Non-peptidic agonists of oxytocin receptors

Abstract

The present invention relates to a non-peptidic agonist of the oxytocin receptor of formula (I), pharmaceutical compositions comprising such a compound and a pharmaceutically acceptable carrier, in particular said compound for use in the treatment of all known conditions in which oxytocin has a beneficial effect, such as autism spectrum disorders, such as autism spectrum disorders, and the like. In particular for treating social interaction impairment in autistic spectrum disorders. # imgabs0 #

Description

[0001] The present invention relates to a non-peptidergic agonist of the oxytocin receptor, a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable carrier, in particular the use of said compound for the treatment of all conditions for which oxytocin is known to have beneficial effects, such as autism spectrum disorder, in particular for the treatment of social interaction impairments in autism spectrum disorder; and alcohol addiction.

[0002] Millions of people worldwide suffer from some form of mental, neurological or behavioural disorder. Among them, many mental disorders are characterized by a fundamental disruption of social behaviour. Common examples include autism spectrum disorder (ASD) and social anxiety disorder (SAD). In addition, some diseases have social withdrawal as a secondary symptom; examples include depression, schizophrenia, major depressive disorder (MDD) and substance use disorder.

[0003] According to the World Health Organization's International Classification of Diseases ICD-11, ASD is characterized by persistent deficits in the ability to initiate and sustain reciprocal social interactions and social communication, as well as a range of restricted, repetitive and rigid patterns of behaviour, interests or activities that are clearly atypical or excessive for the individual's age and sociocultural background. This disorder usually begins in the developmental period (usually early childhood), but symptoms may not fully manifest until later, when social demands exceed limited capabilities. The deficits are severe enough to cause impairment in the individual, family, social, educational, vocational or other important areas of functioning, and are typically a universal feature of the individual's functioning observable in all settings, although they may vary depending on the social, educational or other context. Individuals on the spectrum exhibit a full range of intellectual functions and language abilities.

[0004] Approximately one per cent of children globally are diagnosed with autism spectrum disorder, and the prevalence is estimated to be increasing over time.

[0005] Currently, there are no drugs approved for the core symptoms of ASD, especially the disturbances in social interaction and communication, repetitive behaviors, and restricted social interests. The drug treatments currently prescribed for these disorders (usually selective serotonin reuptake inhibitors (SSRI), serotonin and noradrenaline reuptake inhibitors (SNRI), stimulants, and antipsychotics) only target some related symptoms (such as anxiety, depression, etc.), and at most have limited efficacy, poor compliance, and large side effects because they are indeed inefficient in addressing the core symptoms of ASD.

[0006] Research has shown that a promising target for treating these disorders is the neuropeptide oxytocin (OT). Animal studies have shown that OT has a positive regulatory effect on a variety of social interactions, including maternal behavior, courtship, sexual behavior, and peer interaction. The results of human studies (where OT is usually administered intranasally) show that OT can increase trust and cooperation, improve social memory, and reduce social fear. In addition, recent clinical trials have shown that administering OT to people with autism and social anxiety disorder can restore some aspects of social function. Therefore, OT receptors have potential for drug discovery aimed at alleviating severe mental disorders.

[0007] OT also has beneficial effects on pathologies, diseases, conditions, and disorders such as pain, drug and / or alcohol addiction, depression, post-traumatic stress, anxiety, eating disorders (especially anorexia nervosa, bulimia nervosa, and Prader-Willi syndrome), schizophrenia, neurodevelopmental disorders, social interaction disorders, borderline behavior, skin aging, muscle aging, and bone aging.

[0008] However, OT is not suitable for drug development, especially for CNS disorders, because OT is a large cyclic peptide (MW over 1000 Da), which cannot survive in primary metabolism, has a short physiological half-life (half-life in blood is about 3 minutes), and is not easily penetrable through the blood-brain barrier.

[0009] In addition, OT is not specific because it further binds to OT receptors and then to vasopressin (antidiuretic hormone, vasopressin) 1a receptors (V1aR). In fact, OT receptors have a high degree of homology with V1a receptors, which means that selectivity is likely to be challenging.

[0010] Therefore, there is an urgent need to develop new compounds that can overcome the above-mentioned drawbacks.

[0011] Therefore, an object of the present invention is 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 the treatment of autism, autism spectrum disorder, particularly for the treatment of social interaction impairment in autism spectrum disorder; pain; drug and / or alcohol addiction; depression; post-traumatic stress; anxiety; eating disorders, particularly anorexia nervosa, bulimia nervosa and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorders; social interaction disorders; paraphilic behavior; skin aging; muscle aging; bone aging and any disease for which oxytocin is known to have beneficial effects.

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

[0014] Another object of the present invention is to provide methods for promoting erection, lactation, childbirth, breastfeeding and / or the postpartum period, which methods comprise the step of administering to a subject in need thereof a compound as defined above.

[0015] Another object of the present invention is to provide compounds having improved activity against endogenous OT and / or improved selectivity for endogenous OT, said endogenous OT being particularly against vasopressin V1a, V1b and / or V2 receptors.

[0016] Another object of the present invention is to provide non-peptide small molecule compounds.

[0017] Thus, in one aspect, the present invention relates to compounds of formula (I):

[0018]

[0019] Wherein,

[0020] X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl and -O-CF3, particularly -Me or -Cl, more particularly -Me;

[0021] R is selected from the group consisting of:

[0022] --N3;

[0023] - aryl and heteroaryl optionally substituted with at least one R' group, such as triazole, and in particular,

[0024] - a group of the following formula:

[0025]

[0026] wherein R' is selected from the group consisting of:

[0027] ○ -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0028] ○ -(C1-C6)-alkyl-W group, especially -(CH2) k -W group, said group being optionally further substituted by at least one -W' group, where k ranges from 1 to 6, k is especially 1 or 2, and W and W' are OR a , where R a represents -H or -(C1-C4)-alkyl (especially H or Me) or a PEG group especially of the formula -(CH2-CH2-O) l -H (where l ranges from 1 to 10, especially 2 to 4, for example 2); or W and W' are NR b H, where R b represents -H, -(C1-C4)-alkyl or -(C1-C4)-alkyl-Ar', where Ar' is aryl or heteroaryl, especially furyl;

[0029] ○ -(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl especially tetrazolyl, said saturated heterocyclic groups especially morpholinyl, tetrahydropyranyl, imidazolidinyl, said saturated heterocyclic groups being optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione;

[0030] ○ aryl or heteroaryl, especially pyrazolyl, said group being optionally substituted by at least one R selected from the following c groups: -(C1-C6)-alkyl, and -NH2;

[0031] ○ -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group;

[0032] or R is -F and its geminal hydrogen is replaced by -F, and R together with the carbon atom C to which it is bonded and its geminal -F-substituted hydrogen forms a CF2 residue;

[0033] or its enantiomer, diastereoisomer and / or pharmaceutically acceptable salt or solvate.

[0034] On the other hand, the present invention relates to a compound of the following formula (I):

[0035]

[0036] wherein,

[0037] X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl and -O-CF3, especially -Me or -Cl, more especially -Me; R is selected from the groups including the following:

[0038] --N3;

[0039] -aryl and heteroaryl optionally substituted by at least one R' group, such as triazole, and in particular,

[0040] -a group of the following formula:

[0041]

[0042] wherein R' is selected from the groups including the following:

[0043] ○-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0044] ○-(C1-C6)-alkyl-W group and cyclo-(C3-C6)-alkyl-W group, especially

[0045] -(C1-C6)-alkyl-W group, more especially -(CH2) k -W group, the group is optionally further substituted by at least one -W' group, where k ranges from 1 to 6, k is more especially 1 or 2, and W and W' are independently:

[0046] ■halogen, especially -F,

[0047] ■OR a or SR a , especially OR a , wherein R a represents:

[0048] ●-H,

[0049] ●-(C1-C4)-alkyl, especially Me,

[0050] ●-(C1-C4)-alkyl-W", where W" is halogen, especially -F, such as -(CH2)2-F or -(CH2)3-F, or

[0051] ●PEG group, especially the following formula –(CH2-CH2-O) l-H, where l ranges from 1 to 10, particularly from 2 to 4, for example 2;

[0052] ● a halogenated PEG group, particularly a group represented by the following formula: -(CH2-CH2-O) l -(C1-C4)-alkyl-W”, where W” is a halogen, particularly -F, l ranges from 1 to 10, particularly from 2 to 4, for example l = 2, and the halogenated PEG group is for example -(CH2-CH2-O)2-(CH2)2-F, or for example l = 1, and the halogenated PEG group is for example -(CH2-CH2-O)-(CH2)2-F;

[0053] ■NR b H, where R b represents:

[0054] ● -H,

[0055] ● -(C1-C4)-alkyl, or

[0056] ● -(C1-C4)-alkyl-Ar’, where Ar’ is an aryl or heteroaryl group, particularly a furyl group, and the group is unsubstituted or substituted, particularly substituted by one or more groups selected from -OH and -O-(C1-C4)-alkyl such as -OMe;

[0057] ○ a -(C1-C6)-alkyl-Y-Z group, particularly -(CH2) l -Y-Z, where l ranges from 1 to 6, more particularly 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl groups, particularly a tetrazolyl group, and the saturated heterocyclic groups are particularly a morpholinyl group, a tetrahydropyranyl group, an imidazolidinyl group, and the saturated heterocyclic groups are optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione;

[0058] ○ an aryl or heteroaryl group, particularly a pyrazolyl group, and the group is optionally substituted by at least one R c group selected from: -(C1-C6)-alkyl, -NH2, a halogen such as -F, -OH, and -O-(C1-C4)-alkyl such as -OMe;

[0059] -(C0-C6)-alkyl-C(=O)OR d where R d is H or -(C1-C6)-alkyl, particularly H; -(C0-C6)-alkyl-C(=O)NR d R d ’, R d and R d’ is independently H or -(C1-C6)-alkyl, especially H; -(C0-C6)-alkyl-S(=O)2OR d , R d is H or -(C1-C6)-alkyl, especially H; or -(C0-C6)-alkyl-S(=O)2NR d R d ’ group, R d and R d ’ are independently H, -(C1-C6)-alkyl, especially H; or -NH-C(=O)-C1-C6-alkyl, especially -NH-C(=O)-Me group, more especially -COOH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2 or –(CH2)2-S(=O)2NH2 group; or R is -F and the geminal hydrogen thereto is substituted by -F, and R together with the carbon atom C to which it is bonded and the geminal hydrogen substituted by -F thereof forms a CF2 residue;

[0060] or its enantiomers, diastereomers and / or pharmaceutically acceptable salts or solvates.

[0061] For the purposes of the present invention, the term "pharmaceutically acceptable" is intended to mean useful for the preparation of pharmaceutical compositions and generally safe and non-toxic for pharmaceutical use.

[0062] Within the framework of the present invention, the term "pharmaceutically acceptable salt or solvate" means a salt or solvate of a pharmaceutically acceptable compound as defined above, which has the pharmacological activity of the corresponding compound.

[0063] Pharmaceutically acceptable salts include:

[0064] (1) acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or with organic acids (such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxy naphthoic 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, etc.), and

[0065] (2) base addition salts formed by replacing the acidic proton present in the compound with a metal ion (such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion), or by coordinating with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine and tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

[0066] Solvates acceptable for the therapeutic use of the compounds of the present invention include conventional solvates, such as those formed in the last step of the preparation of the compounds of the present invention due to the presence of a solvent. By way of example, mention may be made of solvates formed due to the presence of water (these solvates are also referred to as hydrates) or ethanol.

[0067] It should be recognized that the compounds of the present invention can exist in various stereoisomeric forms. Thus, the compounds of the present invention include both diastereomers and enantiomers. These compounds are generally prepared as racemates and can be used conveniently as such, but if desired, the individual enantiomers can be separated or synthesized by conventional techniques. Such racemates and individual enantiomers and their mixtures form part of the present invention.

[0068] How to prepare and separate such optically active forms is well known in the art. Specific stereoisomers can be prepared by stereoselective synthesis using enantiomerically pure or enantiomerically enriched starting materials. The specific stereoisomers of the starting materials or products can be resolved and recovered by techniques known in the art, such as resolution of the racemic form, normal-phase, reverse-phase, and chiral chromatography, recrystallization, enzymatic resolution, or fractional recrystallization of addition salts formed with reagents for this purpose. Useful methods for resolving and recovering specific stereoisomers are described in: Eliel, E.L.; Wilen, S.H. Stereochemistry of Organic Compounds; Wiley: New York, 1994, and Jacques, J et al. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, the entire contents of which are incorporated herein by reference.

[0069] In a specific embodiment, the present invention relates to a compound of formula (I) as defined above:

[0070]

[0071] wherein,

[0072] X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl, and -O-CF3, especially -Me or -Cl, more especially -Me; R is selected from the group consisting of:

[0073] --N3;

[0074] - a group of the following formula:

[0075]

[0076] wherein R’ is selected from the group consisting of:

[0077] ○ -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0078] ○ -(C1-C6)-alkyl-W group, especially -(CH2) k -W, where k ranges from 1 to 6, especially 1 or 2, and W is OR a , where R a represents -H or -(C1-C4)-alkyl (especially H or Me) or a PEG group, especially of the formula -(CH2-CH2-O) l -H (where l ranges from 1 to 10, especially 2 to 4, for example 2); or W is NR b H, where R b represents -H, -(C1-C4)-alkyl or -(C1-C4)-alkyl-Ar’, where Ar’ is aryl or heteroaryl, especially furyl;

[0079] ○ -(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl, especially tetrazolyl, and the saturated heterocyclic groups are especially morpholinyl, tetrahydropyranyl, imidazolidinyl, and the saturated heterocyclic groups are optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione;

[0080] ○ heteroaryl, especially pyrazolyl;

[0081] ○ -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group.

[0082] In a specific embodiment, the present invention relates to a compound of formula (I) as defined above:

[0083]

[0084] wherein,

[0085] X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl and -O-CF3, especially -Me or -Cl, more especially -Me; R is selected from the group consisting of:

[0086] --N3;

[0087] - a group of the following formula:

[0088]

[0089] wherein R' is selected from the group consisting of:

[0090] ○-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0091] ○-(C1-C6)-alkyl-W group and -cyclo-(C3-C6)-alkyl-W group, especially

[0092] -(C1-C6)-alkyl-W group, more especially -(CH2) k -W group, wherein k ranges from 1 to 6, k is more especially 1 or 2, and W is:

[0093] ■OR a , wherein R a represents:

[0094] ●-H,

[0095] ●-(C1-C4)-alkyl, especially Me,

[0096] ●-(C1-C4)-alkyl-W", wherein W" is halogen, especially -F, such as -(CH2)2-F or -(CH2)3-F, or

[0097] ●PEG group, especially the group of the formula –(CH2-CH2-O) l -H, wherein l ranges from 1 to 10, especially 2 to 4, for example 2;

[0098] ●halogenated PEG group, especially the group represented by the formula: -(CH2-CH2-O) l -(C1-C4)-alkyl-W", wherein W" is halogen, especially -F, l ranges from 1 to 10, especially 2 to 4, for example l = 2, the halogenated PEG group is for example -(CH2-CH2-O)2-(CH2)2-F; or for example l = 1, the halogenated PEG group is for example -(CH2-CH2-O)-(CH2)2-F;

[0099] ●NR b H, wherein R b represents:

[0100] ●-H,

[0101] ●-(C1-C4)-alkyl, or

[0102] ● -(C1-C4)-alkyl-Ar’, where Ar’ is aryl or heteroaryl, especially furyl, and the group is unsubstituted or substituted, especially substituted by one or more groups selected from -OH and -O-(C1-C4)-alkyl such as -OMe;

[0103] ○ -(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl especially tetrazolyl, and the saturated heterocyclic groups are especially morpholinyl, tetrahydropyranyl, imidazolidinyl, and the saturated heterocyclic groups are optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione;

[0104] ○ Heteroaryl, especially pyrazolyl, and the group is optionally substituted by at least one R c group selected from: -(C1-C6)-alkyl, -NH2, halogen such as -F, -OH, and -O-(C1-C4)-alkyl such as -OMe;

[0105] ○ -(C0-C6)-alkyl-C(=O)OR d where R d is H or -(C1-C6)-alkyl, especially H; -(C0-C6)-alkyl-C(=O)NR d R d ’, R d and R d ’ are independently H or -(C1-C6)-alkyl, especially H; -(C0-C6)-alkyl-S(=O)2OR d where R d is H or -(C1-C6)-alkyl, especially H; or -(C0-C6)-alkyl-S(=O)2NR d R d ’ group, R d and R d ’ are independently H, -(C1-C6)-alkyl, especially H; or -NH-C(=O)-C1-C6-alkyl, especially -NH-C(=O)-Me group, more especially -COOH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2 or –(CH2)2-S(=O)2NH2 group;

[0106] In another specific embodiment, the present invention relates to a compound of formula (I) as defined above:

[0107]

[0108] Wherein,

[0109] X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl and -O-CF3, especially -Me or -Cl, more especially -Me;

[0110] R is selected from groups of the following formula:

[0111]

[0112] Wherein R' is selected from groups including the following:

[0113] ○-(C1-C6)-alkyl-OR a group, especially -(CH2) k -OR a , where k ranges from 1 to 6, k is more especially 1 or 2, R a represents -H or -(C1-C4)-alkyl, especially H or Me;

[0114] ○-(C1-C6)-alkyl-Z group, especially -(CH2) l -Z, where l ranges from 1 to 6, more especially 1 or 2, Z is selected from saturated heterocyclic groups and heteroaryl, especially tetrazolyl, and the saturated heterocyclic group is optionally substituted by at least one =O group, for example, represents imidazolidine-2,4-dione;

[0115] ○-(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially -(C0-C6)-alkyl-S(=O)2NH2 group, especially -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group, more specifically –(CH2)-S(=O)2NH2 group.

[0116] In a specific embodiment, the present invention relates to a compound having one of the following formulas as defined above:

[0117]

[0118]

[0119] where X and R are as defined above.

[0120] In a specific embodiment, the present invention relates to a compound of the following formula (III) as defined above:

[0121]

[0122] Wherein,

[0123] X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl and -O-CF3, especially -Me or -Cl, more especially -Me; R' is selected from groups including the following:

[0124] ○ -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0125] ○ -(C1-C6)-alkyl-W group, especially -(CH2) k -W, where k ranges from 1 to 6, especially 1 or 2, and W is OR a , where R a represents -H or -(C1-C4)-alkyl (especially H or Me) or a PEG group especially of the formula -(CH2-CH2-O) l -H (where l ranges from 1 to 10, especially 2 to 4, for example 2); or W is NR b H, where R b represents -H, -(C1-C4)-alkyl or -(C1-C4)-alkyl-Ar', where Ar' is aryl or heteroaryl, especially furyl;

[0126] ○ -(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl especially tetrazolyl, said saturated heterocyclic groups especially morpholinyl, tetrahydropyranyl, imidazolidinyl, said saturated heterocyclic groups optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione;

[0127] ○ heteroaryl, especially pyrazolyl;

[0128] ○ -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group.

[0129] In a specific embodiment, R' is selected from groups including the following:

[0130] ○ -(C1-C6)-group or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0131] ○ -(C1-C6)-alkyl-W group, especially -(CH2) k -W, where k ranges from 1 to 6, especially 1 or 2, and W is OR a , where R arepresent -H or -(C1-C4)-alkyl (especially H or Me) or a PEG group especially of the formula -(CH2-CH2-O) l -H where l ranges from 1 to 10, especially 2 to 4, for example 2; or W is NR b H, where R b represents -H, -(C1-C4)-alkyl or -(C1-C4)-alkyl-Ar’, where Ar’ is aryl or heteroaryl, especially furyl;

[0132] ○-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl especially tetrazolyl, said saturated heterocyclic groups especially morpholinyl, tetrahydropyranyl, imidazolidinyl, said saturated heterocyclic groups optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione;

[0133] ○heteroaryl, especially pyrazolyl;

[0134] ○-(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group.

[0135] In a more specific embodiment, R’ is selected from the groups comprising:

[0136] ○-(C1-C6)-alkyl-OR a group, especially -(CH2) k -OR a where k ranges from 1 to 6, k is more especially 1 or 2, R a represents -H or -(C1-C4)-alkyl, especially H or Me;

[0137] ○-(C1-C6)-alkyl-Z group, especially -(CH2) l -Z where l ranges from 1 to 6, more especially 1 or 2, Z is selected from saturated heterocyclic groups and heteroaryl especially tetrazolyl, said saturated heterocyclic groups optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione;

[0138] An ○-(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially a -(C0-C6)-alkyl-S(=O)2NH2 group, especially a -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group, more specifically a –(CH2)-S(=O)2NH2 group.

[0139] In a more specific embodiment, the present invention relates to a compound having one of the following formulas, as defined above:

[0140]

[0141]

[0142] wherein X and R’ are as defined above.

[0143] In a specific embodiment, X is Me.

[0144] In another specific embodiment, X is Cl.

[0145] In a specific embodiment, the present invention relates to a compound as defined above, wherein R is selected from:

[0146] -N3,

[0147] In a specific embodiment, the present invention relates to a compound as defined above, wherein R is selected from:

[0148]

[0149] In another aspect, the present invention also relates to a pharmaceutical composition comprising a compound as defined above mixed with at least one pharmaceutically acceptable excipient.

[0150] All of the above embodiments related to the compounds of the present invention apply equally here, either individually or in any combination.

[0151] The compounds or pharmaceutical compositions of the present invention can be administered by any route in the form of conventional pharmaceutical compositions, which include oral, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intracerebroventricular, and joint injection, especially oral, intravenous, or intranasal administration.

[0152] The dose depends on the route of administration, the severity of the disease, the age and weight of the patient, and other factors that a treating physician typically considers when determining the individual treatment regimen and dose level most suitable for a particular patient.

[0153] For the preparation of pharmaceutical compositions from the compounds of the present invention, inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

[0154] The solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizing agents, lubricants, suspending agents, binders, or tablet disintegrating agents; the substance can also be an encapsulating material.

[0155] Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

[0156] Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile aqueous or propylene glycol solutions of the active compounds can be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in aqueous polyethylene glycol solutions.

[0157] Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding, as required, suitable colorants, flavoring agents, stabilizers, and thickening agents. Aqueous solutions for oral use can be prepared by dispersing the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents known in the pharmaceutical formulation art.

[0158] Compositions comprising microspheres based on polymers such as hyaluronic acid, dextran, and / or starch can be used, for example, for intranasal administration.

[0159] Depending on the mode of administration, according to one embodiment of the present invention, the pharmaceutical composition will comprise from 0.05% to 99% by weight (weight percentage) of the compound of the present invention, and according to an alternative embodiment, the pharmaceutical composition will comprise from 0.10 to 50% by weight of the compound of the present invention, all weight percentages being based on the total composition. Those skilled in the art can utilize known criteria, including the age, weight, and response of the individual patient, to determine a therapeutically effective amount for the practice of the present invention and interpret it in the context of the disease being treated or prevented.

[0160] In another aspect, the present invention also relates to a dermatological and / or cosmetic composition comprising the compound as defined above mixed with at least one pharmaceutically acceptable excipient.

[0161] All of the above embodiments related to the compounds of the present invention apply equally herein, either individually or in any combination.

[0162] The dermatological and / or cosmetic composition of the present invention can be administered by any route in the form of conventional dermatological and / or cosmetic compositions, which includes oral administration, topical administration, especially topical administration.

[0163] The dose depends on the route of administration, the severity of the disease, condition or disorder, the age and weight of the patient, and other factors that are normally considered by the attending physician or doctor when determining the individual treatment regimen and dose level most suitable for a particular patient.

[0164] For the preparation of dermatological and / or cosmetic compositions from the compounds of the present invention, an inert, pharmaceutically acceptable carrier can be solid or liquid.

[0165] The composition comprising dermatological and / or cosmetic can be in any suitable form commonly used in cosmetics. In a specific embodiment, the composition is selected from solutions, suspensions, creams, lotions, pastes, emulsions, gels, foundations, serums and ointments.

[0166] Depending on the mode of administration, according to one embodiment of the present invention, the dermatological and / or cosmetic composition will comprise from 0.05% to 99% by weight (weight percentage) of the compound of the present invention, according to an alternative embodiment, the pharmaceutical composition will comprise from 0.10 to 50% by weight of the compound of the present invention, all weight percentages being based on the total composition.

[0167] In another aspect, the present invention also relates to a compound as defined above for the prevention and / or treatment of a disease, condition or disorder which is autism; autism spectrum disorder, especially for the treatment of social interaction impairment in autism spectrum disorder; pain; drug and / or alcohol addiction; depression; post-traumatic stress; anxiety; eating disorders, especially anorexia, bulimia and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorders; social interaction disorders; borderline sexual behavior; skin aging; muscle aging; bone aging; erectile dysfunction and any disease in which oxytocin is known to have a beneficial effect.

[0168] All of the above embodiments related to the compounds of the present invention apply equally here, either individually or in any combination.

[0169] In a specific embodiment, the present invention relates to a compound as defined above for the prevention and / or treatment of a disease, condition or disorder which is autism, autism spectrum disorder, especially for the treatment of social interaction disorder in autism spectrum disorder.

[0170] In another aspect, the present invention also relates to the use of a compound as defined above for relieving or alleviating pain. All of the above embodiments related to the compounds of the present invention apply equally here, either individually or in any combination.

[0171] On the other hand, the present invention also relates to the use of the compounds as defined above for slowing down skin aging, muscle aging, and bone aging, particularly skin aging.

[0172] All of the above-described embodiments related to the compounds of the present invention are equally applicable herein, either alone or in any combination.

[0173] On the other hand, the present invention also relates to the use of the compounds as defined above for promoting erection, lactation, childbirth, breastfeeding, and / or the postpartum period.

[0174] All of the above-described embodiments related to the compounds of the present invention are equally applicable herein, either alone or in any combination.

[0175] On the other hand, the invention also relates to a method for preventing and / or treating a disease, disorder, or condition, which is autism; autism spectrum disorder, particularly for treating social interaction impairment in autism spectrum disorder; pain; drug and / or alcohol addiction; depression; post-traumatic stress; anxiety; eating disorders, particularly anorexia, bulimia, and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorders; social interaction disorders; paraphilic behavior; skin aging; muscle aging; bone aging; erectile dysfunction; and any disease for which oxytocin is known to have a beneficial effect. The method comprises administering to a subject in need thereof a compound as defined above.

[0176] On the other hand, the invention also relates to a method for slowing down skin aging, muscle aging, bone aging (particularly skin aging), or promoting erection, lactation, childbirth, breastfeeding, and / or the postpartum period, the method comprising administering to a subject in need thereof a compound as defined above.

[0177] In another aspect, the invention also relates to a composition comprising at least one compound as defined above and a diuretic, which diuretic is, for example, urea or a salt thereof, or a V2 receptor antagonist, in particular a vaptan, such as tolvaptan, lixivaptan or satavaptan, for use in the simultaneous, separate or sequential treatment in the prevention and / or treatment of a disease, disorder or condition which is autism; an autism spectrum disorder, in particular for treating the social interaction impairment in an autism spectrum disorder; pain; drug and / or alcohol addiction; depression; post-traumatic stress; anxiety; eating disorders, in particular anorexia, bulimia and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorders; social interaction disorders; borderline sexual behavior; skin aging; muscle aging; bone aging; erectile dysfunction and any disease in which oxytocin is known to have a beneficial effect. In another aspect, the 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, for use in simultaneous, separate or sequential treatment to reduce skin aging, muscle aging, bone aging (in particular of the skin), or to promote erection, lactation, childbirth, breast-feeding and / or the postpartum period.

[0178] Definitions

[0179] The following terms and expressions herein are defined as follows:

[0180] As used herein, a range of values in the form “x - y” or “x to y” or “from x to y” includes the integers x, y and the integers therebetween. For example, the phrase “1 - 6” or “1 to 6” or “from 1 to 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 sub-combination of the integers. For example, the preferred integers of “1 - 6” can include 1, 2, 3, 4, 5, 6, 1 - 2, 1 - 3, 1 - 4, 1 - 5, 2 - 3, 2 - 4, 2 - 5, 2 - 6, etc.

[0181] The term “-(C1 - C6)alkyl” as used in the present invention refers to a straight or branched chain saturated hydrocarbon chain containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl, etc.

[0182] The term “aryl” as used in the present invention may be abbreviated as “Ar” and specifically refers to an aromatic hydrocarbon group, preferably comprising 6 to 10 carbon atoms and including one or more (especially 1 or 2) fused rings, such as, for example, phenyl or naphthyl. Advantageously, it will be phenyl.

[0183] The term "-(C1-C4)-alkyl-aryl" as used in the present invention means an aryl as defined above attached to the molecule through an (C1-C4) alkyl as defined above.

[0184] The term "-(C3-C6)-cycloalkyl" as used in the present invention means a saturated hydrocarbon monocyclic ring having 3 to 6 carbon atoms.

[0185] The term "saturated heterocyclic group" as used in the present invention specifically refers to a saturated hydrocarbon monocyclic or polycyclic ring (including fused rings, bridged rings or spiro rings), such as a bicyclic ring, in which one or more carbon atoms, advantageously 1 to 4, more advantageously 1 or 2 carbon atoms are each replaced by a heteroatom selected from nitrogen, oxygen and sulfur atoms, especially nitrogen atoms. Advantageously, the heterocyclic ring contains 5 to 15, especially 5 to 10 atoms in the ring. The heterocyclic ring preferably has 5 or 6 members.

[0186] According to a specific embodiment, the saturated heterocyclic group is especially a saturated, hydrocarbon monocyclic or bicyclic ring (including fused rings, bridged rings or spiro rings, especially fused rings), each ring having 5 or 6 members and 1 to 4, especially 1 or 2 carbon atoms each replaced by a nitrogen or oxygen atom (especially a nitrogen atom).

[0187] The term "heteroaryl" as used in the present invention specifically refers to an aromatic hydrocarbon monocyclic or bicyclic ring (i.e., including fused rings), each ring having 5 or 6, especially 6 members, and 1 to 4, especially 1 or 2 carbon atoms each replaced by a nitrogen or oxygen atom (especially a nitrogen atom).

[0188] Heteroaryl can especially be 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, etc.

[0189] The term "-(C1-C4)-alkyl-heteroaryl" as used in the present invention means an aryl as defined above attached to the molecule through an (C1-C4) alkyl as defined above.

[0190] The term "halogen" as used in the present invention means a fluorine, bromine, chlorine or iodine atom.

[0191] Synthesis

[0192] The compounds of the present invention can be prepared by a variety 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. Appropriate modifications and substitutions will be obvious and well-known to those skilled in the art, or can be readily obtained from the scientific literature. Specifically, such methods can be found in R.C. Larock, Comprehensive Organic Transformations, Wiley-VCH Publishers, 2018.

[0193] All processes disclosed in connection with the present invention are contemplated to be practiced at any scale, including milligram, gram, multi-gram, kilogram, multi-kilogram or commercial industrial scale.

[0194] It should 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. Accordingly, unless a specific stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic, and isomeric forms of the structure are applicable. How to prepare and isolate such optically active forms is well-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, reverse-phase, and chiral chromatography, preferential salting out and recrystallization, etc., or by chiral synthesis from chiral starting materials or by intentional synthesis of the target chiral center.

[0195] The compounds of the present invention can be prepared by a variety of synthetic routes. Reagents and starting materials are commercially available or can be readily synthesized by those of ordinary skill in the art by well-known techniques. Unless otherwise specified, all substituents are as previously defined.

[0196] In the reactions described below, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups (which are required in the final product), to avoid their unnecessary participation in the reaction. Conventional protecting groups can be used according to standard practice, see for example T.W. Greene and P.G.M. 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.

[0197] The reagents and starting materials are commercially available or can be easily synthesized by those of ordinary skill in the art through well-known techniques.

[0198] Specifically, the compounds defined above are obtained according to the following procedure:

[0199]

[0200] wherein X and R are as described above or are protected by a hoc protecting group. Examples

[0201] Example 1: Synthesis of the inventive compound

[0202] The inventive compound has been obtained as follows:

[0203]

[0204] wherein X and R are as described above or are protected by a hoc protecting group.

[0205] Step (i):

[0206] Oxalyl chloride (4 equivalents) was added dropwise to a solution of compound A (2 equivalents) in anhydrous CH2Cl2 and a few drops of DMF. The mixture was stirred at 0 °C for 15 minutes, at room temperature for 2 hours, concentrated under reduced pressure and dried under vacuum for 1 hour. The residue was dissolved in CH2Cl2 and added dropwise at 0 °C to a solution of compound B (1 equivalent) and triethylamine (2 equivalents) in anhydrous CH2Cl2. The resulting mixture was stirred at 0 °C for 30 minutes and then overnight at room temperature. The crude product was dissolved in CH2Cl2 and the organic phase was washed with saturated KHSO4. The aqueous phase was extracted with a CHCl3 / PrOH 8 / 2 v / v mixture. The combined organic phases were washed with saturated NaHCO3, dried over Na2SO4 and evaporated under reduced pressure. The product C was obtained by purification by silica gel chromatography (CH2Cl2 / MeOH, 95 / 5 v / v).

[0207] Step (ii):

[0208] At 0 °C, cobalt(II) chloride hexahydrate (2 equivalents) and sodium borohydride (10 equivalents) were added portionwise to a solution of compound C (1 equivalent) in anhydrous methanol over 10 minutes. The resulting black mixture was stirred at 0 °C for 10 minutes and then at room temperature for 1 hour. 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 formed 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 phases were dried over Na2SO4 and evaporated under reduced pressure to give compound D.

[0209] Step (iii):

[0210] 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. A solution of compound E and DIEA (2.5 equivalents) in DMF was added to this mixture. The reaction mixture was stirred at room temperature overnight and then evaporated under reduced pressure. The residue was purified by semi - preparative HPLC to afford the desired product F.

[0211] The triazole of the R group can be obtained from the compound with R being - N3 by click chemistry, as is well - known to those skilled in the art.

[0212] Generally, the R' group of the final product is introduced by forming an R' - substituted triazole R group.

[0213] The following analytical data were obtained:

[0214]

[0215]

[0216]

[0217] Synthesis of 1 - (2 - methyl - 4 - (4 - methyl - 2,4,5,9 - tetraazatricyclo[8.4.0.0,3,7]tetradeca - 1(14),3(7),5,10,12 - pentaen - 9 - carbonylphenyl)methylamine hydrochloride (LIT - 003_Int2)

[0218]

[0219] Step 1. Synthesis of ethyl 1 - methyl - 5 - [(2 - nitrophenyl)amino]-1H - pyrazole - 4 - carboxylate

[0220] At 0 °C, sodium hydride (32.64 g, 1.36 mol) was added portionwise to a THF solution of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (100.0 g, 591.42 mmol). 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 THF solution of 1-fluoro-2-nitrobenzene (83.4 g, 591.42 mmol) 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, the organic layer was washed with brine, dried over Na2SO4 and evaporated to give the crude product. The crude product was purified by FC (system ACN / CHCl3) to give ethyl 1-methyl-5-[(2-nitrophenyl)amino]-1H-pyrazole-4-carboxylate (115.0 g, 95.0% purity, 376.37 mmol, 63.6% yield).

[0221] Step 2. Synthesis of ethyl 5-[(2-aminophenyl)amino]-1-methyl-1H-pyrazole-4-carboxylate

[0222] 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 in a H2 atmosphere for 16 hours. After 16 hours, the mixture was filtered through diatomaceous earth 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).

[0223] 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

[0224] 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 in 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).

[0225] 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

[0226] Under an argon atmosphere, 4-Methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-penten-8-one (27.0 g, 126.12 mmol) was added portionwise to a stirred suspension of lithium(1+) aluminate (19.18 g, 504.48 mmol) in THF at room temperature. The resulting mixture was heated to reflux for 16 h. After 16 h, the mixture was cooled to room temperature, and another portion of lithium(1+) aluminate (19.18 g, 504.48 mmol) was added portionwise at room temperature. 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 diatomaceous earth, and the filtrate was evaporated to give a crude product, which was purified by FC (system CHCl3 / MeOH) 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).

[0227] Step 5. Synthesis of 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-penten-9-carbonyl)phenyl]methylcarbamate

[0228] 4-Methyl-2,4,5,9-tetraazatricyclo[8.4.0.03,7]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 chlorotetramethylformamidinium 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 88% purity. 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[8.4.0.03,7]tetradeca-1(14),3(7),5,10,12-pentaen-9-yl)carbonylphenyl)methyl]carbamate (2.6 g, 95.0% purity, 5.52 mmol, 69% yield).

[0229] Step 6. Synthesis of 1-(2-methyl-4-(4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),5,10,12-pentaen-9-yl)carbonylphenyl)methanamine hydrochloride

[0230] tert-Butyl N-[(2-methyl-4-(4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),5,10,12-pentaen-9-yl)carbonylphenyl)methyl]carbamate (2.6 g, 5.81 mmol) was dissolved in EA (50 ml), and 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. Then AcN (50 ml) was added to the resulting material, and the precipitate was filtered to give 1-(2-methyl-4-(4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),5,10,12-pentaen-9-yl)carbonylphenyl)methanamine hydrochloride (2.1 g, 95.0% purity, 5.2 mmol, 98.8% yield), LIT-003_Int2. Yield: 18.0 mg, 25.7%; Appearance: white solid; HPLC purity: 100%; C 31 H 37 N 11 O3S Calculated LCMS: 644.31; Observed: 644.4 [M+H] + .

[0231] Synthesis of (2S,4R)-4-azido-2-(dimethylcarbamothioyl)-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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01)

[0232]

[0233] Step 1. Synthesis of tert-butyl (2S,4R)-4-azido-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate

[0234] (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 ethyldi(propan-2-yl)amine (151.28 g, 1.17 mol) were mixed in DCM (2000 ml), stirred at room temperature for 1 h, then dimethylamine hydrochloride (41.13 g, 507.58 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (1000 ml), and the organic layer was washed with water (2 x 1000 ml) and brine (1000 ml), dried over Na2SO4, filtered and evaporated to give a yellow oil (120 g, 65% LCMS). 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).

[0235] Step 2. Synthesis of tert-butyl (2S,4R)-4-azido-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate

[0236] (2S,4R)-tert-Butyl 4-azido-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (3) (67.0 g, 236.61 mmol) and [(disulfanylidene-lambda5-phosphanyl)sulfanyl]-lambda5-phosphanedithione (41.99 g, 189.29 mmol) were mixed in dioxane (3300 ml), heated at 110 °C for 1.2 h, then cooled to room temperature and filtered. The organic layer was evaporated to give a brown oil (78 g, 63% LCMS). The resulting mixture was purified by FC (gradient MTBE / MeOH) to give (2S,4R)-tert-Butyl 4-azido-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate (3) (22.6 g, 95.0% purity, 71.71 mmol, 30.3% yield).

[0237] Step 3. Synthesis of (2S,4R)-4-azido-N,N-dimethylpyrrolidine-2-thioamide; trifluoroacetic acid

[0238] (2S,4R)-tert-Butyl 4-azido-2-(dimethylthiocarbamoyl)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, 86% LCMS). The resulting mixture was purified by FC (gradient MTBE / MeOH) to give (2S,4R)-4-azido-N,N-dimethylpyrrolidine-2-thioamide; trifluoroacetic acid (4) (15.3 g, 95.0% purity, 46.39 mmol, 96.5% yield).

[0239] Step 4. Synthesis of (2S,4R)-4-azido-2-(dimethylthiocarbamoyl)-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-pentaen-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide

[0240] 1-(2-Methyl-4-(4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaen-9-carbonyl)phenyl)methanamine hydrochloride (5) (250.0 mg, 652.48 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (211.66 mg, 1.31 mmol), and ethyldi(propan-2-yl)amine (421.72 mg, 3.27 mmol) were mixed in DMF (20 ml) and stirred at room temperature for 2 h, then (2S,4R)-4-azido-N,N-dimethylpyrrolidine-2-thioamide; trifluoroacetic acid (4) (286.25 mg, 914.29 μmol) was added and the resulting mixture was stirred at room temperature for 16 h. LCMS of the reaction mixture showed the desired product to be 74% in content. The resulting mixture was purified by HPLC (system 0 - 2 - 8 min 13 - 20 - 40% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 572 column: XBRIDGE BEH C18 100*19 mm, 5 microM) to give (2S,4R)-4-azido-2-(dimethylcarbamothioyl)-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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide, LIT-002-01. Yield: 214.0 mg, 54.4%; Appearance: Beige solid; HPLC purity: 100%; C 28 H 32 N 10 O2S Calculated LCMS: 573.27; Observed: 573.0 [M+H] + 。

[0241] (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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-02 - Compound 23) Synthesis

[0242]

[0243] Step 1. Synthesis of prop-2-yn-1-yl 4-methylbenzene-1-sulfonate

[0244] Propargyl alcohol (1) (1.0 g, 17.85 mmol) and 4-methylbenzenesulfonyl chloride (6.78 g, 35.7 mmol) were mixed in Et2O (40 ml), cooled to 0 °C, and then sodium hydroxide (3.57 g, 89.25 mmol) was added in portions. The reaction mixture was stirred at room temperature for 16 h. The resulting solution was concentrated, diluted with CHCl3 (100 ml), and washed with water (3 x 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).

[0245] Step 2. Synthesis of 3-fluoroprop-1-yne

[0246] 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 did not show the presence of starting material. The resulting solution had 3-fluoroprop-1-yne (2) (500 mg, 10.0% purity, 861.26 μmol, 90.4% yield) and was used without further chemical separation.

[0247] 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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide

[0248] (2S,4R)-4-Azido-2-(dimethylcarbamothioyl)-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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) (150 mg, 261.6 μmol), 3-fluoroprop-1-yne (2) (304 mg, 5.23 mmol), copper(II) ion 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 tert-BuOH / H2O (1:2; 6 ml) and stirred at room temperature for 16 h. LCMS of the reaction mixture showed the desired product was 76%. The resulting mixture was purified by HPLC (system 0 - 2 - 8 min 13 - 20 - 40% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 630 column: XBridge BEH C18 100*19 mm, 5 microM) to give (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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide, LIT-002-02 - Compound 23. Yield: 42.0 mg, 24.2%; Appearance: white solid; HPLC purity: 100%; C 31 H 35 FN 10 Calculated LCMS for O2S: 631.3; Observed: 631.2 [M+H] + 。

[0249] (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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-03 - Compound 24) Synthesis

[0250]

[0251] Step 1. Synthesis of 3-(prop-2-yn-1-yloxy)propyl 4-methylbenzene-1-sulfonate

[0252] 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 the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (40 ml) and washed with water (2 x 50 ml), saturated NaHCO3 (2 x 50 ml). The organic layer was evaporated to give a yellow oil (2.6 g, 71% LCMS). The 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).

[0253] Step 2. Synthesis of 3-(3-fluoropropoxy)prop-1-yne

[0254] 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 did not show the presence of starting material, and NMR showed the desired compound. The reaction mixture was evaporated to give 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.

[0255] 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-pentaen-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide

[0256] (2S,4R)-4-azido-2-(dimethylcarbamothioyl)-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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) (200 mg, 349.87 μmol), 3-(3-fluoropropoxy)propyne (1) (812 mg, 7.0 mmol), copper(II) sulfate pentahydrate (35 mg, 139.95 μmol), and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (28 mg, 139.95 μmol) were mixed in tert-BuOH / H2O (1:2; 6 ml) and stirred at room temperature for 16 h. LCMS of the reaction mixture showed the desired product to be present at 80.9%. The resulting mixture was purified by HPLC (system 0 - 2 - 8 min 7 - 15 - 35% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 259 column: Chromatorex C18 SMB100 - 5T 100*19 mm, 5 microM) to give (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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (73.0 mg, 95.0% purity, 100.68 μmol yield, 28.8% recovery), LIT-002-03 - Compound 24. Yield: 73.0 mg, 28.8%; Appearance: yellow solid; HPLC purity: 100%; C 34 H 41 FN 10 O3S Calculated LCMS: 689.35; Observed: 689.2 [M + H] + 。

[0257] Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-methoxy-4-methylbenzenesulfonamide (LIT-002-04 - Compound 25)

[0258]

[0259] Step 1. Synthesis of 2-(prop-2-ynyloxy)ethyl 4-methylbenzenesulfonate

[0260] Dissolve 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) in DCM (20 ml). Cool the reaction mixture to 0 °C and add 4-methylbenzene-1-sulfonyl chloride (2.85 g, 14.99 mmol) portionwise and stir at room temperature for 16 h. Dilute the reaction mixture with DCM (40 ml) and wash with water (2 x 50 ml), saturated NaHCO3 solution (2 x 50 ml) and brine (50 ml). Evaporate the organic layer to give a yellow oil (2.7 g, 68% LCMS). Purify the material 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.

[0261] Step 2. Synthesis of 3-(2-fluoroethoxy)prop-1-yne

[0262] Mix 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) in THF (4 ml) and stir the reaction mixture at 60 °C for 16 h. LCMS of the reaction mixture did not show the presence of starting material and NMR showed the required compound. Evaporate the reaction mixture to give 3-(2-fluoroethoxy)prop-1-yne (2) (1.8 g, 10.0% purity, 1.76 mmol, 89.6% yield) which can be used without further chemical separation.

[0263] 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-pentaen-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide

[0264] (2S,4R)-4-Azido-2-(dimethylcarbamothioyl)-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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-01) (150.1 mg, 262.3 μmol), 3-(2-fluoroethoxy)propyne (2) (535.35 mg, 5.25 mmol), copper(II) 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 combined in tert-BuOH / H2O (1:2; 6 ml) and stirred at room temperature for 16 h. LCMS of the reaction mixture showed the desired product to be present at 72%. The resulting mixture was purified by HPLC (system 0-2-8 min 13-20-40% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 674 column: CHROMATOREX C18 100*19 mm, 5 microM) 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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide, LIT-002-04-compound 25. Yield: 16.0 mg, 8.6%; Appearance: white solid; HPLC purity: 100%; C 33 H 39 FN 10 O3S Calculated LCMS: 675.33; Observed: 675.0 [M+H] + 。

[0265] (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-pentaen-9-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-002-05-compound 26) Synthesis

[0266]

[0267] Step 1. Synthesis of 2-[2-(prop-2-yn-1-yloxy)ethoxy]ethyl 4-methylbenzene-1-sulfonate

[0268] Dissolve 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) in DCM (20 ml). Cool the reaction mixture to 0 °C, add 4-methylbenzene-1-sulfonyl chloride (1.98 g, 10.41 mmol) and stir at room temperature for 16 h. Dilute the reaction mixture with DCM (40 ml) and wash with water (2 x 50 ml) and saturated NaHCO3 solution (2 x 50 ml). Evaporate the organic layer to give a yellow oil (2.2 g, 64% LCMS). Purify the material 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).

[0269] Step 2. Synthesis of 1-fluoro-2-[2-(prop-2-yn-1-yloxy)ethoxy]ethane

[0270] Mix 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) in THF (4 ml) and stir the reaction mixture at 60 °C for 16 h. The LCMS of the reaction mixture did not show the presence of starting material and NMR showed the desired compound. Evaporate the reaction mixture to give 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 can be used without further chemical separation.

[0271] 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-pentaen-9-carbonylphenyl)methyl]pyrrolidine-1-carboxamide

[0272] (2S,4R)-4-azido-2-(dimethylcarbamothioyl)-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-002-01) (200 mg, 349.17 μmol), 1-fluoro-2-[2-(prop-2-yn-1-yloxy)ethoxy]ethane (2) (1.02 g, 6.98 mmol), copper(II) ion pentahydrate (35 mg, 139.67 μmol) and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (28 mg, 139.67 μmol) were mixed in tert-BuOH / H2O (1:2; 6 ml) and stirred at room temperature for 16 h. LCMS of the reaction mixture showed the desired product was 72%. The resulting mixture was purified by HPLC (system 0-2-8 min 13-20-40% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 630 column: Chromatorex PFP SMB100-5T 100*19 mm, 5 microM) to give (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. Yield: 83.0 mg, 31.4%; Appearance: white solid; HPLC purity: 100%; C 35 H 43 FN 10 O4S Calculated LCMS: 719.36; Observed: 719.2 [M+H] + 。

[0273] Example 2: Biological Assay

[0274] Activation constants (EC 50 , in nM) were measured in a CHO cell line expressing the oxytocin receptor by an IP-One IP1 accumulation assay. These values are the mean ± SEM of at least three independent experiments performed in triplicate. Maximal stimulation (E max)Expressed as percentage of maximal stimulation by endogenous agonist (n = 3). When there was only weak stimulation, the results were expressed as percentage of maximal stimulation by endogenous agonist at [ligand] = 1 μM (n = 2). When at [ligand] = 1 μM and response < 10%, the results were not significant (ns) (n = 2).

[0275]

[0276]

[0277]

[0278] Example 3: V1A / OT selectivity test

[0279] A comparison of the efficacy as an OT receptor agonist (measured as described in Example 2) or as a V1A receptor antagonist (measured as calcium signal, as shown below) has been performed.

[0280]

Claims

1. A compound of the following formula (I): wherein, X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl, and -O-CF3, especially -Me or -Cl, more especially -Me; R is selected from the group consisting of: --N3； - aryl and heteroaryl optionally substituted with at least one R' group, such as triazole, and especially, - a group of the following formula: wherein R' is selected from the group consisting of: ○ -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl; ○-(C1-C6)-alkyl-W group and cyclo-(C3-C6)-alkyl-W group, especially -(C1-C6)-alkyl-W group, more especially -(CH2) k -W group, said group being optionally further substituted by at least one -W' group, where k ranges from 1 to 6, k is more especially 1 or 2, and W and W' are independently: ■ halogen, especially -F, ■OR a or SR a ,especially OR a ,where R a represents: ●-H， ● -(C1-C4)-alkyl, especially Me, ● -(C1-C4)-alkyl-W", where W" is halogen, especially -F, such as -(CH2)2-F or -(CH2)3-F, or ● A PEG group, especially of the formula –(CH2-CH2-O) l -H, where l ranges from 1 to 10, especially from 2 to 4, for example 2; ● A halogenated PEG group, especially a group represented by the following formula: -(CH2-CH2-O) l -(C1-C4)-alkyl-W”, where W” is a halogen, especially -F, l ranges from 1 to 10, especially from 1 to 4, for example l = 2, and the halogenated PEG group is, for example, -(CH2-CH2-O)2-(CH2)2-F, or for example l = 1, and the halogenated PEG group is, for example, -(CH2-CH2-O)-(CH2)2-F; ■NR b H, where R b represents: ●-H， ● -(C1-C4)-alkyl, or ● -(C1-C4)-alkyl-Ar', where Ar' is aryl or heteroaryl, especially furyl, said group being unsubstituted or substituted, especially substituted with one or more groups selected from -OH and -O-(C1-C4)-alkyl such as -OMe; ○-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl, especially tetrazolyl, said saturated heterocyclic groups especially morpholinyl, tetrahydropyranyl, imidazolidinyl, said saturated heterocyclic groups optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione; ○ an aryl or heteroaryl group, especially a pyrazolyl group, said group optionally being substituted by at least one R selected from the group consisting of: -(C1-C6)-alkyl, -NH2, a halogen such as -F, -OH, and -O-(C1-C4)-alkyl such as -OMe; c groups: -(C1-C6)-alkyl, -NH2, a halogen such as -F, -OH, and -O-(C1-C4)-alkyl such as -OMe; ○-(C0-C6)-alkyl-C(=O)OR d , where R d is H or -(C1-C6)-alkyl, especially H; -(C0-C6)-alkyl-C(=O)NR d R d ’, R d and R d ’ are independently H or -(C1-C6)-alkyl, especially H; -(C0-C6)-alkyl-S(=O)2OR d , R d is H or -(C1-C6)-alkyl, especially H; or -(C0-C6)-alkyl-S(=O)2NR d R d ’ group, R d and R d ’ are independently H, -(C1-C6)-alkyl, especially H; or -NH-C(=O)-C1-C6-alkyl, especially -NH-C(=O)-Me group, more especially -COOH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2 or –(CH2)2-S(=O)2NH2 group; or its enantiomers, diastereomers and / or pharmaceutically acceptable salts or solvates.

2. The compound according to claim 1, having the following formula (I): wherein, X is -Me or -Cl, especially -Me; R is selected from the group consisting of: --N3； - a group of the following formula: wherein R' is selected from the group consisting of: ○ -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl; ○-(C1-C6)-alkyl-W group and cyclo-(C3-C6)-alkyl-W group, especially -(C1-C6)-alkyl-W group, more especially -(CH2) k -W group, where k ranges from 1 to 6, k is more especially 1 or 2, and W is: ■ halogen, especially -F, ■OR a , where R a represents: ●-H， ● -(C1-C4)-alkyl, especially Me, ● -(C1-C4)-alkyl-W", where W" is halogen, especially -F, such as -(CH2)2-F or -(CH2)3-F, or ● PEG groups, in particular of the formula –(CH2-CH2-O) l -H, where l ranges from 1 to 10, in particular from 2 to 4, for example 2; ● A halogenated PEG group, especially a group represented by the following formula: -(CH2-CH2-O) l -(C1-C4)-alkyl-W", where W" is a halogen, especially -F, l ranges from 1 to 10, especially from 1 to 4, for example l = 2, and the halogenated PEG group is for example -(CH2-CH2-O)2-(CH2)2-F, or for example l = 1, and the halogenated PEG group is for example -(CH2-CH2-O)-(CH2)2-F ■NR b H, where R b represents: ●-H， ● -(C1-C4)-alkyl, or ● -(C1-C4)-alkyl-Ar', where Ar' is aryl or heteroaryl, especially furyl, said group being unsubstituted or substituted, especially substituted with one or more groups selected from -OH and -O-(C1-C4)-alkyl such as -OMe; ○-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl, especially tetrazolyl, and the saturated heterocyclic groups are especially morpholinyl, tetrahydropyranyl, imidazolidinyl, and the saturated heterocyclic groups are optionally substituted by at least one =O group, for example, representing imidazolidine-2,4-dione; ○Heteroaryl, especially pyrazolyl, said group optionally being substituted by at least one R selected from the group consisting of:-(C1-C6)-alkyl, -NH2, halogen such as -F, -OH, and -O-(C1-C4)-alkyl such as -OMe; c Group substitution: -(C1-C6)-alkyl, -NH2, halogen such as -F, -OH, and -O-(C1-C4)-alkyl such as -OMe; ○-(C0-C6)-alkyl-C(=O)OR d , wherein R d is H or -(C1-C6)-alkyl, especially H; -(C0-C6)-alkyl-C(=O)NR d R d ’, R d and R d ’ are H or -(C1-C6)-alkyl, especially H; -(C0-C6)-alkyl-S(=O)2OR d , R d is H or -(C1-C6)-alkyl, especially H; or -(C0-C6)-alkyl-S(=O)2NR d R d ’ group, R d and R d ’ are H or -(C1-C6)-alkyl, especially H; more particularly -COOH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2 or –(CH2)2-S(=O)2NH2 group.

3. The compound according to claim 1, having the following formula (I): wherein, X is -Me or -Cl, especially -Me; R is selected from the group of the following formula: wherein R' is selected from the group consisting of: ○-(C1-C6)-alkyl-OR a group, especially -(CH2) k -OR a , where k ranges from 1 to 6, k is more particularly 1 or 2, R a represents -H or -(C1-C4)-alkyl, especially H or Me; ○-(C1-C6)-alkyl-Z group, especially -(CH2) l -Z, where l ranges from 1 to 6, more especially 1 or 2, and Z is selected from saturated heterocyclic groups and heteroaryl, especially tetrazolyl, and the saturated heterocyclic groups are optionally substituted by at least one =O group, for example representing imidazolidine-2,4-dione; ○ -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially -(C0-C6)-alkyl-S(=O)2NH2 group, especially -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group, more specifically –(CH2)-S(=O)2NH2 group.

4. The compound according to claim 1, having one of the following formulas: wherein X and R are as defined in claim 1.

5. The compound according to claim 1, having the following formula (III): wherein, X is -Me or -Cl, especially -Me; R’ is selected from the group consisting of: ○ -(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl; ○-(C1-C6)-alkyl-W group, especially -(CH2) k -W, where k ranges from 1 to 6, especially 1 or 2, and W is OR a , where R a represents -H or -(C1-C4)-alkyl, especially H or Me, or a PEG group, especially of the formula -(CH2-CH2-O) l -H, where l ranges from 1 to 10, especially 2 to 4, for example 2; or W is NR b H, where R b represents -H, -(C1-C4)-alkyl or -(C1-C4)-alkyl-Ar’, where Ar’ is aryl or heteroaryl, especially furyl; ○-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl, especially tetrazolyl, and the saturated heterocyclic groups are especially morpholinyl, tetrahydropyranyl, imidazolidinyl, and the saturated heterocyclic groups are optionally substituted by at least one =O group, for example, representing imidazolidine-2,4-dione; ○ heteroaryl, especially pyrazolyl; ○ -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 groups, especially -C(=O)NH2 or –(CH2)2-S(=O)2NH2 groups.

6. The compound according to claim 5, which has one of the following formulas: wherein X and R’ are as defined in claim 1.

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

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

9. A compound according to any one of claims 1 to 8, wherein R is selected from: -N3、 10. A pharmaceutical composition, dermatological composition or cosmetic composition, which comprises a compound according to any one of claims 1 to 9 mixed with at least one pharmaceutically acceptable excipient.

11. The compound according to any one of claims 1 to 9, which is used for preventing and / or treating a disease, disorder or condition, said disease, disorder or condition being autism; autism spectrum disorder, especially for treating social interaction impairment in autism spectrum disorder; pain; drug and / or alcohol addiction; depression; post-traumatic stress; anxiety; eating disorder, especially anorexia, bulimia and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorder; social interaction disorder; borderline sexual behavior; skin aging; muscle aging; bone aging and any disease in which oxytocin is known to have beneficial effects.

12. A composition, which comprises at least one compound according to any one of claims 1 to 9 and a diuretic, said diuretic being, for example, urea or its salt, or a V2 receptor antagonist, and the composition is used for simultaneous, separate or divided therapeutic use in preventing and / or treating a disease, disorder or condition, said disease, disorder or condition being autism; autism spectrum disorder, especially for treating social interaction impairment in autism spectrum disorder; pain; drug and / or alcohol addiction; depression; post-traumatic stress; anxiety; eating disorder, especially anorexia, bulimia and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorder; social interaction disorder; borderline sexual behavior; skin aging; muscle aging; bone aging and any disease in which oxytocin is known to have beneficial effects as a combined product.

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