0 × 106 cells / mL, depending on the turnover rate of the test compound. The cells are incubated in a cell culture incubator (37 °C, 10% CO 2 After a 30 minute pre-incubation in 500 mL of DMSO, the test compound solution is spiked into the hepatocyte suspension to give a final test compound concentration of 10 μM and a final DMSO concentration of 0.05%.

[0140] The cell suspension is incubated at 37° C. (cell culture incubator, horizontal shaker). At the end of the incubation period (maximum 6 h), samples are quenched with acetonitrile (containing an internal standard) and pelleted by centrifugation. Supernatants are transferred to 96 deep-well plates and prepared for analysis of parent compound loss by HPLC-MS / MS. The fraction metabolized (fm) was calculated for each of the CYP isoenzymes taking into account the in vitro formation of each metabolite in human hepatocytes and the relative abundance of each enzyme in the liver based on scaling factors according to Yeo et al. (Br. J. Clin. Pharmacol. 2004, 57, 687-688).

[0141] 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 and an acceptor chamber separated by an ultrathin semipermeable membrane with a molecular weight cut-off of 5 kDa. Stock solutions of each test compound are 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 dialysis solution of the test compound is dispensed into the plasma chamber. Incubation is performed for 2 hours at 37° C. under rotation. 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). An aliquot of 25 μL of 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 performed by adding 200 μL of ACN. A 50 μL aliquot of the buffered dialysate is transferred to a deep well plate and mixed with 25 μL blank plasma, 25 μL internal standard solution and 200 μL ACN. The samples are run 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 100.

[0142] Solubility evaluation The aqueous solubility of the test compound is determined by comparing the amount dissolved in the buffer with the amount in 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 shaking for 24 hours, 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 DMSO concentration of 2.5%. If the compound is more than 90% soluble in the buffer, this value is noted with a ">".

[0143] Evaluation of pharmacokinetic characteristics in rodents Test compounds are administered either intravenously to fed rats or orally to fasted rats. At several time points following 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 noncompartmental PK analysis (NCA). The trapezoidal rule is applied (lin up-log down) and the area under 0-tz ) to calculate the area under the individual curves. AUC 0-Inf is the terminal phase extrapolated, and the AUC tz-∞ AUC 0-tz The individual CL values ​​are calculated according to Equation 1.

number

number

[0144] Cytotoxicity assessment 14-day repeat dose assay of human liver microtissues (hLIMT-3D): cellular ATP content

[0145] Experimental procedure Co-cultured hLIMT are obtained by InSphero. They are formed by seeding cryopreserved human hepatocytes and cryopreserved human non-parenchymal cells in liver microtissue medium into 96-well spheroid plates. Cells are incubated at 37°C and 5% CO until microtissues form. 2 The cells are incubated with 0.5% DMSO and then treated with compound. Test compounds are diluted in vehicle (DMSO) and dilutions are made in 0.5% vehicle in liver microtissue culture medium. Eight concentrations of test compounds are then incubated in triplicate or quadruplicate for 14 days, with compound re-administration at regular intervals. Chlorpromazine and / or other known cytotoxic agents are used as positive controls. At the end of the incubation period, cellular ATP content is measured using CellTiter-Glo® (Promega).

[0146] Data analysis. Vehicle control wells are used to determine normal ATP content, which is then set to 100%. Ratios to the control are calculated for each compound concentration. Dose-response curves are described using a four-parameter non-linear curve fit. EC 50 is calculated from this dose-response curve. Additionally, vehicle control wells are used to determine the lower limit of significance. The intersection of the dose-response curve with the lower limit of significance gives the lowest effective concentration (LEC). * The lowest test concentration that exceeds the lower limit of significance (the mean and the standard deviation outside the lower limit) is called the first effective concentration (FEC). ** is required. * LEC = lowest effective concentration calculated from the intersection of the lower or upper significance limit and the dose-response curve **FEC = First Effective Concentration below the Lower Significance Limit (including standard deviation)

[0147] Treatment Method In another aspect of the present invention, the compound of formula (I) or its pharma- ceutically acceptable salt has suitable properties for use in therapy, i.e., for use as a medicament.In particular, the compound of formula (I) or its pharma-ceutically acceptable salt, as well as pharmaceutical compositions containing the same, may be useful in treating diseases or conditions that can be affected by antagonizing platelet activating factor receptor (PAFR), e.g., mediated by undesirable activity of PAFR, or in which antagonism of PAFR is beneficial, in a patient. Diseases and conditions that can be affected by antagonizing PAFR, for example, those mediated by undesirable activity of PAFR or that would benefit from antagonism of PAFR activity, include ophthalmic diseases, cardiovascular diseases, cancer, neurological and neurodegenerative disorders, renal disorders, liver diseases, 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, bifurcation, or hemiretinal vein occlusion), diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CMED), and other conditions that may be affected by antagonizing PAFR. 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;nonexudative choroidal neovascularization), subretinal fibrosis (e.g., associated with nonexudative 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-associated edema, spinal cord injury, pain, ischemia, focal cerebral ischemia, neurological deficits and agnosia, deep vein thrombosis, stroke, myocardial infarction, atherosclerosis, acquired angioedema, hereditary angioedema (HAE), drug-related (ACE inhibitor) edema, high altitude cerebral edema, cytotoxic cerebral edema, penetrating cerebral edema The present invention is intended to be used in the treatment of: cerebral edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, traumatic brain injury, hemorrhagic stroke (e.g. cerebral or subarachnoid stroke), intracerebral hemorrhage, hemorrhagic transformation of ischemic stroke, brain trauma associated with 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 (such as multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease, excessive daytime sleepiness, essential hypertension, diabetes or may be due to hyperlipidemia-related elevated blood pressure, renal failure, renal impairment (including chronic kidney disease), interstitial cystitis / bladder pain syndrome, cardiac 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, and metabolic syndrome. complications due to chronic obstructive pulmonary disease (COPD), 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 (breast cancer, colon cancer, esophageal cancer, lung cancer, liver cancer, pancreatic cancer, skin cancer (including melanoma), cervical cancer, etc.), and other diseases;

[0148] Thus, the compounds and pharmaceutical compositions according to the 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 invention are particularly suitable for the treatment of allergy and inflammation related conditions and diseases, such as urticaria and NASH.

[0149] 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) is usually 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.

[0150] The compounds and compositions, 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.Of the possible administration methods, oral or intravitreal administration, especially oral administration, is preferred.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), including pharma- ceutically acceptable salts thereof, for use as pharmaceuticals.

[0151] In another aspect, the invention provides a method of treating a 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, in a patient in need thereof. Similarly, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in a method of treating a disease or condition mediated by undesirable activity of the platelet activating factor receptor, or in which antagonism of the platelet activating factor receptor is beneficial, in a patient in need thereof. Similarly, the invention provides the use of a compound of formula (I) or a pharma- ceutically 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 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) or a pharma- ceutically acceptable salt thereof in a method of treating a disease or condition mediated by undesirable activity of the platelet activating factor receptor, or in which antagonism of the platelet activating factor receptor is beneficial, in a patient in need thereof.

[0152] According to one embodiment, the method of treatment comprises administering to the patient one or more compounds of formula (I) or a pharma- ceutically acceptable salt thereof, preferably administering to the patient a therapeutically effective amount of one or more compounds of formula (I) or a pharma- ceutically acceptable salt 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 undesirable activity of the platelet activating factor receptor or in which antagonism of the platelet activating factor receptor is beneficial is selected from ophthalmic 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 undesirable activity of the platelet activating factor receptor or in which antagonism of the 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.

[0153] Pharmaceutical Compositions In another aspect of the invention, it is stated that the compounds of the invention, or pharma- ceutically acceptable salts thereof, may be used as active ingredients in pharmaceutical compositions.

[0154] Suitable preparations for administering the compounds of the present invention, which may be combined 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, powders, etc. Oral preparations, especially solid forms such as tablets or capsules, are preferred. For intravitreal injection, solutions are preferred. The content of the pharma- ceutical active compound is advantageously in the range of 0.1-90% by weight, for example 1-70% by weight, of the composition as a whole.

[0155] Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula (I) with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants. The tablet may also consist of several layers. The specific excipients, carriers and / or diluents suitable for the desired preparation will be familiar to the person skilled in the art, based on the expert's knowledge. Preference is given to those suitable for the specific formulation and the desired method of administration. The preparations or formulations according to the invention can be prepared using methods known per se, with which the person skilled in the art is familiar, such as, for example, by mixing or combining at least one compound according to formula (I) according to the invention or a pharma- ceutically 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), or a pharma- ceutically acceptable salt thereof, optionally together with one or more inert carriers and / or diluents.

[0156] Similarly, pharmaceutical compositions comprising one or more of the above compounds, or pharma- ceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents, are provided for use in methods of treating, in a patient in need thereof, diseases or conditions mediated by undesirable activity of PAFR or in which antagonism of PAFR is beneficial. In particular, the present invention provides pharmaceutical compositions according to the present invention for use in methods of treating ophthalmic 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 the treatment of 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 the treatment of a disease or condition in a patient, preferably a human, in which antagonism of PAFR is beneficial.

[0157] According to one embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula (I) or a pharma- ceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents. For example, the composition comprises a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0158] 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, in particular 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. Additional therapeutic agents suitable for such combinations include in particular those which, for example, enhance the therapeutic effect of one or more active substances for one of the mentioned indications and / or those which 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.

[0159] 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 protein tyrosine phosphatase 1, such as 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, alpha 2-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, e.g. 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 regulators.

[0160] Therapeutic agents for treating overweight and / or obesity are, for example, antagonists of the cannabinoid 1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor, dual agonists of the GLP-1 and glucagon receptors. 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, antagonists of alpha-2-adrenergic receptors, inhibitors of neutral endopeptidase, platelet activity inhibitors, etc., or combinations thereof, are preferred. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of hypertension, and diabetic complications, often combined with diuretics such as hydrochlorothiazide.

[0161] 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.

[0162] Therapeutic agents for treating NASH include, for example, FXR agonists, FXR / TGR5 agonists, THR-β agonists, ACC inhibitors, TGF-b1 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, GLP-1 / GIP / glucagon receptor triple agonists, and the like. The therapeutic agents may include agonists, AOC3 inhibitors, JNK1 inhibitors, CCR2 / 5 inhibitors, ACC inhibitors, DGAT inhibitors, KHK inhibitors, PPARα / δ agonists, FGF19 agonists, β-Klotho / FGFR1c agonists, PNPLA3 inhibitors, NLRP3 inhibitors, THR-β agonists, HSD17β13 inhibitors, galectin-3 inhibitors, SCD1 inhibitors, ASK1 inhibitors, endothelin receptor A antagonists, FASN inhibitors, calpain inhibitors, autotaxin inhibitors, TREM2 agonists, sGC inhibitors, PKK inhibitors, RORc inhibitors, TLR4 inhibitors, and IL11 inhibitors.

[0163] 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. Dosages for the above combination partners are usually from 1 / 5 of the lowest recommended dose to 1 / 1 of the recommended dose. The use of the compounds according to the invention in combination with an additional therapeutic agent may be carried out simultaneously or at staggered times.

[0164] 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, optionally together with 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 undesirable activity of the platelet activating factor receptor or in which antagonism of PAFR is beneficial in a patient in need thereof, comprising administering to the patient one or more compounds of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with one or more additional therapeutic agents as described hereinbefore and hereinafter; Preferably, the methods provided herein include the step of administering to a patient a therapeutically effective amount of one or more compounds of formula (I), or a pharma- ceutically 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) or a pharma- ceutically acceptable salt thereof, in combination with one or more additional therapeutic agents as described hereinbefore or hereinafter, for use 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. Similarly, the invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treating a disease or condition mediated by undesirable activity of PAFR, or in which antagonism of PAFR is beneficial, in a patient in need thereof, in combination with one or more additional therapeutic agents as described hereinbefore or hereinafter. Similarly, the invention provides the use of a compound of formula (I) or a pharma- ceutically 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.

[0165] According to one embodiment, the method of treatment comprises the steps of administering to a patient one or more compounds of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with one or more additional therapeutic agents as described hereinbefore and hereinafter; Preferably, the method comprises administering to a patient a therapeutically effective amount of one or more compounds of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents described hereinbefore and hereinafter.

[0166] According to another embodiment, the method of treatment comprises the step of 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, optionally 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, in particular from such agents specifically mentioned above.

[0167] 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 retinopathy, 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. 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 embodiments which illustrate, by way of example, the principles of the invention.

[0168] 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.

[0169] Abbreviation Ac Acetyl ACN Acetonitrile ATP Adenosine Triphosphate BPR Back Pressure Regulator BSA Bovine Serum Albumin d number of days DAD Diode Array Detector DAPI 4',6-diamidino-2-phenylindole dba Dibenzylideneacetone DCM Dichloromethane Dioxane 1,4-Dioxane DIPEA N,N-Diisopropylethylamine DMEM Dulbecco's Modified Eagle's Medium DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EDTA Ethylenediaminetetraacetate ESI electrospray ionization (MS) EtOAc Ethyl acetate EtOH Ethanol FITC Fluorescein isothiocyanate h time HPLC High Performance Liquid Chromatography IPA Isopropanol KHMDS Potassium bis(trimethylsilyl)amide LC Liquid Chromatography LC-MS Liquid Chromatography - Mass Spectrometry M Molar concentration (mol / L) MeCN Acetonitrile MeOH Methanol min minutes MS mass spectrometry NMR nuclear magnetic resonance OAc Acetate PBS Phosphate Buffered Saline PET Polyethylene terephthalate pet. petroleum RPE retinal pigment epithelium 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 TLC Thin Layer Chromatography Tol-BINAP 2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl UV ultraviolet light XPhos Dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane

[0170] The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20°C, for example, between 15 and 25°C. in general, 1 H-NMR and / or mass spectra are obtained for the compounds prepared.

[0171] Unless otherwise specified, compounds containing chiral centers have the stereochemistry as 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.

[0172] Analysis method: [Table 11]

[0173] [Table 12]

[0174] [Table 13]

[0175] [Table 14]

[0176] [Table 15]

[0177] [Table 16]

[0178] [Table 17]

[0179] [Table 18]

[0180] Synthesis of intermediates: Intermediate 1 (13'S)-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2 ,6.0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid [ka]

[0181] 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 chromatography on silica gel (petroleum ether / DCM 50:50) and then recrystallized from MeOH to give the title compound.

[0182] Step 2: Methyl 2-(1-{[(tert-butoxy)carbonyl]amino}cyclopropanamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate To a stirred solution of methyl 2-amino-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (100 g) and 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (90 g) in DCM (1000 mL) is added 2-chloro-1-methylpyridinium iodide (91 g), triethylamine (116 mL) and 4-dimethylaminopyridine (18 g). The resulting mixture is stirred at 55° C.-60° C. for 2 days. The mixture is diluted with MeOH and water and the precipitate is isolated by filtration to give the title compound.

[0183] Step 3: Methyl 2-(1-aminocyclopropanamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate To methyl 2-(1-{[(tert-butoxy)carbonyl]amino}cyclopropanamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (70 g) in DCM (400 mL) is added 4M HCl in dioxane (400 mL) at 0° C. The cooling bath is removed and the mixture is stirred at room temperature for 12 h. The mixture is concentrated to give the crude title compound which is used directly in the next reaction step.

[0184] Step 4: Methyl 13'-(2-chlorophenyl)-10'-oxo-7'-thia-9',12'-diazaspiro[cyclopropane-1,11'-tricyclo[6.5.0.0 2,6 ]Tridecane]-1'(8'),2'(6'),12'-triene-4'-carboxylate To a stirred solution of methyl 2-(1-aminocyclopropanamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopenta[b]thiophene-5-carboxylate (60 g) in toluene (600 mL) is added pyridine (180 mL) and glacial acetic acid (60 mL). The mixture is stirred at 120° C. for 24 h and then concentrated. The crude compound is purified by chromatography on silica gel (30% EtOAc / 70% petroleum ether) to give the title compound.

[0185] Step 5: Methyl 9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylate Methyl 13'-(2-chlorophenyl)-10'-oxo-7'-thia-9',12'-diazaspiro[cyclopropane-1,11'-tricyclo[6.5.0.0 in THF (300 mL) 2,6 A stirred solution of ]tridecane]-1'(8'),2'(6'),12'-triene-4'-carboxylate (20 g) is cooled to -78°C. Potassium tert-butoxide (6.1 g) is added and the reaction mixture is warmed to -10°C and then to room temperature. After 30 min, the mixture is cooled to -78°C and diethyl chlorophosphate (10.3 g) is added. The mixture is stirred at -10°C for 45 min. Acetyl hydrazide (7.4 g) is added and the mixture is stirred at room temperature for 45 min. IPA (300 mL) is added and the reaction mixture is stirred at 90°C for 1 h. The mixture is concentrated and the residue is purified by chromatography on silica gel (DCM / MeOH 96:4) to give the title compound.

[0186] Step 6: 9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid Methyl 9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 in THF (100 mL) and water (40 mL) 2,6 .0 11,15]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylate (10g) was added to LiOH * H 2 O (4.8 g) is added. The mixture is stirred at room temperature for 4 h. The THF is evaporated and the aqueous layer is acidified with concentrated HCl at 0° C. The precipitate is isolated by filtration and dried in vacuum to give the title compound.

[0187] Step 7: (13'S)-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid 9'-(2-Chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]hexa-decane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid (racemic mixture, 2.6 g) was subjected to SFC on a chiral phase [column: Chiralpak IC (30x250 mm, 5 μm); isocratic conditions: 55:45 CO 2 : MeOH; total flow: 100 g / min; BPR: 100 bar; load / injection: 40 mg; number of injections: 90] to give the title compound.

[0188] Example Synthesis: Example 1 (13'S)-N-{bicyclo[1.1.1]pentan-1-yl}-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxamide [ka] (13'S)-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 [Hexa-decane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid (intermediate 1; 50 mg) and bicyclo[1.1.1]pentan-1-amine (15 mg) are dissolved in DMF (1 mL). DIPEA (41 μL) and TBTU (38 mg) are added and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with DMF and purified by chromatography on reverse phase (HPLC; ACN / water / aqueous ammonia) to give the title compound. LC-MS (method 1):t R = 0.93 min; Mass Spectrum (ESI + ):m / z=491[M+H] + . Chiral SFC (Method 6): R = 2.33 min; Mass Spectrum (ESI + ): m / z=490.1[M] + .

[0189] Example 2 4-Chloro-3-[(13'S)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaen-9'-yl]benzonitrile [ka] 4-Chloro-3-[(13'S)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0] in THF (1 mL).2,6 .0 11,15 ]hexadecane]-1'(10'),3',5',8',11'(15')-pentaen-9'-yl]aniline (Example 6; 65 mg) was added to H 2 Add 1 mL of H2O and 20 μL of sulfuric acid. 2 Sodium nitrite (11 mg) dissolved in O (50 μL) is added dropwise.

[0190] In a separate flask, add a stir bar, potassium cyanide (42 mg), and H 2 Add 500 μL of O and cool to 0 °C. Add 15 mg of CuCN, 15 mg of NaHCO 3 (85 mg) and EtOAc (1 mL) are added. The first solution (diazonium salt) is added dropwise to the latter and the resulting mixture is stirred at room temperature overnight. 2 O is added and the mixture is extracted with EtOAc (3x). The combined organic extracts are dried (Na 2 SO 4 ) and concentrate. Chromatograph the residue on silica gel (DCM / MeOH 95:5) to give the title compound. LC-MS (method 2):t R = 0.83 min; Mass Spectrum (ESI + ):m / z=519[M+H] + .

[0191] Example 3 (13'S)-9'-(2,5-dichlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene [ka] CuCl in MeCN (2 mL) 2(16 mg) and tert-butyl nitrite (17 μL) were added to 4-chloro-3-[(13'S)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0] in MeCN (1 mL) at 0 °C. 2,6 .0 11,15 [hexadecane]-1'(10'),3',5',8',11'(15')-pentaen-9'-yl]aniline (Example 6; 50.0 mg) is added. The mixture is warmed to room temperature and stirred overnight. The mixture is poured into 1M aqueous HCl and stirred for 5 minutes. After neutralization with 1M aqueous NaOH, the mixture is extracted with EtOAc. The combined organic extracts are dried (Na 2 SO 4 ) and concentrate. The residue is chromatographed on reverse phase (HPLC; ACN / water / aqueous ammonia) to give the title compound. LC-MS (method 1):t R = 0.90 min; Mass Spectrum (ESI + ):m / z=528 / 530[M+H] + .

[0192] Example 4 (13'S)-9'-(5-bromo-2-chlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene [ka] CuBr in MeCN (2 mL) 2 (26 mg) and tert-butyl nitrite (16 μL) were added to 4-chloro-3-[(13'S)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0] in MeCN (1 mL) at 0 °C.2,6 .0 11,15 [hexadecane]-1'(10'),3',5',8',11'(15')-pentaen-9'-yl]aniline (Example 6; 50 mg) is added. The mixture is warmed to 70° C. and stirred for 2 h. The mixture is poured into 1M aqueous HCl and stirred for 5 min. After neutralization with 1M aqueous NaOH, the mixture is extracted with EtOAc. The combined organic extracts are dried (Na 2 SO 4 ) and concentrate. The residue is chromatographed on reverse phase (HPLC; ACN / water / aqueous ammonia) to give the title compound. LC-MS (method 1):t R = 0.91 min; Mass Spectrum (ESI + ):m / z=572 / 574[M+H] + .

[0193] Reference Example 5 (13'S)-9'-(2-chloro-5-nitrophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene [ka] (13'S)-9'-(2-chlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene (Example 114; 300 mg) is dissolved in sulfuric acid (2 mL) and cooled to 0° C. A mixture of nitric acid (47 μL) and sulfuric acid (162 μL) is added and the mixture is stirred at room temperature overnight. If the reaction is not complete (by TLC or HPLC), an additional mixture of nitric acid (30 μL) and sulfuric acid (100 μL) is added and stirring at room temperature is continued for 5 hours. The mixture is poured into ice water and the resulting mixture is subjected to K 2 CO 3 The mixture was neutralized with ethyl acetate (pH approx. 8) and extracted with EtOAc. The combined organic extracts were dried (Na 2 SO 4 ) and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH 95:5) to give the title compound. LC-MS (Method 1): R = 0.86 min; Mass Spectrum (ESI + ):m / z=539[M+H] + .

[0194] Example 6 4-Chloro-3-[(13'S)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaen-9'-yl]aniline [ka] (13'S)-9'-(2-chloro-5-nitrophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraaza-spiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 [hexadecane]-1'(10'),3',5',8',11'(15')-pentaene (Reference Example 5, 135 mg), iron (140 mg), THF (5 mL) and H 2A mixture of 1 mL of 2H2O and 100% ethanol is stirred at 80° C. for 4 h. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is chromatographed on silica gel (dichloromethane / methanol 95:5) to give the title compound. LC-MS (Method 1): R = 0.75 min; Mass Spectrum (ESI + ):m / z=509[M+H] + .

[0195] Example 7 Example 7 is a preparation of (13'S)-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0] by following a procedure similar to that described for Example 1. 2,6 .0 11,15 ]hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid (intermediate 1).

[0196] [Table 19]

[0197] Example 8 (13'S)-3'-Methyl-9'-(2-methylphenyl)-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene

[0198] [ka] (13'S)-9'-(2-chlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2 ,6.0 11,15 ]hexadecane]-1'(10'),3',5',8',11'(15')-pentaene (Example 114; 50 mg), methylboronic acid (12 mg) and potassium phosphate (65 mg) were added to H 2 The mixture was purged with Ar for 5 min, and then Pd(OAc) 2 (1.1 mg) and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (SPhos) (4.1 mg) are added. The mixture is stirred in a microwave oven at 140°C for 30 minutes. After cooling to room temperature, the mixture is diluted with ACN and chromatographed on reversed phase (HPLC; ACN / water / aqueous ammonia) to give the title compound. LC-MS (Method 1):t R = 0.78 min; Mass Spectrum (ESI + ):m / z=474[M+H] + . Chiral SFC [Column: Chiral Art® Cellulose_SB (4.6 mm × 250 mm, 5 μm); Column temperature: 40 °C; Flow rate: 4.0 mL / min; BPR: 2175 bar; Isocratic conditions: 65:35 CO 2 :IPA(20mM NH 3 )]:t R = 3.65 min; Mass Spectrum (ESI + ):m / z=474.0[M+H] + .

[0199] Example 9 2-[(13'S)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaen-9'-yl]phenol

[0200] [ka] Step 1: (13'S)-9'-(2-chlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.02,6.011,15]hexadecane]-1'(10'),3',5',8',11'(15')-pentaene (Example 114; 50 mg), bis(pinacolato)diboron (39 mg) and potassium acetate (30 mg) are dissolved in dioxane (1 mL). The mixture is purged with Ar for 5 min and then eluted with Pd 2 dba 3 (3.0 mg) and XPhos (2.5 mg) are added. The mixture is stirred in a microwave oven at 120° C. for 30 min. After cooling to room temperature, the mixture is diluted with dioxane and filtered through Celite. The separated solid is washed with dioxane, dried in vacuum and used in the next reaction step without further purification.

[0201] Step 2: The crude product from step 1 (51 mg) is dissolved in THF (1 mL). The mixture is cooled to 0° C. and hydrogen peroxide (H 2 35% in 20O; 53 μL) and aqueous 4M NaOH (51 μL) are added. The mixture is stirred overnight while warming to room temperature. The mixture is diluted with EtOAc and diluted with Na 2 S 2 O 3 The organic layer was dried (Na 2 SO 4 ) and concentrate. The residue is chromatographed on reverse phase (HPLC; ACN / water / aqueous ammonia) to give the title compound. LC-MS (Method 1): R = 0.81 min; Mass Spectrum (ESI + ):m / z=476[M+H] + . Chiral SFC (Method 7): R = 4.78 min; Mass Spectrum (ESI + ):m / z=476.0[M+H] + .

[0202] (Examples 10 to 103) By following a procedure similar to that described for Example 1, (13'S)-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid (Intermediate 1) gives Examples 10 to 103, which are summarized in the table below.

[0203] [Table 20] TIFF2025501761000101.tif170156 TIFF2025501761000102.tif156156 TIFF2025501761000103.tif236156 TIFF2025501761000104.tif162156 TIFF2025501761000105.tif161156 TIFF2025501761000106.tif161156 TIFF2025501761000107.tif238156 TIFF2025501761000108.tif232156 TIFF2025501761000109.tif228156 TIFF2025501761000110.tif166156 TIFF2025501761000111.tif230156 TIFF2025501761000112.tif238156 TIFF2025501761000113.tif228156 TIFF2025501761000114.tif236156 TIFF2025501761000115.tif161156 TIFF2025501761000116.tif160156 TIFF2025501761000117.tif161156 TIFF2025501761000118.tif234156 TIFF2025501761000119.tif162156 TIFF2025501761000120.tif161156 TIFF2025501761000121.tif156156 TIFF2025501761000122.tif170156 TIFF2025501761000123.tif161156 TIFF2025501761000124.tif230156 TIFF2025501761000125.tif232156 TIFF2025501761000126.tif227156 TIFF2025501761000127.tif162156 TIFF2025501761000128.tif166156 TIFF2025501761000129.tif170156 TIFF2025501761000130.tif165156 TIFF2025501761000131.tif161156 TIFF2025501761000132.tif165156 TIFF2025501761000133.tif163156 TIFF2025501761000134.tif160156 TIFF2025501761000135.tif163156 TIFF2025501761000136.tif165156 TIFF2025501761000137.tif163156 TIFF2025501761000138.tif158156 TIFF2025501761000139.tif165156 TIFF2025501761000140.tif164156

[0204] (Example 104) (13'S)-9'-(2-chlorophenyl)-3'-methyl-N,N-dipropyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxamide [ka]

[0205] (13S)-9-(2-chlorophenyl)-3-methyl-N,N-dipropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] in DMSO (2 mL) 2,6 .0 11,15 ]Hexadeca-1(10),3,5,8,11(15)-pentaene-13-carboxamide (for synthesis, see EP 0388789, 100 mg) is added at room temperature with (2-bromoethyl)diphenylsulfanium trifluoromethanesulfonate (184 mg) and KHMDS (1.0M in THF; 830 μL). The mixture is stirred overnight at room temperature. Additional (2-bromoethyl)diphenylsulfanium trifluoromethanesulfonate (184 mg) and KHMDS (1.0M in THF; 830 μL) are added and stirring is continued for 2 hours. The mixture is diluted with DMF, filtered and chromatographed on reverse phase (HPLC; ACN / water / aqueous ammonia) to give the title compound. LC-MS (method 1):t R = 1.03 min; Mass Spectrum (ESI + ):m / z=508[M+H] + .

[0206] (Examples 105 to 118) By following a procedure similar to that described for Example 1, (13'S)-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid (Intermediate 1) gives Examples 105-118, which are summarized in the table below.

[0207] [Table 21] TIFF2025501761000143.tif165156 TIFF2025501761000144.tif170156 TIFF2025501761000145.tif161156 TIFF2025501761000146.tif156156 TIFF2025501761000147.tif165156 TIFF2025501761000148.tif159156 TIFF2025501761000149.tif82156

[0208] (Example 119) (13'S)-9'-(2-chlorophenyl)-3'-ethyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene

[0209] [ka] To diisopropylamine (19 μL) in THF (1 mL) is added n-butyllithium (1.6 M in hexanes; 76 μL) at −78° C. After stirring for 10 min, (13'S)-9'-(2-chlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclo-propane-1,7'-tetracyclo[8.6.0.0]) in THF (1 mL) is added. 2,6 .0 11,15]hexadecane]-1'(10'),3',5',8',11'(15')-pentaene (Example 114; 50 mg) is added and the mixture is stirred at -78°C for 30 min. Iodomethane (7 μL) is added and the mixture is stirred at -78°C for 1 h. The reaction is cooled to NH 4 The mixture is quenched with aqueous Cl and extracted with EtOAc. The combined organic extracts are dried (Na 2 SO 4 ) and concentrate. The residue is chromatographed on reverse phase (HPLC; ACN / water / aqueous ammonia) to give the title compound. LC-MS (method 1):t R = 0.87 min; Mass Spectrum (ESI + ):m / z=508[M+H] + . Chiral SFC (Method 6): R = 5.41 min; Mass Spectrum (ESI + ):m / z=508.2[M+H] + .

[0210] (Example 120) (13'S)-3'-Methyl-13'-(morpholine-4-carbonyl)-9'-phenyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene

[0211] [ka]

[0212] (13'S)-9'-(2-chlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0] in MeOH (8 mL). 2,6 .0 11,15[Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene (Example 114; 75 mg) is added with Raney Nickel (75.0 mg) at room temperature. The mixture is shaken under hydrogen atmosphere (50 psi) at 50° C. for 6 days. The mixture is filtered and the filtrate is concentrated. The residue is chromatographed on reverse phase (HPLC; ACN / water / aqueous TFA) to give the title compound. LC-MS (method 1):t R = 0.72 min; Mass Spectrum (ESI + ):m / z=460[M+H] + .

[0213] (Examples 121 to 129) By following a procedure similar to that described for Example 1, (13'S)-9'-(2-chlorophenyl)-3'-methyl-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene-13'-carboxylic acid (Intermediate 1) gives Examples 121-129, which are summarized in the table below.

[0214] [Table 22] TIFF2025501761000153.tif168156 TIFF2025501761000154.tif165156 TIFF2025501761000155.tif165156 TIFF2025501761000156.tif165156

[0215] (Example 130) (13'S)-9'-(2-methoxyphenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 2,6 .0 11,15 ]Hexadecane]-1'(10'),3',5',8',11'(15')-pentaene

[0216] [ka] (13'S)-9'-(2-chlorophenyl)-3'-methyl-13'-(morpholine-4-carbonyl)-16'-thia-2',4',5',8'-tetraazaspiro[cyclopropane-1,7'-tetracyclo[8.6.0.0 in toluene (1 mL) 2,6 .0 11,15 [hexadecane]-1'(10'),3',5',8',11'(15')-pentaene (Example 114; 80 mg) was added with sodium methoxide (25% by weight in methanol; 53.0 mg). After purging the mixture with Ar, Pd 2 (dba) 3 (7.5 mg) and Tol-BINAP (13.5 mg) are added. The mixture is stirred at 130° C. for 2 h and then concentrated in vacuo. The residue is chromatographed on reverse phase (HPLC; ACN / water / aqueous TFA) to give the title compound as a mixture containing its enantiomers (approximately 3:1). LC-MS (method 1):t R = 0.72 min; Mass Spectrum (ESI + ):m / z=490[M+H] + . Chiral SFC [Column: Chiral Art® Amylose-SA (4.6 mm × 250 mm, 5 μm); Column temperature: 40 °C; Flow rate: 4.0 mL / min; BPR: 2175 bar; Isocratic conditions: 75:25 CO 2 :IPA(20mM NH 3 )]:t R = 4.72 min; Mass Spectrum (ESI +):m / z=490.2[M+H] + 。

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, R 1 is C 1-4 - alkyl (optionally substituted by 1 to 3 F) and C 3-4 -R consisting of cycloalkyl 1 - selected from the group G1, n is selected from the group n-G1 consisting of 0, 1, 2, and 3; R 2 is R 2 - independently selected from the group G1; 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 O-C 1-4 -alkyl), and C 3-4 -cycloalkyl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, NH 2 , OH, —O—C 1-4 -alkyl (optionally substituted with 1 to 3 F), -S(O) r -C 1-4 - alkyl (r=0, 1 or 2), R 3 is H and C optionally substituted by 1 to 5 F 1-4 - R consisting of alkyl 3 - selected from the group G1, R 4 is C 1-6 - R consisting of alkyl 4 - selected from the group G1a, 1-6 -Alkyl is may be 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 —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 -R consisting of heterocyclyl 4 - selected from the group G1b, 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 base is 【Chemistry 2】 may be replaced by a part, 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), >NCOO(C 1-4 -alkyl), >NS(=O) 2 (C 1-4 -alkyl), >N-phenyl, >N-pyridinyl, >N-pyrimidinyl and O, containing 1 to 2 ring members independently selected from >C=O, >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 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 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), >S(=O) 2 -C 1-4 -Alkyl 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 4 - selected from the group G1c, 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 base is 【Transformation 3】 Part or 【Chemistry 4】 may be replaced by a moiety, or One of the alkylene groups is —CH 2 -CH 2 The - group is 【Transformation 5】 Part or 【Transformation 6】 may be replaced by a part, the heteroaryl is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing 1 to 2 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 R 4 R consists of a 7- to 12-membered fused bicyclic aryl, heteroaryl, or heterocyclyl 4 - selected from the group G1d, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I) 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) and one aromatic ring selected from phenyl, pyrrole, furan and thiophene, in each of which one to two CH ring members may be replaced by N; said bicyclic aryl, heteroaryl or heterocyclyl being optionally substituted by 1 to 4 F; 1 to 4 C optionally substituted by 1 to 4 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, HO-C 1-3 -Alkylene-, C 1-3 -Alkyl-O-C 1-3 -Alkylene-, NH 2 , 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 4 together with the amide N atom to which they are attached to form a 3- to 8-membered saturated monocyclic heterocyclyl 3 / 4 - 3- to 8-membered saturated monocyclic heterocyclyl selected from the group G1a, >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 N-N, N-O and N-S(=O) between 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, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, HO-C 1-3 -Alkylene-, C 1-3 -Alkyl-O-C 1-3 -Alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -Alkyl-S(=O) 2 -NH-, OH and C 1-3 -alkyl-O- (optionally substituted by 1 to 3 F), 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 5- to 12-membered saturated bicyclic heterocyclyl; R 3 / 4 - 5- to 12-membered saturated bicyclic heterocyclyl selected from the group G1b, >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 N-N, N-O and N-S(=O) between 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, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, HO-C 1-3 -Alkylene-, C 1-3 -Alkyl-O-C 1-3 -Alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -Alkyl-S(=O) 2 -NH-, OH and C 1-3 -alkyl-O-) Or its salt.

2. R 1 But CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CHF 2 , C.F. 3 and R consisting of cyclopropyl 1 The compound or salt thereof according to claim 1, selected from Group -G2.

3. R 2 But, R 2 - independently selected from the group G2; 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-O-C 1-2 -Alkyl, NH 2 , OH, —O—C 1-3 -alkyl (optionally substituted by 2 or 3 F), -SC 1-3 The compound or salt thereof according to claim 1, wherein the compound or salt comprises - alkyl.

4. R 3 C optionally substituted with H and 1 to 3 F 1-3 - R consisting of alkyl 3 - selected from the group G2, R 4 But C 1-6 - R consisting of alkyl 4 - selected from the group G2a, 1-6 -Alkyl is optionally substituted by 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 —O—C 1-2 -alkyl (optionally substituted by 1 to 3 F), or R 4 But, -C 0-2 -Alkylene-C 3-8 -cycloalkyl and -C 0-2 -Alkylene-C 3-9 -heterocyclyl, wherein the cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems; The heterocyclyl is N, NH, >NCOCH 3 , >NCOO (C 1-2 -alkyl), >NS(=O) 2 CH 3 , >N-pyrimidinyl, O and >S(=O) 2 and containing one ring member selected from The cycloalkyl and heterocyclyl may be substituted with 1 to 2 F, and may be substituted with —CN, OH, —OCH 3 , > S (= O) 2 CH 3 and C 1-3 -Alkyl (with 2-3 F or -CN, OH, -O-C 1-4 -alkyl), 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 base is 【Transformation 7】 Part or 【Transformation 8】 may be replaced by a moiety, or One of the alkylene groups is —CH 2 -CH 2 - group, 【Chemistry 9】 Part or 【Chemistry 10】 may be replaced by a part, 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 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 (with 1 to 3 F or -CN and -O-C 1-2 -alkyl), or R 4 R consists of an 8- to 11-membered fused bicyclic aryl, heteroaryl, or heterocyclyl 4 - selected from the G2d group, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I) is >N-, >NH, >NCH 3 , >NCOCH 3 , >NS(=O) 2 CH 3 and O, C=O and S(=O) 2 a non-aromatic ring which may contain one ring member selected from and one aromatic ring selected from phenyl, pyrrole, furan and thiophene, in each of which one CH ring member may be replaced by N; the bicyclic aryl, heteroaryl or heterocyclyl is optionally substituted by 1 to 2 F; 1 to 2 C optionally substituted by 1 to 2 F 1-2 - optionally substituted by alkyl, Cl, -CN, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -COOH, -COO-C 1-2 -Alkyl, HO-C 1-3 -Alkylene-, CH 3 -O-C 1-3 -Alkylene-, NH 2 , C.H. 3 -CO-NH-, CH 3 -S(=O) 2 -NH-, OH and CH 3 -alkyl-O- (optionally substituted by 1 to 3 F), 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 a 4- to 7-membered saturated monocyclic heterocyclyl 3 / 4 - 4- to 7-membered saturated monocyclic heterocyclyl selected from the group G2a, >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) 2 and However, the heterocyclyl does not have N-S(=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 2 C optionally substituted by 2 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CON(C 1-3 -alkyl) 2 , -COO-C 1-3 -Alkyl, C 1-3 -Alkyl-O-C 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 to form a 6- to 11-membered saturated bicyclic heterocyclyl 3 / 4 - a 6- to 11-membered saturated bicyclic heterocyclyl selected from the group G2b, >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), provided that said heterocyclyl does not contain any O—S bonds between ring members; The heterocyclyl is optionally substituted by 1 to 4 F; 1 to 3 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CONH 2 , -CONH(C 1-4 -alkyl), -CON(C 1-4 -alkyl) 2 , -COOH, -COO-C 1-4 -Alkyl, HO-C 1-3 -Alkylene-, C 1-3 -Alkyl-O-C 1-3 -Alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -Alkyl-S(=O) 2 -NH-, OH and C 1-3 -alkyl-O-, The compound or salt thereof according to claim 1.

5. R 3 C optionally substituted with H and 1 to 3 F 1-3 - R consisting of alkyl 3 - selected from the group G2, R 4 But C 1-4 - R consisting of alkyl 4 - selected from the group G3a, 1-4 - alkyl is optionally substituted by 1 to 3 F; -CN, -CONH 2 , —COOH, OH and —O—C 1-2 -alkyl (optionally substituted by 1 to 3 F), or R 4 But, -C 0-1 -Alkylene-C 3-7 -cycloalkyl and C 3-9 -R consisting of heterocyclyl 4 - selected from the group G3b, wherein the cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems; The heterocyclyl is N, NH, >NCOCH 3 , >NCOO (C 1-2 -alkyl), >NS(=O) 2 CH 3 , >N-pyrimidinyl, O and >S(=O) 2 and containing one ring member selected from The cycloalkyl may be optionally substituted by 1 to 2 F or 1 to 2 CH 3 may be substituted by a group, or CH 2 CH 3 , -CN, CH 2 OH, C(CH 3 ) 2 OH, CHF 2 , C.F. 3 , OH, -OCH 3 and >S(=O) 2 CH 3 and optionally substituted with one substituent selected from The heterocyclyl may be substituted by two F or one to two CH 3 may be substituted by a group, or CH 2 CH 3 and C(CH 3 ) 2 H, or or R 4 But, -C 1-2 - alkylene-phenyl and C 0-1 -alkylene-heteroaryl 4 - selected from the group G3c, One of the alkylene groups >CH 2 The base is 【Chemistry 11】 Part or 【Chemistry 12】 may be replaced by a moiety, or One of the alkylene groups is —CH 2 -CH 2 - group, 【Chemistry 13】 Part or 【Chemistry 14】 may be replaced by a part, the heteroaryl is a 5- to 6-membered monocyclic ring containing one ring member =N-, and optionally containing one ring member independently selected from =N- and O; The phenyl and heteroaryl are selected from the group consisting of F, Cl, OCH 3 and CH 3 or may be substituted by 1 to 2 substituents independently selected from or R 4 R consists of a 9- to 10-membered fused bicyclic aryl, heteroaryl, or heterocyclyl 4 - selected from the group G3d, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I), which may contain one ring member selected from >N- and O and consisting of one aromatic ring selected from phenyl, pyridine, pyrazole and thiazole; The bicyclic aryl, heteroaryl or heterocyclyl is selected from the group consisting of F, CH 3 , C.H. 2 CH 3 , -CN, NH 2 and OH, or 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 a 4- to 6-membered saturated monocyclic heterocyclyl 3 / 4 - 4- to 6-membered saturated monocyclic heterocyclyl selected from the group G3a, may further contain one ring member O that is not adjacent to the amide N atom, The heterocyclyl may be optionally substituted by 1 to 2 F or 1 to 2 CH 3 or may be substituted by or R 3 and R 4 But, R 3 and R 4 R taken 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 3 / 4 - a 6- to 11-membered saturated bridged bicyclic heterocyclyl or spiro bicyclic heterocyclyl selected from the group G3b, Not adjacent to the amide N atom, >N-, >NH, >N(C 1-4 -alkyl) and O; said heterocyclyl being optionally substituted by 1 to 2 F; 1 to 2 C optionally substituted by 1 to 3 F 1-3 - optionally substituted by alkyl, Cl, -CN, -CON(C 1-3 -alkyl) 2 , -COO-C 1-3 -Alkyl, C 1-3 -Alkyl-O-C 1-3 -Alkylene- and C 1-3 -alkyl-O-, The compound or salt thereof according to claim 1.

6. R 3 C optionally substituted with H and 1 to 3 F 1-3 - R consisting of alkyl 3 - selected from the group G2, R 4 However, F and OCF 3 C optionally substituted with one group selected from 1-4 - R consisting of alkyl 4 - selected from the group G4a; or R 4 But, -C 0-1 -Alkylene-C 3-7 -cycloalkyl and C 3-9 -R consisting of heterocyclyl 4 - selected from the group G3b, wherein the cycloalkyl and heterocyclyl are saturated monocyclic or bicyclic ring systems; The heterocyclyl is N, NH, >NCOCH 3 , >NCOO (C 1-2 -alkyl), >NS(=O) 2 CH 3 , >N-pyrimidinyl, O and >S(=O) 2 and containing one ring member selected from The cycloalkyl may be optionally substituted by 1 to 2 F or 1 to 2 CH 3 may be substituted by a group, or CH 2 CH 3 , -CN, CH 2 OH, C(CH 3 ) 2 OH, CHF 2 , C.F. 3 , OH, -OCH 3 and >S(=O) 2 CH 3 and optionally substituted with one substituent selected from The heterocyclyl may be substituted by two F or one to two CH 3 may be substituted by a group, or CH 2 CH 3 and C(CH 3 ) 2 H, or or R 4 But, -C 1-2 - alkylene-phenyl and C 0-1 -alkylene-heteroaryl 4 - selected from the group G3c, One of the alkylene groups >CH 2 The base is 【Chemistry 15】 Part or 【Chemistry 16】 may be replaced by a moiety, or One of the alkylene groups is —CH 2 -CH 2 - group, 【Chemistry 17】 Part or [Chemistry 18] may be replaced by a part, the heteroaryl is a 5- to 6-membered monocyclic ring containing one ring member =N-, and optionally containing one ring member independently selected from =N- and O; The phenyl and heteroaryl are selected from the group consisting of F, Cl, OCH 3 and CH 3 or may be substituted by 1 to 2 substituents independently selected from or R 4 R consists of a 9- to 10-membered fused bicyclic aryl, heteroaryl, or heterocyclyl 4 - selected from the group G3d, The bicyclic aryl, heteroaryl or heterocyclyl is One non-aromatic ring attached to the amide N atom in formula (I), which may contain one ring member selected from >N- and O and consisting of one aromatic ring selected from phenyl, pyridine, pyrazole and thiazole; The bicyclic aryl, heteroaryl or heterocyclyl is selected from the group consisting of F, CH 3 , C.H. 2 CH 3 , -CN, NH 2 and OH, or 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 a 4- to 6-membered saturated monocyclic heterocyclyl 3 / 4 - 4- to 6-membered saturated monocyclic heterocyclyl selected from the group G3a, may further contain one ring member O that is not adjacent to the amide N atom, The heterocyclyl may be optionally substituted by 1 to 2 F or 1 to 2 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 to form a 6- to 8-membered saturated bridged bicyclic heterocyclyl or spiro bicyclic heterocyclyl, which may contain one ring member O that is not adjacent to the amide N atom 3 / 4 - selected from the group G4b, The compound or salt thereof according to claim 1.

7. R 3 But H, CH 3 , C.H. 2 CH 3 and CH 2 CH 2 CH 3 R consisting of 3 - selected from the group G3, R 4 but, 【Chemistry 19】 R consisting of 4 - selected from group G5a; or R 4 but, 【Chemistry 20-1】 【Chemistry 20-2】 R consisting of 4 - selected from the group G4b; or R 4 but, 【Chemistry 21】 R consisting of 4 - selected from the group G4c; or R 4 but, 【Chemistry 22】 R consisting of 4 - selected from the group G4d; 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 a heterocyclyl 3 / 4 - selected from the group G4a, wherein heterocyclyl is 【Chemistry 23】 or selected from the group consisting of 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 a heterocyclyl 3 / 4 - selected from the group G5b, wherein heterocyclyl is 【Chemistry 24】 selected from the group consisting of The compound or salt thereof according to claim 1.

8. R 3 and R 4 But, R 3 and R 4 together with the amide N atom to which they are attached to form a heterocyclyl 3 / 4 - selected from the group G7a, wherein heterocyclyl is 【Chemistry 25】 selected from the group consisting of The compound or salt thereof according to claim 7.

9. below: 【Chemistry 26】 2. The compound of claim 1, or a salt thereof, selected from the group consisting of:

10. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 9.

11. 10. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 9, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

12. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 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 non-exudative choroidal neovascularization, and for treating allergy and inflammation related conditions and diseases, preferably urticaria and NASH.

13. 10. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ocular diseases, preferably diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy and non-exudative choroidal neovascularization, and for treating allergy and inflammation related conditions and diseases, preferably urticaria and NASH.

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