Cyclopentanethiophenecarboxamide derivatives as platelet activating factor receptor antagonists

Abstract

Disclosed are cyclopentathienyl carboxamides of Formula (I.0), and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 and n are as defined in the specification and the claims attached hereto. The cyclopentathienyl carboxamides of Formula (I.0), and pharmaceutically acceptable salts thereof, can be used in methods of treating diseases that can be affected by antagonizing the activity mediated by the platelet-activating factor receptor.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180076849.5 (filed on November 12, 2021, entitled "Cyclopentanothiophene formamide derivative as a platelet activating factor receptor antagonist"). Technical Field

[0002] This invention relates to novel cyclopentanothiophene formamide derivatives and their pharmaceutically acceptable salts, which are platelet-activating factor receptor antagonists. Furthermore, this invention relates to pharmaceutical compositions and combinations comprising said compounds and their use in methods of treating diseases affected by antagonism of platelet-activating factor receptors. In particular, the pharmaceutical compositions of this invention are suitable for the prevention and / or treatment of eye diseases, allergies, and inflammation-related conditions and diseases, especially dry and wet age-related macular degeneration, geographic atrophy, urticaria, and NASH. Background Technology

[0003] Platelet-activating factor (PAF) is an ether phospholipid and is known to be the most potent lipid mediator. PAF is synthesized continuously or in response to specific stimuli by various cells, including 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 for the PAF receptor (PAFR), a G protein-coupled receptor. PAFR exhibits restricted expression on specific target cells of the immune, hemostatic, and inflammatory systems. The signaling function of PAF is primarily associated with acute and chronic inflammation in virtually all organs.

[0004] PAFRs are believed to play a role in many inflammatory disorders and have a wide range of effects in ocular diseases, cardiovascular diseases, cancer, neurological and neurodegenerative disorders, kidney diseases, liver diseases, and allergies. Therefore, inhibition of PAFR activation (e.g., via PAFR antagonists and / or inverse agonists) is considered suitable for treating a broad range of disorders that can be affected by antagonistic and / or inversely agonistic PAFRs, such as those mentioned in the context; in particular, PAFR antagonists and / or inverse agonists should be suitable for the prevention or treatment of ocular diseases such as dry or wet age-related macular degeneration and geographic atrophy, or allergy and inflammation-related disorders such as urticaria and non-alcoholic steatohepatitis (NASH).

[0005] PAFR antagonists and / or inverse agonists suitable for therapeutic use should be potent and bind to PAFRs with high selectivity. The PAFR antagonists and / or inverse agonists should be well absorbed from the gastrointestinal tract, sufficiently metabolically stable, and possess favorable pharmacokinetic properties. The PAFR antagonists and / or inverse agonists should be non-toxic and have been shown to have no or virtually no side effects.

[0006] Low molecular weight PAFR antagonists are known in the art, for example, compounds described in EP0194416A1 and EP0254245A1 by Weber et al. (Med. Res. Rev. 1989, 9, 181-218) and Summers et al. (Curr. Pharm. Des. 1995, 1, 161-190). Thiophene-triazolidine diazepams, as disclosed therein, have been reported to undergo hydrolytic degradation in acidic solutions (e.g., Gallo et al. (J. Heterocyclic Chem. 1988, 25, 867-869), Legouin et al. (J. Heterocyclic Chem. 2000, 37, 127-129)). Some of these compounds have also been identified as inverse agonists of PAFR (Dupré et al. (J. Pharm. Exp. Ther. 2001, 299, 1, 358-365), Cellai et al. (Exp. Hematol. 2009, 37, 1176-1185)).

[0007] Other methods suitable for the synthesis and isolation of the said and related compounds are disclosed in DE4132763A1, EP0388789A1, EP0450504A1, US7015213B1, WO2008 / 063667A1, Tahara et al. (Arzneimittel-forschung 1978,28,1153-1158), Sung et al. (Archiv der Pharmazie 1996,329,291-300), Fier et al. (Org. Lett. 2017,19,1454-1457) and Brenna et al. (Green Chem. 2017,19,5122-5130). Summary of the Invention

[0008] In a first aspect, the present invention relates to compounds of formula (I.0).

[0009]

[0010] in

[0011] R 1 Choose any C that has been replaced by 1 to 3 Fs.1-4 -alkyl and C 3-4 -Group R composed of cycloalkyl groups 1 -G1;

[0012] R 2 Choose from F, Cl, Br, I, substituted with 1 to 3 F atoms, or substituted with 1 -CN, 1 OH, or 1 -OC atom. 1-4 -alkyl-substituted C 1-4 -alkyl group, further composed of C 3-4 -cycloalkyl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, OH, -OC optionally substituted with 1 to 3 Fs 1-4 -alkyl group, and -S(O) with r = 0, 1 or 2. r -C 1-4 -Group R composed of alkyl groups 2 -G1;

[0013] n can be freely selected from 0, 1, 2, and 3 to form a group n-G1;

[0014] R 3 Choose H freely and any C replaced by 1 to 5 Fs. 1-4 -Group R composed of alkyl groups 3 -G1; and

[0015] R 4 Choose freely by substitution of 1 to 3 Fs and by 1 to 2 independently selected from -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and -OC optionally substituted with 1 to 3 F atoms 1-3 -alkyl substituents substituted C 1-6 -Group R composed of alkyl groups 4 -G1a;

[0016] or

[0017] R 4 Choose freely - C 0-3 -alkylene-C 3-10 -Cycloalkyl and -C 0-3 -alkylene-C 3-10 -Group R composed of heterocyclic groups 4-G1b, wherein the alkylene group is optionally substituted with one or two substituents selected from F and CH3.

[0018] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0019] The cycloalkyl and heterocyclic groups are saturated monocyclic or bicyclic systems.

[0020] The heterocyclic group contains one or two independently selected ions from N, NH, >N(C) 1-4 -alkyl), >NCO(C) 1-4 -alkyl), >NS(=O)2(C 1-4 -alkyl) and O ring members, and optionally one >S(=O) selected from >C=O and r=0, 1 or 2. r The ring members,

[0021] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r＝1,2 Any heteroatom-heteroatom bond outside, and

[0022] The cycloalkyl and heterocyclic groups are optionally substituted with 1 to 2 F groups and optionally with 1 to 2 independently selected from Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, OH, -OC optionally substituted with 1 to 3 Fs 1-3 -alkyl group, and selected from one to three F groups or one group selected from -CN, OH, -OC. 1-4 -alkyl substituents substituted C 1-4 -Substituents of alkyl groups;

[0023] or

[0024] R 4 Choose freely - C 0-3 -alkylene-phenyl and -C 0-3 Group R, composed of -alkylene-heteroaryl groups 4 -G1c,

[0025] The alkylene group may be optionally substituted with one or two substituents selected from F and CH3.

[0026] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0027] The heteroaryl group is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing one to two ring members N, or a 6-membered monocyclic ring containing one to two ring members N.

[0028] The phenyl group and the heteroaryl group are optionally selected from 1 to 3 independently from F, Cl, Br, C. 3-4 -cycloalkyl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, -NHCO-C 1-4 -alkyl, -NHS(=O)2-C 1-4 -alkyl, r = 0, 1 or 2, -S (=O) r -C 1-4 -alkyl group, selected from -OC group which is optionally substituted with 1 to 3 F atoms. 1-4 -alkyl group, and selected from one to three F groups or one group selected from -CN, OH and -OC. 1-4 -alkyl substituents substituted C 1-4 -Substituents of alkyl groups;

[0029] or

[0030] R 3 and R 4 Selected from group R 3 / 4 -G1a, where R 3 and R 4 Together with the amide N atom it binds to, they form saturated 3- to 8-membered monocyclic heterocyclic groups.

[0031] It may further contain one or two independently selected from >NH, >N(C) 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0032] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r The ring members,

[0033] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r＝1,2 Any heteroatom-heteroatom bond outside of the bond,

[0034] The heterocyclic group is optionally substituted with 1 to 4 F groups.

[0035] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[0036] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-OC 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C optionally substituted with 1 to 3 Fs 1-3 Substituents of -alkyl-O- groups;

[0037] or

[0038] R 3 and R 4 Selected from group R 3 / 4 -G1b, where R 3 and R 4 Together with the amide N atom it binds to, they form a saturated 5- to 12-membered bicyclic heterocyclic group.

[0039] It may optionally contain 1 to 3 independently selected from >N-, >NH, >N(C) 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0040] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r The ring members,

[0041] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r＝1,2 Any heteroatom-heteroatom bond outside of the bond,

[0042] The heterocyclic group is optionally substituted with 1 to 6 F groups.

[0043] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[0044] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C1-3 -alkyl-OC 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 Substituents of -alkyl-O- groups;

[0045] or

[0046] R 3 and R 4 Selected from group R 3 / 4 -G1c, where R 3 and R 4 Together with the amide N atom it binds to, they form a 7- to 12-membered fused bicyclic system.

[0047] The bicyclic system is composed of heterocyclic or heteroaryl groups consisting of the following:

[0048] A non-aromatic ring containing the amide N atom and optionally further containing one or two atoms independently selected from =N-, >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0049] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r A ring member is defined if there are no members other than NN, NO, and NS (=O) among the members of this non-aromatic ring. r＝1,2 External heteroatom-heteroatom bonds,

[0050] and consists of the following:

[0051] An aromatic ring selected from a 5-membered monocyclic ring containing one ring member selected from NH, N, O and S and optionally one or two more ring members N, and a 6-membered monocyclic ring containing 0, 1 or 2 ring members N.

[0052] The dual-ring system can be arbitrarily replaced by 1 to 4 Fs.

[0053] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[0054] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C1-3 -alkyl-OC 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C optionally substituted with 1 to 3 Fs 1-3 Substituents of -alkyl-O- groups;

[0055] In any of the definitions mentioned above and unless otherwise specified, any alkyl or alkylene group may be straight-chain or branched-chain.

[0056] Its isomers, stereoisomers, tautomers, metabolites, prodrugs, solvates, hydrates, eutectics and salts, especially pharmaceutically acceptable salts, or combinations thereof.

[0057] In a second aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I.0), as defined in the context, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

[0058] In a third aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of formula (I.0), as defined in the context, or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

[0059] In a fourth aspect, the present invention relates to compounds of formula (I.0), as defined in the context, or pharmaceutically acceptable salts thereof, which are used as pharmaceutical agents.

[0060] In a fifth aspect, the present invention relates to a method for treating a disease or condition in a patient in need that may be affected by antagonism of platelet-activating factor receptor, the method comprising administering to the patient one or more compounds of formula (I.0), as defined in the context, or pharmaceutically acceptable salts thereof.

[0061] In addition, the present invention relates to the use of one or more compounds of formula (I.0), as defined in the context, or pharmaceutically acceptable salts thereof, for the manufacture of medicaments for treating diseases or conditions that may be affected by antagonistic platelet-activating factor receptors.

[0062] Furthermore, the present invention relates to a compound of formula (I.0), as defined in the context, or a pharmaceutically acceptable salt thereof, in a method of treating a disease or condition in patients in need that may be affected by antagonism of platelet-activating factor receptor.

[0063] Other aspects of the invention will become apparent to those skilled in the art directly from the foregoing and the following description and embodiments.

[0064] General terms and definitions

[0065] Terms not explicitly defined herein shall have the meanings that those skilled in the art, based on the invention and the text thereof, would have. However, when used in this specification, unless otherwise specified, the following terms shall have the meanings indicated herein and shall be governed by the following conventions.

[0066] The terms “compound according to the invention”, “compound of formula (I.0)”, “compound of the invention” and similar terms refer to compounds of formula (I.0) according to the invention, including their tautomers, stereoisomers, mixtures thereof and their salts, especially their pharmaceutically acceptable salts, and solvates, hydrates and cocrystals of these compounds, including solvates, hydrates and cocrystals of these tautomers, stereoisomers and their salts.

[0067] Furthermore, unless otherwise expressly indicated, throughout the specification and appended claims, the given chemical formula or name shall include tautomers and all isolated, optical and geometric isomers (e.g., enantiomers, non-mirror image isomers, E / Z isomers, etc.), their racemic derivatives and mixtures of individual enantiomers in different proportions, mixtures of non-mirror image isomers, or mixtures in which any of these isomers and enantiomers in the aforementioned forms are present, and salts, including pharmaceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates, including solvates of the free compound or solvates of salts of the compound.

[0068] The term “pharmaceutically acceptable” as used in this article refers to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0069] As used herein, “pharmaceutically acceptable salt” means a derivative of the compound disclosed herein, wherein the parent compound is modified by producing its acid or base salt. Examples of pharmaceutically acceptable salts include (but are not limited to) mineral or organic salts of basic residues (such as amines); base or organic salts of acidic residues (such as carboxylic acids); and the like.

[0070] For example, these salts include those derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentian acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0071] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, these salts can be prepared by reacting the free acidic or basic form of these compounds with a sufficient amount of a suitable base or acid in water or an organic diluent (such as ether, EtOAc, EtOH, isopropanol, or MeCN, or mixtures thereof).

[0072] In addition to those mentioned above, salts of other acids, such as those suitable for purifying or separating the compounds of the present invention (e.g., trifluoroacetate), also constitute a part of the present invention.

[0073] In the case of any discrepancy between the chemical names and formulas used to describe the compounds of this invention, the formula shall prevail.

[0074] In the groups, radicals, or portions defined below, the number of carbon atoms is usually specified before the group, for example, C 1-6 -alkyl means an alkyl group or free radical having 1 to 6 carbon atoms.

[0075] An asterisk may be used in a sub-formula to indicate a bond connected to a core molecule as defined herein. For example, in the case of a sub-formula with more than one bond (i.e., more than one asterisk), the asterisk may be further specified by parentheses in the connecting portion of the core molecule.

[0076] The numbering of the atoms of the substituents starts from the atom closest to the core or group to which the substituent is bonded.

[0077] For example, the term "3-carboxypropyl" indicates the following substituents:

[0078]

[0079] The carboxyl group is the third carbon atom bonded to the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" represent the following groups:

[0080]

[0081] As used herein, the term “substituted” means that any one or more hydrogen atoms on a specified atom, radical, or portion are replaced by a selector from an indicator group, provided that the substitution does not exceed the normal valence of the atom and that the substitution results in an acceptablely stable compound.

[0082] In the definition of a group, the terms "wherein each of the X, Y, and Z groups may optionally be substituted with ..." and similar expressions indicate that each of the X, Y, and Z groups, as individual groups or as parts of a constituent group, may be substituted as defined herein. For example, defining "R ex Represents H and C 1-3 -alkyl, C3-6 -cycloalkyl, C 1-3 -alkyl-C 3-6 -cycloalkylene- or C 1-3 -alkyl-O-, wherein each alkyl group is optionally annealed via one or more L- ex The term "substitution" or similar means that in each of the aforementioned groups containing the term alkyl, that is, in the C group... 1-3 -alkyl, C 1-3 -alkyl-C 3-6 -cycloalkylene- and C 1-3 In each of the -alkyl-O- groups, the alkyl moiety can be defined as above via L... ex replace.

[0083] Term "C" 1-n -alkyl (where n is an integer greater than 1, alone or in combination with another group) represents an acyclic, saturated, straight-chain or branched hydrocarbon group having 1 to n carbon atoms. For example, the term C 1-5 -Alkyl groups include H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0084] Term "C" 1-n -alkylene (where n is an integer greater than 1, alone or in combination with another group) refers to an acyclic, straight-chain or branched divalent alkyl group having 1 to n carbon atoms. For example, the term C 1-4-Alkylene includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(C H3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH 2-, -CH2-CH(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH (CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH(CH3))2-, and -C(CH3)(CH2CH3)-.

[0085] Term "C" 3-n -Cycloalkyl (where n is an integer greater than 3, alone or in combination with another group) represents a cyclic, saturated, unbranched hydrocarbon group having 3 to n carbon atoms. The cyclic group can be monocyclic, bicyclic, tricyclic or spirocyclic, preferably monocyclic. Examples of these cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclic [3.2.1.]octyl, spiro[4.5]decyl, norpinel, norbornyl, norcarel, adamantyl, etc.

[0086] The term "heterocyclic group" refers to a saturated or unsaturated monocyclic or polycyclic system, optionally containing an aromatic ring, which contains one or more elements selected from N, O, or S(O). r The heteroatom, where r = 0, 1, or 2, consists of 3 to 14 ring atoms, none of which is part of an aromatic ring. The term "heterocyclic group" is intended to include all possible isomers.

[0087] Therefore, the term "heterocyclic group" includes the following exemplary structures; they are not depicted as groups because each form may be optionally coupled to any atom via covalent bonding, as long as the appropriate valence is maintained:

[0088]

[0089]

[0090]

[0091] The term "heteroaryl" means containing one or more molecules selected from N, O, or S(O). rA monocyclic or polycyclic aromatic ring system of heteroatoms, wherein r = 0, 1, or 2, consisting of 5 to 14 ring atoms, wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all possible isomers.

[0092] Therefore, the term "heteroaryl" includes the following exemplary structures; they are not depicted as groups because each form is optionally bonded to any atom via covalent bonds, as long as the appropriate valence is maintained:

[0093]

[0094] The term "bicyclic system" refers to a group consisting of two connected ring substructures, including spirocyclic, fused, and bridging ring systems.

[0095] Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above independently of each other.

[0096] As used in this article, the term "treatment / treating" includes both therapeutic (i.e., curative and / or palliative) and preventative (i.e., preventative) treatment.

[0097] Therapeutic treatment refers to the treatment of patients who have developed one or more of the aforementioned conditions in an obvious, acute, or chronic form. Therapeutic treatment can be symptomatic treatment to relieve symptoms of a specific indication or causal treatment to reverse or partially reverse the condition of the indication or to stop or slow the progression of the disease.

[0098] Preventive treatment (“prevention”) refers to treating patients who are at risk of developing one or more of the aforementioned conditions before the clinical onset of the disease, in order to reduce that risk.

[0099] The term "treatment" includes the application of one or more active compounds to prevent or delay the onset of symptoms or complications and to prevent or delay the development of a disease, condition or disorder and / or to eliminate or control the disease, condition or disorder and to alleviate symptoms or complications associated with the disease, condition or disorder.

[0100] When this invention relates to patients requiring treatment, it primarily relates to the treatment of mammals (especially humans).

[0101] The term “therapeutic effective amount” means the amount of the compound of the present invention that (i) treats or prevents a particular disease or condition, (ii) alleviates, improves or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein. Detailed Implementation

[0102] This invention discloses a novel cyclopentanothiophene formamide derivative that is an effective platelet-activating receptor (PAFR) antagonist and has suitable pharmacological and pharmacokinetic properties for use as a pharmaceutical agent to prevent or treat diseases and / or conditions that can be affected by PAFR antagonism, including (but not limited to) ocular diseases and inflammation-related conditions and diseases, particularly geographic atrophy, wet age-related macular degeneration, and allergies.

[0103] The compounds of the present invention offer several advantages, such as enhanced potency, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desirable plasma protein binding, enhanced bioavailability, improved pharmacokinetic profile, and the possibility of forming stable salts.

[0104] The compounds of the present invention

[0105] In a first aspect of the invention, compounds of formula (I.0) were discovered.

[0106]

[0107] Where R 1 R 2 R 3 R 4 As defined in the context, the compound is a potent PAFR antagonist and exhibits favorable properties regarding selectivity, safety and tolerability, metabolic and / or chemical stability, pharmacokinetics and physicochemical properties, solubility, permeability, plasma protein binding, bioavailability, and the potential for stable salt formation. In particular, it provides high in vitro potency as a PAFR antagonist and demonstrates good in vivo efficacy in animal models of choroidal angiogenesis. Furthermore, it has been found to act as a PAFR inverse agonist in in vitro models, which further contributes to the favorable pharmacological effects. Additionally, the compound according to the invention exhibits favorable chemical stability, particularly favorable solubility even at low pH values ​​and across a wide range of pH values ​​(i.e., also in acidic media); while its renal clearance remains sufficiently low.

[0108] Therefore, compounds of formula (I.0) as defined in the context, or pharmaceutically acceptable salts thereof, are expected to be suitable for the treatment of diseases and / or conditions that may be affected by PAFR antagonism.

[0109] Surprisingly, the compound of formula (I.0) also extensively binds to melanin, affecting the biodistribution and pharmacokinetic properties of the compound; in particular, this leads to the accumulation of the compound and prolonged drug retention in the eye. Therefore, the compounds of the present invention are expected to be particularly suitable for the treatment of ocular diseases.

[0110] Therefore, according to one aspect of the invention, a compound of formula (I.0) is provided.

[0111]

[0112] Where R 1 R 2 R 3 R 4 and n as defined in the context,

[0113] And its isomers, stereoisomers, tautomers, metabolites, prodrugs, solvates, hydrates, eutectics and salts, especially their pharmaceutically acceptable salts.

[0114] Unless otherwise stated, groups, residues and substituents, especially R 1 R 2 R 3 R 4 and n as defined in the context. The substituent R of compound (I.0) 1 R 2 R 3 R 4 Preferred meanings of n- and phenyl substitution patterns and stereochemistry will be given below as embodiments of the invention. Any and all of these definitions and embodiments may be combined with each other.

[0115] R 1 :

[0116] According to one implementation plan, R 1 Choose any C that has been replaced by 1 to 3 Fs. 1-4 -alkyl and C 3-4 -Group R composed of cycloalkyl groups 1 -G1.

[0117] According to another implementation scheme, R 1 Group R is composed of CH3, CH2CH3, CH2CH2CH3, CHF2, CF3 and cyclopropyl groups. 1 -G2.

[0118] According to another implementation scheme, R 1 Group R is composed of CH3, CH2CH3, CH2CH2CH3 and cyclopropyl groups. 1 -G3.

[0119] According to another implementation scheme, R 1 Choose the group R composed of CH3. 1 -G4.

[0120] According to another implementation scheme, R 1 Selected from group R 1-G5, which is selected from CH2CH3, CH2CH2CH3 and cyclopropyl.

[0121] R 2 :

[0122] The compound of formula (I.0) contains more than one substituent R. 2 That is, when n = 2 or 3, each R 2 Each of the implementation schemes and groups R, as defined below, is selected independently from the other. 2 -G1 to R 2 -G8.

[0123] According to one implementation plan, R 2 Choose from F, Cl, Br, I, substituted with 1 to 3 F atoms, or substituted with 1 -CN, 1 OH, or 1 -OC atom. 1-4 -alkyl-substituted C 1-4 -alkyl group, further composed of C 3-4 -cycloalkyl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, OH, -OC optionally substituted with 1 to 3 Fs 1-4 -alkyl group, and -S(O) with r = 0, 1 or 2. r -C 1-4 -Group R composed of alkyl groups 2 -G1.

[0124] According to another implementation scheme, R 2 Choose freely from F, Cl, Br, or C substituted with 2 or 3 F atoms. 1-3 -alkyl group, further composed of cyclopropyl, -CN, -C 1-3 -alkylene-OH, -C 1-2 -alkylene-OC 1-2 -alkyl, OH, -OC optionally substituted with 2 or 3 Fs 1-3 -alkyl group, and composed of -SC 1-3 -Group R composed of alkyl groups 2 -G2.

[0125] According to another implementation scheme, R 2 Choose from group R, which consists of F, Cl, Br, CH3, CH2CH3, cyclopropyl, CF3, CH2OH, OH, OCH3, and S-CH3. 2 -G3.

[0126] According to another implementation scheme, R 2 Choose from F, Cl, and Br, with the group R consisting of Cl being the preferred choice.2 -G4.

[0127] According to another implementation scheme, R 2 Select group R composed of CH3 and CH2CH3. 2 -G5.

[0128] According to another implementation scheme, R 2 Group R is composed of free cyclopropyl and CF3. 2 -G6.

[0129] According to another implementation scheme, R 2 Choose group R, which is composed of CH2OH and OH. 2 -G7.

[0130] According to another implementation scheme, R 2 Select group R, which consists of OCH3 and S-CH3. 2 -G8.

[0131] n:

[0132] According to one implementation scheme, n is selected from the group n-G1 composed of 0, 1, 2 and 3.

[0133] According to another implementation scheme, n is selected from the group n-G2 composed of 0, 1 and 2.

[0134] According to another implementation scheme, n is a group consisting of 0, n-G3.

[0135] According to another implementation scheme, n is a group of 1s, n-G4.

[0136] According to another implementation scheme, n is a group consisting of 2, n-G5.

[0137] Phenyl substitution mode:

[0138] The following carbon atom numbers are used for the substitution pattern of the benzene ring shown in description formula (I.0):

[0139]

[0140] Generally speaking, n substituents R 2 It can bind to any of the carbon atoms from C-2 to C-6, and to any combination thereof.

[0141] With n=1, according to one implementation scheme, R 2 Integrating into carbon atom 2; according to another embodiment, R 2 It binds to carbon atom 4.

[0142] With n=2, according to one implementation scheme, an R 2Combined with carbon atom 2 and another R 2 Integrating into carbon atom 5; according to another embodiment, an R 2 Combined with carbon atom 3 and another R 2 It binds to carbon atom 5.

[0143] R 2 , n and phenyl substitution patterns:

[0144] According to one implementation plan, select R 2 The , n, and phenyl substitution modes result in the substituted benzene ring shown in formula (I.0) being selected from the group Ph-G1 consisting of:

[0145] and

[0146] According to another implementation scheme, R is selected. 2 The , n, and phenyl substitution modes result in the substituted benzene ring shown in formula (I.0) being selected from the group Ph-G2 consisting of:

[0147] and Preferred

[0148] According to another implementation scheme, R is selected. 2 The , n, and phenyl substitution modes result in the substituted benzene ring shown in formula (I.0) being selected from the group Ph-G3 consisting of:

[0149] and

[0150] According to another implementation scheme, R is selected. 2 The , n, and phenyl substitution modes result in the substituted benzene ring shown in formula (I.0) being selected from the group Ph-G4 consisting of:

[0151] and

[0152] According to another implementation scheme, R is selected. 2 The , n, and phenyl substitution modes result in the substituted benzene ring shown in formula (I.0) being selected from the group Ph-G5 consisting of the following:

[0153] and

[0154] According to another implementation scheme, R is selected. 2The , n, and phenyl substitution modes result in the substituted benzene ring shown in formula (I.0) being selected from the group Ph-G6 consisting of:

[0155] and

[0156] According to another implementation scheme, R is selected. 2 The , n and phenyl substitution modes make the resulting substituted benzene ring shown in formula (I.0) selected from the group Ph-G7 consisting of:

[0157] and

[0158] According to another implementation scheme, R is selected. 2 The , n, and phenyl substitution modes allow the resulting substituted benzene ring shown in formula (I.0) to be selected from the group Ph-G8 consisting of:

[0159]

[0160] R 3 and R 4 :

[0161] According to one implementation plan, R 3 Choose H freely and any C replaced by 1 to 5 Fs. 1-4 -Group R composed of alkyl groups 3 -G1.

[0162] According to another implementation scheme, R 3 Choose H freely and any C replaced by 1 to 3 Fs. 1-3 -Group R composed of alkyl groups 3 -G2.

[0163] According to another implementation scheme, R 3 Select group R, which consists of H, CH3, and CH2CH2CH3. 3 -G3.

[0164] According to one implementation plan, R 4 Choose freely by substitution of 1 to 3 Fs and by 1 to 2 independently selected from -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and -OC optionally substituted with 1 to 3 F atoms 1-3 -alkyl substituents substituted C1-6 -Group R composed of alkyl groups 4 -G1a.

[0165] According to another implementation scheme, R 4 Choose freely by substituting 1 to 3 Fs and choose freely by substituting 1 from -CN, -CONH2, -CONH(C) 1-2 -alkyl), -CON(C) 1-2 -alkyl)2, -COOH, -COO-C 1-2 -alkyl, C 1-2 -alkyl-CO-NH-, C 1-2 -alkyl-S(=O)2-NH-, OH and -OC optionally substituted with 1 to 3 F atoms 1-2 -alkyl substituents substituted C 1-6 -Group R composed of alkyl groups 4 -G2a.

[0166] According to another implementation scheme, R 4 Choose freely substituted with 1 to 3 Fs and freely substituted with 1 F from -CN, -CONH2, -COOH, OH and freely substituted with 1 to 3 Fs -OC. 1-2 -alkyl substituents substituted C 1-4 -Group R composed of alkyl groups 4 -G3a.

[0167] According to another implementation scheme, R 4 Choose any C that has been substituted with one of the following substituents: F, OH, or OCF3. 1-4 -Group R composed of alkyl groups 4 -G4a.

[0168] According to another implementation scheme, R 4 Choose the freely formed group R 4 -G5a:

[0169] and

[0170] According to one implementation plan, R 4 Choose freely - C 0-3 -alkylene-C 3-10 -Cycloalkyl and -C 0-3 -alkylene-C 3-10 -Group R composed of heterocyclic groups 4 -G1b,

[0171] The alkylene group may be optionally substituted with one or two substituents selected from F and CH3.

[0172] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0173] The cycloalkyl and heterocyclic groups are saturated monocyclic or bicyclic systems.

[0174] The heterocyclic group contains one or two independently selected ions from N, NH, >N(C) 1-4 -alkyl), >NCO(C) 1-4 -alkyl), >NS(=O)2(C 1-4 -alkyl) and O ring members, and optionally one >S(=O) selected from >C=O and r=0, 1 or 2. r The ring members,

[0175] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r = 1,2 Any heteroatom-heteroatom bond outside, and

[0176] The cycloalkyl and heterocyclic groups are optionally substituted with 1 to 2 F groups and optionally with 1 to 2 independently selected from Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, OH, -OC optionally substituted with 1 to 3 Fs 1-3 -alkyl group, and selected from one to three F groups or one group selected from -CN, OH, -OC. 1-4 -alkyl substituents substituted C 1-4 - Alkyl substituents.

[0177] According to another implementation scheme, R 4 Choose freely - C 0-2 -alkylene-C 3-8 -Cycloalkyl and -C 0-2 -alkylene-C 3-8 -Group R composed of heterocyclic groups 4 -G2b,

[0178] The cycloalkyl and heterocyclic groups are saturated monocyclic or bicyclic systems.

[0179] The heterocyclic group contains one ring member selected from N, NH and O.

[0180] The cycloalkyl and heterocyclic groups are optionally substituted with 1 to 2 F groups and optionally substituted with 1 to 2 substituents independently selected from Cl, -CN, OCH3, CH3 and CH2CH3.

[0181] According to another implementation scheme, R 4 Choose freely - C 0-1 -alkylene-C 3-6 -Group R composed of cycloalkyl groups 4 -G3b, wherein the cycloalkyl group is a saturated monocyclic or bicyclic system, and

[0182] The cycloalkyl group may be optionally substituted with 1 to 2 F atoms and optionally substituted with 1 CH3 or CH2CH3 atom.

[0183] According to another implementation scheme, R 4 Choose from the following groups R 4 -G4b:

[0184] and

[0185] According to another implementation scheme, R 4 Choose from the following groups R 4 -G5b:

[0186] and

[0187] According to another implementation scheme, R 4 Choose from the following groups R 4 -G6b:

[0188] and

[0189] According to another implementation scheme, R 4 Choose from the following groups R 4 -G7b:

[0190] and

[0191] According to one implementation plan, R 4 Choose freely - C 0-3 -alkylene-phenyl and -C 0-3 Group R, composed of -alkylene-heteroaryl groups 4 -G1c,

[0192] The alkylene group may be optionally substituted with one or two substituents selected from F and CH3.

[0193] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0194] The heteroaryl group is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing one to two ring members N, or a 6-membered monocyclic ring containing one to two ring members N.

[0195] The phenyl group and the heteroaryl group are optionally selected from 1 to 3 independently from F, Cl, Br, C. 3-4 -cycloalkyl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, -NHCO-C 1-4 -alkyl, -NHS(=O)2-C 1-4 -alkyl, r = 0, 1 or 2, -S (=O) r -C 1-4 -alkyl group, selected from -OC group which is optionally substituted with 1 to 3 F atoms. 1-4 -alkyl group, and selected from one to three F groups or one group selected from -CN, OH and -OC. 1-4 -alkyl substituents substituted C 1-4 - Alkyl substituents.

[0196] According to another implementation scheme, R 4 Choose freely - C 0-2 -alkylene-phenyl and -C 0-2 Group R, composed of -alkylene-heteroaryl groups 4 -G2c,

[0197] The alkylene group may be optionally substituted with one or two CH3 groups.

[0198] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0199] The heteroaryl group is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing one ring member N, or a 6-membered monocyclic ring containing one to two ring members N.

[0200] The phenyl group and heteroaryl group are optionally substituted with 1 to 3 independently selected F, Cl, Br, -CN, or -OC groups optionally substituted with 1 to 3 F groups. 1-3 -alkyl, and selected from 1 to 3 F or 1 selected from -CN and -OC. 1-2 -alkyl substituents substituted C 1-3 - Alkyl substituents.

[0201] According to another implementation scheme, R 4 Choose freely - C0-1 -alkylene-phenyl and -C 0-1 Group R, composed of -alkylene-heteroaryl groups 4 -G3c,

[0202] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0203] The heteroaryl group is a 5- to 6-membered monocyclic ring containing one ring member =N- and optionally one ring member selected from =N-, >NH, S, and O.

[0204] The phenyl group and heteroaryl group are optionally substituted by one to three independent substituents selected from F, Cl, -CN, OCH3, OCHF2, OCF3, CH3, CHF2 and CF3.

[0205] According to another implementation scheme, R 4 Choose from the following groups R 4 -G4c:

[0206] and According to another implementation scheme, R 4 Choose from the following groups R 4 -G5c:

[0207] and According to another implementation scheme, R 4 Choose from the following groups R 4 -G6c: and

[0208] According to another implementation scheme, R 4 Choose from the following groups R 4 -G7c:

[0209] and

[0210] According to another implementation scheme, R 4 Choose from the following groups R 4 -G8c:

[0211] and

[0212] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4-G1a, where R 3 and R 4 Together with the amide N atom it binds to, they form saturated 3 to 8 membered monocyclic heterocyclic groups.

[0213] Optionally contains 1 to 2 independently selected from >NH, >N(C 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0214] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r The ring members,

[0215] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r = 1,2 Any heteroatom-heteroatom bond outside of the bond,

[0216] The heterocyclic group is optionally substituted with 1 to 4 F groups.

[0217] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[0218] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-OC 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C optionally substituted with 1 to 3 Fs 1-3 -alkyl-O- substituents.

[0219] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G2a, where R 3 and R 4 Together with the amide N atom it binds to, they form saturated 3- to 8-membered monocyclic heterocyclic groups.

[0220] It may further contain one selected from >NH, >N(C) 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C1-3 Cyclic members consisting of alkyl groups and O, and optionally containing one S (=O) selected from >C=O and r=0, 1 or 2. r A ring member, provided that the heterocyclic group does not contain any elements other than NS (=O) between ring members. r = 1,2 Any heteroatom-to-heteroatom bond outside the heterocyclic group, wherein the heterocyclic group is optionally substituted with 1 to 2 F atoms.

[0221] C can be substituted by 1 to 4 or by 2 to 3 F. 1-3 -alkyl substitution, and

[0222] Choose one or two from Cl, -CN, -CON(C) 1-4 -alkyl)2、-COO-C 1-4 -alkyl, C 1-3 -alkyl-OC 1-3 -alkylene- and C 1-3 -alkyl-O- substituents.

[0223] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G3a, where R 3 and R 4 Together with the amide N atom it binds to, they form a saturated 4- to 6-membered monocyclic heterocyclic group.

[0224] Its optionality further includes 1 selected from >N(C 1-4 -alkyl) and a ring member of O not adjacent to the N atom of the amide, wherein the heterocyclic group is optionally substituted with 1 to 2 F atoms.

[0225] C can be substituted by 1 to 4 or by 2 to 3 F. 1-3 -alkyl substitution, and

[0226] Choose one or two from Cl, -CN, -CON(C) 1-4 -alkyl)2、-COO-C 1-4 -alkyl, C 1-3 -alkyl-OC 1-3 -alkylene- and C 1-3 -alkyl-O- substituents.

[0227] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G4a, where R 3 and R 4 Together with the amide N atom it binds to, they form a saturated 4- to 6-membered monocyclic heterocyclic group.

[0228] It may optionally contain one ring member O that is not adjacent to the N atom of the amide.

[0229] The heterocyclic group may be optionally substituted with two F atoms and optionally substituted with one to two CH3 atoms.

[0230] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G5a, where R 3 and R 4 Together with the amide N atom it binds to, it forms a heterocyclic group selected from the group consisting of:

[0231] and

[0232] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G6a, where R 3 and R 4 Together with the amide N atom it binds to, it forms a heterocyclic group selected from the group consisting of:

[0233] and

[0234] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G7a, where R 3 and R 4 Together with the amide N atom it binds to, they form a heterocyclic group.

[0235]

[0236] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G8a, where R 3 and R 4 Together with the amide N atom it binds to, it forms a heterocyclic group selected from the group consisting of:

[0237] and

[0238] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G1b, where R 3 and R 4Together with the amide N atom it binds to, they form a saturated 5- to 12-membered bicyclic heterocyclic group.

[0239] It may optionally contain 1 to 3 independently selected from >N-, >NH, >N(C) 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0240] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r The ring members,

[0241] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r = 1,2 Any heteroatom-heteroatom bond outside of the bond,

[0242] The heterocyclic group is optionally substituted with 1 to 6 F groups.

[0243] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[0244] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-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- substituents.

[0245] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G2b, where R 3 and R 4 Together with the amide N atom it binds to, they form a saturated 6- to 11-membered bicyclic heterocyclic group.

[0246] It may optionally contain one or two independently selected from >N-, >NH, >N(C) 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0247] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r The ring members,

[0248] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r = 1,2 Any heteroatom-heteroatom bond outside of the bond,

[0249] The heterocyclic group is optionally substituted with 1 to 6 F groups.

[0250] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[0251] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-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- substituents.

[0252] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G3b, where R 3 and R 4 Together with the N atom of the amide it binds to, it forms a saturated 6- to 11-membered bridging or spirobicyclic heterocyclic group.

[0253] Optionally contains 1 to 2 independently selected from >N-, >NH, >N(C) 1-4 -alkyl), and ring members of O that are not adjacent to the N atom of the amide,

[0254] The condition is that the heterocyclic group does not contain any OO bonds between ring members.

[0255] The heterocyclic group is optionally substituted with 1 to 4 F groups.

[0256] C can be substituted by 1 to 2 or 1 to 3 F. 1-3 -alkyl substitution, and

[0257] Choose one or two from Cl, -CN, -CON(C)1-4 -alkyl)2、-COO-C 1-4 -alkyl, C 1-3 -alkyl-OC 1-3 -alkylene- and C 1-3 -alkyl-O- substituents.

[0258] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G4b, where R 3 and R 4 Together with the amide N atom it binds to, it forms a saturated 6- to 10-membered bridging or spirobicyclic heterocyclic group, which optionally contains one ring member O that is not adjacent to the amide N atom.

[0259] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G5b, where R 3 and R 4 Together with the amide N atom it binds to, it forms a heterocyclic group selected from the group consisting of:

[0260] and

[0261] According to one implementation plan, R 3 and R 4 Selected from group R 3 / 4 -G1c, where R 3 and R 4 Together with the amide N atom it binds to, they form a 7- to 12-membered fused bicyclic system.

[0262] The bicyclic system is composed of heterocyclic or heteroaryl groups consisting of the following:

[0263] A non-aromatic ring containing the amide N atom and optionally further containing one or two atoms independently selected from =N-, >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0264] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r A ring member is defined if there are no members other than NN, NO, and NS (=O) among the members of this non-aromatic ring. r＝1,2 External atom-heteroatomic bonds,

[0265] and consists of the following:

[0266] An aromatic ring is selected from a 5-membered monocyclic ring containing one ring member selected from NH, N, O, and S and optionally further containing one or two ring members N, and a 6-membered monocyclic ring containing 0, 1, or 2 ring members N.

[0267] The dual-ring system can be arbitrarily replaced by 1 to 4 Fs.

[0268] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[0269] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-OC 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C optionally substituted with 1 to 3 Fs 1-3 -alkyl-O- substituents.

[0270] According to another implementation scheme, R 3 and R 4 Selected from group R 3 / 4 -G2c, where R 3 and R 4 Together with the amide N atom it binds to, it forms an 8- to 10-membered fused bicyclic system.

[0271] The bicyclic system is composed of heterocyclic or heteroaryl groups consisting of the following:

[0272] A non-aromatic ring containing the amide N atom and optionally one ring member selected from =N-, >N-, and O, and consisting of the following:

[0273] An aromatic ring, selected from a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing one ring member N, and composed of phenyl and pyridine.

[0274] The dual-ring system can be arbitrarily replaced by 1 to 2 Fs.

[0275] C can be substituted by 1 to 2 or 1 to 3 F. 1-2 -alkyl substitution, and

[0276] C substituted with 1 to 2 C atoms selected from Cl and substituted with 1 to 3 F atoms 1-2-alkyl-O- substituents.

[0277] According to another implementation scheme, R 3 and R 4 Selected from group R 3 / 4 -G3c, where R 3 and R 4 Together with the amide N atom it binds to, they form an 8- to 9-membered fused bicyclic heteroaryl group.

[0278] The heteroaryl group consists of a non-aromatic ring containing the amide N atom and optionally a ring member >N- that is not adjacent to the amide N atom.

[0279] and consists of a pyrazole ring or an imidazole ring,

[0280] The heteroaryl group may be optionally substituted with 1 to 2 CH3 groups.

[0281] According to another implementation scheme, R 3 and R 4 Selected from group R 3 / 4 -G4c, where R 3 and R 4 Together with the N atom of the amide it binds to, it forms a heteroaryl group.

[0282]

[0283] Stereochemistry:

[0284] According to one embodiment, the stereochemistry of the compound of formula (I.0) is based on formula (I.1).

[0285]

[0286] According to another embodiment, the stereochemistry of the compound of formula (I.0) is based on formula (I.2).

[0287]

[0288] Other preferred subclasses of the compound of formula (I.0) are described in Table 1 below as embodiments (Ia) to (Iz), wherein the substituents defined above are used. For example, row R 1 and the entry R in column (Ia) 1 -G1 means that in implementation scheme (Ia), the substituent R 1 Selected from R 1 -The definition of G1. This also applies to other variables incorporated into the general formula.

[0289] Table 1:

[0290]

[0291]

[0292] *Including the corresponding substitution modes defined in Ph-G1, Ph-G2 and Ph-G8 respectively.

[0293] Particularly preferred are those subclass implementation schemes (Ia) to (Iz), regarding R 1 R 2 R 3 R 4 The definition of n corresponds to the subclass implementations (Ia) to (Iz) in Table 1, especially (Iw) to (Iz), and the stereochemistry of said compound is according to formula (I.1), i.e., implementations (I.1-w), (I.1-x), (I.1-y) and (I.1-z).

[0294] Particularly preferred compounds, their salts, or any solvates or hydrates thereof are those described in the Examples and Experimental Data sections.

[0295] According to one embodiment, the compound of formula (I.0) is selected from the group consisting of:

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0304]

[0305]

[0306]

[0307] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0308]

[0309]

[0310]

[0311] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0312]

[0313]

[0314]

[0315] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0316]

[0317] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0318]

[0319] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0320]

[0321]

[0322]

[0323] According to another embodiment, the compound of formula (I.0) and / or (I.1) is

[0324]

[0325] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0326]

[0327] According to another embodiment, the compounds of formula (I.0) and / or (I.1) are selected from the group consisting of:

[0328]

[0329] preparation

[0330] The compounds and intermediates according to the invention can be obtained using synthetic methods known to those skilled in the art and described in references to organic chemistry (e.g., standard textbooks, monographs, and reviews covering fundamental, advanced, and specialized topics in organic chemistry, particularly organic synthesis). Preferably, the compounds are obtained by preparation methods similar to those explained more fully below, particularly those described in the experimental section. In some cases, the order of the reaction schemes employed can be varied. Variations of these reactions known to those skilled in the art but not described in detail herein can also be used. Those skilled in the art will understand the general methods used to prepare the compounds according to the invention when studying the following schemes. The starting compounds can be commercially available or prepared by methods described in the references or herein, or prepared in a similar or analogous manner. Prior to the reaction, any corresponding functional groups in the starting compounds can be protected with conventional protecting groups. These protecting groups can be re-cleaved at appropriate stages within the reaction sequence using methods familiar to those skilled in the art and described in references for the use of protecting groups in organic synthesis.

[0331] Option 1:

[0332]

[0333] Option 1: Compounds of formula (I), such as (I.0), (I.1), or (I.2), and compounds of formula (IV) may be derived from the respective acids of formulas (II) and (V) (in the form of free acids or with suitable metal cations such as Li). + Na + K + The preparation of a suitable amine of formula (III) (in the form of a carboxylate, etc.) and a suitable amine (in the form of a free lysine or a salt such as a hydrochloride, hydrobromide, etc.) is carried out in a suitable solvent (e.g., O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureonium tetrafluoroborate (TBTU), (benzotriazol-1-oxy)tri-pyrrolidine phosphonium hexafluorophosphate (PyBOP), carbodiimide reagent, etc.) and a base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, etc.) at a suitable solvent (e.g., DCM, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone) at a temperature of -20°C to 100°C; R in Scheme 1 1 R 2 R 3 R 4And n has the meaning as defined above. Alternatively, individual carboxylic acids are converted into carboxylic acid chlorides (e.g., oxalyl chloride or thionyl chloride used in DCM) and thus coupled with amines (III) in the presence of a suitable base (e.g., triethylamine, N,N-diisopropylethylamine, pyridine, etc.).

[0334] Compounds of formula (IV) have been reported in the references and can also be obtained by enantiomer enrichment or in pure form (see, for example, DE4132763A1, EP0388789A1, EP0254245A1, EP0450504A1 and Med. Res. Rev. 1989, 9, 181-218).

[0335] Option 2:

[0336]

[0337] Scheme 2: Imines of formula (IV) and (V) (where R) 1 R 2 R 3 R 4 (and n has the meaning as defined above) can be reduced to the corresponding amines (II) and (I) respectively by using hydrogen in the presence of a transition metal catalyst or a suitable hydride source. Suitable hydride sources can be borohydrides (such as NaBH4, KBH4, Na(NC)BH3, NaHB(OAc)3, Me4NBH4 and... n Bu4NBH4), aluminum hydrides (such as LiAlH4), tris(second butyl)borohydrides (such as lithium tris(second butyl)borohydride, HAl) i Bu2), boranes (such as pinacolborane, H3B*THF, 9-BBN-H and Et2BH), silanes (such as Et3SiH and Cl3SiH), depending on the hydride source, in Lewis acid or Boubner acid ( In the presence of an acid or transition metal, the reduction of imines can be carried out in a suitable solvent (e.g., toluene, DCM, THF, MeCN, H2O, or mixtures thereof, depending on the hydride used and the conditions) at low to high temperatures (-70°C to 100°C). More commonly used, more specific experimental protocols include NaBH4 and an acid (e.g., aqueous HCl or acetic acid) in 1,2-dichloroethane at 0°C to 40°C. Active catalysts that can be used in combination with molecular hydrogen are preferably derived from (e.g.) Co, Ni, Pd, Pt, Rh, Ru, and Ir. In the presence of one of these transition metal catalysts, optionally in the presence of ligands coordinated to the transition metal and other additives, the reduction of imines can be carried out with hydrogen (1 to 200 bar) in a suitable solvent (e.g., DCM, EtOAc, EtOH, THF, etc.) at 0°C to 150°C. The compounds (I) and (II) obtained according to this procedure are, depending on the applied reducing agent and conditions, non-mirror image isomers or mixtures of pure non-mirror image isomers and can be separated into individual stereoisomers by methods known to those skilled in the art to provide pure stereoisomers (e.g., (I.1) or (I.2)).

[0338] The reduction of imines (IV) or (V) can also be carried out stereoselectively using chiral hydrides or hydrogen in the presence of a chiral catalyst, providing compounds (I) or (II) as enriched or pure stereoisomers, depending on the enantiomeric purity of the starting imine (IV) or (V) and the application conditions. For example, by... n Bu4NBH4 and (S)- or (R)-N-benzyloxycarbonyl (Cbz)-proline (→ n The chiral hydride formed by the reaction of Bu4NHB((S) or (R)-N-Cbz-proline)3) is a suitable reagent for the highly stereochemically selective reduction of imines (IV) and (V). This reaction is preferably carried out in a DCM at -78°C to 40°C with the chiral hydride formed in situ in a separate step or before the addition of the imine.

[0339] The reduction of imine can also be carried out using ester (VI) (Scheme 3) under some of the conditions described above to provide the corresponding amine, which can be converted into compound (II) by hydrolysis of the ester group (Scheme 3) as described below and then converted into compound (I) by coupling with amine (III) (Scheme 1) as further described above.

[0340] Option 3

[0341]

[0342] R'=C 1-4 -alkyl or benzyl

[0343] Scheme 3: The acid of formula (V) (where R) 1 R2 (and n has the meaning as defined above) is preferably prepared from the corresponding ester (VI) by hydrolysis or hydrogenolysis, depending on the nature of R'. Low-carbon alkyl esters (such as ethyl or methyl esters) are preferably cracked by hydrolysis in a mixture of hydroxide salts (such as NaOH, LiOH, or KOH) in water and a suitable miscible solvent (e.g., THF, MeOH, EtOH, 1,4-dioxane, or mixtures thereof) at ambient or high temperature. The acid may be separated as a salt of a metal cation or as a carboxylic acid. Tert-butyl ester is preferably cracked by treatment with an acid (e.g., hydrochloric acid or TFA) in a suitable solvent (e.g., DCM, 1,4-dioxane, MeOH, EtOH, THF, water, or mixtures thereof). Benzyl ester is preferably cracked by hydrogenolysis in a suitable solvent (e.g., EtOH, MeOH, THF, DCM, or EtOAc) under a hydrogen atmosphere (preferably 1 to 5 bar) using a suitable catalyst (e.g., carbon-supported palladium).

[0344] Compounds of formula (V) have been reported in the references and can also be obtained by enantiomeric enrichment or in pure form (see, for example, EP0388789A1, EP0254245A1 and DE4132763A1).

[0345] Option 4

[0346]

[0347] R'=C 1-4 -alkyl or benzyl

[0348] Scheme 4: Ester of formula (VI) (where R) 1 R 2 (and n has the meaning as defined above) can be prepared from amide (VII) using different synthetic strategies. A more preferred procedure involves 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 a moderate temperature (preferably between 0°C and 40°C) to convert the amide group in (VII) to the corresponding iminoyl chloride or phosphate anhydride. Subsequently, the correspondingly modified acylhydrazine (R 1 -CO-NHNH2) is added to this activated amide to provide an N-acylaminoamidine derivative, which can be converted into a triazole by heating (sometimes up to 140°C).

[0349] Alternatively, triazole (VI) can be obtained via a three-step procedure via the thioamide of amide (VII), which is then treated with hydrazine to produce the corresponding N-aminoamidinium, which is obtained by treatment with a suitable orthoester (R). 1 -C(OC 1-2-alkyl)3) treatment further converts to triazole. This procedure, its variations, and alternative synthetic routes are reported in organic chemistry references and are known to those skilled in the art (see, for example, EP0388789A1 and EP0254245A1).

[0350] Compounds of formula (VI) have been reported in the references and can also be obtained by enantiomer enrichment or in pure form (see, for example, EP0388789A1).

[0351] Option 5

[0352]

[0353] R'=C 1-4 -alkyl or benzyl

[0354] Scheme 5: Ester of formula (VII) (where R 2 (and n has the meaning as defined above) can be prepared from ketone (VIII) in one, two, or three separate synthetic steps. The mature synthesis of compound (VII) proceeds via an N-bromoacetyl derivative of compound (VIII), which can be obtained by treating compound (VIII) with bromoacetyl bromide in the presence of a base (e.g., NaHCO3) in a suitable solvent (e.g., toluene and water) at 0°C to 80°C. This intermediate is then treated with an ammonia source (e.g., ammonia water or ammonia in THF) to replace the bromine and produce the corresponding N-aminoacetyl derivative. Compound (VII) is then produced by reacting the amino group with the ketone group in a suitable solvent (e.g., silica gel in toluene, pyridine in HOAc, or methanesulfonic acid in 1,4-dioxane) at high temperature (preferably between 30°C and 130°C) with the aid of a suitable additive to form a seven-membered ring.

[0355] This procedure has also been reported in the references and is applicable to the synthesis of enantiomeric enrichment or pure compounds (see, for example, EP0254245A1 and EP0388789A1).

[0356] Compound (VII) can also be obtained in a single reaction step from compound (VIII) as reported in Org. Lett. 2017, 19, 1454-1457.

[0357] Option 6

[0358]

[0359] R'=C 1-4 -alkyl or benzyl

[0360] Scheme 6: Compound (VIII) can be prepared from cyanoketone (IX) and ketone (X) following a scheme reported for the so-called Gewald reaction; R in Scheme 6 2 And n has the meaning as defined above. Therefore, compounds (IX) and (X) are combined and treated with a base (e.g., NEt3, HNEt2, morpholine, piperidine, pyridine, etc.) in the presence of elemental sulfur in a solvent (e.g., MeOH, EtOH, DMF, 1,4-dioxane, etc.) at 0°C to 120°C.

[0361] Alternatively, this transformation can be carried out in two separate steps, with compounds (IX) and (X) forming a condensation product in the first step (Knoevenagel reaction) and product (VIII) formed in the second step after treatment with elemental sulfur and a base.

[0362] These procedural changes have been reported in the organic chemistry references.

[0363] Compound (IX) is a known compound or can be prepared in a similar manner. Major and specific acquisitions of enantiomeric enrichment or pure compounds (X) have also been reported in organic chemistry references (see, for example, EP0388789A1, Archiv der Pharmazie 1996, 329, 291-300 and Green Chem. 2017, 19, 5122-5130).

[0364] Option 7

[0365]

[0366] R” = C 1-4 -alkyl or benzyl

[0367] Scheme 7: Cyanoketone of formula (IX) (where R) 2 (and n has the meaning as defined above) preferably consists of the corresponding ester (XI) and deprotonated acetonitrile (NCCH2) - The species are prepared in a suitable solvent (e.g., THF, toluene, MeCN, DMF, DMSO, 1,4-dioxane, etc.) at -78°C to 100°C. The deprotonated acetonitrile species are prepared from acetonitrile by reacting it with a suitable base (e.g., NaH, LiN). i Pr2, LiN(SiMe3)2, KO t The compound is prepared by deprotonation at -78°C to 40°C in one of the solvents used for subsequent reactions with the ester (XI), preferably depending on the base used. Other synthetic routes and procedures for preparing compounds of formula (IX) are reported in the references of Organic Chemistry.

[0368] Option 8

[0369]

[0370] R'=C 1-4 -alkyl or benzyl; R” = C 1-4 -alkyl or benzyl

[0371] Scheme 8: Compound (I) can also be obtained by following the route described in Scheme 8; R 2 R 3 R 4The terms "n" have the meanings defined above. The synthetic sequence begins with a Gwald reaction of the ketone (X) and cyano ester (XII) to provide aminothiophene (XIII) (see Experimental Section and WO2008 / 063667A1 for specific reaction conditions). Aminothiophene (XIII) can be acetylated on N with methoxyacetyl chloride in the presence of a base (e.g., pyridine) in an inert solvent (e.g., DCM) at ambient temperature to provide compound (XIV). The methoxy group acts as a masked leaving group, which is to be replaced by amine to introduce an amino group later in the synthesis. Therefore, many other masked or protected amino equivalents, such as phenoxy groups instead of methoxy groups, can be considered for this purpose. Compound (XIV) can then be converted to triazole (XVI) via thioamide (XV). The latter compound can be obtained by treatment (XIV) with Lawson's reagent (or phosphorus pentasulfide) in a solvent (e.g., 1,4-dioxane or toluene) at high temperatures (60°C to 120°C). Triazoles (XVI) can be formed by treating thioamide (XV) with hydrazine in a solvent (e.g., THF or 1,4-dioxane) at ambient temperature to provide an N-aminoamidinium intermediate, followed by reaction with a trialkyl orthoacetate (e.g., MeC(OMe)3) or an acetamide dialkyl acetal (e.g., MeC(OMe)2(NMe2)), optionally in the presence of an acid (e.g., p-TsOH or MeCOOH), at high temperature (about 60°C to 120°C). Alternatively, acetylhydrazine can be used instead to provide triazoles under similar conditions. Bromines (XVIII) can be generated from compounds (XVI) by direct substitution of the methoxy group with bromide, depending on the application conditions, or via alcohol derivatives (XVII). The procedure via alcohol requires cleavage of the methoxy ether (e.g., BBr3 for DCM) and subsequent substitution of the hydroxyl group with Br (e.g., MeSO2Br and NEt3 for DCM). Compound (XIX) can then be obtained by treating the bromide (XVIII) with ammonia (e.g., in methanol at ambient temperature) and optionally heating the product in the presence of another base (e.g., NEt3) to simultaneously achieve cyclization and amide formation. The thioamide (XIX) packed in (XX) can be treated with Lawson's reagent or P2S5 in an inert solvent (e.g., toluene or 1,4-dioxane) at high temperatures (preferably between 60°C and 120°C). The ester functional group in (XX) can be converted to the corresponding amide to provide compound (XXII) by following the main procedure (ester hydrolysis) described in Scheme 3 and Scheme 1 (amide formation); ester hydrolysis can be carried out using NaOH in a mixture of water and methanol at ambient temperature, while amide formation can be carried out using the desired amine (R). 3 R 4The reaction of NH) and carbonyl diimidazole is carried out in DMF at room temperature. Methylation of sulfur in thioamide (XXII) can be achieved in a solvent (e.g., acetone or MeCN) at ambient temperature using iodomethane or methyl trifluoromethanesulfonate, optionally in the presence of a base (e.g., KOtBu), to produce compound (XXIII), which contains a functional group (-N=C(SMe)-) suitable for transition metal-catalyzed coupling with an aromatic nucleophile (such as boric acid or zinc halide) to bind the functional group of the aromatic residue. Coupling of compound (XXIII) with aromatic boric acid (RB(OH)2) can be carried out in a solvent (e.g., NMP or 1,4-dioxane) at ambient temperature or a high temperature (preferably between 20°C and 120°C) using a Pd-based transition metal catalyst (e.g., Pd(PPh3)4) and a Cu-based additive (e.g., thiophene-2-carboxylic acid ketone (I)) to provide compound (I'), i.e., wherein R 1 Compound (I) is methyl. The synthetic scheme described in Scheme 8 is not limited to that targeting R. 1 Compounds carrying methyl groups can, in principle, be extended to compounds containing R as defined above. 1 The meaning includes any other residues.

[0372] Compounds of formula (I) can be resolved into their enantiomers and / or non-mirror image isomers as mentioned below. Thus, for example, a mixture of cis / trans can be resolved into its cis and trans isomers, a mixture of non-mirror image isomers can be separated into its non-mirror image isomers, and a racemic compound can be separated into its enantiomers.

[0373] A mixture of cis / trans isomers can be resolved, for example, by chromatography to its cis and trans isomers. A mixture of formula (I) compounds appearing as racemates can be separated into its optical enantiomers by methods known per se, and a mixture of non-mirror image isomers of general formula (I) compounds can be separated into its non-mirror image isomers by methods known per se (e.g., chromatography and / or fractional crystallization) taking advantage of their different physicochemical properties; if the resulting compound is a racemate, it can be separated into the enantiomers mentioned below.

[0374] Racemic compounds are preferably resolved by column chromatography in a chiral phase, or by crystallization in an optically active solvent, or by reaction with an optically active substance that forms a salt or derivative (such as an ester or amide) with the racemic compound. For basic compounds, salts can be formed with enantiomerically pure acids, and for acidic compounds, salts can be formed with enantiomerically pure bases. Non-mirror image derivatives are formed from enantiomerically pure auxiliary compounds, such as acids, their activated derivatives, or alcohols. The separation of mixtures of non-mirror image isomers of the resulting salts or derivatives can be achieved by utilizing their different physicochemical properties (e.g., differences in solubility); free enantiomers can be released from pure non-mirror image isomer salts or derivatives by the action of suitable reagents. Optically active acids commonly used for this purpose and optically active alcohols suitable as auxiliary residues are known to those skilled in the art.

[0375] As mentioned above, compounds of formula (I) (e.g., compounds of (I.0)) can be converted into salts, particularly pharmaceutically acceptable salts for pharmaceutical use. As used herein, a "pharmaceutically acceptable salt" refers to a derivative of the compounds disclosed herein, wherein the parent compound is modified by making its acid or base salt.

[0376] The compounds according to the invention can also be advantageously obtained using the methods described in the following examples, and for this purpose, the methods described can also be combined with methods known to those skilled in the art from the references.

[0377] Pharmacological activity and suitability for drug application

[0378] The activity of the compounds of the present invention and their suitability for pharmaceutical applications can be confirmed by the following analyses:

[0379] Biological methods

[0380] The ability of compound (I.0) to inhibit PAF C-16 ligand (PAF) activation of PAF receptor (PAFR) was determined using the following cell HTRF IP1 assay (from Cisbio, catalog number: 62IP1APEJ IP1Gq assay kit) in assay buffer (1x HBSS, 20 mM Hepes, pH 7.4, 50 mM LiCl and containing 0.1% (w / v) BSA):

[0381] Inhibition of PAFR activation was assessed using endpoint analysis.

[0382] HEK293 cells overexpressing human PAFR (internal generation) were seeded in capped, poly-D-lysine-coated 384-well microtiter assay dish for leukocyte culture (15,000 cells / well). The dish was then incubated overnight at 37°C / 5% CO2. The next day, the cells were washed and various concentrations of the test compound (compound in 100% DMSO; final DMSO concentration in wells 1%) were added to the assay dish via an Echo 555 acoustic liquid processor. The dish was then incubated capped at 37°C / 5% CO2 for 90 minutes. Subsequently, PAF ligand (Cayman Chemical Company, Item No.: 60900) was added at a final concentration of 11 nM. The dish was then incubated capped at 37°C / 5% CO2 for 60 minutes. Then, 5 μl of anti-IP1 antibody cavitation compound solution and 5 μl of IP1-d2 solution per well were added to all wells of the dish, and the dish was incubated in the dark at room temperature for another 60 minutes. Emission at 620 nm and 665 nm (excitation wavelength: 320 nm) was measured using an Envision Reader (PerkinElmer).

[0383] IC of the compound according to the present invention 50 The values ​​are shown in the table below. The compound numbers correspond to the example numbers in the experimental section. In the case of tests conducted with a mixture of isomers of the C-13 configuration, the observed activity can be attributed primarily to the (13S)-isomer, which is an isomer according to the invention. This is readily apparent from direct comparisons of (reference) Examples 67 to 71 and 74 to 78.

[0384] Table 2:

[0385]

[0386]

[0387] *Reference embodiments outside the scope of this invention

[0388] Using endpoint analysis to evaluate reverse facilitation patterns

[0389] Due to the constitutive activity of PAFR, basal HTRF IP1 signaling was higher in HEK293 cells overexpressing human PAFR compared to untransfected HEK293 cells. The ability of the test compounds to act as inverse agonists of the PAF receptor was determined using a modified protocol for cellular HTRF IP1 analysis described above. Various concentrations of the test compounds were added to analysis dishes containing HEK293 cells overexpressing human PAFR and cultured at 37°C / 5% CO2 for 340 min without the addition of PAF ligands. The inverse agonist effect of the test compounds was confirmed by a decrease in HTRF IP1 signaling to levels seen in untransfected HEK293 cells.

[0390] In vivo efficacy assessment of an animal model of laser-induced choroidal angiogenesis in brown Norwegian rats

[0391] Male brown Norwegian rats (BN / Crl) weighing between 160g and 180g were obtained from Charles River Labs (Sulzfeld, Germany). Animals were housed in enclosures with a 12-hour / 12-hour light / dark cycle (lights on at 6:00 AM) and acclimatized for one week prior to the start of the study. The animals had free access to standard food (Provimi Kliba No. 3438) and tap water. The test compound was administered to the animals via oral gavage once daily for two weeks.

[0392] Under anesthesia, animals were placed in front of a fundus camera on day 1 to center the optic nerve in the image. Laser treatment was performed using a Micron IV system (Phoenix Research Laboratories, Pleasanton, CA) with a 532 nm wavelength green argon laser (Merilas). The laser beam diameter was matched to the diameter of the optic nerve, and laser pulses with an energy of 400 mW and a duration of 150 ms were used to create four lesions per eye. The lesions were located between large blood vessels and approximately twice the diameter of the optic nerve. Successful destruction of the Bruch's membrane was identified by bubbles that formed immediately after the laser beam and confirmed by OCT scanning.

[0393] Fourteen days after laser treatment, animals were euthanized under anesthesia via cervical dislocation. Eyes were removed and cut along the serrated edge. The cornea, iris, lens, vitreous body, and retina were removed, along with the remaining eye patch (composed of RPE, choroid, and sclera). The patch was fixed in PFA (4%) at 4°C for 1 hour and then transferred to PBS containing 0.1% Triton X-100 at 4°C for 1 hour. The eye patch was stained overnight in the dark at room temperature with FITC-labeled isolectin B4 (10 μg / ml in saline; obtained from Sigma-Aldrich, catalogue number L9381) and washed three times with PBS. The eye patch was transferred to a slide and cut four times to achieve a flattened cloverleaf structure. The tissue was covered with mounting medium (Vectashield H-1200 containing DAPI) and a coverslip was placed on top to obtain an RPE / choroid / sclera flatmount (RPE side up). Store the slices in the dark at 4°C until analysis.

[0394] Samples were analyzed and lesion images were obtained using an LSM 700 confocal laser scanning microscope (Carl Zeiss, Jena; gain 650, laser intensity 2%) at a wavelength of 488 nm. Lesion size was measured using Zen Blue software. Utility readings were given as the size of the lesion in the RPE-choroidal tile stained with isohemagglutinin B4.

[0395] Evaluate the binding of compounds to melanin.

[0396] The ability of a compound to bind to melanin (Sigma-Aldrich, catalog number: M2649) from the squid (Sepia officinalis) was determined using in vitro analysis in analytical buffer (phosphate buffer, pH 6.5, 0.9% (w / v) NaCl). To measure this binding, a 1 mg / mL (w / v) melanin suspension and a 0.1% (w / v) BSA solution (control buffer) were prepared in analytical buffer. The compound was incubated on a microtiter plate with the 1 mg / mL melanin suspension (for determining the free compound concentration) and a melanin-free control buffer (for determining the total compound concentration) at a final compound concentration of 1 μM (the compound was added to the plate in DMSO:analytical buffer (40:60); final DMSO concentration 1%). The plate was incubated at 37°C with orbital shaking at 900 rpm for 2 hours. After incubation, the plate was centrifuged to aggregate the melanin and unbound compound into particles. Samples were taken from the supernatant of melanin and control wells, and the concentration was measured by LC-MS. The unbound concentration was calculated by subtracting the free compound concentration from the total compound concentration.

[0397] Assessment of chemical stability

[0398] Degradation studies were used to simulate the chemical stability of the compounds in the acidic portion of the gastrointestinal tract. The compounds of this invention exhibit high chemical stability in acidic aqueous media (pH approximately 1.2), which makes their application as medical drugs for treating human diseases less restricted and troublesome.

[0399] The chemical stability of the compounds of the present invention at a pH of about 1.2 was determined as follows:

[0400] The compound was dissolved in an acetonitrile / 0.1M HCl aqueous solution mixture (ratio: 2:3; pH approximately 1.2) in an HPLC vial to obtain a concentration of approximately 0.25 mg / mL. The vial was then transferred to an HPLC autosampler system and maintained at 37°C. The first sample was collected and immediately injected into a standard HPLC system equipped with a UV DAD detector. Subsequent samples were injected after 24 hours. The recovery rate [%] of the compound injected after 24 hours was determined using a standard HPLC gradient method to measure the amount of degraded compound. Therefore, the peak area (AU) of the main peak of the first injection was... t0 The value was determined and set to 100%. The peak area (AU) of the main peak was also measured for a 24-hour injection. 24h And represented as (AU) 24h ) / (AU t0 The percentage of )

[0401] The chemical stability of the exemplary compounds according to the present invention was tested as described above. For all of them, the amount of degrading compounds was found to be no more than 3%.

[0402] The table below shows the degree of degradation of individual compounds of the present invention. The numbers of these individual compounds correspond to the numbers of the examples in the experimental section.

[0403] Table 3:

[0404]

[0405] Permeability assessment

[0406] Caco-2 cells (1-2 x 10⁻⁶) 5 Cells / 1cm 2 The inoculum (area) was inoculated onto filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days.

[0407] The compound was dissolved in a suitable solvent (such as DMSO, 1 to 20 mM stock solution). The stock solution was diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4x 7H2O, 0.41 mM NaH2PO4xH2O, 15 mM HEPES, 20 mM glucose, pH 7.2) to prepare a transport solution (0.1 to 300 μM compound, final DMSO <= 0.5%). This transport solution (TL) was applied to the donor side at the tip or substrate to measure AB or BA permeability, respectively (3 filters replicate). The receiver end contained HTP-4 buffer supplemented with 2% BSA. Samples were collected from the donor at the beginning and end of the experiment, and also from the receiver at various time intervals for up to 2 hours, for concentration determination by HPLC-MS / MS or scintillation. The receiving volume of the sample was replaced with fresh receiving solution.

[0408] Assessment of metabolic stability in human or rat liver microsomes

[0409] Metabolic degradation of the compound was assessed using a mixture of human or rat liver microsomes at 37°C. At each time point, a final culture volume of 100 μL contained 0.1 M TRIS buffer (pH 7.6), magnesium chloride (5 mM), microsomal protein (1 mg / mL), and a final concentration of the test compound at 1 μM.

[0410] After a brief incubation at 37°C, the reaction was initiated by adding the reduced form of β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM), and the reaction was terminated by transferring aliquots to the solvent at different time points. Additionally, NADPH-independent degradation was monitored in NADPH-free cultures, ending at the final time point. The quenched cultures were aggregated into particles by centrifugation (10000 g, 5 min). The amount of the parent compound in the aliquots of the supernatant was analyzed by LC-MS / MS. The half-life (t1 / 2 in vitro) was determined by the slope of the semi-logarithmic plot of the concentration-time curve.

[0411] Assessment of metabolic stability in human or rat hepatocytes

[0412] The metabolic degradation of the test compounds was analyzed in hepatocyte suspension. Hepatocytes (usually cryopreserved) were cultured in an appropriate buffer system containing 5% species serum (e.g., Durbeco-modified Igor medium with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL, and 3.75 mg hydrocortisone / 500 mL).

[0413] After pre-culturing (usually) for 30 minutes in an incubator (37°C, 10% CO2), add 5 μL of the test compound solution (80 μM; derived from 2 mM of DMSO stock solution diluted 1:25 with medium) to 395 μL of hepatocyte suspension (cell density from 0.25 to 5 Mio cells / mL, usually 1 Mio cells / mL; final concentration of test compound 1 μM, final concentration of DMSO 0.05%).

[0414] Cells were cultured for six hours (in a culture vessel or on a fixed-track shaker) and samples (25 μL) were collected at 0, 0.5, 1, 2, 4, and 6 hours. The samples were transferred to an ACN and agglomerated by centrifugation (5 min). The supernatant was transferred to a new 96-well plate, evaporated under nitrogen, and resuspended.

[0415] The decline of the parent compound was analyzed by HPLC-MS / MS. CLint was calculated as follows: CL_INTRINSIC = dose / AUC = (C0 / CD) / (AUD + clast / k) x 1000 / 60. C0: initial concentration in culture [μM], CD: cell density of viable cells [10e6 cells / mL], AUD: area under the data [μM x h], clast: concentration of the last data point [μM], k: slope of the parent compound decay regression line [h-1].

[0416] Assessment of plasma protein binding

[0417] This balanced dialysis (ED) technique was used to determine the approximate in vitro fractional binding of test compounds to plasma proteins. A Dianorm Teflon dialysis tank (0.2 μm) was used. Each tank consisted of donor and acceptor chambers separated by an ultrathin semipermeable membrane with a 5 kDa molecular weight cutoff. Stock solutions for each test compound were prepared at 1 mM in DMSO and diluted to a final concentration of 1.0 μM. Subsequent dialysis solutions were prepared in a mixture of human or rat plasma (containing NaEDTA) from male and female donors. Aliquots of 200 μL of dialysis buffer (100 mM potassium phosphate, pH 7.4) were dispensed into the buffer chambers. Aliquots of 200 μL of the test compound dialysis solution were dispensed into the plasma chambers. Incubation was performed at 37°C for 2 hours under rotation.

[0418] At the end of the dialysis period, the dialysate was transferred to a reaction tube. The tube used to buffer the elution fraction contained 0.2 mL ACN / water (80 / 20). A 25 μL aliquot of the plasma dialysate was transferred to a deep-well plate and mixed with 25 μL ACN / water (80 / 20), 25 μL buffer, 25 μL calibration solution, and 25 μL internal standard solution. Protein precipitation was then performed by adding 200 μL ACN.

[0419] Transfer 50 μL of buffer dialysate into a deep well plate and mix with 25 μL of blank plasma, 25 μL of internal standard solution and 200 μL of ACN.

[0420] Samples were measured on an HPLC-MS / MS system and evaluated using Analyst software.

[0421] The binding percentage is calculated using the following formula: Binding % = (Plasma concentration - Buffer concentration / Plasma concentration) x 100

[0422] Solubility assessment

[0423] The water solubility of the test compounds was determined by comparing the amount dissolved in the buffer solution with the amount dissolved in an ACN / water (1 / 1) solution. Starting with a 10 mM DMSO stock solution, aliquots were diluted with either ACN / water (1 / 1) or the buffer solution. After shaking for 24 hours, the solutions were filtered and analyzed by LC-UV. The amount dissolved in the buffer solution was compared with the amount dissolved in the ACN solution.

[0424] Solubility will typically be measured from 0.001 to 0.125 mg / mL at a 2.5% DMSO concentration. If more than 90% of the compound dissolves in the buffer solution, the value is marked with ">".

[0425] The compounds of this invention also exhibit favorable solubility at low pH values ​​(pH 2.2, simulating the acidic portion of the gastrointestinal tract), a desirable characteristic for drug development and administration purposes. The table below shows data for selected compounds of this invention.

[0426] Table 4:

[0427]

[0428]

[0429] Evaluation of pharmacokinetic properties in rodents

[0430] The test compound was administered intravenously to fed rats or orally to fasted rats. Blood samples were collected at several time points after administration of the test compound, anticoagulated, and centrifuged.

[0431] The concentration of the analyte (administered compound and / or metabolite) in plasma samples was quantified by LC-MS / MS. To determine renal clearance, urine samples were collected 24 hours after intravenous administration, and the urinary concentration of the administered compound was quantified by LC-MS / MS.

[0432] PK parameters were calculated using non-compartmental PK analysis (NCA). The trapezoidal rule (linear up, logarithmic down) was applied to determine the area under the curve (AUC) for each individual concentration from time zero to the last measured concentration. 0-tz By inferring the terminal phase and AUC tz-∞ Add to AUC 0-tz Calculate AUC 0-Inf Calculate the individual CL values ​​according to Equation 1.

[0433]

[0434] Among them CL tot Total clearance (renal + non-renal), dose is the administered dose, AUC 0-Inf The area under the curve is calculated, and 1000 represents the factor providing the clearance rate in mL / min / kg (a unit usually reported in the references).

[0435] In the second step, Equation 2 is used to calculate the drug-specific renal clearance rate for each animal.

[0436]

[0437] Among them CL ren For renal clearance and A e,urine This refers to the fraction of an intravenous drug that is excreted into the urine within 24 hours after administration.

[0438] Treatment

[0439] In another aspect of the invention, the compound of formula (I.0) or a pharmaceutically acceptable salt thereof has properties suitable for use in therapy (i.e., as a pharmaceutical agent). In particular, the compound of formula (I.0) or a pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising thereof are suitable for treating patients with diseases or conditions that may be affected by antagonism of platelet-activating factor receptor (PAFR), for example, mediated by unwanted PAFR activity or in which antagonism of PAFR is beneficial.

[0440] Additional benefits can be provided by the reverse facilitation effect of PAFR.

[0441] Diseases and conditions that may be affected by antagonistic and / or inversely agonistic PAFRs, such as those mediated by unwanted PAFR activity or where antagonism and / or inverse agonism of PAFR activity are beneficial, include eye diseases, cardiovascular diseases, cancer, neurological and neurodegenerative disorders, kidney diseases, liver diseases, and allergies. These conditions include (but are not limited to) retinopathy or diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular ischemia (DMI), geographic atrophy, Stargardt disease, glaucoma retinal degeneration, short-sighted macular degeneration, chronic panuveitis, retinitis pigmentosa, retinal vein occlusion (such as central, branch, or hemiretinal vein occlusion), diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), post-cataract extraction CME, cryotherapy-induced CME, uveitis-induced CME, endophthalmitis, post-vascular occlusion (e.g., central retinal vein occlusion, branch retinal vein occlusion, or hemiretinal vein occlusion), retinal edema, complications associated with cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, dry and wet age-related macular degeneration (AMD), polypoid choroidal vascular disease (PCV), and choroidal neovascularization (CNV).Examples include nonexudative choroidal angiogenesis, subretinal fibrosis (e.g., associated with nonexudative or exudative choroidal angiogenesis), posterior vitreous detachment (PVD), ischemia-reperfusion injury (e.g., in all types associated with tissue and / or organ transplantation), surgery-induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-associated edema, spinal cord injury, pain, local ischemia, focal cerebral ischemia, neurological and cognitive impairment, deep vein thrombosis, stroke, myocardial infarction, atherosclerosis, acquired angioedema, hereditary angioedema (HAE), drug-related (ACE inhibitor) edema, and high-altitude cerebral edema. Cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, traumatic brain injury, hemorrhagic stroke (e.g., cerebrospinal stroke or subarachnoid stroke), intracranial hemorrhage, hemorrhagic transformation of ischemic stroke, brain trauma related to injury or surgery, encephalomyelitis, amyotrophic lateral sclerosis (ALS), neuropathic pain, cerebral aneurysm, arteriovenous malformation, reducing blood loss during surgery (e.g., cardiothoracic surgery, such as cardiopulmonary bypass or coronary artery bypass grafting), coagulation disorders (such as thrombosis), pruritus, diseases with inflammatory components (such as multiple sclerosis), epilepsy, encephalitis, Alzheimer's disease. Diseases such as excessive daytime sleepiness, essential hypertension, elevated blood pressure associated with diabetes or hyperlipidemia, renal insufficiency, kidney disease (including chronic kidney disease), interstitial cystitis / bladder pain syndrome, heart failure, microalbuminuria, proteinuria, protein in urine, diseases associated with increased vascular permeability (e.g., increased retinal vascular permeability, increased leg, foot, and ankle vascular permeability), cerebral hemorrhage, deep vein thrombosis, coagulation resulting from post-fibrinolysis treatment, angina pectoris, angioedema, sepsis, arthritis (e.g., rheumatoid arthritis, osteoarthritis, septic arthritis), and ulcerative colitis. Pancreatitis, lupus, gout, psoriasis, inflammatory bowel disease, diabetes, diabetic complications, complications arising from metabolic syndrome, non-alcoholic steatohepatitis (NASH), allergies, bacterial and viral infections (including HIV infection), allergies, 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, Creutzfeld-Jacob disease, stroke, epilepsy and trauma (e.g., brain trauma), allergic edema (e.g., airflow obstruction in chronic allergic sinusitis or perennial rhinitis); airflow obstruction in acute asthma;Systemic lupus erythematosus (SLE) associated with serositis, acute respiratory distress syndrome (ARDS), cancers such as breast cancer, colorectal cancer, esophageal cancer, lung cancer, liver cancer, pancreatic cancer, skin cancer (including melanoma and cervical cancer), and other diseases.

[0442] Therefore, the compounds and pharmaceutical compositions according to the present invention are particularly suitable for treating ocular diseases, including diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, dry and wet age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vascular disease (PCV), and choroidal neovascularization (CNV; e.g., non-exudative choroidal neovascularization).

[0443] In addition, the compounds and pharmaceutical compositions according to the present invention are particularly suitable for treating allergy and inflammation-related conditions and diseases, such as urticaria and NASH.

[0444] The compounds and pharmaceutical compositions according to the present invention are most particularly suitable for treating diabetic macular edema (DME), dry and wet age-related macular degeneration (AMD), geographic atrophy, non-exudative choroidal angiogenesis (CNV), urticaria, and NASH.

[0445] The daily applicable dose range for compound of formula (I.0) is typically 0.01 to 10 mg per kilogram of body weight.

[0446] The actual therapeutically effective amount or dosage will, of course, depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of the disease. In any case, the compound or composition will be administered in a dosage and manner that allows for the delivery of a therapeutically effective amount based on the patient's unique condition.

[0447] The compounds and compositions according to the invention (including any combination with one or more other therapeutic agents) may be administered orally, intravitreally, transdermally, by inhalation, non-enterally, or sublingually. Among the possible methods of administration, oral and intravitreal administration are preferred, particularly oral administration. In the case of intravitreal injection, the preferred dose should not exceed 5 mg / eye.

[0448] The patients to be treated are preferably mammals, with human patients being the best option.

[0449] Therefore, in another aspect, the present invention provides compounds of formula (I.0), including pharmaceutically acceptable salts thereof, for use as pharmaceutical agents.

[0450] In another aspect, the present invention provides a method for treating diseases or conditions in patients in need that are mediated by unwanted platelet-activating factor receptor activity or in which antagonism of the platelet-activating factor receptor is advantageous.

[0451] Similarly, the present invention provides a compound of formula (I.0) or a pharmaceutically acceptable salt thereof for use in a method of treating a disease or condition in patients in need, mediated by unwanted platelet-activating factor receptor activity or wherein antagonism of the platelet-activating factor receptor is advantageous.

[0452] Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof for manufacturing an agent in a method for treating a disease or condition in patients in need mediated by unwanted platelet-activating factor receptor activity or wherein antagonism of the platelet-activating factor receptor is advantageous.

[0453] Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in a method of treating a disease or condition in patients in need of treatment mediated by unwanted platelet-activating factor receptor activity or wherein antagonism of the platelet-activating factor receptor is advantageous.

[0454] According to one embodiment, the method of treatment includes administering one or more of the formula (I.0) compound or a pharmaceutically acceptable salt thereof to the patient, preferably administering a therapeutically effective amount of one or more of the formula (I.0) compound or a pharmaceutically acceptable salt thereof to the patient.

[0455] According to another embodiment, the method of treatment includes administering the pharmaceutical composition according to the invention to the patient.

[0456] According to one implementation scheme, the disease or condition mediated by unwanted platelet-activating factor receptor activity or in which antagonism of platelet-activating factor receptor is beneficial is selected from ophthalmic indications, such as diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, dry and wet age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vascular disease (PCV), and choroidal angiogenesis (CNV).

[0457] According to another embodiment, the disease or condition mediated by undesired platelet-activating factor receptor activity or in which antagonism of platelet-activating factor receptor is beneficial is selected from allergy and inflammation-related conditions and diseases, such as urticaria and NASH.

[0458] According to another embodiment, the disease or condition mediated by unwanted platelet-activating factor receptor activity or in which antagonism of platelet-activating factor receptor is beneficial is selected from diabetic complications associated with diabetic retinopathy, such as diabetic macular edema, diabetic macular ischemia, and proliferative diabetic retinopathy.

[0459] According to one implementation plan, the patients are human patients.

[0460] Pharmaceutical Composition

[0461] In another aspect of the invention, the compounds described herein or their pharmaceutically acceptable salts may be used as active ingredients in pharmaceutical compositions.

[0462] Formulations suitable for administering the compounds of the present invention, optionally in combination with one or more other therapeutic agents, are known to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, oral tablets, solutions, syrups, elixirs, sachets, injectables, inhalants, and powders. Orally prepared formulations, particularly in solid form, are preferred, for example, tablets or capsules. For intravitreal injection, solutions are preferred. The content of the pharmaceutically active compound is preferably in the range of 0.1 to 90% by weight of the whole composition, for example, 1 to 70% by weight.

[0463] Suitable tablets can be obtained, for example, by mixing one or more compounds according to formula (I.0) with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants. Tablets may also consist of several layers. Those skilled in the art will be familiar with the specific excipients, carriers, and / or diluents suitable for the desired formulation based on their expertise. Those suitable for the specific formulation and method of administration are preferred. Formulations or formulations according to the invention can be prepared using methods familiar to those skilled in the art, such as, for example, by mixing or combining at least one compound according to formula (I.0) or a pharmaceutically acceptable salt thereof, with one or more excipients, carriers, and / or diluents.

[0464] Therefore, according to another aspect of the invention, a pharmaceutical composition comprising one or more compounds of formula (I.0) or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents, is provided.

[0465] In addition, a pharmaceutical composition comprising one or more of the compounds mentioned above or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and / or diluents, is provided for use in the treatment of a disease or condition in patients in need mediated by unwanted PAFR activity or wherein antagonism of PAFR is advantageous.

[0466] In particular, the present invention provides pharmaceutical compositions according to the invention for use in the treatment of ophthalmic indications such as diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), retinal vein occlusion, dry and wet age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vascular disease (PCV) and choroidal angiogenesis (CNV; e.g., nonexudative choroidal angiogenesis) and allergic and inflammatory conditions and diseases such as urticaria and NASH.

[0467] Furthermore, the present invention relates to the use of pharmaceutical compositions according to the invention for treating diseases or conditions mediated by unwanted PAFR activity in patients (preferably in humans).

[0468] Furthermore, the present invention relates to the use of pharmaceutical compositions according to the invention for treating patients (preferably humans) in which the antagonistic effect of PAFR is beneficial in treating diseases or conditions.

[0469] According to one embodiment, a pharmaceutical composition is provided comprising one or more compounds of formula (I.0) or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

[0470] For example, this composition comprises a compound of formula (I.0) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents.

[0471] Combination therapy

[0472] The compounds of the present invention can be further combined with one or more (preferably one) additional therapeutic agents.

[0473] According to one implementation scheme, the additional therapeutic agent is selected from the group of therapeutic agents suitable for treating the diseases or conditions described above, particularly eye diseases, allergy and inflammation-related conditions and diseases, such as diabetic macular edema (DME), dry and wet age-related macular degeneration (AMD), geographic atrophy, non-exudative choroidal angiogenesis (CNV), urticaria and NASH, or metabolic diseases or conditions, such as, for example, diabetes, obesity, diabetic complications, hypertension and hyperlipidemia.

[0474] Additional therapeutic agents suitable for these combinations include, in particular, those that enhance the therapeutic effect of one or more active substances in relation to one of the indications mentioned herein and / or allow for a reduction in the dosage of one or more active substances.

[0475] Therefore, the compounds of the present invention can be combined with one or more other therapeutic agents selected from the group consisting of: antidiabetic agents, agents for treating overweight and / or obesity, agents for treating hypertension, heart failure and / or atherosclerosis, agents for treating eye diseases, and agents for treating allergies and inflammation-related conditions and diseases.

[0476] Antidiabetic agents include, for example, metformin, sulfonylurea, nateglinide, repaglinide, thiazolinone, PPAR-(α, γ, or α / γ) agonists or modulators, α-glucosidase inhibitors, DPPIV inhibitors, SGLT2 inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs or amyloids and amyloid analogs, dual agonists containing GLP-1 activity along with glucagon or GIP activity, cycloset, and 11β-HSD inhibitors. Other suitable combination partners are inhibitors of protein tyrosine phosphatase 1 (a substance that affects the dysregulation of glucose production in the liver), such as, for example, inhibitors of glucose-6-phosphatase or fructose-1,6-bisphosphatase, glycogen phosphorylation enzyme, glucagon receptor antagonists and phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase inhibitors, α2-antagonists, CCR-2 antagonists, or glucokinase activators. One or more lipid-lowering agents are also suitable as combination partners, such as, for example, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and its derivatives, PPAR-(α, γ, or α / γ) agonists or modulators, PPAR-δ agonists, ACAT inhibitors or cholesterol absorption inhibitors, such as bile acid conjugates, such as inhibitors of ileal bile acid transport, MTP inhibitors, or compounds that increase HDL, such as CETP inhibitors or ABC1 modulators.

[0477] Therapeutic agents used to treat overweight and / or obesity include, for example, cannabinoid 1 receptor antagonists, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, β3-agonists, leptin or leptin mimics, 5HT2c receptor agonists, and dual agonists of GLP-1 and glucagon receptors.

[0478] Suitable therapeutic agents for treating hypertension, chronic heart failure, and / or atherosclerosis include, for example, A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium channel blockers, centrally acting antihypertensives, α-2-adrenergic receptor antagonists, neutral endopeptidase inhibitors, platelet activation inhibitors, or combinations thereof. Angiotensin II receptor antagonists are preferred for the treatment or prevention of hypertension and complications of diabetes, and are usually combined with diuretics (such as hydrochlorothiazide).

[0479] Therapeutic agents used to treat eye diseases may include, for example, intravitreal corticosteroids, intravitreal 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, and PKK inhibitors.

[0480] Other treatments for eye diseases may include laser coagulation therapy.

[0481] Treatment agents for urticaria may include, for example, antihistamines, steroids (such as corticosteroids), adrenaline, antibodies against immunoglobulin E, immunosuppressants (such as cyclosporine A), and leukotriene receptor antagonists.

[0482] Therapeutic agents used to treat NASH may include, for example, FXR agonists, FXR / TGR5 agonists, THR-β agonists, ACC inhibitors, TGF-β1 antagonists, LTA4 hydrolase inhibitors, SGLT inhibitors, activin type 2 receptor antagonists, NLRP3 inhibitors, avβ1 integrin inhibitors, cGAS / STING inhibitors, GLP-1R agonists, FGF21 agonists, GLP-1 / glucagon receptor dual agonists, GLP-1 / GIP receptor dual agonists, GLP-1 / FGF21 receptor dual agonists, GLP-1 / GIP / glucagon receptor triple agonists, AOC3 inhibitors, and JNK1 inhibitors. Inhibitors, including CCR2 / 5 inhibitors, ACC inhibitors, DGAT inhibitors, KHK inhibitors, PPARα / δ agonists, FGF19 agonists, β-clotho / FGFR1c agonists, PNPLA3 inhibitors, NLRP3 inhibitors, THR-β agonists, HSD17β13 inhibitors, galactoglobin-3 inhibitors, SCD1 inhibitors, ASK1 inhibitors, endothelin receptor A antagonists, FASN inhibitors, calpain inhibitors, autocrine motor factor inhibitors, TREM2 agonists, sGC inhibitors, PKK inhibitors, RORc inhibitors, TLR4 inhibitors, and IL11 inhibitors.

[0483] The compounds of the present invention and / or pharmaceutical compositions comprising the compounds of the present invention, optionally in combination with one or more other therapeutic agents, may be administered in conjunction with exercise and / or diet.

[0484] The dosage used for the combined partner mentioned above is typically 1 / 5 to 1 / 1 of the usually recommended minimum dose.

[0485] The compounds according to the invention can be used simultaneously or alternately in combination with other therapeutic agents.

[0486] The compounds according to the invention and one or more other therapeutic agents may be present together in a formulation (e.g., tablets or capsules) or separately in two identical or different formulations (e.g., as so-called kit-of-parts).

[0487] Therefore, 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 described in the context, optionally together with one or more inert carriers and / or diluents.

[0488] According to another aspect, the present invention provides a method for treating a disease or condition in a patient in need that is mediated by unwanted platelet-activating factor receptor activity or in which antagonism of PAFR is advantageous, the method comprising administering to the patient one or more of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents described in the context, preferably administering to the patient a therapeutically effective amount of one or more of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more other therapeutic agents described in the context.

[0489] Similarly, the present invention provides a combination of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof with one or more other therapeutic agents described in the context, in a method of treating a disease or condition in patients in need mediated by unwanted PAFR activity or in which antagonism of PAFR is advantageous.

[0490] Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents described in the context for the manufacture of a medicament in a method for treating a disease or condition in patients in need mediated by unwanted PAFR activity or in which antagonism of PAFR is advantageous.

[0491] Similarly, the present invention provides the use of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents described in the context in a method of treating a disease or condition in patients in need mediated by unwanted PAFR activity or in which antagonism of PAFR is advantageous.

[0492] According to one embodiment, the method of treatment includes administering to a patient one or more of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents described in the context, preferably administering to the patient a therapeutically effective amount of one or more of a compound of formula (I.0) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more other therapeutic agents described in the context.

[0493] According to another embodiment, the method of treatment includes administering to a patient a pharmaceutical composition comprising one or more compounds according to the invention and one or more additional therapeutic agents described in the context, optionally together with one or more inert carriers and / or diluents.

[0494] According to one embodiment, one or more additional therapeutic agents are selected from antidiabetic agents, agents for treating overweight and / or obesity, agents for treating hypertension, heart failure and / or atherosclerosis, and agents for treating eye diseases, particularly those explicitly mentioned above.

[0495] According to one implementation scheme, diseases or conditions mediated by unwanted PAFR activity or in which PAFR antagonism is beneficial are selected from ophthalmic indications, such as diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), dry and wet age-related macular degeneration (AMD), geographic atrophy, polypoid choroidal vascular disease (PCV), and choroidal angiogenesis (CNV); allergy and inflammation-related conditions and diseases (such as urticaria or NASH); and diabetic complications associated with diabetic retinopathy, such as diabetic macular edema, diabetic macular ischemia, and proliferative diabetic retinopathy.

[0496] According to one implementation plan, the patients are human patients.

[0497] Other features and advantages of the invention will become apparent from the following more detailed examples, which illustrate the principles of the invention through embodiments.

[0498] Examples and Experimental Data

[0499] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0500] abbreviation:

[0501] Acetyl group

[0502] ACN Acetonitrile

[0503] BPR back pressure regulator

[0504] BSA (Bovine Serum Albumin)

[0505] Cbz benzyloxycarbonyl

[0506] d day

[0507] DABCO 1,4-diazabicyclo[2.2.2]octane

[0508] DAD Diode Array Detector

[0509] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0510] DCE 1,2-Dichloroethane

[0511] DCM dichloromethane

[0512] DMEM Dürbeco modified Igor medium

[0513] DMF N,N-dimethylformamide

[0514] DMSO dimethyl sulfoxide

[0515] EDTA ethylenediaminetetraacetic acid ester

[0516] Ethyl acetate (EtOAc)

[0517] EtOH (ethanol)

[0518] h hours

[0519] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium-hexafluorophosphate

[0520] HPLC (High Performance Liquid Chromatography)

[0521] High-performance liquid chromatography-mass spectrometry analysis coupled with HPLC-MS

[0522] IPA isopropanol

[0523] LC (Liquid Chromatography)

[0524] LC-MS coupled liquid chromatography-mass spectrometry analysis

[0525] M (mol / L)

[0526] MeTHF 2-methyltetrahydrofuran

[0527] MeOH (methanol)

[0528] min minutes

[0529] MS mass spectrometry analysis

[0530] NADPH (Nicotinamide Adenine Dinucleotide Phosphate)

[0531] NMP (N-methyl-2-pyrrolidone)

[0532] NMR (Nuclear Magnetic Resonance)

[0533] PET (Polyethylene p-phthalate)

[0534] petroleum

[0535] PyBop (benzotriazole-1-oxy)tripyrrolidinephosphonium hexafluorophosphate

[0536] R f Retention factor

[0537] rt / RT room temperature

[0538] t R Retention time (in HPLC / LC)

[0539] sc supercritical

[0540] SFC (Supercritical Fluid Chromatography)

[0541] TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureonium tetrafluoroborate

[0542] TFA (trifluoroacetic acid)

[0543] THF Tetrahydrofuran

[0544] UV ultraviolet rays

[0545] The terms “ambient temperature” and “room temperature” are used interchangeably and indicate a temperature of approximately 20°C, for example, 15 to 25°C.

[0546] As is customary, the prepared compound has been obtained 1 H-NMR and / or mass spectrometry.

[0547] Unless otherwise specified, compounds containing a chiral center possess the stereochemistry described herein. Stereochemical partitioning has been achieved through the use of chiral starting materials with known stereochemistry, through stereoselective synthesis with known stereochemistry, or by biological activity.

[0548] Analytical methods

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560] Synthesis of intermediates:

[0561] Intermediate 1

[0562] 9-(2-Chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11-(15)-pentane-13-carboxylic acid

[0563]

[0564] Step 1: Methyl 2-amino-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid

[0565] A mixture of 126 g of 3-(2-chlorophenyl)-3-oxopropionitrile, methyl 3-oxocyclopentane-1-carboxylate (100 g), sulfur (22.5 g), morpholine (61.8 mL), and MeOH (800 mL) was stirred under reflux for 4 hours. After cooling to room temperature, the reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / DCM 50:50) and then recrystallized from MeOH to yield the title compound.

[0566] Step 2: 3-(2-chlorobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0567] 41.9 g of bromoacetyl bromide was added to a stirred mixture of methyl 2-amino-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid ester (100 g), NaHCO3 (30.0 g), toluene (1200 mL), and water (100 mL) at 0 °C. The cooling bath was removed, and the mixture was stirred at 60 °C for 4 hours. After cooling to room temperature, water was added, and the resulting mixture was extracted with EtOAc (2×). The combined extract was dried (Na2SO4) and concentrated. The residue was chromatographically analyzed on silica gel (petroleum ether / EtOAc 70:30) to yield the title compound.

[0568] Step 3: 2-(2-aminoacetamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0569] Methyl 3-(2-chlorobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid (10.0 g) and ammonia (0.5 mol / L in THF; 70.0 mL) were added to a flask fitted with a stir bar at room temperature. The flask was sealed, and the mixture was stirred overnight. The mixture was concentrated to remove excess ammonia and most of the THF, and EtOAc was added. The resulting mixture was washed with water, dried (Na2SO4), and concentrated to provide the crude title compound, which could be used in the next reaction step without further purification.

[0570] Step 4: 13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0571] Silica gel (3.05 g) was added to a solution of methyl 2-(2-aminoacetamido)-3-(2-chlorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid (8.00 g) in toluene (80.0 mL). The resulting mixture was then supplemented with… Molecular sieve (1.00 g). The reaction mixture was stirred at 110 °C for 24 hours. After cooling to room temperature, the mixture was filtered and concentrated, and the residue was chromatographically analyzed on silica gel (petroleum ether / EtOAc 70:30) to yield the title compound.

[0572] Step 5: 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentane-13-carboxylic acid methyl ester

[0573] ClPO(OEt)₂ (3.01 mL) and DBU (3.02 mL) were added to 13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] at room temperature. 2,6 A solution of methyl tridecano-1(8),2(6),12-trien-4-carboxylic acid (5.05 g) in THF (50.0 mL) was prepared. The mixture was stirred for 10 minutes, and then acetylhydrazine (1.56 g) was added. After stirring for another 30 minutes at room temperature, the mixture was stirred at 60 °C for 4 hours. After cooling to room temperature, EtOAc was added, and the resulting mixture was washed with water, an aqueous solution of NaHCO3, and brine. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographically analyzed on silica gel (DCM / MeOH 99:1->95:5) to yield the title compound.

[0574] Intermediate 2

[0575] 9-(2-Chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0576]

[0577] NaOH (4 mol / L in water; 35.0 mL) was added to 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] at room temperature. 2,6 .0 11,15 A solution of methyl hexadecano-1(10),3,5,8,11(15)-pentaen-13-carboxylic acid (20.0 g) in THF (150 mL) was prepared. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, and HCl (4 mol / L in water) was added to adjust the pH of the mixture to approximately 4.5. The mixture was then extracted with DCM (5×). The combined organic extract was washed with brine, dried (Na2SO4), and concentrated to produce the crude title compound for use in the next reaction step.

[0578] Intermediate 3 and reference intermediate 4

[0579] (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15[Hexadecane-1(10),3,5,8,11(15)-pentane-13-carboxylic acid (intermediate 3) and (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid (refer to intermediate 4)]

[0580]

[0581] 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 The title compound was isolated by dissolving hexadec-1(10),3,5,8,11(15)-pentane-13-carboxylic acid (racemic mixture, 10.0 g) in EtOH / DCM2:1 (50 mg / mL) and then by SFC on a chiral phase [column: Lux C4 (30 mm x 250 mm, 5 μm); column temperature: 40 °C; flow rate: 50 mL / min; BPR: 100 bar; injection volume: 500 μL (25 mg); isocratic conditions: 50:50 CO2:EtOH (0.2% v / v formic acid)].

[0582] Intermediate 3: LC (Method 3):t R = 4.87 minutes; mass spectrometry (ESI) + ):m / z=399 / 401(Cl)[M+H] + ;

[0583] Reference intermediate 4: LC (Method 3):t R = 4.26 minutes; mass spectrometry (ESI) + ):m / z=399 / 401(Cl)[M+H] + .

[0584] Intermediate 5

[0585] (13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0586]

[0587] HATU (10.0 mg) was added to (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] at room temperature. 2,6 .0 11,15 A mixture of hexadec-1(10),3,5,8,11(15)-pentaen-13-carboxylic acid (10.0 mg), N,N-diisopropylethylamine (0.010 mL), and DMF (1.00 mL) was prepared. After stirring for 5 minutes, morpholine (5.00 mg) was added, and the resulting mixture was stirred for 1 hour. The reaction mixture was diluted with DMF and purified by reversed-phase chromatography (HPLC; ACN / water / ammonia) to yield the title compound.

[0588] Intermediate 6

[0589] 9-(2-Chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0590]

[0591] The title compound consists of 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2, 6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentene-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5.

[0592] Reference intermediate 7

[0593] (13R)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0594]

[0595] The title compound is composed of (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15Hexadecane-1(10),3,5,8,11(15)-pentene-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5.

[0596] Intermediate 8

[0597] (9R,13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15 [Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxylic acid]

[0598]

[0599] Tetrabutylborohydride (16.6 g) was added in portions to a stirred solution of N-Cbz-L-proline (48.1 g) in DCM (80 ml) at 0 °C. After hydrogen evaporation ceased, the mixture was stirred for another hour at room temperature. The resulting solution was then added dropwise to (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] cooled to -10 °C. 2,6 .0 11,15 A solution of hexadecane-1(10),3,5,8,11(15)-pentaen-13-carboxylic acid (8.6 g) in DCM (120 mL) was prepared, and the reaction mixture was stirred at -10 °C for 1 hour and then at room temperature for another 1 hour. HCl aqueous solution (1 M) was added to adjust the pH of the mixture to 1, and the mixture was extracted with HCl aqueous solution (1 M, 3×). The pH of the combined aqueous layer was carefully adjusted with NaOH aqueous solution (4 M) until pH 4.5 was achieved and a white precipitate appeared. The mixture was extracted with DCM (3×). The combined organic extract was dried (MgSO4) and concentrated. The crude product was purified by reversed-phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound. LC (Method 2): t R =0.67 minutes; Mass spectrometry (ESI+): m / z = 401 [M+H] + .

[0600] Reference intermediate 9

[0601] (9R,13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15 [Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxylic acid]

[0602]

[0603] The title compound is composed of (13R)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 8. LC (Method 2): t R =0.70 minutes; Mass spectrometry (ESI+): m / z = 401 [M+H] + .

[0604] Intermediate 10

[0605] (9S,13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15 [Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxylic acid]

[0606]

[0607] (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15 Hexadecano-1(10),3,5,8,11(15)-pentane-13-carboxylic acid (1.00 g) was dissolved in DCM (35 mL), followed by the addition of aqueous HCl solution (4 M, 1.25 mL) and sodium borohydride (379 mg). The reaction mixture was stirred at room temperature for 1.25 hours. Aqueous HCl solution (4 M) was added and the mixture was stirred until gas escape stopped, followed by the addition of MeOH and THF. The precipitate was filtered and the filtrate was concentrated. The residue was dissolved in MeTHF and stirred at room temperature for 1 hour. The precipitate was filtered and washed with additional MeTHF. The crude product, consisting of a mixture of intermediate 8 and non-mirror image isomers of the title compound, was purified by reversed-phase chromatography (HPLC; ACN / water / TFA) to obtain the isolated title compound.

[0608] LC (Method 2):t R =0.71 minutes; Mass spectrometry (ESI+): m / z = 401 [M+H] + .

[0609] Intermediate 11

[0610] 9-(4-Chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0611]

[0612] Step 1: Methyl 2-amino-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid

[0613] The title compound was prepared from 3-(4-chlorophenyl)-3-oxopropionitrile and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1.

[0614] LC (Method 2):t R = 1.04 minutes; mass spectrometry (ESI) + ):m / z=336[M+H] + .

[0615] Step 2: 3-(4-chlorobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0616] The title compound was prepared from methyl 2-amino-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid and bromoacetyl bromide following a procedure similar to that described in step 2 of intermediate 1.

[0617] LC (Method 2):t R = 1.14 minutes; mass spectrometry (ESI) + ):m / z=456 / 458(Br)[M+H] + .

[0618] Step 3: 2-(2-aminoacetamido)-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0619] The title compound was prepared from methyl 3-(4-chlorobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 3 of intermediate 1.

[0620] LC (Method 2):t R = 0.82 minutes; mass spectrometry (ESI) + ):m / z=393[M+H + .

[0621] Step 4: 13-(4-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0622] The title compound was prepared from methyl 2-(2-aminoacetamido)-3-(4-chlorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 4 of intermediate 1.

[0623] LC (Method 2):t R =0.75 minutes; mass spectrometry (ESI) + ):m / z=375[M+H + .

[0624] Step 5: 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid

[0625] The title compound consists of 13-(4-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2,6 Methyl 1-tetrate-1(8),2(6),12-triene-4-carboxylic acid was prepared following a procedure similar to that described in step 5 of intermediate 1.

[0626] LC (Method 2):t R = 0.88 minutes; mass spectrometry (ESI) + ):m / z=413[M+H + .

[0627] Step 6: 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0628] The title compound consists of 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2 ,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 2. LC (Method 2): t R =0.75 minutes; mass spectrometry (ESI)+ ):m / z=399[M+H] + .

[0629] Step 7: 9-(4-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0630] The title compound consists of 9-(4-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2 ,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentene-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5.

[0631] LC (Method 2):t R = 0.78 minutes (non-mirror image isomer); mass spectrometry (ESI) + ):m / z=468[M+H] + .

[0632] Intermediate 12

[0633] 9-(2-Ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0634]

[0635] Step 1: Methyl 2-amino-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid

[0636] The title compound was prepared from 3-(2-ethylphenyl)-3-oxopropionitrile and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1.

[0637] LC (Method 2):t R = 1.05 minutes; mass spectrometry (ESI) + ):m / z=330[M+H + .

[0638] Step 2: methyl 3-(2-ethylbenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid

[0639] The title compound was prepared from methyl 2-amino-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid and bromoacetyl bromide following a procedure similar to that described in step 2 of intermediate 1.

[0640] LC (Method 2):t R = 1.17 minutes; Mass spectrometry (ESI) + ):m / z=450 / 452(Br)[M+H + .

[0641] Step 3: 2-(2-aminoacetamido)-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0642] The title compound was prepared from methyl 3-(2-ethylbenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid following a procedure similar to that described in step 3 of intermediate 1.

[0643] LC (Method 2):t R = 0.82 minutes; mass spectrometry (ESI) + ):m / z=387[M+H] + .

[0644] Step 4: 13-(2-ethylphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0645] The title compound was prepared from methyl 2-(2-aminoacetamido)-3-(2-ethylbenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 4 of intermediate 1.

[0646] LC (Method 2):t R =0.75 minutes; mass spectrometry (ESI) + ):m / z=369[M+H] + .

[0647] Step 5: 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid

[0648] The title compound consists of 13-(2-ethylphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2 ,6 Methyl 1-tetrate-1(8),2(6),12-triene-4-carboxylic acid was prepared following a procedure similar to that described in step 5 of intermediate 1.

[0649] LC (Method 2):t R = 0.84 minutes; mass spectrometry (ESI) + ):m / z=407[M+H + .

[0650] Step 6: 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0651] The title compound consists of 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 2. LC (Method 2): t R = 0.74 minutes; mass spectrometry (ESI) + ):m / z=393[M+H + .

[0652] Step 7: 9-(2-Ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0653] The title compound consists of 9-(2-ethylphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2 ,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentane-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5. LC (Method 2): t R=0.75 minutes; mass spectrometry (ESI) + ):m / z=462[M+H + .

[0654] Intermediate 13

[0655] 9-(2-Methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0656]

[0657] Step 1: Methyl 2-amino-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid

[0658] The title compound was prepared from 3-(2-methoxyphenyl)-3-oxopropionitrile and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1.

[0659] LC (Method 2):t R = 0.95 minutes; mass spectrometry (ESI) + ):m / z=332[M+H + .

[0660] Step 2: 3-(2-methoxybenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0661] The title compound was prepared from methyl 2-amino-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid and bromoacetyl bromide following a procedure similar to that described in step 2 of intermediate 1.

[0662] LC (Method 2):t R = 1.08 minutes; mass spectrometry (ESI) + ):m / z=452 / 454(Br)[M+H] + .

[0663] Step 3: 2-(2-aminoacetamido)-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0664] The title compound was prepared from methyl 3-(2-methoxybenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 3 of intermediate 1.

[0665] LC (Method 2):t R = 0.92 minutes; mass spectrometry (ESI) + ):m / z=389[M+H] + .

[0666] Step 4: 13-(2-methoxyphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0667] The title compound was prepared from methyl 2-(2-aminoacetamido)-3-(2-methoxybenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 4 of intermediate 1.

[0668] LC (Method 2):t R = 0.70 minutes; mass spectrometry (ESI) + ):m / z=371[M+H] + .

[0669] Step 5: 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2, 6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid

[0670] The title compound consists of 13-(2-methoxyphenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2 ,6 Methyl 1-tetrate-1(8),2(6),12-triene-4-carboxylic acid was prepared following a procedure similar to that described in step 5 of intermediate 1.

[0671] LC (Method 2):t R = 0.73 minutes; mass spectrometry (ESI) + ):m / z=409[M+H + .

[0672] Step 6: 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2, 6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0673] The title compound consists of 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 2. LC (Method 2): t R = 0.64 minutes; mass spectrometry (ESI) + ):m / z=395[M+H + .

[0674] Step 7: 9-(2-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0675] The title compound consists of 9-(2-methoxyphenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentene-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5.

[0676] LC (Method 2):t R = 0.66 minutes (non-mirror image isomer); mass spectrometry (ESI) + ):m / z=464[M+H + .

[0677] Intermediate 14

[0678] 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0679]

[0680] Step 1: Methyl 2-amino-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid

[0681] The title compound was prepared from 3-(2-fluorophenyl)-3-oxopropionitrile and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1.

[0682] LC (Method 2):t R = 0.98 minutes; mass spectrometry (ESI) + ):m / z=320[M+H + .

[0683] Step 2: 3-(2-fluorobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0684] The title compound was prepared from methyl 2-amino-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid and bromoacetyl bromide following a procedure similar to that described in step 2 of intermediate 1.

[0685] LC (Method 2):t R = 1.11 minutes; Mass spectrometry (ESI) + ):m / z=440 / 442(Br)[M+H + .

[0686] Step 3: 2-(2-aminoacetamido)-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0687] The title compound was prepared from methyl 3-(2-fluorobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 3 of intermediate 1.

[0688] LC (Method 2):t R = 0.76 minutes; mass spectrometry (ESI) + ):m / z=377[M+H] + .

[0689] Step 4: 13-(2-fluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0690] The title compound was prepared from methyl 2-(2-aminoacetamido)-3-(2-fluorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 4 of intermediate 1.

[0691] LC (Method 2):t R = 0.70 minutes; mass spectrometry (ESI) + ):m / z=359[M+H + .

[0692] Step 5: 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid

[0693] The title compound consists of 13-(2-fluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2,6 Methyl 1-tetrate-1(8),2(6),12-triene-4-carboxylic acid was prepared following a procedure similar to that described in step 5 of intermediate 1.

[0694] LC (Method 2):t R = 0.82 minutes; mass spectrometry (ESI) + ):m / z=397[M+H] + .

[0695] Step 6: 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0696] The title compound consists of 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2 ,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 2. LC (Method 2): t R = 0.71 minutes; mass spectrometry (ESI) + ):m / z=383[M+H] + .

[0697] Step 7: 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0698] The title compound consists of 9-(2-fluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2 ,6 .0 11,15Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5. LC (Method 2): t R = 0.73 minutes; mass spectrometry (ESI) + ):m / z=452[M+H + .

[0699] Intermediate 15

[0700] 3-Methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0701]

[0702] Step 1: Methyl 2-amino-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid

[0703] The title compound was prepared from 2-(trifluoromethyl)benzoyl cyanide and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1. Mass spectrometry (ESI) + ):m / z=370[M+H + .

[0704] Step 2: 2-(2-bromoacetamyl)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid methyl ester

[0705] The title compound was prepared from methyl 2-amino-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid and bromoacetyl bromide following a procedure similar to that described in step 2 of intermediate 1. LC (Method 2): t R = 1.14 minutes; mass spectrometry (ESI) + ):m / z=490 / 492(Br)[M+H] + .

[0706] Step 3: 2-(2-aminoacetamido)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid methyl ester

[0707] The title compound was prepared from methyl 2-(2-bromoacetamyl)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid following a procedure similar to that described in step 3 of intermediate 1.

[0708] LC (Method 2):t R = 0.80 minutes; mass spectrometry (ESI) + ):m / z=427[M+H + .

[0709] Step 4: 10-oxo-13-[2-(trifluoromethyl)phenyl]-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0710] The title compound was prepared from methyl 2-(2-aminoacetamido)-3-[2-(trifluoromethyl)benzoyl]-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid following a procedure similar to that described in step 4 of intermediate 1.

[0711] LC (Method 2):t R = 0.78 minutes; mass spectrometry (ESI) + ):m / z=409[M+H + .

[0712] Step 5: 3-Methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2 ,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid

[0713] The title compound consists of 10-oxo-13-[2-(trifluoromethyl)phenyl]-7-thia-9,12-diazatricyclo-[6.5.0.0]. 2,6 Methyl tridecanoate-1(8),2(6),12-triene-4-carboxylic acid was prepared following a procedure similar to that described in step 5 of intermediate 1. LC (Method 2): t R = 0.91 minutes; mass spectrometry (ESI) + ):m / z=447[M+H + .

[0714] Step 6: 3-Methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2 ,6 .0 11,15[Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0715] The title compound is composed of 3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 2. LC (Method 2): t R = 0.80 minutes; mass spectrometry (ESI) + ):m / z=433[M+H + .

[0716] Step 7: 3-Methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0717] The title compound is composed of 3-methyl-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2,6 .0 11,15 Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5. LC (Method 2): t R = 0.82 minutes; mass spectrometry (ESI) + ):m / z=502[M+H + .

[0718] Intermediate 16

[0719] 9-(2-Bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0720]

[0721] Step 1: Methyl 2-amino-3-(2-bromobenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid

[0722] The title compound was prepared from 3-(2-bromophenyl)-3-oxopropionitrile and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1.

[0723] LC (Method 2):t R = 0.99 minutes; mass spectrometry (ESI) + ):m / z=380 / 382(Br)[M+H + .

[0724] Step 2: 3-(2-bromobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0725] The title compound was prepared from methyl 2-amino-3-(2-bromobenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid and bromoacetyl bromide following a procedure similar to that described in step 2 of intermediate 1.

[0726] LC (Method 2):t R = 1.14 minutes; mass spectrometry (ESI) + ):m / z=500 / 502 / 504(2Br)[M+H] + .

[0727] Step 3: 2-(2-aminoacetamido)-3-(2-bromobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0728] The title compound was prepared from methyl 3-(2-bromobenzoyl)-2-(2-bromoacetamyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 3 of intermediate 1.

[0729] LC (Method 2):t R = 0.79 minutes; mass spectrometry (ESI) + ):m / z=437 / 439(Br)[M+H] + .

[0730] Step 4: 13-(2-bromophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0731] The title compound was prepared from methyl 2-(2-aminoacetamido)-3-(2-bromobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 4 of intermediate 1.

[0732] LC (Method 2):tR = 0.74 minutes; mass spectrometry (ESI) + ):m / z=419 / 421(Br)[M+H + .

[0733] Step 5: 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid

[0734] The title compound consists of 13-(2-bromophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2,6 Methyl 1-tetrate-1(8),2(6),12-triene-4-carboxylic acid was prepared following a procedure similar to that described in step 5 of intermediate 1.

[0735] LC (Method 2):t R = 0.88 minutes; mass spectrometry (ESI) + ):m / z=457 / 459(Br)[M+H] + .

[0736] Step 6: 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0737] The title compound consists of 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2 ,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 2. LC (Method 2): t R = 0.78 minutes; mass spectrometry (ESI) + ):m / z=443 / 445(Br)[M+H] + .

[0738] Step 7: 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0739] The title compound consists of 9-(2-bromophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2 ,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentene-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5.

[0740] LC (Method 2):t R = 0.79 minutes; mass spectrometry (ESI) + ):m / z=512 / 514(Br)[M+H + .

[0741] Intermediate 17

[0742] 9-(3,5-Difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0743]

[0744] Step 1: Methyl 2-amino-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid

[0745] The title compound was prepared from 3-(3,5-difluorophenyl)-3-oxopropionitrile and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1.

[0746] LC (Method 2):t R = 1.04 minutes; mass spectrometry (ESI) + ):m / z=338[M+H] + .

[0747] Step 2: 2-(2-bromoacetamyl)-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid methyl ester

[0748] The title compound was prepared from methyl 2-amino-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopentyl[b]thiophene-5-carboxylic acid and bromoacetyl bromide following a procedure similar to that described in step 2 of intermediate 1.

[0749] LC (Method 2):t R = 1.14 minutes; mass spectrometry (ESI) +):m / z=460[M+H + .

[0750] Step 3: 13-(3,5-difluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0] 2,6 Methyl 13-carboxylic acid (1(8),2(6),12-triene-4-carboxylic acid)

[0751] The title compound was prepared directly from methyl 2-(2-bromoacetamyl)-3-(3,5-difluorobenzoyl)-4H,5H,6H-cyclopentathiophene-5-carboxylic acid following a procedure similar to that described in step 3 of intermediate 1.

[0752] LC (Method 2):t R = 0.77 minutes; mass spectrometry (ESI) + ):m / z=377[M+H] + .

[0753] Step 4: 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2, 6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid

[0754] The title compound consists of 13-(3,5-difluorophenyl)-10-oxo-7-thia-9,12-diazatricyclo-[6.5.0.0]. 2,6 Methyl tridecanoate-1(8),2(6),12-triene-4-carboxylic acid was prepared following a procedure similar to that described in step 5 of intermediate 1. LC (Method 2): t R = 0.91 minutes; mass spectrometry (ESI) + ):m / z=415[M+H + .

[0755] Step 5: 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2, 6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid]

[0756] The title compound consists of 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2,6 .0 11,15Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid was prepared following a procedure similar to that described for intermediate 2. LC (Method 2): t R = 0.79 minutes; mass spectrometry (ESI) + ):m / z=401[M+H + .

[0757] Step 6: 9-(3,5-difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0758] The title compound consists of 9-(3,5-difluorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]. 2,6 .0 11,15 Hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid and morpholine were prepared following a procedure similar to that described for intermediate 5. LC (Method 2): t R = 0.81 minutes; mass spectrometry (ESI) + ):m / z=470[M+H + .

[0759] Intermediate 18

[0760] 3-Methyl-9-(methylhydrothio)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0761]

[0762] Step 1: 2-Amino-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester

[0763] The title compound was prepared from methyl cyanoacetate and methyl 3-oxocyclopentane-1-carboxylic acid following a procedure similar to that described in step 1 of intermediate 1.

[0764] LC (Method 2):t R = 1.93 minutes; mass spectrometry (ESI) + ):m / z=256[M+H + .

[0765] Step 2: 2-(2-methoxyacetamido)-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester

[0766] 2-Amino-4H,5H,6H-cyclopentathiophene-3,5-dicarboxylic acid 3,5-dimethyl ester (26.8 g) and pyridine (12.7 mL) were dissolved in DCM (200 mL). Methoxyacetyl chloride (9.56 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water, and the organic phase was then separated, dried (Na2SO4), and concentrated to dryness to provide the title compound.

[0767] LC (Method 2):t R =1.01 minutes; Mass spectrometry (ESI+): m / z = 328 [M+H] + .

[0768] Step 3: 2-(2-methoxyethiocarbamate)-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester

[0769] 36.0 g of 3,5-dimethyl 2-(2-methoxyacetamido)-4H,5H,6H-cyclopentathiophene-3,5-dicarboxylic acid was dissolved in 1,4-dioxane (150 mL) and Lawson's reagent (48.9 g) was added. The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was ground with methanol to yield the title compound. LC (Method 2): t R = 1.16 minutes; Mass spectrometry (ESI+): m / z = 344 [M+H] + .

[0770] Step 4: 2-[3-(methoxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester

[0771] 3.00 g of 3,5-dimethyl 2-(2-methoxyethiocarbamate)-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid was dissolved in THF (45 mL) and hydrazine hydrate (0.849 mL) was added. The reaction mixture was stirred at room temperature for 0.75 h. N,N-dimethylacetamide dimethyl acetal (5.1 mL) was added and the reaction mixture was stirred at room temperature for another 1.5 h. Acetic acid (15.3 mL) was added and the reaction mixture was stirred at 100 °C for 3.5 days. The reaction mixture was diluted with water and EtOAc, alkalized with NaHCO3 and extracted with EtOAc (3×). The combined organic extract was dried (MgSO4) and concentrated to dryness. The residue was chromatographically analyzed on silica gel (petroleum ether / EtOAc / methanol 80:16:4 → 20:64:16) to yield the title compound.

[0772] LC(Method 1):t R =0.82 minutes; Mass spectrometry (ESI+): m / z = 366 [M+H] + .

[0773] Step 5: 2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester

[0774] 2.79 g of 3,5-dimethyl 2-[3-(methoxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid was dissolved in DCM (40 mL), followed by the addition of boron tribromide (1 M in DCM, 15.3 mL). The reaction mixture was stirred at room temperature for 1.75 h. The reaction mixture was diluted with DCM and a saturated aqueous solution of NaHCO3 and stirred for 15 min, followed by extraction with DCM (2×). The combined organic extract was dried (MgSO4) and concentrated to provide the title compound.

[0775] LC (Method 2):t R =0.75 minutes; Mass spectrometry (ESI+): m / z = 352 [M+H] + .

[0776] Step 6: 2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester

[0777] 2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester (2.47 g) was dissolved in DCM (30 mL), followed by the addition of Et3N (2.2 mL) and methanesulfonyl bromide (1.3 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 solution and extracted with DCM (2×). The combined organic extract was dried (MgSO4) and concentrated to provide the title compound, which was used directly in the next step.

[0778] LC (Method 2):t R =0.88 minutes; Mass spectrometry (ESI+): m / z = 414 / 416 (Br) [M+H] + .

[0779] Step 7: 3-Methyl-9-oxo-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecane-1(10),3,5,11(15)-tetraene-13-carboxylate

[0780] 3.20 g of 2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-4H,5H,6H-cyclopentyl[b]thiophene-3,5-dicarboxylic acid 3,5-dimethyl ester was dissolved in a solution of ammonia in methanol (7 M, 30 mL). The reaction mixture was stirred at room temperature for 3.75 h and then concentrated to dryness. The resulting crude intermediate was dissolved in methanol (40 mL) and Et3N (1.0 mL) was added. The reaction mixture was stirred at 80 °C for 7 h and then concentrated to dryness. The residue was chromatographically analyzed on silica gel (petroleum ether / EtOAc / methanol 95:4:1→0:80:20) to yield the title compound. LC (Method 2): t R =0.71 minutes; Mass spectrometry (ESI+): m / z = 319 [M+H] + .

[0781] Step 8: 3-Methyl-9-carbon-sulfur double bond-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0] 2,6 .0 11,15 Methyl hexadecane-1(10),3,5,11(15)-tetraene-13-carboxylate

[0782] 3-Methyl-9-oxo-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15Methyl hexadecane-1(10),3,5,11(15)-tetraen-13-carboxylic acid (1.00 g) and Lawson's reagent (3.00 g) were dissolved in 1,4-dioxane (20 mL). The reaction mixture was stirred at 65 °C for 16 h. An additional batch of Lawson's reagent (1.00 g) was added and the mixture was stirred at 65 °C for 10 h. The reaction mixture was diluted with aqueous NaHCO3 solution and extracted with DCM (2×). The combined organic extract was washed with brine, dried (MgSO4), and concentrated to provide the title compound, which was used directly in the next reaction. LC (Method 2): t R =0.79 minutes; Mass spectrometry (ESI+): m / z = 335 [M+H] + .

[0783] Step 9: 3-Methyl-9-carbon-sulfur double bond-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0] 2,6 .0 11,15 [Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxylic acid]

[0784] The 3-methyl-9-carbon-sulfur double bond-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,11(15)-tetraen-13-carboxylic acid (1.70 g) was suspended in methanol (20 mL) and an aqueous solution of NaOH (4 M, 5.00 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated to near dryness. The reaction mixture was acidified with TFA and the resulting precipitate was collected by filtration to yield the title compound.

[0785] LC (Method 2):t R =0.68 minutes; Mass spectrometry (ESI+): m / z = 321 [M+H] + .

[0786] Step 10: 3-Methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2, 6 .0 11,15 [Hexadecane-1(10),3,5,11(15)-tetraene-9-thione]

[0787] The 3-methyl-9-carbon-sulfur double bond-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15Hexadecano-1(10),3,5,11(15)-tetraen-13-carboxylic acid (1.65 g) and 1,1'-carbonyldiimidazole (0.92 g) were dissolved in DMF (30 mL). The solution was stirred at 50 °C for 1 hour. Morpholine (0.68 mL) was added and the solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water / salt water (1:1) and extracted with EtOAc (3×). The combined organic extract was washed with brine, dried (MgSO4), and concentrated to dryness. The residue was purified by reversed-phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound. LC (Method 2): t R =0.71 minutes; Mass spectrometry (ESI+): m / z = 390 [M+H] + .

[0788] Step 11: 3-Methyl-9-(methylhydrothio)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0789] 3-Methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraen-9-thione (0.60 g) and potassium tert-butoxide (0.175 g) were dissolved in acetone (10 mL), followed by the addition of iodomethane (0.77 mL). The solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with DCM (2×). The combined organic extract was washed with brine, dried (MgSO4), and concentrated to dryness to provide the title compound.

[0790] LC (Method 2):t R =0.70 minutes; Mass spectrometry (ESI+): m / z = 404 [M+H] + .

[0791] Intermediate 19

[0792] 9-(2-Cyclopropylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0793]

[0794] 3-Methyl-9-(methylhydrothio)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] was subjected to an argon atmosphere. 2,6 .0 11,15 Hexadecane-1 (10),3,5,8,11 (15)-pentaene (100 mg) and copper 3-methylsalicylate (I) (160 mg) were suspended in NMP (2.00 mL). (2-Cyclopropylphenyl)boronic acid (100 mg) and tetra(triphenylphosphine)palladium (0) (30 mg) were added, and the reaction mixture was stirred at 50 °C for 1 hour. If the conversion was incomplete, additional amounts of (2-cyclopropylphenyl)boronic acid (50 mg) and tetra(triphenylphosphine)palladium (0) (30 mg) were added, and the mixture was stirred at 50 °C for 2 hours. Once complete, the reaction mixture was diluted with an aqueous solution of NaHCO3 (1 M) and extracted with EtOAc (3×). The combined organic extract was dried (MgSO4) and concentrated. The crude product was purified by reversed-phase chromatography (HPLC; ACN / water / NH3) to obtain the title compound. LC (Method 2): t R =0.75 minutes; Mass spectrometry (ESI+): m / z = 474 [M+H] + .

[0795] Intermediate 20

[0796] {2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]} 2,6 .0 11 ,15 [hexadec-1(10),3,5,8,11(15)-pentaen-9-yl]phenylmethanol

[0797]

[0798] The title compound consists of 3-methyl-9-(methylhydrothio)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentane and 2-(hydroxymethyl)phenylboronic acid were prepared following a procedure similar to that described for intermediate 19.

[0799] LC (Method 2):t R =0.66 minutes; Mass spectrometry (ESI+): m / z = 464 [M+H] + .

[0800] Intermediate 21

[0801] 2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadec-1(10),3,5,8,11(15)-pentaen-9-yl]phenol

[0802]

[0803] The title compound consists of 3-methyl-9-(methylhydrothio)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentane and (2-hydroxyphenyl)boronic acid were prepared following a procedure similar to that described for intermediate 19.

[0804] LC (Method 2):t R =0.73 minutes; Mass spectrometry (ESI+): m / z = 450 [M+H] + .

[0805] Intermediate 22

[0806] 9-(2-chloro-5-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0807]

[0808] The title compound consists of 3-methyl-9-(methylhydrothio)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentane and (2-chloro-5-methoxyphenyl)boronic acid were prepared following a procedure similar to that described for intermediate 19.

[0809] LC (Method 2):t R =0.84 minutes; Mass spectrometry (ESI+): m / z = 498 [M+H] + .

[0810] Intermediate 23

[0811] 9-(2-Methylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0812]

[0813] Equipped with a stir bar, 9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 A vial containing hexadec-1(10),3,5,8,11(15)-pentaene (50 mg), methylboronic acid (13 mg), K3PO4 (71 mg), Pd(OAc)2 (1.2 mg), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.4 mg) was purged with Ar for 5 minutes. Water (25 μL) and toluene (0.25 mL) were added, the vial was sealed, and the mixture was stirred in a microwave oven at 140°C for 30 minutes. Another portion of methylboronic acid (13 mg), Pd(OAc)2 (1.2 mg), and dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (4.4 mg) was added at room temperature, and the mixture was stirred in a microwave oven at 140°C for 30 minutes. After cooling to room temperature, MeOH was added, the resulting mixture was filtered, and the filtrate was chromatographically analyzed on reversed phase (HPLC; ACN / water / TFA) to provide the title compound.

[0814] LC (Method 2):t R =0.72 minutes; Mass spectrometry (ESI+): m / z = 448 [M+H] + .

[0815] Intermediate 24

[0816] 3-Methyl-13-(morpholine-4-carbonyl)-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2, 6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0817]

[0818] The title compound can be obtained from 3-methyl-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] using a two-step procedure. 2,6 .0 11,15Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid (see EP0254245A1 for the synthesis), the procedure of which includes hydrolysis of the methyl ester (similar to the description for intermediate 2) and amide coupling of the resulting carboxylic acid with morpholine (similar to the description for intermediate 5). LC (Method 2): t R =0.69 minutes; Mass spectrometry (ESI+): m / z = 434 [M+H] + .

[0819] The intermediates edited in the table below were produced by following a procedure similar to that described for intermediate 5 using (13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentane-13-carboxylic acid or 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2 ,6 .0 11,15 [Obtained by hexadec-1(10),3,5,8,11(15)-pentene-13-carboxylic acid and various amines.]

[0820]

[0821] Intermediate 28

[0822] 9-(2-Chlorophenyl)-3-ethyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecyl-1(10),3,5,8,11(15)-pentaene]

[0823]

[0824] The title compound is obtained from 13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2 ,6 Methyl 1-(8),2-(6),12-triene-4-carboxylic acid and propionyl hydrazine are provided by following a procedure similar to that described in step 5 of intermediate 1 to provide 9-(2-chlorophenyl)-3-ethyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15The procedure for methyl hexadecane-1(10),3,5,8,11(15)-pentane-13-carboxylic acid ester. Subsequently, the ester is saponified by following a procedure similar to that described for intermediate 2, and the resulting carboxylic acid is converted to the title compound by following a procedure similar to that described for intermediate 5. Alternatively, 9-(2-chlorophenyl)-3-ethyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid can be obtained from 13-(2-chlorophenyl)-10-carbon-sulfur double bond-7-thia-9,12-diazatricyclo[6.5.0.0] by following a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or US7015213B1. 2,6 Methyl tridecanoate-1(8),2(6),12-triene-4-carboxylic acid.

[0825] LC (Method 2):t R =0.82 minutes; Mass spectrometry (ESI+): m / z = 482 [M+H] + .

[0826] Intermediate 29

[0827] 9-(2-Chlorophenyl)-3-propyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0828]

[0829] The title compound is obtained from 13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2 ,6 Methyl 1-(8),2-(6),12-triene-4-carboxylic acid and butyrylhydrazine are provided by following a procedure similar to that described in step 5 of intermediate 1 to provide 9-(2-chlorophenyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15The procedure for methyl hexadecane-1(10),3,5,8,11(15)-pentane-13-carboxylic acid ester. Subsequently, the ester is saponified by following a procedure similar to that described for intermediate 2, and the resulting carboxylic acid is converted to the title compound by following a procedure similar to that described for intermediate 5. Alternatively, 9-(2-chlorophenyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid can be obtained from 13-(2-chlorophenyl)-10-carbon-sulfur double bond-7-thia-9,12-diazatricyclo[6.5.0.0] by following a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or US7015213B1. 2,6 Methyl tridecanoate-1(8),2(6),12-triene-4-carboxylic acid.

[0830] LC (Method 2):t R =0.87 minutes; Mass spectrometry (ESI+): m / z = 496 [M+H] + .

[0831] Intermediate 30

[0832] 9-(2-Chlorophenyl)-3-cyclopropyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,8,11(15)-pentaene

[0833]

[0834] The title compound is obtained from 13-(2-chlorophenyl)-10-oxo-7-thia-9,12-diazatricyclo[6.5.0.0]. 2 ,6 [Methyl 1(8),2(6),12-triene-4-carboxylic acid and cyclopropane carbohydrazine, provided by following a step similar to that described in intermediate 1, in step 5, for 9-(2-chlorophenyl)-3-cyclopropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15The procedure for methyl hexadecano-1(10),3,5,8,11(15)-pentaene-13-carboxylic acid ester. Subsequently, the ester is saponified by following a procedure similar to that described for intermediate 2, and the resulting carboxylic acid is converted to the title compound by following a procedure similar to that described for intermediate 5. Alternatively, 9-(2-chlorophenyl)-3-cyclopropyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2, 6 .0 11,15 Methyl hexadecyl-1(10),3,5,8,11(15)-pentane-13-carboxylic acid can be obtained from 13-(2-chlorophenyl)-10-carbon-sulfur double bond-7-thia-9,12-diazatricyclo[6.5.0.0] by following a procedure similar to that reported in Arzneimittelforschung 1978, 28, 1153-8 or US7015213B1. 2,6 Methyl tridecanoate-1(8),2(6),12-triene-4-carboxylic acid.

[0835] LC (Method 2):t R =0.83 minutes; Mass spectrometry (ESI+): m / z = 494 [M+H] + .

[0836] Intermediate 31

[0837] (3-Methyl-9-[2-(methylhydrothio)phenyl]-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,11(15)-pentaene

[0838]

[0839] 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadecane-1(10),3,5,8,11(15)-pentaene (135 mg), copper iodide (I) (50 mg), and DABCO (59 mg) were dissolved in anhydrous DMSO (2.0 mL). The reaction mixture was stirred at 130 °C under argon for 16 hours. The mixture was diluted with acetonitrile, filtered, and purified by reversed-phase chromatography (HPLC; ACN / water / TFA) to yield the title compound. LC (Method 2): t R = 0.74 minutes; mass spectrometry (ESI) + ):m / z=480[M+H +.

[0840] Synthesis of the Implementation Examples:

[0841] Example 1

[0842] 9-(2-Chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,11(15)-tetraene

[0843]

[0844] NaBH4 (32 mg) and HCl (4 M in water; 0.26 mL) were further added to 9-(2-chlorophenyl)-3-methyl-13-(morpholin-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] at room temperature. 2,6 .0 11,15 A solution of hexadecane-1(10),3,5,8,11(15)-pentaene (200 mg) in DCE (1 mL) was prepared. The mixture was stirred for 2 hours, and then another portion of NaBH4 (16 mg) and HCl (4 mol / L in water; 0.26 mL) were added. The reaction was stirred further at room temperature until complete; if the reaction was not complete, more NaBH4 and HCl were added. The resulting mixture was extracted with DCM (3×) by adding NaHCO3 aqueous solution. The combined organic extract was dried (Na2SO4) and concentrated. The residue was purified by reversed-phase chromatography (HPLC; ACN / water / ammonia) to yield the title compound as a mixture of two racemic non-mirror image isomers (approximately 60 / 40).

[0845] LC (Method 2):t R = 0.72 minutes; mass spectrometry (ESI) + ):m / z=470[M+H + .

[0846] Example 2 and Example 3

[0847] (9R,13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [-Hexadecane-1(10),3,5,11(15)-tetraene (Example 2) and (9S,13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholin-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]2,6 .0 11,15 ]-Hexadec-1(10),3,5,11(15)-tetraene (Example 3)

[0848]

[0849] At room temperature, HCl (4 M in water, 1.07 mL) and NaBH4 (323 mg) were further added to (13S)-9-(2-chlorophenyl)-3-methyl-13-(morpholin-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 A solution of hexadecane-1(10),3,5,8,11(15)-pentaene (1.00 g) in DCM (25 mL). The mixture was stirred for 1 hour until complete. The mixture was diluted with water and an aqueous solution of HCl (1 M) to achieve a pH of 8 to 9 and extracted with DCM (2×). The combined organic extract was dried (Na2SO4) and concentrated. The residue was repeatedly purified by reverse-phase chromatography (HPLC; ACN / water / aqueous TFA) to produce the TFA salt of the completely separated non-mirror image isomers. The non-mirror image isomers were released from their salt forms by extracting the resulting mixture with DCM by adding an aqueous solution of NaHCO3 and concentrating the organic extract to produce the title compound.

[0850] Example 2: LC (Method 2):t R = 0.72 minutes; mass spectrometry (ESI) + ):m / z=470[M+H + ;

[0851] Example 3: LC (Method 2):t R = 0.73 minutes; mass spectrometry (ESI) + ):m / z=470[M+H + .

[0852] Example 4

[0853] (9R,13S)-9-(2-chlorophenyl)-3-methyl-13-[(2S)-2-methylmorpholine-4-carbonyl]-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0854]

[0855] The title compound is composed of (9R,13S)-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxylic acid and (2S)-2-methyl-morpholine hydrochloride were prepared following a procedure similar to that described for intermediate 5.

[0856] LC (Method 4):t R = 0.50 minutes; mass spectrometry (ESI) + ):m / z=484[M+H + .

[0857] The example edited in the table below (Ex.) uses 9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] by following a procedure similar to that described for intermediate 5. 2,6 .0 11,15 The product was obtained as a stereoisomer or mixture of stereoisomers of hexadecane-1(10),3,5,11(15)-tetraen-13-carboxylic acid and individual amines. Examples 11 and 12 were obtained by separation using SFC [Column: Chiral]. Amylose-SA (10 mm x 250 mm, 5 μm); column temperature: 40 °C; flow rate: 10 mL / min; BPR: 150 bar; injection volume: 250 μL (2.5 mg); isocratic conditions: 70:30 CO2:MeOH (20 mM NH3)], and Examples 13 and 14 [column: IA (10 mm x 250 mm, 5 μm); column temperature: 40 °C; flow rate: 10 mL / min; BPR: 150 bar; injection volume: 200 μL (2 mg); isocratic conditions: 65:35 CO2:EtOH (20 mM NH3)).

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882] Example 52

[0883] 9-(4-Chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0884]

[0885] The title compound consists of 9-(4-chlorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.72 minutes; Mass spectrometry (ESI+): m / z = 470 [M+H] + .

[0886] Example 53

[0887] 9-(2-Ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0888]

[0889] The title compound is composed of 9-(2-ethylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.72 / 0.74 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 464 [M+H] + .

[0890] Example 54

[0891] 9-(2-Methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,11(15)-tetraene

[0892]

[0893] The title compound is composed of 9-(2-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.68 minutes; Mass spectrometry (ESI+): m / z = 466 [M+H] + .

[0894] Example 55

[0895] 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0896]

[0897] The title compound consists of 9-(2-fluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.78 / 0.79 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 454 [M+H] + .

[0898] Example 56

[0899] 3-Methyl-13-(morpholine-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,11(15)-tetraene

[0900]

[0901] The title compound is composed of 3-methyl-13-(morpholin-4-carbonyl)-9-[2-(trifluoromethyl)phenyl]-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.76 minutes; Mass spectrometry (ESI+): m / z = 504 [M+H] + .

[0902] Example 57

[0903] 9-(2-Bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .011,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0904]

[0905] The title compound is composed of 9-(2-bromophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 The hexadecane-1(10),3,5,8,11(15)-pentaene was prepared following a procedure similar to that described for Example 1.

[0906] LC (Method 2):t R =0.71 / 0.72 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 514 / 516 (Br) [M+H] + .

[0907] Example 58

[0908] 9-(3,5-Difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,11(15)-tetraene

[0909]

[0910] The title compound is composed of 9-(3,5-difluorophenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.72 minutes; Mass spectrometry (ESI+): m / z = 472 [M+H] + .

[0911] Example 59

[0912] 9-(2-Cyclopropylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 ]-Hexadec-1(10),3,5,11(15)-tetraene

[0913]

[0914] The title compound is composed of 9-(2-cyclopropylphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.73 / 0.75 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 476 [M+H] + .

[0915] Example 60

[0916] {2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]} 2,6 .0 11 ,15 [Hexadec-1(10),3,5,11(15)-tetraen-9-yl]phenylmethanol

[0917]

[0918] The title compound consists of {2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]} 2,6 .0 11,15 [Hexadec-1(10),3,5,8,11(15)-pentaen-9-yl]phenylmethanol was prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.64 / 0.65 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 466 [M+H] + .

[0919] Example 61

[0920] 2-[3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadec-1(10),3,5,11(15)-tetraen-9-yl]phenol

[0921]

[0922] The title compound consists of 2-[3-methyl-13-(morpholin-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15Hexadecyl-1(10),3,5,8,11(15)-pentaen-9-yl]phenol was prepared following a procedure similar to that described for Example 1. LC (Method 1): t R =0.74 / 0.75 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 452 [M+H] + .

[0923] Example 62

[0924] 9-(2-chloro-5-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0925]

[0926] The title compound is composed of 9-(2-chloro-5-methoxyphenyl)-3-methyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.73 minutes; Mass spectrometry (ESI+): m / z = 500 [M+H] + .

[0927] Examples 63 and 64

[0928] (9R,13S)-3-methyl-9-(2-methylphenyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [-Hexadec-1(10),3,5,11(15)-tetraene (Example 63) and (9S,13S)-3-methyl-9-(2-methylphenyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11 ,15 ]-Hexadec-1(10),3,5,11(15)-tetraene (Example 64)

[0929]

[0930] The title compound is composed of (13S)-3-methyl-9-(2-methylphenyl)-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 The hexadecane-1(10),3,5,8,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. The non-mirror image isomers were separated by reversed-phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound.

[0931] Example 63: LC (Method 2):t R =0.71 minutes; Mass spectrometry (ESI+): m / z = 450 [M+H] + ;

[0932] Example 64: LC (Method 2):t R =0.69 minutes; Mass spectrometry (ESI+): m / z = 450 [M+H] + .

[0933] Example 65

[0934] (13S)-9-(2-chlorophenyl)-N-(1-hydroxy-2-methylpropane-2-yl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0] 2,6 .0 11,15 [Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxamide]

[0935]

[0936] The title compound is composed of (13S)-9-(2-chlorophenyl)-N-(1-hydroxy-2-methylpropane-2-yl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,8,11(15)-pentene-13-carboxamide was prepared following a procedure similar to that described for Example 1.

[0937] LC (Method 2):t R =0.72 minutes; Mass spectrometry (ESI+): m / z = 472 [M+H] + .

[0938] Example 66

[0939] 13-{5-azaspiro[2.5]octane-5-carbonyl}-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo-[8.6.0.0]2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0940]

[0941] The title compound is composed of 13-{5-azaspiro[2.5]octane-5-carbonyl}-9-(2-chlorophenyl)-3-methyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 1): t R =0.99 minutes; Mass spectrometry (ESI+): m / z = 494 [M+H] + .

[0942] The examples edited in the table below were obtained by following a procedure similar to that described for Example 1 from 9-(2-chlorophenyl)-3-ethyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 [Hexadecyl-1(10),3,5,11(15)-pentaene. Individual stereoisomers were obtained by chiral SFC: First separation yielded Examples 68 and 69 [Column: IA (20mm x 250mm, 5μm); column temperature: 40℃; flow rate: 60mL / min; BPR: 150bar; injection volume: 250μL (2.5mg); isocratic conditions: 70:30CO2:EtOH (20mM NH3)], followed by a second separation of the mixed eluent to obtain Reference Example 70 and Reference Example 71 [column: Chiral Amylose-SA (10 mm x 250 mm, 5 μm); column temperature: 40 °C; flow rate: 10 mL / min; BPR: 150 bar; injection volume: 200 μL (4 mg); isocratic conditions: 80:20 CO2:MeOH (20 mM NH3)).

[0943]

[0944]

[0945] *Reference embodiments outside the scope of this invention

[0946] Examples 72 and 73

[0947] (9S,13S)-9-(2-chlorophenyl)-3-methyl-N,N-dipropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 [Hexadecane-1(10),3,5,11(15)-tetraen-13-carboxamide (Example 72) and (9R,13S)-9-(2-chlorophenyl)-3-methyl-N,N-dipropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]] 2,6 .0 11,15 [Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxamide (Example 73)]

[0948]

[0949] The title compound is composed of (13S)-9-(2-chlorophenyl)-3-methyl-N,N-dipropyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene-13-carboxamide was prepared following a procedure similar to that described for Example 1. Non-mirror image isomers were separated by chiral SFC [column: Chiral]. Amylose-SA (10mm x 250mm, 5μm); column temperature: 40℃; flow rate: 10mL / min; BPR: 150bar; injection volume: 100μL (2mg); isocratic conditions: 75:25CO2:MeOH (20mM NH3)].

[0950] Example 72: LC (Method 7):t R = 2.10 minutes; Mass spectrometry (ESI+): m / z = 484 [M+H] + ;

[0951] Example 73: LC (Method 7):t R = 3.02 minutes; Mass spectrometry (ESI+): m / z = 484 [M+H] + .

[0952] The examples edited in the table below were obtained by following a procedure similar to that described for Example 1 from 3-methyl-13-(morpholino-4-carbonyl)-9-phenyl-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15Hexadec-1(10),3,5,8,11(15)-pentaene. Trans and cis non-mirror image isomers were separated by reversed-phase chromatography (HPLC; ACN / water / TFA). The racemic non-mirror image isomers were further separated into individual enantiomers by chiral SFC to produce Reference Examples 75 and 76 [Column: Chiralpak IA (20 mm x 250 mm, 5 μm); Column temperature: 40 °C; Flow rate: 10 mL / min; BPR: 150 bar; Injection volume: 200 μL (3 mg); Isocratic conditions: 70:30 scCO2:MeOH (20 mM NH3)] and Reference Examples 77 and 78 ... Cellulose-SB (10 x 250 mm, 5 μm); column temperature: 40 °C; flow rate: 10 mL / min; BPR: 150 bar; injection volume: 200 μL (2 mg); isocratic conditions: 70:30 CO2:iPrOH (20 mM NH3)).

[0953]

[0954]

[0955] *Reference embodiment outside the scope of this invention Example 79

[0956] 3-Methyl-9-[2-(methylhydrothio)phenyl]-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0957]

[0958] The title compound is composed of (3-methyl-9-[2-(methylhydrothio)phenyl]-13-(morpholin-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 The hexadecane-1(10),3,5,11(15)-pentaene was prepared following a procedure similar to that described for Example 1.

[0959] LC (Method 2):t R =0.70 / 0.71 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 482 [M+H] + .

[0960] Example 80

[0961] 9-(2-Chlorophenyl)-13-(morpholine-4-carbonyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclic [8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0962]

[0963] The title compound is composed of 9-(2-chlorophenyl)-13-(morpholin-4-carbonyl)-3-propyl-16-thia-2,4,5,8-tetraazatetracyclic rings.

[0964] [8.6.0.0 2,6 .0 11,15 The hexadecane-1(10),3,5,11(15)-pentaene was prepared following a procedure similar to that described for Example 1.

[0965] LC (Method 2):t R =0.77 / 0.78 minutes (non-mirror image isomer); Mass spectrometry (ESI+): m / z = 498 [M+H] + .

[0966] Example 81

[0967] 9-(2-Chlorophenyl)-3-cyclopropyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0] 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-tetraene

[0968]

[0969] The title compound is composed of 9-(2-chlorophenyl)-3-cyclopropyl-13-(morpholine-4-carbonyl)-16-thia-2,4,5,8-tetraazatetracyclo[8.6.0.0]. 2,6 .0 11,15 Hexadecane-1(10),3,5,11(15)-pentaenes were prepared following a procedure similar to that described for Example 1. LC (Method 2): t R =0.75 minutes; Mass spectrometry (ESI+): m / z = 496 [M+H] + .

[0970] In summary, the present invention includes, but is not limited to, the following:

[0971] 1. A compound of formula (I.0),

[0972]

[0973] in

[0974] R 1 Choose any C that has been replaced by 1 to 3 Fs. 1-4 -alkyl and C 3-4 The group consisting of cycloalkyl groups;

[0975] R 2 Choose from F, Cl, Br, I, substituted with 1 to 3 F atoms, or substituted with 1 -CN, 1 OH, or 1 -OC atom. 1-4 -alkyl-substituted C 1-4 The group consisting of -alkyl groups, the group further including C 3-4 -cycloalkyl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, OH, -OC optionally substituted with 1 to 3 Fs 1-4 -alkyl groups, and -S(O) groups with r = 0, 1, or 2. r -C 1-4 -alkyl;

[0976] n can be any combination of 0, 1, 2, and 3;

[0977] R 3 Choose H freely and any C replaced by 1 to 5 Fs. 1-4 The group consisting of alkyl groups; and

[0978] R 4 Choose freely by substitution of 1 to 3 Fs and by 1 to 2 independently selected from -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and -OC optionally substituted with 1 to 3 F atoms 1-3 -alkyl substituents substituted C 1-6 The group consisting of alkyl groups;

[0979] or

[0980] R 4 Choose freely - C 0-3 -alkylene-C 3-10 -Cycloalkyl and -C 0-3 -alkylene-C 3-10 - A group composed of heterocyclic groups.

[0981] The alkylene group may be optionally substituted with one or two substituents selected from F and CH3.

[0982] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0983] The cycloalkyl and heterocyclic groups are saturated monocyclic or bicyclic systems.

[0984] The heterocyclic group contains one or two independently selected ions from N, NH, >N(C) 1-4 -alkyl), >NCO(C) 1-4 -alkyl), >NS(=O)2(C 1-4 -alkyl) and O ring members, and optionally one >S(=O) selected from >C=O and r=0, 1 or 2. r The ring members,

[0985] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r＝1,2 Any heteroatom-heteroatom bond outside, and

[0986] The cycloalkyl and heterocyclic groups are optionally substituted with 1 to 2 F groups and optionally with 1 to 2 independently selected from Cl, -CN, -CONH2, -CONH(C 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, OH, -OC optionally substituted with 1 to 3 Fs 1-3 -alkyl, and selected from those optionally substituted with 1 to 3 F or with 1 selected from -CN, OH, -OC 1-4 -alkyl substituents substituted C 1-4 -Substituents of alkyl groups;

[0987] or

[0988] R 4 Choose freely - C 0-3 -alkylene-phenyl and -C 0-3 The group consisting of -alkylene-heteroaryl groups.

[0989] The alkylene group may be optionally substituted with one or two substituents selected from F and CH3.

[0990] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[0991] The heteroaryl group is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing one to two ring members N, or a 6-membered monocyclic ring containing one to two ring members N.

[0992] The phenyl group and the heteroaryl group are optionally selected from 1 to 3 independently from F, Cl, Br, C. 3-4 -cycloalkyl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, -NHCO-C 1-4 -alkyl, -NHS(=O)2-C 1-4 -alkyl, r = 0, 1 or 2, -S (=O) r -C 1-4 -alkyl group, selected from -OC group which is optionally substituted with 1 to 3 F atoms. 1-4 -alkyl group, and selected from one to three F groups or one group selected from -CN, OH and -OC. 1-4 -alkyl substituents substituted C 1-4 -Substituents of alkyl groups;

[0993] or

[0994] R 3 and R 4 Selected from the following groups, where R 3 and R 4 Together with the amide N atom it binds to, they form saturated 3- to 8-membered monocyclic heterocyclic groups.

[0995] It may further contain one or two independently selected from >NH, >N(C) 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[0996] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r The ring members,

[0997] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r＝1,2 Any heteroatom-heteroatom bond outside of the bond,

[0998] The heterocyclic group is optionally substituted with 1 to 4 F groups.

[0999] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[1000] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-OC 1-3 -alkylene-, C 1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C optionally substituted with 1 to 3 Fs 1-3 Substituents of -alkyl-O- groups;

[1001] or

[1002] R 3 and R 4 Selected from the following groups, where R 3 and R 4 Together with the amide N atom it binds to, they form a saturated 5- to 12-membered bicyclic heterocyclic group.

[1003] It may optionally contain 1 to 3 independently selected from >N-, >NH, >N(C) 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[1004] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r The ring members,

[1005] The condition is that the heterocyclic group does not contain any compounds other than NN, NO, and NS (=O) among the ring members. r＝1,2 Any heteroatom-heteroatom bond outside of the bond,

[1006] The heterocyclic group is optionally substituted with 1 to 6 F groups.

[1007] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[1008] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-OC 1-3 -alkylene-, C1-3 -alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C 1-3 Substituents of -alkyl-O- groups;

[1009] or

[1010] R 3 and R 4 Selected from the following groups, where R 3 and R 4 Together with the amide N atom it binds to, they form a 7- to 12-membered fused bicyclic system.

[1011] The bicyclic system is composed of heterocyclic or heteroaryl groups consisting of the following:

[1012] A non-aromatic ring containing the amide N atom and optionally further containing one or two atoms independently selected from =N-, >N-, >NH, >N(C 1-4 -alkyl), >N(CO-C) 1-3 -alkyl), >N(S(=O)2-C 1-3 -alkyl) and O ring members, and

[1013] Choose any S(=O) containing one element selected from >C=O and r=0, 1, or 2. r A ring member is defined if there are no members other than NN, NO, and NS (=O) among the members of this non-aromatic ring. r＝1,2 External heteroatom-heteroatom bonds,

[1014] and consists of the following:

[1015] An aromatic ring selected from a 5-membered monocyclic ring containing one ring member selected from NH, N, O and S and optionally one or two more ring members N, and a 6-membered monocyclic ring containing 0, 1 or 2 ring members N.

[1016] The dual-ring system can be arbitrarily replaced by 1 to 4 Fs.

[1017] C can be substituted by 1 to 4 Fs or by 1 to 3 Fs. 1-3 -alkyl substitution, and

[1018] Choose one or two from Cl, -CN, -CONH2, -CONH(C) 1-4 -alkyl), -CON(C) 1-4 -alkyl)2, -COOH, -COO-C 1-4 -alkyl, HO-C 1-3 -alkylene-, C 1-3 -alkyl-OC 1-3 -alkylene-, C 1-3-alkyl-CO-NH-, C 1-3 -alkyl-S(=O)2-NH-, OH and C optionally substituted with 1 to 3 Fs 1-3 Substituents of -alkyl-O- groups;

[1019] Or its salt.

[1020] 2. According to the compound in item 1, where

[1021] R 3 and R 4 Together with the amide N atom it bonds to, it forms a heterocycle selected from the group consisting of:

[1022] and

[1023] Or its salt.

[1024] 3. The compound according to claim 1 or 2, wherein

[1025] R 1 Choose the group consisting of CH3, CH2CH3, CH2CH2CH3, CHF2, CF3 and cyclopropyl groups;

[1026] Or its salt.

[1027] 4. The compound according to claim 1 or 2, wherein

[1028] R 1 Choose the group consisting of CH3, CH2CH3, CH2CH2CH3 and cyclopropyl groups;

[1029] Or its salt.

[1030] 5. The compound according to claim 1 or 2, wherein

[1031] R 1 It is CH3;

[1032] Or its salt.

[1033] 6. According to any one of items 1 to 5, among which

[1034] R 2 Choose freely from F, Cl, Br, or C substituted with 2 or 3 F atoms. 1-3 The group consisting of -alkyl groups, further including cyclopropyl, -CN, -C 1-3 -alkylene-OH, -C 1-2 -alkylene-OC 1-2 -alkyl, OH, -OC optionally substituted with 2 or 3 Fs 1-3 -alkyl, and including -SC 1-3 -alkyl;

[1035] n can be any combination of 0, 1, and 2;

[1036] Or its salt.

[1037] 7. According to any one of items 1 to 5, among which

[1038] R 2 Choose from the group consisting of F, Cl, Br, CH3, CH2CH3, cyclopropyl, CF3, CH2OH, OH, OCH3, and S-CH3; and

[1039] n can be any combination of 0, 1, and 2;

[1040] Or its salt.

[1041] 8. According to the compound in item 2, where

[1042] R 1 It is CH3;

[1043] R 2 For Cl;

[1044] n is 1;

[1045] Or its salt.

[1046] 9. According to any one of items 1 to 8, among which

[1047] The stereochemistry of the compound is based on formula (I.1).

[1048]

[1049] Or its salt.

[1050] 10. The compound according to item 2, wherein the compound is selected from:

[1051]

[1052]

[1053]

[1054]

[1055] 11. The compound according to claim 10, wherein the compound is:

[1056]

[1057] 12. The compound according to claim 10, wherein the compound is:

[1058]

[1059] 13. The compound according to claim 10, wherein the compound is:

[1060]

[1061] 14. The compound according to claim 10, wherein the compound is:

[1062]

[1063] 15. The compound according to claim 10, wherein the compound is:

[1064]

[1065] 16. The compound according to claim 1, wherein

[1066] R 3 Choose H freely and any C replaced by 1 to 3 Fs. 1-3 The group consisting of alkyl groups; and

[1067] R 4 Choose any C substituted with one substituent selected from F, OH and OCF3. 1-4 The group consisting of alkyl groups;

[1068] or

[1069] R 4 Choose freely - C 0-1 -alkylene-C 3-6 -A group consisting of cycloalkyl groups

[1070] Wherein the cycloalkyl group is a saturated monocyclic or bicyclic system, and

[1071] The cycloalkyl group may be optionally substituted with 1 to 2 F groups and optionally substituted with 1 independent substituent selected from CH3 or CH2CH3;

[1072] or

[1073] R 4 Choose freely - C 0-2 -alkylene-phenyl and -C 0-2 The group consisting of -alkylene-heteroaryl groups.

[1074] The alkylene group may be optionally substituted with one or two CH3 groups.

[1075] In this alkylene group, the two H atoms of one >CH2 group are optionally replaced by an ethylene (-CH2-CH2-) bridge to form a cyclopropylene moiety >C (-CH2-CH2-).

[1076] The heteroaryl group is a 5-membered monocyclic ring containing one ring member selected from N, NH, O, and S, and optionally further containing one ring member N, or a 6-membered monocyclic ring containing one to two ring members N.

[1077] The phenyl group and heteroaryl group are optionally substituted with 1 to 3 independently selected F, Cl, Br, -CN, or -OC groups optionally substituted with 1 to 3 F groups. 1-3 -alkyl, and selected from 1 to 3 F or 1 selected from -CN and -OC. 1-2 -alkyl substituents substituted C 1-3 -Substituents of alkyl groups;

[1078] or

[1079] R 3 and R 4 Selected from the following groups, where R 3 and R 4 Together with the amide N atom it bonds to, it forms a heterocyclic group selected from the following:

[1080] and Or its salt.

[1081] 17. The compound according to claim 16, wherein

[1082] R 1 It is CH3;

[1083] R 2 Choose the group consisting of F, Cl, and Br;

[1084] n is 1;

[1085] R 3 Choose the group consisting of H, CH3, and CH2CH2CH3; and

[1086] R 4 Choose from the following groups:

[1087] and

[1088] or

[1089] R 3 and R 4 Selected from the following groups, where R 3 and R 4 Together with the amide N atom it bonds to, it forms a heterocycle selected from the group consisting of:

[1090] and Or its salt.

[1091] 18. The compound according to claim 17, wherein

[1092] Select R 2 The substitution modes of n and phenyl make the resulting substituted benzene ring shown in formula (I.0) selected from the group consisting of the following groups.

[1093]

[1094] Or its salt.

[1095] 19. The compound according to claim 16, wherein the compound is selected from:

[1096]

[1097]

[1098]

[1099]

[1100]

[1101] Or its salt.

[1102] 20. The compound according to claim 19, wherein the compound is:

[1103]

[1104] 21. The compound according to claim 19, wherein the compound is:

[1105]

[1106] 22. The compound according to claim 19, wherein the compound is:

[1107]

[1108] 23. The compound according to claim 19, wherein the compound is:

[1109]

[1110] 24. The compound according to claim 19, wherein the compound is:

[1111]

[1112] 25. The compound according to claim 19, wherein the compound is:

[1113]

[1114] 26. The compound according to claim 19, wherein the compound is:

[1115]

[1116] 27. According to any one of items 1 to 26, among which

[1117] The stereochemistry of the compound is based on formula (I.1).

[1118]

[1119] Or its salt.

[1120] 28. A pharmaceutically acceptable salt of a compound according to any one of items 1 to 27.

[1121] 29. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 27, or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and / or diluents.

[1122] 30. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 27 or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and / or diluents.

[1123] 31. The pharmaceutical composition according to item 30,

[1124] The one or more additional therapeutic agents are selected from the group consisting of: antidiabetic agents, agents for treating overweight and / or obesity, agents for treating hypertension, heart failure and / or atherosclerosis, agents for treating eye diseases, and agents for treating allergies and inflammation-related conditions and diseases.

[1125] 32. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 27, used as a medicine.

[1126] 33. A method for treating an eye disease in a patient in need, preferably diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy, and non-exudative choroidal angiogenesis, and for treating allergy and inflammation-related conditions and diseases, preferably urticaria and NASH, the method comprising administering to the patient one or more compounds according to any one of claims 1 to 27 or pharmaceutically acceptable salts thereof.

[1127] 34. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 27, used for the treatment of eye diseases, preferably diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy and non-exudative choroidal angiogenesis, and for the treatment of allergic and inflammatory conditions and diseases, preferably urticaria and NASH.

[1128] 35. Use of the compound of any one of items 1 to 27 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating eye diseases, preferably diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy and non-exudative choroidal angiogenesis, and for treating allergic and inflammatory conditions and diseases, preferably urticaria and NASH.

Claims

1. A compound of formula (I.1) or a salt thereof ， in R 1 Selected from C that has been substituted with 1 to 3 Fs. 1-4 -alkyl and C 3-4 The group consisting of cycloalkyl groups; R 2 For Cl; n is 1; and R 3 and R 4 The amide N atom attached to it forms a heterocycle selected from the group consisting of: , , , , and .

2. The compound of claim 1 or a salt thereof, wherein R 1 The group is selected from CH3, CH2CH3, CH2CH2CH3, CHF2, CF3 and cyclopropyl groups.

3. The compound of claim 1 or a salt thereof, wherein R 1 Selected from the group consisting of CH3, CH2CH3, CH2CH2CH3 and cyclopropyl groups.

4. The compound of claim 1 or a salt thereof, wherein R 1 It is CH3.

5. The compound of claim 1 or a salt thereof, wherein Select R 2 The substitution mode of n and phenyl makes the resulting substituted benzene ring shown in formula (I.1) be 。 6. The compound of claim 1 or a salt thereof, wherein the compound is selected from: 。 7. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 6.

8. The compound of claim 6, wherein the compound is 。 9. The compound of claim 6, wherein the compound is 。 10. The compound of claim 6, wherein the compound is 。 11. The compound of claim 6, wherein the compound is 。 12. The compound of claim 6, wherein the compound is 。 13. A pharmaceutically acceptable salt of the compound of claim 6, wherein the compound is 。 14. A pharmaceutically acceptable salt of the compound of claim 6, wherein said compound is 。 15. A pharmaceutically acceptable salt of the compound according to claim 6, wherein said compound is 。 16. A pharmaceutically acceptable salt of the compound of claim 6, wherein said compound is 。 17. A pharmaceutically acceptable salt of the compound of claim 6, wherein the compound is 。 18. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 or 8 to 12, or one or more pharmaceutically acceptable salts according to any one of claims 7 or 13 to 17, optionally together with one or more inert carriers and / or diluents.

19. Use of a compound of any one of claims 1 to 6 or 8 to 12, or a pharmaceutically acceptable salt of any one of claims 7 or 13 to 17, in the preparation of a medicament for the prevention or treatment of eye diseases or for the prevention or treatment of allergic and inflammatory conditions and diseases.

20. The use according to claim 19, wherein the eye disease to be prevented or treated is selected from the group consisting of: diabetic macular edema, dry and wet age-related macular degeneration, geographic atrophy, and non-exudative choroidal angiogenesis.

21. The use according to claim 19, wherein the allergy and inflammation-related condition and disease to be prevented or treated is urticaria or NASH.

Images