Non-peptide agonists of the oxytocin receptor

Abstract

The present invention relates to non-peptide agonists of the oxytocin receptor of formula (I), to pharmaceutical compositions comprising said compounds and a pharmaceutically acceptable vehicle, and in particular to said compounds for the treatment of any known condition in which oxytocin has a beneficial effect, such as autism spectrum disorder, in particular for the treatment of social interaction disorders in autism spectrum disorder. TIFF2025537920000040.tif49170

Description

[Technical Field]

[0001] The present invention relates to non-peptide agonists of the oxytocin receptor, pharmaceutical compositions comprising said compounds and a pharmaceutically acceptable vehicle, and in particular to said compounds for the treatment of any known condition in which oxytocin has a beneficial effect, such as autism spectrum disorders, in particular social interaction impairments in autism spectrum disorders, and for the treatment of alcoholism. [Background technology]

[0002] Millions of people worldwide suffer from some form of psychiatric, neurological, or behavioral disorder. Many psychiatric disorders are characterized by a fundamental disruption of social behavior. Common examples include autism spectrum disorder (ASD) and social anxiety disorder (SAD). Furthermore, some disorders involve social withdrawal as a secondary symptom. Examples include depression, schizophrenia, major depressive disorder (MDD), and substance use disorders.

[0003] As described in the World Health Organization's International Classification of Diseases (ICD-11), ASD is characterized by persistent deficits in the ability to initiate and maintain reciprocal social interactions and social communication, as well as a restricted, repetitive, and inflexible pattern of behaviors, interests, or activities that are clearly inappropriate or excessive given the individual's age and sociocultural background. The disorder begins developmentally, typically in early childhood, but symptoms may not fully manifest until later, when social demands exceed the individual's limited capabilities. The deficits may be sufficiently severe to cause impairment in personal, family, social, educational, occupational, or other important areas of functioning, and are usually pervasive features of an individual's functioning that can be observed across settings, but may vary across social, educational, and other contexts. Individuals on this spectrum exhibit a wide range of intellectual functioning and language abilities.

[0004] It is estimated that approximately 1 in 100 children worldwide is diagnosed with an autism spectrum disorder, and the prevalence is increasing every year.

[0005] Currently, there are no approved medications that target the core symptoms of ASD, particularly disturbances in social interaction and communication, repetitive behaviors, and poor social interest. Currently prescribed medications for these disorders (typically selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), stimulants, and antipsychotics) target only a few associated symptoms (e.g., anxiety, depression) and, at best, have limited efficacy, poor compliance, and a wide range of side effects. This explains why these medications are practically ineffective in addressing the core symptoms of ASD.

[0006] Research has suggested the neuropeptide oxytocin (OT) as a promising target for treating these disorders. Animal studies have shown that OT positively regulates various social interactions, including maternal behavior, courtship, sexual behavior, and peer interactions. Studies in humans, typically administered intranasally, have shown that OT can increase trust and cooperation, improve social memory, and reduce social fear. Furthermore, recent clinical trials have shown that administering OT to humans with autism and social anxiety can partially restore social function. Therefore, the OT receptor offers potential for drug discovery aimed at alleviating serious psychiatric disorders.

[0007] OT also has beneficial effects on conditions, diseases, conditions and disorders such as pain, drug and / or alcohol addiction, depression, post-traumatic stress, anxiety, eating disorders, especially anorexia nervosa, bulimia and Prader-Willi syndrome, schizophrenia, neurodevelopmental disorders, impaired social interaction, borderline behavior, and ageing of the skin, muscles and bones.

[0008] However, OT is a large cyclic peptide (molecular weight over 1000 Da) that cannot undergo primary metabolism, has a short physiological half-life (blood half-life of approximately 3 minutes), and does not easily cross the blood-brain barrier, making it unsuitable for drug development, particularly for CNS disorders.

[0009] Furthermore, OT is not specific because it binds to the vasopressin 1a receptor (V1aR) in addition to the OT receptor, and in fact the OT receptor is highly homologous to the V1a receptor, meaning that selectivity can be extremely difficult to achieve.

[0010] Therefore, there is a strong demand for the development of novel compounds that overcome the above-mentioned drawbacks. Summary of the Invention [Problem to be solved by the invention]

[0011] It is therefore an object of the present invention to provide novel compounds that target the core symptoms of ASD.

[0012] Another object of the present invention is to provide pharmaceutical compositions and compounds for use in the treatment of autism, autism spectrum disorders, in particular social interaction disorders in autism spectrum disorders, pain, drug and / or alcohol addiction, depression, post-traumatic stress, anxiety, eating disorders, in particular anorexia nervosa, bulimia and Prader-Willi syndrome, schizophrenia, neurodevelopmental disorders, social interaction disorders, borderline behavior, ageing of the skin, muscles and bones, erectile dysfunction, and any disorder in which oxytocin may have a beneficial effect.

[0013] Another object of the present invention is to provide dermatological and / or cosmetic compositions and methods for reducing skin aging.

[0014] Another object of the present invention is to provide a method for promoting erection, lactation, parturition, lactation, and / or the postpartum period, comprising administering to a subject in need thereof a compound as defined above.

[0015] Another object of the present invention is to provide compounds with improved activity and / or selectivity for endogenous OT, particularly at the vasopressin V1a receptor, vasopressin V1b receptor and / or vasopressin V2 receptor.

[0016] Another object of the present invention is to provide compounds that are non-peptide small molecules. [Means for solving the problem]

[0017] Thus, in one aspect, the present invention relates to a compound of formula (I) below, or an enantiomer, diastereoisomer and / or pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X is selected from -H, halogen, -(C1-C6)-alkyl groups, -O-(C1-C6)-alkyl groups and -O-CF3, in particular -Me or -Cl, more in particular -Me, R is -N3, Aryl and heteroaryl groups, such as triazoles, optionally substituted with at least one R′ group, in particular A group of the formula: [ka] wherein R' is selected from the group including: -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, in particular cyclopropyl, -(C1-C6)-alkyl-W groups, especially -(CH2) k -W groups, which are optionally further substituted with at least -W' groups, where k ranges from 1 to 6, more particularly k is 1 or 2, and W and W' are OR a (where R ais -H or -(C1-C4)-alkyl, in particular H or Me, or a PEG group, in particular -(CH2-CH2-O) l -H, where l is a number ranging from 1 to 10, in particular from 2 to 4, e.g., 2; or W and W' are NR b H (where R b represents -H, a -(C1-C4)-alkyl group or -(C1-C4)-alkyl-Ar', where Ar' is an aryl or heteroaryl group, in particular furanyl, -(C1-C6)-alkyl-YZ groups, especially -(CH2) l -YZ, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl, Aryl or heteroaryl groups, in particular pyrazolyl (these groups are each independently selected from the group consisting of -(C1-C6)-alkyl and -NH2 groups). c optionally substituted by a group, -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2, in particular -C(=O)NH2 or -(CH2)2-S(=O)2NH2) or selected from the group comprising: R is -F, whose geminal hydrogen is replaced by -F, and R, together with the carbon atom C to which it is attached and its geminal hydrogen replaced by -F, forms a CF2 residue).

[0018] In another aspect, the present invention relates to a compound of formula (I) or an enantiomer, diastereoisomer and / or pharmaceutically acceptable salt or solvate thereof: [ka] (In the formula, X is selected from -H, halogen, -(C1-C6)-alkyl groups, -O-(C1-C6)-alkyl groups and -O-CF3, in particular -Me or -Cl, more in particular -Me, R is -N3, Aryl and heteroaryl groups, such as triazoles, optionally substituted with at least one R′ group, in particular A group of the formula: [ka] wherein R' is selected from the group including: -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, in particular cyclopropyl, -(C1-C6)-alkyl-W groups and cyclo-(C3-C6)-alkyl-W groups, in particular -(C1-C6)-alkyl-W groups, more in particular -(CH2) k a -W group, which is optionally further substituted with at least one -W' group, wherein k ranges from 1 to 6, more particularly k is 1 or 2, and W and W' are independently Halogens, especially -F, OR a or SR a , especially OR a (where R a teeth, -H, -(C1-C4)-alkyl, in particular Me; -(C1-C4)-alkyl-W" (wherein W" is halogen, in particular -F), such as -(CH2)2-F or -(CH2)3-F, or PEG groups, especially -(CH2-CH2-O) l PEG groups of the formula -H, where l is in the range of 1 to 10, in particular 2 to 4, for example 2; Halogenated PEG groups, especially -(CH2-CH2-O) la halogenated PEG group of the formula -(C1-C4)-alkyl-W" (wherein W" is halogen, in particular -F, and l ranges from 1 to 10, in particular from 2 to 4, e.g., if l=2, then the halogenated PEG group is, for example, -(CH2-CH2-O)2-(CH2)2-F, or, e.g., if l=1, then the halogenated PEG group is, for example, -(CH2-CH2-O)2-(CH2)2-F), NR b H (where R b teeth, -H, -(C1-C4)-alkyl group, or -(C1-C4)-alkyl-Ar', where Ar' represents an aryl or heteroaryl group, in particular furanyl, which is unsubstituted or substituted, in particular by one or more groups selected from -OH and -O-(C1-C4)-alkyl groups, for example -OMe, -(C1-C6)-alkyl-YZ groups, especially -(CH2) l -YZ, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl, An aryl or heteroaryl group, in particular a pyrazolyl group (said group being a group having at least one R selected from -(C1-C6)-alkyl, -NH2, halogen, e.g. -F, -OH and -O-(C1-C4)-alkyl groups, e.g. -OMe groups). c optionally substituted by a group, -(C0-C6)-Alkyl-C(=O)OR d group (where R d is H or -(C1-C6)-alkyl group, in particular H), -(C0-C6)-alkyl-C(=O)NR d R d 'Group(R d and R d' is independently H or a -(C1-C6)-alkyl group, in particular H), -(C0-C6)-alkyl-S(=O)2OR d Group(R d is H or a -(C1-C6)-alkyl group, in particular H), or -(C0-C6)-alkyl-S(=O)NR d R d 'Group(R d and R d ' is independently selected from the group comprising H, a -(C1-C6)-alkyl group, in particular H), or a -NH-C(=O)-C1-C6-alkyl group, in particular a -NH-C(=O)-Me group, more in particular a -COOH group, a -C(=O)NH2 group, a -S(=O)2OH group, a -S(=O)2NH2 group or a -(CH2)2-S(=O)2NH2 group), or R is -F, whose geminal hydrogen is replaced by -F, and R together with the carbon atom C to which it is bonded and the geminal hydrogen replaced by -F form a CF2 residue).

[0019] For the purposes of the present invention, the term "pharmaceutically acceptable" is intended to mean something that is useful in the preparation of pharmaceutical compositions and that is generally safe and non-toxic for pharmaceutical use.

[0020] The term "pharmaceutically acceptable salts or solvates" is intended, in the framework of the present invention, to mean salts or solvates of compounds which are pharmaceutically acceptable as defined above and which possess the pharmacological activity of the corresponding compounds.

[0021] Pharmaceutically acceptable salts include: (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid, and (2) Base addition salts formed when an acid proton present in a compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion, or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0022] Acceptable solvates for the therapeutic application of the compounds of the present invention include conventional solvates such as those formed in the final steps of the preparation of the compounds of the present invention in the presence of solvents. As examples, mention may be made of solvates in the presence of water (these solvates are also called hydrates) or solvates in the presence of ethanol.

[0023] It is recognized that the compounds of the present invention can exist in various stereoisomeric forms. As such, the compounds of the present invention include both diastereomers and enantiomers. The compounds are typically prepared as racemates and can be suitably used as such, although individual enantiomers can be isolated or synthesized by conventional techniques, if desired. Such racemates and individual enantiomers, as well as mixtures thereof, form part of the present invention.

[0024] Methods for preparing and isolating such optically active forms are known in the art. Specific stereoisomers can be prepared by stereospecific synthesis by using starting materials that are enantiomerically pure or enriched in one enantiomer over the other. Specific stereoisomers of either the starting material or the product can be resolved and recovered by techniques known in the art, such as resolution of racemic forms, normal-phase, reverse-phase, and chiral chromatography, recrystallization, enzymatic resolution, or fractional crystallization of addition salts formed with reagents used for that purpose. Useful methods for resolving and recovering specific stereoisomers are described in Eliel, EL; Wilen, SH, Stereochemistry of Organic Compounds; Wiley: New York, 1994, and Jacques, J, et al. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, each of which is incorporated herein by reference in its entirety.

[0025] In a particular embodiment, the present invention relates to compounds as defined above of formula (I): [ka] (In the formula, X is selected from -H, halogen, -(C1-C6)-alkyl groups, -O-(C1-C6)-alkyl groups and -O-CF3, in particular -Me or -Cl, more in particular -Me, R is -N3, A group of the formula: [ka] wherein R' is selected from the group including: -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, in particular cyclopropyl, -(C1-C6)-alkyl-W groups, especially -(CH2) k-W group, where k is in the range of 1 to 6, more particularly k is 1 or 2, and W is OR a (where R a is -H or -(C1-C4)-alkyl, in particular H or Me, or a PEG group, in particular -(CH2-CH2-O) l -H, where l is a number ranging from 1 to 10, in particular from 2 to 4, e.g., 2, or W is NR b H (where R b represents -H, a -(C1-C4)-alkyl group or -(C1-C4)-alkyl-Ar', where Ar' is an aryl or heteroaryl group, in particular furanyl, -(C1-C6)-alkyl-YZ groups, especially -(CH2) l -YZ, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl, heteroaryl groups, especially pyrazolyl; -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2, in particular -C(=O)NH2 or -(CH2)2-S(=O)2NH2).

[0026] In a particular embodiment, the present invention relates to compounds as defined above of formula (I): [ka] (In the formula, X is selected from -H, halogen, -(C1-C6)-alkyl groups, -O-(C1-C6)-alkyl groups and -O-CF3, in particular -Me or -Cl, more in particular -Me, R is -N3, is selected from the group comprising groups of the formula: [ka] wherein R' is selected from the group including: -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, in particular cyclopropyl, -(C1-C6)-alkyl-W groups and cyclo-(C3-C6)-alkyl-W groups, in particular -(C1-C6)-alkyl-W groups, more in particular -(CH2) k -W group, where k ranges from 1 to 6, more particularly k is 1 or 2, and W is OR a (where R a teeth, -H, -(C1-C4)-alkyl, in particular Me; -(C1-C4)-alkyl-W" (wherein W" is halogen, in particular -F), such as -(CH2)2-F or -(CH2)3-F, or PEG groups, especially -(CH2-CH2-O) l PEG groups of the formula -H, where l is in the range of 1 to 10, in particular 2 to 4, for example 2; Halogenated PEG groups, especially -(CH2-CH2-O) l a halogenated PEG group of the formula -(C1-C4)-alkyl-W" (wherein W" is halogen, in particular -F, and l ranges from 1 to 10, in particular from 2 to 4, for example, when l=2, the halogenated PEG group is, for example, -(CH2-CH2-O)2-(CH2)2-F, and for example, when l=2, the halogenated PEG group is, for example, -(CH2-CH2-O)2-(CH2)2-F), NR b H (where R b teeth, -H, -(C1-C4)-alkyl group, or -(C1-C4)-alkyl-Ar', where Ar' represents an aryl or heteroaryl group, in particular furanyl, which is unsubstituted or substituted, in particular by one or more groups selected from -OH and -O-(C1-C4)-alkyl groups, for example -OMe, -(C1-C6)-alkyl-YZ groups, especially -(CH2) l -YZ, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl, Heteroaryl groups, in particular pyrazolyl (said groups are each a group having at least one R selected from -(C1-C6)-alkyl, -NH2, halogen, e.g. -F, -OH and -O-(C1-C4)-alkyl groups, e.g. -OMe groups). c optionally substituted by a group, -(C0-C6)-Alkyl-C(=O)OR d group (where R d is H or -(C1-C6)-alkyl group, in particular H), -(C0-C6)-alkyl-C(=O)NR d R d 'Group(R d and R d ' is independently H or a -(C1-C6)-alkyl group, in particular H), -(C0-C6)-alkyl-S(=O)2OR d Group(R d is H or a -(C1-C6)-alkyl group, in particular H), or -(C0-C6)-alkyl-S(=O)NR d R d 'Group(R d and R d' are independently H, a -(C1-C6)-alkyl group, in particular H), or a -NH-C(=O)-C1-C6-alkyl group, in particular a -NH-C(=O)-Me group, more in particular a -COOH group, a -C(=O)NH2 group, a -S(=O)2OH group, a -S(=O)2NH2 group or a -(CH2)2-S(=O)2NH2 group).

[0027] In another particular embodiment, the present invention relates to compounds as defined above of formula (I): [ka] (In the formula, X is selected from -H, halogen, -(C1-C6)-alkyl groups, -O-(C1-C6)-alkyl groups and -O-CF3, in particular -Me or -Cl, more in particular -Me, R is selected from the group of the formula: [ka] wherein R' is selected from the group including: -(C1-C6)-Alkyl-OR a The group, especially -(CH2) k -OR a where k ranges from 1 to 6, more particularly k is 1 or 2, and R a represents -H or -(C1-C4)-alkyl, in particular H or Me), -(C1-C6)-alkyl-Z groups, especially -(CH2) l -Z, wherein l ranges from 1 to 6, more particularly l is 1 or 2, and Z is selected from saturated heterocyclic groups optionally substituted with at least one =O group, e.g., imidazolidine-2,4-dione, and heteroaryl groups, in particular tetrazolyl, A -(C0-C6)-alkyl-C(=O)NH2 group or a -(C0-C6)-alkyl-S(=O)2NH2 group, especially a -(C0-C6)-alkyl-S(=O)2NH2 group, in particular a -C(=O)NH2 group or a -(CH2)2-S(=O)2NH2 group, more in particular a -(CH2)-S(=O)2NH2 group).

[0028] In a particular embodiment, the present invention relates to a compound as defined above of one of the following formulae: [ka] where X and R are as defined above.

[0029] In a particular embodiment, the present invention relates to a compound as defined above of formula (III): [ka] (In the formula, X is selected from -H, halogen, -(C1-C6)-alkyl groups, -O-(C1-C6)-alkyl groups and -O-CF3, in particular -Me or -Cl, more in particular -Me, R' is selected from the group including: -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, in particular cyclopropyl, -(C1-C6)-alkyl-W groups, especially -(CH2) k -W, where k ranges from 1 to 6, k is more particularly 1 or 2, and W is OR a (where R a is -H or -(C1-C4)-alkyl, in particular H or Me, or a PEG group, in particular -(CH2-CH2-O) l -H, where l is a number ranging from 1 to 10, in particular 2 to 4, e.g., 2, or W is a PEG group of formula NR b H (where R b represents -H, a -(C1-C4)-alkyl group, or -(C1-C4)-alkyl-Ar', where Ar' is an aryl or heteroaryl group, in particular furanyl, -(C1-C6)-alkyl-YZ groups, especially -(CH2) l-YZ, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl, heteroaryl groups, especially pyrazolyl; a -(C0-C6)-alkyl-C(=O)NH2 group or a -(C0-C6)-alkyl-S(=O)2NH2 group, in particular a -C(=O)NH2 group or a -(CH2)2-S(=O)2NH2 group).

[0030] In certain embodiments, R' is selected from the group comprising: -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, in particular cyclopropyl, -(C1-C6)-alkyl-W groups, especially -(CH2) k -W, where k ranges from 1 to 6, k is more particularly 1 or 2, and W is OR a (where R a is -H or -(C1-C4)-alkyl, in particular H or Me, or a PEG group, in particular -(CH2-CH2-O) l -H, where l is a number ranging from 1 to 10, in particular 2 to 4, e.g., 2, or W is a PEG group of formula NR b H (where R b represents -H, a -(C1-C4)-alkyl group, or -(C1-C4)-alkyl-Ar', where Ar' is an aryl or heteroaryl group, in particular furanyl, -(C1-C6)-alkyl-YZ groups, especially -(CH2) l-YZ, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl, heteroaryl groups, especially pyrazolyl; a -(C0-C6)-alkyl-C(=O)NH2 group or a -(C0-C6)-alkyl-S(=O)2NH2 group, in particular a -C(=O)NH2 group or a -(CH2)2-S(=O)2NH2 group).

[0031] In more particular embodiments, R' is selected from the group comprising: -(C1-C6)-Alkyl-OR a The group, especially -(CH2) k -OR a where k ranges from 1 to 6, more particularly k is 1 or 2, and R a represents -H or -(C1-C4)-alkyl, in particular H or Me), -(C1-C6)-alkyl-Z groups, especially -(CH2) l -Z, wherein l ranges from 1 to 6, more particularly l is 1 or 2, and Z is selected from saturated heterocyclic groups optionally substituted with at least one =O group, e.g., imidazolidine-2,4-dione, and heteroaryl groups, in particular tetrazolyl, A -(C0-C6)-alkyl-C(=O)NH2 group or a -(C0-C6)-alkyl-S(=O)2NH2 group, especially a -(C0-C6)-alkyl-S(=O)2NH2 group, in particular a -C(=O)NH2 group or a -(CH2)2-S(=O)2NH2 group, more in particular a -(CH2)-S(=O)2NH2 group).

[0032] In a more particular embodiment, the present invention relates to a compound as defined above of one of the following formulae: [ka] where X and R' are as defined above.

[0033] In certain embodiments, X is Me.

[0034] In another particular embodiment, X is Cl.

[0035] In certain embodiments, the present invention provides a compound wherein R is -N3, [ka] The present invention relates to a compound as defined above selected from:

[0036] In certain embodiments, the present invention provides a compound wherein R is [ka] The present invention relates to a compound as defined above selected from:

[0037] In another aspect, the present invention also relates to a pharmaceutical composition comprising a compound as defined above in admixture with at least one pharmaceutically acceptable excipient.

[0038] All of the embodiments described above with respect to the compounds of the invention, alone or in any combination, also apply here.

[0039] The compounds or pharmaceutical compositions of the present invention can be administered in the form of conventional pharmaceutical compositions by any route, including oral, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intraventricular, and intraarticular injection, particularly oral, intravenous, or intranasal.

[0040] The dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician in determining the individual regimen and dosage level most appropriate for a particular patient.

[0041] For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

[0042] A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.

[0043] Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

[0044] Liquid compositions include solutions, suspensions, and emulsions.For example, sterile aqueous solutions or propylene glycol solutions of active compounds can be liquid preparations suitable for parenteral administration.Liquid compositions can also be prepared by dissolving in aqueous polyethylene glycol solutions.

[0045] Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners as desired. Oral aqueous solutions can be made by dispersing the finely divided active ingredient in water together with viscous substances such as natural synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents known in the pharmaceutical formulation art.

[0046] Compositions comprising microspheres based on polymers such as hyaluronic acid, dextran and / or starch can be used, for example, for intranasal administration.

[0047] Depending on the mode of administration, the pharmaceutical composition may contain from 0.05% to 99% by weight (weight percent) of the compound of the invention according to one embodiment of the invention, and from 0.10% to 50% by weight according to alternative embodiments, all weight percentages being based on the total composition. Therapeutically effective amounts in the practice of the invention can be determined using known criteria, including the age, weight, and response of the individual patient, and can be interpreted by those skilled in the art depending on the condition of the disease being treated or prevented.

[0048] In another aspect, the present invention also relates to a dermatological and / or cosmetic composition comprising a compound as defined above in admixture with at least one pharmaceutically acceptable excipient.

[0049] All of the embodiments described above with respect to the compounds of the invention, alone or in any combination, also apply here.

[0050] The dermatological and / or cosmetic compositions of the present invention may be administered by any route, including orally, topically, and especially topically, in the form of conventional dermatological and / or cosmetic compositions.

[0051] The dosage will depend on the route of administration, the severity of the disease, condition or disorder, the age and weight of the patient, and other factors normally considered by the attending physician or practitioner in determining the individual regimen and dosage level most appropriate for a particular patient.

[0052] For preparing dermatological and / or cosmetic compositions from the compounds of the present invention, the inert, pharmaceutically acceptable carriers can be either solid or liquid.

[0053] The dermatological and / or cosmetic composition can be in any suitable form commonly used in cosmetics, hi certain embodiments, the composition is selected from a solution, a suspension, a cream, a lotion, a paste, an emulsion, a gel, a foundation, a serum, and an ointment.

[0054] Depending on the mode of administration, the dermatological and / or cosmetic compositions comprise from 0.05% to 99% by weight (weight percent) of the compounds of the invention according to one embodiment of the invention, and from 0.10% to 50% by weight according to alternative embodiments, all weight percentages being based on the total composition.

[0055] In another aspect, the present invention also relates to a compound as defined above for the prevention and / or treatment of diseases, conditions or disorders which are related to the treatment of autism, autism spectrum disorders, in particular social interaction disorders in autism spectrum disorders, pain, drug and / or alcohol addiction, depression, post-traumatic stress, anxiety, eating disorders, in particular anorexia nervosa, bulimia and Prader-Willi syndrome, schizophrenia, neurodevelopmental disorders, social interaction disorders, borderline behavior, ageing of the skin, muscles and bones, erectile dysfunction, and any disease in which oxytocin is known to have a beneficial effect.

[0056] All of the embodiments described above with respect to the compounds of the invention, alone or in any combination, also apply here.

[0057] In a particular embodiment, the present invention relates to compounds as defined above for the prevention and / or treatment of diseases, conditions or disorders, such as autism, autism spectrum disorders, in particular those relating to the treatment of social interaction disorders in autism spectrum disorders.

[0058] In another aspect, the present invention also relates to the use of the compounds as defined above for alleviating or reducing pain. All of the embodiments described above for the compounds of the invention, alone or in any combination, also apply here.

[0059] In another aspect, the present invention also relates to the use of the compounds as defined above for reducing ageing of the skin, muscles and bones, in particular skin ageing.

[0060] All of the embodiments described above with respect to the compounds of the invention, alone or in any combination, also apply here.

[0061] In another aspect, the present invention also relates to the use of a compound as defined above for promoting erection, lactation, parturition, lactation, and / or the postpartum period.

[0062] All of the embodiments described above with respect to the compounds of the invention, alone or in any combination, also apply here.

[0063] In another aspect, the present invention also relates to the treatment of social interaction disorders in autism, autism spectrum disorders, in particular in autism spectrum disorders, pain, drug and / or alcohol addiction, depression, post-traumatic stress, anxiety, eating disorders, in particular anorexia nervosa, bulimia and Prader-Willi syndrome, schizophrenia, neurodevelopmental disorders, social interaction disorders, borderline behavior, ageing of the skin, muscles and bones, erectile dysfunction, and any disease in which oxytocin is known to have a beneficial effect, said method comprising administering to a subject in need thereof a compound as defined above.

[0064] In another aspect, the present invention also relates to a method for reducing skin, muscle, bone aging, in particular skin aging, or for promoting erection, lactation, parturition, lactation, and / or the postpartum period, said method comprising administering to a subject in need thereof a compound as defined above.

[0065] In another aspect, the present invention also relates to a composition comprising at least one compound as defined above and a diuretic, such as urea or a salt thereof, or a V2 receptor antagonist, in particular a vaptan, such as tolvaptan, lixivaptan or satavaptan, as a combination product for simultaneous, separate or broad therapeutic application in the prevention and / or treatment of diseases, conditions or disorders: autism, autism spectrum disorders, in particular social interaction disorders in autism spectrum disorders, pain, drug and / or alcoholism, depression, post-traumatic stress, anxiety, eating disorders, in particular anorexia nervosa, bulimia and Prader-Willi syndrome, schizophrenia, neurodevelopmental disorders, social interaction disorders, borderline behavior, ageing of the skin, muscles and bones, erectile dysfunction, and any disease in which oxytocin is known to have a beneficial effect. In another aspect, the present invention also relates to a composition comprising at least one compound as defined above and a diuretic, such as urea or a salt thereof, or a V2 receptor antagonist, in particular a vaptan, such as tolvaptan, lixivaptan or satavaptan, as a combination product for simultaneous, separate or broad therapeutic application for reducing skin, muscle or bone ageing, in particular skin ageing, or for promoting erection, lactation, childbirth, lactation and / or the postpartum period.

[0066] definition The following terms and expressions contained herein are defined as follows:

[0067] As used herein, a value range of the form "x to y ("xy" or "x to y" or "x through y")" includes the integers x, y, and any integers therebetween. For example, the phrase "1 to 6 ("1-6", or "1 to 6" or "1 through 6")" is intended to include the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments include each individual integer within the range, as well as any subcombination of integers. For example, preferred integers for "1 to 6" include 1, 2, 3, 4, 5, 6, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 2 to 6, etc.

[0068] The term "-(C1-C6) alkyl" as used herein refers to a linear or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0069] The term "aryl", sometimes abbreviated as "Ar", as used herein, particularly refers to an aromatic hydrocarbon group, preferably containing 6 to 10 carbon atoms and containing one or more, especially one or two, fused rings, such as a phenyl or naphthyl group. Advantageously, it is a phenyl group.

[0070] The term "-(C1-C4)-alkyl-aryl" as used in the present invention refers to an aryl group as defined above attached to the molecule via a (C1-C4) alkyl group as defined above.

[0071] The term "-(C3-C6)-cycloalkyl" as used herein refers to a saturated hydrocarbon monocyclic ring having members of 3 to 6 carbon atoms.

[0072] The term "saturated heterocyclic group" as used herein refers in particular to saturated hydrocarbon monocyclic or saturated hydrocarbon polycyclic rings (including fused, bridged or spirocyclic rings), such as bicyclic rings, in which one or more, preferably one to four, more preferably one or two carbon atoms are each replaced by a heteroatom selected from nitrogen, oxygen and sulfur atoms, in particular a nitrogen atom. Advantageously, the heterocyclic ring contains 5 to 15, in particular 5 to 10 atoms in the ring(s). The ring(s) of the heterocyclic ring preferably have 5 or 6 members.

[0073] According to a particular embodiment, the saturated heterocyclic group is in particular a saturated hydrocarbon monocycle or saturated hydrocarbon bicycle (including fused, bridged or spirocycles, especially fused rings), each ring having 5 or 6 members, in which 1 to 4, especially 1 or 2, carbon atoms are replaced by nitrogen or oxygen atoms, especially nitrogen atoms, respectively.

[0074] The term "heteroaryl" as used herein refers, in particular, to aromatic hydrocarbon monocyclic or bicyclic rings (i.e., including fused rings), each ring having 5 or 6 members, especially 6 members, in which 1 to 4, especially 1 or 2, carbon atoms are each replaced by a nitrogen or oxygen atom, especially a nitrogen atom.

[0075] Heteroaryl can be, among others, thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole (1,2,3-triazole and 1,2,4-triazole), benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, and the like.

[0076] The term "-(C1-C4) alkyl-heteroaryl" as used herein refers to an aryl group, as defined above, attached to the molecule via a (C1-C4) alkyl group, as defined above.

[0077] As used herein, the term "halogen" refers to a fluorine, bromine, chlorine or iodine atom. DETAILED DESCRIPTION OF THE INVENTION

[0078] synthesis The compounds of the present invention can be prepared by a number of methods known to those skilled in the art (including, but not limited to, those described below) or by modifying these methods by applying standard techniques known to those skilled in the art of organic synthesis. Suitable modifications and substitutions are readily apparent to those skilled in the art and are known or readily available in the scientific literature. In particular, such methods can be found in RC Larock, Comprehensive Organic Transformations, Wiley-VCH Publishers, 2018.

[0079] All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.

[0080] It will be understood that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms and may be isolated in optically active or racemic forms. Therefore, all chiral, diastereomeric, racemic, and isomeric forms of a structure are contemplated, unless a specific stereochemistry or isomeric form is specifically indicated. Methods for preparing and isolating such optically active forms are known in the art. For example, mixtures of stereoisomers can be separated by standard techniques, including, but not limited to, resolution of racemic forms, normal-phase chromatography, reverse-phase chromatography, and chiral chromatography, preferential salt formation, recrystallization, etc., or by either chiral synthesis from chiral starting materials or intentional synthesis of targeted chiral centers.

[0081] The compounds of the present invention can be prepared by a variety of synthetic routes. The reagents and starting materials are commercially available or readily synthesized by known techniques by one of ordinary skill in the art. All substituents are as defined above unless otherwise indicated.

[0082] In the reactions described below, if reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, are desired in the final product, it may be necessary to protect these groups to prevent their unwanted participation in the reaction. Conventional protecting groups can be used according to standard practice. See, for example, TW Greene and PGM Wuts in Protective Groups in Organic Chemistry, 3 rd ed., John Wiley and Sons, 1999; J. F. W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

[0083] The reagents and starting materials are commercially available or readily synthesized by known techniques by one of ordinary skill in the art.

[0084] In particular, the compounds defined above are obtained according to the following procedure: [ka] where X and R are as described above or are protected by special protecting groups. [Example]

[0085] Example 1: Synthesis of compounds of the present invention The compounds of the present invention were obtained as follows: [ka] where X and R are as described above or are protected by special protecting groups.

[0086] Process (i): Oxalyl chloride (4 equiv.) was added dropwise to a solution of compound A (2 equiv.) in anhydrous CHCl and a few drops of DMF. The mixture was stirred at 0°C for 15 minutes and at room temperature for 2 hours, concentrated under reduced pressure, and dried under vacuum for 1 hour. The residue was dissolved in CHCl and added dropwise to a solution of compound B (1 equiv.) and triethylamine (2 equiv.) in anhydrous CHCl at 0°C. The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. The crude product was dissolved in CHCl, and the organic phase was washed with saturated KHSO. The aqueous phase was extracted with a CHCl / PrOH (8 / 2 v / v) mixture. The combined organic phase was washed with saturated NaHCO, dried over NaSO, and evaporated under reduced pressure. Purification by silica gel chromatography (CHCl / MeOH, 95 / 5 v / v) gave product C.

[0087] Step (ii): To a solution of compound C (1 equiv.) in anhydrous methanol at 0°C, cobalt chloride hexahydrate (2 equiv.) and sodium borohydride (10 equiv.) were added portionwise over 10 min. The resulting black mixture was stirred at 0°C for 10 min and then at room temperature for 1 h. The mixture was neutralized to pH 7-8 with 1 M KHSO4 solution. Methanol was evaporated under reduced pressure. The residue was dissolved in 1 M KHSO4. The resulting precipitate was filtered and washed with diethyl ether. The aqueous phase was extracted with diethyl ether and then basified to pH > 10 with 10 M NaOH solution. The aqueous phase was extracted again with diethyl ether. The combined organic phase was dried over Na2SO4 and evaporated under reduced pressure to give compound D.

[0088] Step (iii): A solution of compound D (1 equivalent), carbonyldiimidazole (1.2 equivalents), and DIEA (1.5 equivalents) in DMF was stirred at room temperature for 3 hours. To this mixture was added a solution of compound E and DIEA (2.5 equivalents) in DMF. The reaction mixture was stirred at room temperature overnight and then evaporated under reduced pressure. The residue was purified by semi-preparative HPLC to give the desired product F.

[0089] The triazole R group can be obtained by click chemistry from compounds where R is -N3, as known to those skilled in the art.

[0090] Typically, the R' group of the final product is introduced by formation of an R'-substituted triazole R group.

[0091] The following analytical data was obtained:

[0092] [Table 1] TIFF2025537920000020.tif249170

[0093] Synthesis of 1-(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methanamine hydrochloride (LIT-003_Int2) [ka]

[0094] Step 1. Synthesis of ethyl 1-methyl-5-[(2-nitrophenyl)amino]-1H-pyrazole-4-carboxylate To a stirred solution of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (100.0 g, 591.42 mmol) in THF at 0° C., sodium hydroxide (32.64 g, 1.36 mol) was added portionwise, and the reaction mixture was warmed to room temperature and stirred at room temperature for 4 hours. After 4 hours, the mixture was cooled to 0° C., and a solution of 1-fluoro-2-nitrobenzene (83.4 g, 591.42 mmol) in THF was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. After 16 hours, the mixture was poured into water, extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, and evaporated to give the crude product. The crude product was purified by FC (ACN / CHCl3 system) to give ethyl 1-methyl-5-[(2-nitrophenyl)amino]-1H-pyrazole-4-carboxylate (115.0 g, purity 95.0%, 376.37 mmol, yield 63.6%).

[0095] Step 2. Synthesis of ethyl 5-[(2-aminophenyl)amino]-1-methyl-1H-pyrazole-4-carboxylate Ethyl 1-methyl-5-[(2-nitrophenyl)amino]-1H-pyrazole-4-carboxylate (115.0 g, 396.41 mmol) was dissolved in MeOH, and 10% palladium (10.5 g, 99.1 mmol) was added at room temperature. The reaction mixture was stirred under an H atmosphere for 16 hours. After 16 hours, the mixture was filtered through Celite, and the filtrate was evaporated to give ethyl 5-[(2-aminophenyl)amino]-1-methyl-1H-pyrazole-4-carboxylate (85.0 g, 96.0% purity, 313.49 mmol, 79.1% yield).

[0096] Step 3. Synthesis of 4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaen-8-one A solution of ethyl 5-[(2-aminophenyl)amino]-1-methyl-1H-pyrazole-4-carboxylate (85.0 g, 326.76 mmol) in acetic acid / 2-propanol (1:9, 2000 mL) was heated to reflux for 5 days. After 5 days, the reaction mixture was concentrated, and the residue was triturated with ACN. The resulting precipitate was filtered, washed with ACN, and dried under reduced pressure to give 4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaen-8-one (31.0 g, 144.71 mmol, 44.3% yield).

[0097] Step 4. Synthesis of 4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene To a stirred suspension of lithium(1+) ion aluminide (19.18 g, 504.48 mmol) in THF under an argon atmosphere at room temperature, 4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaen-8-one (27.0 g, 126.12 mmol) was added portionwise, and the resulting mixture was heated to reflux for 16 h. After 16 h, the mixture was cooled to room temperature, and additional lithium(1+) ion aluminide (19.18 g, 504.48 mmol) was added portionwise at room temperature, and the mixture was again heated to reflux for 32 h. After 32 h, the mixture was cooled to 0 °C, and 35% ammonia solution (50 mL) was added dropwise. The mixture was stirred at room temperature for 1 h, filtered through Celite, and the filtrate was evaporated to give the crude product. This was purified by FC (CHCl3 / MeOH system) to give 4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene (8.1 g, 40.45 mmol, 32.1% yield).

[0098] Step 5. Synthesis of tert-butyl N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]carbamate 4-Methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene (1.6 g, 8.0 mmol), 4-([(tert-butoxy)carbonyl]aminomethyl)-3-methylbenzoic acid (2.12 g, 8.0 mmol), 1-methyl-1H-imidazole (1.57 g, 19.19 mmol), and chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (2.69 g, 9.59 mmol) were mixed in DMF / AcN (1:1, 30 mL), and the reaction mixture was stirred at room temperature for 16 h. LCMS of the reaction mixture showed a purity of 88%. The resulting mixture was purified by FC (gradient CHCl3 / AcN) to give tert-butyl N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]carbamate (2.6 g, 95.0% purity, 5.52 mmol, 69% yield).

[0099] Step 6. Synthesis of 1-(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methanamine hydrochloride tert-Butyl N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]carbamate (2.6 g, 5.81 mmol) was dissolved in EA (50 ml), hydrogen chloride (2.09 g, 58.15 mmol, 14.54 ml, 10.0 equiv) was added, the reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated. AcN (50 ml) was then added to the resulting material, and the precipitate was filtered to give 1-(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methanamine hydrochloride (2.1 g, purity 95.0%, 5.2 mmol, yield 98.8%) (LIT-003_Int2). Yield: 18.0 mg, 25.7%, Appearance: White solid, HPLC purity: 100%, LCMS C 31 H 37 N 11 Calculated value for O3S: 644.31, Found value: 644.4 [M+H] + .

[0100] Synthesis of (2S,4R)-4-azido-2-(dimethylcarbamothioyl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) [ka]

[0101] Step 1. Synthesis of tert-butyl (2S,4R)-4-azido-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (2S,4R)-4-Azido-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1) (100.0 g, 390.45 mmol), (3-[(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (97.01 g, 507.58 mmol), 1H-1,2,3-benzotriazol-1-ol (68.55 g, 507.58 mmol), and ethylbis(propan-2-yl)amine (151.28 g, 1.17 mol) were mixed in DCM (2000 ml) and stirred at room temperature for 1 hour. After that, dimethylamine hydrochloride (41.13 g, 507.58 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (1000 ml), and the organic layer was washed with water (2 × 1000 ml) and brine (1000 ml), dried over NaSO, filtered, and evaporated to give a yellow oil (120 g, LCMS 65%). The resulting mixture was purified by FC (gradient MTBE / MeOH) to give tert-butyl (2S,4R)-4-azido-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (2) (67.0 g, 95.0% purity, 224.65 mmol, 57.5% yield).

[0102] Step 2. Synthesis of tert-butyl (2S,4R)-4-azido-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate tert-Butyl (2S,4R)-4-azido-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (3) (67.0 g, 236.61 mmol) and [(disulfanylidene-λ5-phosphanyl)sulfanyl]-λ5-phosphanedithione (41.99 g, 189.29 mmol) were mixed in dioxane (3300 ml) and heated to 110° C. for 1.2 h, then cooled to room temperature, filtered and the organic layer evaporated to give a brown oil (78 g, LCMS 63%). The resulting mixture was purified by FC (gradient MTBE / MeOH) to give tert-butyl (2S,4R)-4-azido-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate (3) (22.6 g, purity 95.0%, 71.71 mmol, yield 30.3%).

[0103] Step 3. Synthesis of (2S,4R)-4-azido-N,N-dimethylpyrrolidine-2-carbothioamide; trifluoroacetic acid tert-Butyl (2S,4R)-4-azido-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate (22.6 g, 75.55 mmol) and trifluoroacetic acid (3) (86.12 g, 755.48 mmol) were mixed in DCM (450 ml) and stirred at room temperature for 16 h. The reaction mixture was evaporated to give a brown oil (33.8 g, LCMS 86%). The resulting mixture was purified by FC (gradient MTBE / MeOH) to give (2S,4R)-4-azido-N,N-dimethylpyrrolidine-2-carbothioamide trifluoroacetic acid (4) (15.3 g, 95.0% purity, 46.39 mmol, 96.5% yield).

[0104] Step 4. Synthesis of (2S,4R)-4-azido-2-(dimethylcarbamothioyl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide 1-(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methanamine hydrochloride (5) (250.0 mg, 652.48 μmol), 1-(1H-imidazole-1-carbonyl)-1H-imidazole (211.66 mg, 1.31 μmol), (2S,4R)-4-azido-N,N-dimethylpyrrolidine-2-carbothioamide; trifluoroacetic acid (4) (286.25 mg, 914.29 μmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. LCMS of the reaction mixture showed the desired product content to be 74%. The resulting mixture was purified by HPLC (0-2-8 min, 13-20-40% HO / ACN 30 ml / min system (loading pump 4 ml ACN), target mass 572, column: XBRIDGE BEH C18 100 mm x 19 mm, 5 μM) to give (2S,4R)-4-azido-2-(dimethylcarbamothioyl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01). Yield: 214.0 mg, 54.4%, Appearance: Beige solid, HPLC purity: 100%, LCMS C 28 H 32 N 10 Calculated value of O2S: 573.27, Measured value: 573.0 [M+H] + .

[0105] Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-02 - Compound 23) [ka]

[0106] Step 1. Synthesis of prop-2-yn-1-yl 4-methylbenzene-1-sulfonate Prop-2-yn-1-ol (1) (1.0 g, 17.85 mmol) and 4-methylbenzene-1-sulfonyl chloride (6.78 g, 35.7 mmol) were mixed in EtO (40 mL) and cooled to 0 °C. Sodium hydroxide (3.57 g, 89.25 mmol) was added portionwise, and the reaction mixture was stirred at room temperature for 16 h. The resulting solution was concentrated, diluted with CHCl (100 mL), and washed with water (3 × 50 mL). The organic layer was dried and evaporated to give prop-2-yn-1-yl 4-methylbenzene-1-sulfonate (LIT-002-02_INT2) (3.5 g, 95.0% purity, 15.81 mmol, 88.6% yield).

[0107] Step 2. Synthesis of 3-fluoroprop-1-yne Prop-2-yn-1-yl 4-methylbenzene-1-sulfonate (LIT-002-02_INT2) (200 mg, 952.22 μmol) and tetrabutylammonium fluoride (348 mg, 1.33 mmol) were mixed in THF (4 mL), and the reaction mixture was stirred at 60 °C for 16 h. LCMS of the reaction mixture showed no content of starting material. The resulting solution contained 3-fluoroprop-1-yne (2) (500 mg, 10.0% purity, 861.26 μmol, 90.4% yield) and was used without further chemical separation.

[0108] Step 3. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (2S,4R)-4-Azido-2-(dimethylcarbamothioyl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) (150 mg, 261.6 μmol), 3-fluoropropanediol Pa-1-ine (2) (304 mg, 5.23 mmol), copper(2+) sulfate pentahydrate (26 mg, 104.64 μmol), and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (21 mg, 104.64 μmol) were mixed in t-BuOH / HO (1:2, 6 mL) and stirred at room temperature for 16 h. LCMS of the reaction mixture indicated a 76% content of the desired product. The resulting mixture was purified by HPLC (0-2-8 min 13-20-40% HO / ACN, 30 ml / min system (loading pump 4 ml ACN), target mass 630, column: XBridge BEH C18 100 mm × 19 mm, 5 μM) to give (2S,4R)-2-(dimethylcarbamothioyl)-4-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-02 - Compound 23). Yield: 42.0 mg, 24.2%, appearance: white solid, HPLC purity: 100%, LCMS C 31 H 35 FN10 Calculated value of O2S: 631.3, Measured value: 631.2 [M+H] + .

[0109] Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-4-[(3-fluoropropoxy)methyl]-1H-1,2,3-triazol-1-yl-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-03 - Compound 24) [ka]

[0110] Step 1. Synthesis of 3-(prop-2-yn-1-yloxy)propyl 4-methylbenzene-1-sulfonate 3-(Prop-2-yn-1-yloxy)propan-1-ol (1) (1.0 g, 8.77 mmol), N,N-dimethylpyridin-4-amine (54 mg, 438.27 μmol), and 4-methylbenzene-1-sulfonyl chloride (2.5 g, 13.15 mmol) were dissolved in DCM (20 mL). The reaction mixture was cooled to 0° C., and triethylamine (1.77 g, 17.53 mmol) was added dropwise and stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (40 mL), washed with water (2 × 50 mL), saturated NaHCO (2 × 50 mL), and the organic layer was evaporated to give a yellow oil (2.6 g, LCMS 71%). This material was purified by FC (gradient Hex / MTBE) to give 3-(prop-2-yn-1-yloxy)propyl 4-methylbenzene-1-sulfonate (LIT-002-03_INT2) (1.8 g, 95.0% purity, 6.37 mmol, 72.7% yield).

[0111] Step 2. Synthesis of 3-(3-fluoropropoxy)prop-1-yne 3-(Prop-2-yn-1-yloxy)propyl 4-methylbenzene-1-sulfonate (LIT-002-03_INT2) (500 mg, 1.87 mmol) and tetrabutylammonium fluoride (684 mg, 2.62 mmol) were mixed in THF (4 mL), and the reaction mixture was stirred at 60 °C for 16 h. LCMS of the reaction mixture showed no starting material, and NMR showed the desired compound. Evaporation of the reaction mixture gave 3-(3-fluoropropoxy)prop-1-yne (2) (1.3 g, 15.0% purity, 1.68 mmol, 89.9% yield), which was used without further chemical separation.

[0112] Step 3. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-4-[(3-fluoropropoxy)methyl]-1H-1,2,3-triazol-1-yl-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (2S,4R)-4-Azido-2-(dimethylcarbamothioyl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) (200 mg, 349.87 μmol), 3-(3-fluoropropionyl)-2- ... (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (28 mg, 139.95 μmol) were mixed in t-BuOH / HO (1:2, 6 mL) and stirred at room temperature for 16 hours. LCMS of the reaction mixture indicated a desired product content of 80.9%. The resulting mixture was purified by HPLC (0-2-8 min, 7-15-35% HO / ACN 30 mL / min system (loading pump 4 mL ACN), target mass 259). Column: Chromatorex C18 SMB100-5T Purification by HPLC (100 mm x 19 mm, 5 μM) gave (2S,4R)-2-(dimethylcarbamothioyl)-4-4-[(3-fluoropropoxy)methyl]-1H-1,2,3-triazol-1-yl-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (73.0 mg, 95.0% purity, 100.68 μmol, 28.8% yield) (LIT-002-03 - Compound 24). Yield: 73.0 mg, 28.8%, Appearance: Yellow solid, HPLC purity: 100%, LCMS C 34 H 41 FN 10 Calculated value for O3S: 689.35, Found value: 689.2 [M+H] + .

[0113] Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-methoxy-4-methylbenzene-1-sulfonamide (LIT-002-04 - Compound 25) [ka]

[0114] Step 1. Synthesis of 2-(prop-2-yn-1-yloxy)ethyl 4-methylbenzene-1-sulfonate 2-(Prop-2-yn-1-yloxy)ethan-1-ol (1) (1.0 g, 9.99 mmol), triethylamine (2.02 g, 19.99 mmol), and N,N-dimethylpyridin-4-amine (61.02 mg, 499.8 μmol) were dissolved in DCM (20 mL). The reaction mixture was cooled to 0° C., and 4-methylbenzene-1-sulfonyl chloride (2.85 g, 14.99 mmol) was added portionwise and stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (40 mL) and washed with water (2 × 50 mL), saturated NaHCO (2 × 50 mL), and brine (50 mL). The organic layer was evaporated to give a yellow oil (2.7 g, LCMS 68%). This material was purified by FC (gradient Hex / MTBE) to give 2-(prop-2-yn-1-yloxy)ethyl 4-methylbenzene-1-sulfonate (LIT-002-04_INT2) (1.5 g, 95.0% purity, 5.6 mmol, 56.1% yield) as a yellow oil.

[0115] Step 2. Synthesis of 3-(2-fluoroethoxy)prop-1-yne 2-(Prop-2-yn-1-yloxy)ethyl 4-methylbenzene-1-sulfonate (LIT-002-04_INT2) (500.0 mg, 1.97 mmol) and tetrabutylammonium fluoride (1.03 g, 3.94 mmol) were mixed in THF (4 mL), and the reaction mixture was stirred at 60 °C for 16 h. LCMS of the reaction mixture showed no starting material, and NMR showed the desired compound. Evaporation of the reaction mixture gave 3-(2-fluoroethoxy)prop-1-yne (2) (1.8 g, 10.0% purity, 1.76 mmol, 89.6% yield), which was used without further chemical separation.

[0116] Step 3. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-4-[(2-fluoroethoxy)methyl]-1H-1,2,3-triazol-1-yl-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (2S,4R)-4-Azido-2-(dimethylcarbamothioyl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) (150.1 mg, 262.3 μmol), 3-(2-fluoroethoxy)propanol Pa-1-ine (2) (535.35 mg, 5.25 mmol), copper(2+) sulfate pentahydrate (26.12 mg, 104.92 μmol), and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (20.78 mg, 104.92 μmol) were mixed in t-BuOH / HO (1:2, 6 mL) and stirred at room temperature for 16 h. LCMS of the reaction mixture indicated a 72% content of the desired product. The resulting mixture was purified by HPLC (0-2-8 min, 13-20-40% HO / ACN 30 ml / min system (loading pump 4 ml ACN), target mass 674, column: CHROMATOREX C18 100 mm × 19 mm, 5 μM) to give (2S,4R)-2-(dimethylcarbamothioyl)-4-4-[(2-fluoroethoxy)methyl]-1H-1,2,3-triazol-1-yl-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-04 - Compound 25). Yield: 16.0 mg, 8.6%, appearance: white solid, HPLC purity: 97.94%, LCMS C 33 H 39 FN 10 Calculated value for O3S: 675.33, Found value: 675.0 [M+H] + .

[0117] Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-(4-[2-(2-fluoroethoxy)ethoxy]methyl-1H-1,2,3-triazol-1-yl)-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-05 - Compound 26) [ka]

[0118] Step 1. Synthesis of 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethan-1-ol (1) (1.0 g, 6.94 mmol), triethylamine (1.4 g, 13.88 mmol), and N,N-dimethylpyridin-4-amine (42 mg, 347.07 μmol) were dissolved in DCM (20 mL). The reaction mixture was cooled to 0° C., and 4-methylbenzene-1-sulfonyl chloride (1.98 g, 10.41 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (40 mL), washed with water (2 × 50 mL), saturated NaHCO (2 × 50 mL), and the organic layer was evaporated to give a yellow oil (2.2 g, LCMS 64%). This material was purified by FC (gradient Hex / MTBE) to give 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate (LIT-002-05_INT2) (600 mg, 95.0% purity, 1.91 mmol, 27.5% yield).

[0119] Step 2. Synthesis of 1-fluoro-2-[2-(prop-2-yn-1-yloxy)ethoxy]ethane 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate (LIT-002-05_INT2) (500 mg, 1.68 mmol) and tetrabutylammonium fluoride (613 mg, 2.35 mmol) were mixed in THF (4 mL), and the reaction mixture was stirred at 60 °C for 16 h. LCMS of the reaction mixture showed no starting material, and NMR showed the desired compound. Evaporation of the reaction mixture gave 1-fluoro-2-[2-(prop-2-yn-1-yloxy)ethoxy]ethane (2) (1.4 g, 15.0% purity, 1.44 mmol, 85.7% yield), which was used without further chemical separation.

[0120] Step 3. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-(4-[2-(2-fluoroethoxy)ethoxy]methyl-1H-1,2,3-triazol-1-yl)-N-[(2-methyl-4-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (2S,4R)-4-Azido-2-(dimethylcarbamothioyl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) (200 mg, 349.17 μmol), 1-fluoro-2-[2-(propionyl)-2-yl]pyrrolidine-1-carboxamide (LIT-002-01) (200 mg, 349.17 μmol), [(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (28 mg, 139.67 μmol) was mixed in t-BuOH / HO (1:2, 6 mL) and stirred at room temperature for 16 hours. LCMS of the reaction mixture indicated a desired product content of 81.2%. The resulting mixture was purified by HPLC (0-2-8 min 13-20-40% HO / ACN, 30 mL / min system (loading pump 4 mL ACN), target mass 718, column: Chromatorex PFP SMB100-5T 100 mm × 19 mm, 5 μM) to give (2S,4R)-2-(dimethylcarbamothioyl)-4-(4-[2-(2-fluoroethoxy)ethoxy]methyl-1H-1,2,3-triazol-1-yl)-N-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaene-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-05 - Compound 26). Yield: 83.0 mg, 31.4%, appearance: white solid, HPLC purity: 100%, LCMS C 35 H 43 FN 10 Calculated value for O4S: 719.36, Found value: 719.2 [M+H] + .

[0121] Example 2: Biological Assays In a CHO cell line expressing the oxytocin receptor, the activation constant (EC 50 The maximum stimulation (E , nM) was measured. These values ​​are the mean ± SEM of at least three independent experiments performed in triplicate. max ) are expressed as a percentage of the maximal stimulation of the endogenous agonist (n = 3). In the case of only weak stimulation, results are expressed as a percentage of the maximal stimulation of the endogenous agonist at [ligand] = 1 μM (n = 2). If the response is less than 10% at [ligand] = 1 μM, the result is considered not significant (ns) (n = 2).

[0122] [Table 2] TIFF2025537920000028.tif251170

[0123] Example 3: V1A / OT selectivity assay Comparisons were made of their efficacy as OT receptor agonists (measured as described in Example 2) or as V1A receptor antagonists (measured as calcium signal as follows).

[0124] [Table 3]

Claims

1. A compound of formula (I) below, or an enantiomer, diastereoisomer and / or pharmaceutically acceptable salt or solvate thereof: 【Chemistry 1】 (In the formula, X is -H, halogen, -(C １ ~C ６ )-alkyl group, —O—(C １ ~C ６ )-alkyl group and —O—CF ３ , in particular -Me or -Cl, more in particular -Me; R is -N ３ 、 Aryl and heteroaryl groups, such as triazoles, optionally substituted with at least one R′ group, in particular is selected from the group comprising groups of the formula: 【Chemistry 2】 wherein R' is selected from the group including: -(C １ ~C ６ )-alkyl or -cyclo-(C ３ ~C ６ )-alkyl, in particular cyclopropyl, -(C １ ~C ６ )-alkyl-W groups and cyclo-(C ３ ~C ６ )-alkyl-W groups, especially -(C １ ~C ６ )-alkyl-W groups, more particularly -(CH ２ ) ｋ a -W group, which is optionally further substituted with at least a -W' group, wherein k ranges from 1 to 6, more particularly k is 1 or 2, and W and W' are independently halogens, especially —F; OR ａ or SR ａ , especially OR ａ (where R ａ teeth, -H, -(C １ ~C ４ )-alkyl, in particular Me, -(C １ ~C ４ )-alkyl-W″ (where W″ is halogen, especially —F), such as —(CH ２ ) ２ -F or -(CH ２ ) ３ -F, or PEG groups, especially -(CH ２ -CH ２ -O) ｌ a PEG group of the formula -H, where l ranges from 1 to 10, particularly 2 to 4, e.g., 2; Halogenated PEG groups, especially -(CH ２ -CH ２ -O) ｌ -(C １ ~C ４ Halogenated PEG groups of the formula -(CH)-alkyl-W" (where W" is a halogen, especially -F, and l ranges from 1 to 10, especially 1 to 4, e.g., when l=2, the halogenated PEG group is e.g. ... ２ -CH ２ -O) ２ - (CH ２ ) ２ -F, or, for example, if l=1, the halogenated PEG group is, for example, -(CH ２ -CH ２ —O)—(CH ２ ) ２ -F) NR ｂ H (where R ｂ teeth, -H, -(C １ ~C ４ )-alkyl group, or -(C １ ~C ４ )-alkyl-Ar′, where Ar′ is an aryl or heteroaryl group, especially furanyl, which may be unsubstituted or may be substituted with, especially, —OH and —O—(C １ ~C ４ )-alkyl groups, for example, -OMe, -(C １ ~C ６ )-alkyl-Y-Z groups, especially -(CH ２ ) ｌ -Y-Z, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl; an aryl or heteroaryl group, particularly a pyrazolyl group (said group being -(C １ ~C ６ )-alkyl, -NH ２ , halogen, such as —F, —OH and —O—(C １ ~C ４ )-alkyl groups, for example, an -OMe group; ｃ optionally substituted by a group), -(C ０ ~C ６ )-alkyl-C(═O)OR ｄ group (where R ｄ is H or -(C １ ~C ６ )-alkyl group, particularly H), -(C ０ ~C ６ )-alkyl-C(═O)NR ｄ R ｄ 'Group (R ｄ and R ｄ ' are independently H or -(C １ ~C ６ )-alkyl group, particularly H), -(C ０ ~C ６ )-Alkyl-S(=O) ２ OR ｄ Group (R ｄ is H or -(C １ ~C ６ )-alkyl group, especially H), or -(C ０ ~C ６ )-Alkyl-S(=O) ２ NR ｄ R ｄ 'Group (R ｄ and R ｄ ' are independently H, -(C １ ~C ６ )-alkyl group, especially H), or —NH—C(═O)—C １ ~C ６ - an alkyl group, in particular an -NH-C(=O)-Me group, more in particular a -COOH group, -C(=O)NH ２ Group, -S (=O) ２ OH group, -S (=O) ２ NH ２ group or -(CH ２ ) ２ -S(=O) ２ NH ２ basis)).

2. The compound according to claim 1 of the following formula (I): 【Transformation 3】 (In the formula, X is -Me or -Cl, especially -Me; R is -N ３ 、 is selected from the group comprising groups of the formula: 【Chemistry 4】 wherein R' is selected from the group including: -(C １ ~C ６ )-alkyl or -cyclo-(C ３ ~C ６ )-alkyl, in particular cyclopropyl, -(C １ ~C ６ )-alkyl-W groups and cyclo-(C ３ ~C ６ )-alkyl-W groups, especially -(C １ ~C ６ )-alkyl-W groups, more particularly -(CH ２ ) ｋ -W group, where k ranges from 1 to 6, more particularly k is 1 or 2, and W is halogens, especially —F; OR ａ (where R ａ teeth, -H, -(C １ ~C ４ )-alkyl, in particular Me, -(C １ ~C ４ )-alkyl-W″ (where W″ is halogen, especially —F), such as —(CH ２ ) ２ -F or -(CH ２ ) ３ -F, or PEG groups, especially -(CH ２ -CH ２ -O) ｌ a PEG group of the formula -H, where l ranges from 1 to 10, particularly 2 to 4, e.g., 2; Halogenated PEG groups, especially -(CH ２ -CH ２ -O) ｌ -(C １ ~C ４ Halogenated PEG groups of the formula -(CH)-alkyl-W" (where W" is a halogen, especially -F, and l ranges from 1 to 10, especially 1 to 4, for example, if l=2, the halogenated PEG group may be, for example, -(CH)-alkyl-W" ２ -CH ２ -O) ２ - (CH ２ ) ２ -F, or, for example, if l=1, the halogenated PEG group is, for example, -(CH ２ -CH ２ —O)—(CH ２ ) ２ -F) NR ｂ H (where R ｂ teeth, -H, -(C １ ~C ４ )-alkyl group, or -(C １ ~C ４ )-alkyl-Ar′, where Ar′ is an aryl or heteroaryl group, especially furanyl, which may be unsubstituted or may be substituted with, especially, —OH and —O—(C １ ~C ４ )-alkyl groups, for example, -OMe, -(C １ ~C ６ )-alkyl-Y-Z groups, especially -(CH ２ ) ｌ -Y-Z, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl; Heteroaryl groups, especially pyrazolyl (the group is -(C １ ~C ６ )-alkyl, -NH ２ , halogen, such as —F, —OH and —O—(C １ ~C ４ )-alkyl groups, for example, an -OMe group; ｃ optionally substituted by a group), -(C ０ ~C ６ )-alkyl-C(═O)OR ｄ group (where R ｄ is H or -(C １ ~C ６ )-alkyl group, particularly H), -(C ０ ~C ６ )-alkyl-C(═O)NR ｄ R ｄ 'Group (R ｄ and R ｄ ' is H or -(C １ ~C ６ )-alkyl group, particularly H), -(C ０ ~C ６ )-Alkyl-S(=O) ２ OR ｄ Group (R ｄ is H or -(C １ ~C ６ )-alkyl group, especially H), or -(C ０ ~C ６ )-Alkyl-S(=O) ２ NR ｄ R ｄ 'Group (R ｄ and R ｄ ' is H or -(C １ ~C ６ ) -alkyl groups, especially H), more especially -COOH groups, -C(=O)NH ２ Group, -S (=O) ２ OH group, -S (=O) ２ NH ２ group or -(CH ２ ) ２ -S(=O) ２ NH ２ basis)).

3. The compound according to claim 1 of the following formula (I): 【Transformation 5】 (In the formula, X is -Me or -Cl, especially -Me; R is selected from the group of the formula: 【Transformation 6】 wherein R' is selected from the group including: -(C １ ~C ６ )-alkyl-OR ａ groups, particularly -(CH ２ ) ｋ -OR ａ where k ranges from 1 to 6, more particularly k is 1 or 2, and R ａ is -H or -(C １ ~C ４ )-alkyl, in particular H or Me), -(C １ ~C ６ )-alkyl-Z groups, especially -(CH ２ ) ｌ -Z, wherein l ranges from 1 to 6, more particularly l is 1 or 2, and Z is selected from saturated heterocyclic groups, optionally substituted with at least one =0 group, and heteroaryl groups, in particular tetrazolyl, for example imidazolidine-2,4-dione; -(C ０ ~C ６ )-Alkyl-C(=O)NH ２ group or -(C ０ ~C ６ )-Alkyl-S(=O) ２ NH ２ groups, especially -(C ０ ~C ６ )-Alkyl-S(=O) ２ NH ２ groups, especially -C(=O)NH ２ group or -(CH ２ ) ２ -S(=O) ２ NH ２ group, more particularly -(CH ２ ) -S(=O) ２ NH ２ basis)).

4. A compound according to claim 1 having one of the following formulas: 【Transformation 7】 wherein X and R are as defined in claim 1.

5. The compound according to claim 1 of the following formula (III): 【Transformation 8】 (In the formula, X is -Me or -Cl, especially -Me; R' is selected from the group including: -(C １ ~C ６ )-alkyl or -cyclo-(C ３ ~C ６ )-alkyl, in particular cyclopropyl, -(C １ ~C ６ )-alkyl-W groups, especially —(CH ２ ) ｋ -W, where k ranges from 1 to 6, k is more particularly 1 or 2, and W is OR ａ (where R ａ is -H or -(C １ ~C ４ )-alkyl, especially H or Me, or a PEG group, especially —(CH ２ -CH ２ -O) ｌ -H, where l is in the range of 1 to 10, in particular 2 to 4, e.g., 2, or W is NR ｂ H (where R ｂ is -H, -(C １ ~C ４ )-alkyl group, or -(C １ ~C ４ )-alkyl-Ar′, where Ar′ represents an aryl or heteroaryl group, in particular furanyl; -(C １ ~C ６ )-alkyl-Y-Z groups, especially -(CH ２ ) ｌ -Y-Z, wherein l ranges from 1 to 6, more particularly l is 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups, in particular morpholinyl, tetrahydropyranyl, imidazolidinyl (said saturated heterocyclic groups optionally substituted with at least one =O group, e.g. representing imidazolidine-2,4-dione), and heteroaryl groups, in particular tetrazolyl; heteroaryl groups, especially pyrazolyl; -(C ０ ~C ６ )-Alkyl-C(=O)NH ２ group or -(C ０ ~C ６ )-Alkyl-S(=O) ２ NH ２ groups, especially -C(=O)NH ２ group or -(CH ２ ) ２ -S(=O) ２ NH ２ basis).

6. Compounds according to claim 5 of one of the following formulae: 【Chemistry 9】 wherein X and R' are as defined in claim 1.

7. The compound of any one of claims 1 to 6, wherein X is Me.

8. The compound of any one of claims 1 to 6, wherein X is Cl.

9. R is, -N ３ 、 【Chemistry 10】 The compound according to any one of claims 1 to 8, selected from:

10. A pharmaceutical, dermatological or cosmetic composition comprising a compound according to any one of claims 1 to 9 in admixture with at least one pharmaceutically acceptable excipient.

11. 10. A compound according to any one of claims 1 to 9 for the prevention and / or treatment of diseases, conditions or disorders which are related to the treatment of autism, autism spectrum disorders, in particular social interaction disorders in autism spectrum disorders, pain, drug and / or alcohol addiction, depression, post-traumatic stress, anxiety, eating disorders, in particular anorexia nervosa, bulimia and Prader-Willi syndrome, schizophrenia, neurodevelopmental disorders, social interaction disorders, borderline behaviour, ageing of the skin, muscles, bones and any disease in which oxytocin is known to have a beneficial effect.

12. 10. A composition comprising at least one compound according to any one of claims 1 to 9 and a diuretic, such as urea or a salt thereof, or a V2 receptor antagonist, as a combination product for simultaneous, separate or broad therapeutic application in the prevention and / or treatment of diseases, conditions or disorders which are related to the treatment of social interaction disorders in autism, autism spectrum disorders, in particular autism spectrum disorders, pain, drug and / or alcohol addiction, depression, post-traumatic stress, anxiety, eating disorders, in particular anorexia nervosa, bulimia and Prader-Willi syndrome, schizophrenia, neurodevelopmental disorders, social interaction disorders, borderline behavior, ageing of the skin, muscles, bones, and any disease in which oxytocin is known to have a beneficial effect.

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