Non-peptidic agonists of oxytocin receptors

Abstract

The present invention relates to a non-peptidic agonist of the oxytocin receptor of formula (I), a pharmaceutical composition comprising such a compound and a pharmaceutically acceptable carrier, and in particular said compound is used for 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 vehicle, and in particular the use of said compound for the treatment of all disorders in which oxytocin is known to have a beneficial effect, such as autism spectrum disorder, and in particular for the treatment of social interaction impairments and alcohol addiction in autism spectrum disorder.

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

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

[0004] Approximately 1 in 100 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 that target the core symptoms of ASD, particularly social interaction and communication disorders, repetitive behaviors, and restricted social interests. Currently, prescription medications used to treat these disorders (typically selective serotonin reuptake inhibitors (SSRI), serotonin and noradrenaline reuptake inhibitors (SNRI), stimulants, and antipsychotics) only target some of the related symptoms (anxiety, depression, etc.), and at best have limited efficacy, poor compliance, and significant side effects because they are truly inefficient at 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 behavior, sexual behavior, and reciprocal interactions. Results from human studies in which OT is typically administered intranasally have shown 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 the potential for drug discovery aimed at alleviating severe mental illnesses.

[0007] OT also has beneficial effects on pathologies, diseases, conditions, and disorders (e.g., 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, borderline sexual behavior, skin, muscle, and bone aging).

[0008] However, OT is not suitable for drug development, particularly for treating CNS disorders, because OT is a large cyclic peptide (with a molecular weight of over 1000 Da), which cannot survive in primary metabolism, has a short physiological half-life (a half-life in the blood of approximately 3 minutes), and is not easily able to penetrate the blood-brain barrier.

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

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

[0011] Therefore, the object of the present invention is to provide new 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, 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, muscle, bone aging; erectile dysfunction; and any disease in which oxytocin may have a beneficial effect.

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

[0014] Another object of the present invention is to provide a method for promoting erection, lactation, childbirth, breastfeeding and / or the postpartum period, which comprises 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 a compound that has improved activity against endogenous OT and / or improved selectivity for endogenous OT, especially vasopressin V1a, V1b and / or V2 receptors.

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

[0017] Therefore, in one aspect, the present invention relates to a compound of formula (I):

[0018]

[0019] Wherein,

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

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

[0022] --(C1-C6)-alkyl group, especially -Me;

[0023] --O-(C1-C4)-alkyl group, especially -OMe;

[0024] --S-(C1-C4)-alkyl group, especially -SMe;

[0025] --O-(C2-C4)-alkyl-OH group, especially -O-(CH2) i -OH, where i ranges from 2 to 4, and i is more particularly 2;

[0026] --O(-(C2-C4)-alkyl) n -OH group, especially -O(-CH2-CH2) n -OH, where n ranges from 2 to 4, and n is more particularly 2;

[0027] --O-(C2-C4)-alkyl-O-(C1-C4)-alkyl group, especially -O-(CH2) i -OMe, where i ranges from 2 to 4, and i is more particularly 2;

[0028] --O(-(C2-C4)-alkyl) m -(C1-C4)-alkyl group, especially -O(-CH2-CH2) m -OMe or -O(-CH2-CH2) m -OEt, where m ranges from 2 to 4, and m is more particularly 2;

[0029] --O-(C1-C4)-alkyl-Ar, especially -O-(CH2) j -Ar, where j ranges from 1 to 4, and j is more particularly 1, and Ar is an aryl group optionally substituted by at least one R” group, especially at least one -OH group, and the -O-(C1-C4)-alkyl-Ar group is for example of the following formula:

[0030]

[0031] R” is selected from the following group:

[0032] ο-OH;

[0033] ο-O-(C1-C6)-alkyl or -O-cyclo-(C3-C6)-alkyl, especially -O-cyclopropyl;

[0034] ο-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0035] ο-(C1-C6)-alkyl-W group, especially -(CH2) k -W group, which group is optionally further substituted by at least one -W’ group, where k ranges from 1 to 6, and k is more particularly 1 or 2, and W and W’ are 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 and W’ are NR b H, where R b represents -H, a -(C1-C4)-alkyl group or a -(C1-C4)-alkyl-Ar’, where Ar’ is an aryl or heteroaryl group, especially furyl;

[0036] an ο-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, l is more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl groups, the saturated heterocyclic groups especially morpholinyl, tetrahydropyranyl, imidazolidinyl, the saturated heterocyclic groups optionally being substituted by at least one =O group, representing for example imidazolidine-2,4-dione; the heteroaryl especially tetrazolyl;

[0037] an ο aryl or heteroaryl group, especially pyrazolyl, the aryl or heteroaryl group optionally being substituted by at least one R selected from -(C1-C6)-alkyl and -NH2 groups c groups;

[0038] an ο-(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, especially a -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group;

[0039] -halogen, especially -F;

[0040] --CF3;

[0041] 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 the geminal hydrogen replaced by its -F forms a CF2 residue;

[0042] or its enantiomers, diastereomers and / or pharmaceutically acceptable salts or solvates.

[0043] On the other hand, the present invention relates to compounds of the following formula (I):

[0044]

[0045] wherein,

[0046] X is selected from -H, halogen, -(C1-C6)-alkyl, -O-(C1-C6)-alkyl, -S-(C1-C6)-alkyl, and -O-CF3, -S-CF3, especially -Me or -Cl, more especially -Me;

[0047] R is selected from the group consisting of:

[0048] --(C1-C6)-alkyl group, especially -Me;

[0049] --(C1-C6)-alkyl-V group, especially -CH2-CH2--V, where V is halogen, especially -F;

[0050] --O-(C1-C4)-alkyl group, especially -OMe;

[0051] --S-(C1-C4)-alkyl group, especially -SMe;

[0052] --O-(C2-C4)-alkyl-OH and -S-(C2-C4)-alkyl-OH groups, especially -O-(CH2) i -OH, where i ranges from 2 to 4, and i is more especially 2, 3, or 4;

[0053] --O(-(C2-C4)-alkyl-O) n -H and -S(-(C2-C4)-alkyl-O) n -H group, especially -O(-CH2-CH2-O) n -H, where n ranges from 2 to 4, and n is more especially 2;

[0054] --O-(C2-C4)-alkyl-O-(C1-C4)-alkyl, -S-(C2-C4)-alkyl-O-(C1-C4)-alkyl, -O-(C2-C4)-alkyl-S-(C1-C4)-alkyl, and -S-(C2-C4)-alkyl-S-(C1-C4)-alkyl groups, especially -O-(CH2) i -OMe, where i ranges from 2 to 4, and i is more especially 2;

[0055] --O-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -S-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -O-(C2-C4)-alkyl-S-(C1-C4)-alkyl-W”, and -S-(C2-C4)-alkyl-S-(C1-C4)-alkyl-W” groups, where W” is halogen, especially -F, such as –O-CH2-CH2-O-(CH2)2-F;

[0056] --O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl and -S(-(C2-C4)-alkyl-O) m -(C1-C4)-, especially -O(-CH2-CH2-O) m -Me or -O(-CH2-CH2-O) m -Et, where m ranges from 2 to 4, and m is more especially 2;

[0057] --O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W”-S(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W” group, where W” is halogen, especially -F, for example –O(-CH2-CH2-O)2-(CH2)2-F;

[0058] --O-(C1-C6)-alkyl-V and -S-(C1-C6)-alkyl-V groups, especially -CH2-CH2-V;

[0059] V is a group selected from the group consisting of:

[0060] ο-C(=O)NR d R d ’, R d and R d ’ are independently H or -(C1-C6) alkyl group, especially H;

[0061] ο-S(=O)2NR d R d ’, R d and R d ’ are independently H or -(C1-C6)-alkyl group, especially H;

[0062] ο-C(=O)OR d , where R d is H or -(C1-C6)-alkyl group;

[0063] ο-S(=O)2OH;

[0064] ο halogen, especially -F;

[0065] ο-cyclo-(C3-C6)-alkyl group, which is optionally substituted by at least one group selected from -(C1-C6)-alkyl and =O groups;

[0066] ο-heterocyclo-(C3-C6)-alkyl group, which is optionally substituted by at least one group selected from -(C1-C6)-alkyl and =O groups, for example imidazolidine-2,4-dione group;

[0067] The O-(C1-C6)-alkyl-V group is, for example, of the following formula:

[0068]

[0069] -O-(C1-C4)-alkyl-Ar, in particular -O-(CH2) j -Ar, where j ranges from 1 to 4, j is in particular 1 or 2, and Ar is an aryl group such as phenyl, or a heteroaryl group such as indolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and the aryl or heteroaryl group is optionally substituted by at least one R” group, in particular at least one -OH group,

[0070] R” is selected from the group consisting of:

[0071] ο-OH;

[0072] ο-halogen, in particular -F;

[0073] ο-O-(C1-C6)-alkyl and -S-(C1-C6)-alkyl, in particular -OMe, or -O-cyclo-(C3-C6)-alkyl, in particular -O-cyclopropyl;

[0074] ο-O-(C2-C4)-alkyl-OH and -S-(C2-C4)-alkyl-OH groups, in particular -O-(CH2) i -OH, where i ranges from 2 to 4, i is more particularly 2, 3 or 4;

[0075] ο-O(-(C2-C4)-alkyl-O) n -H and -S(-(C2-C4)-alkyl-O) n -H group, in particular -O(-CH2-CH2-O) n -H, where n ranges from 2 to 4, n is more particularly 2;

[0076] ο-O-(C2-C4)-alkyl-O-(C1-C4)-alkyl, -S-(C2-C4)-alkyl-O-(C1-C4)-alkyl, -O-(C2-C4)-alkyl-S-(C1-C4)-alkyl and -S-(C2-C4)-alkyl-S-(C1-C4)-alkyl groups, in particular -O-(CH2) i -OMe, where i ranges from 2 to 4, i is more particularly 2;

[0077] ο-O-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -S-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -O-(C2-C4)-alkyl-S-(C1-C4)-alkyl-W” and -S-(C2-C4)-alkyl-S-(C1-C4)-alkyl-W” groups, where W” is a halogen, especially -F, for example –O-CH2-CH2-O-(CH2)2-F; -O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl groups, especially -O(-CH2-CH2-O) m -Me or -O(-CH2-CH2-O) m -Et, where m ranges from 2 to 4, m is especially 2;

[0078] ο-O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W” and -S(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W” groups, where W” is a halogen, especially -F, for example –O(-CH2-CH2-O)2-(CH2)2-F;

[0079] ο-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0080] ο-(C1-C6)-alkyl-W groups, especially -(CH2) k -W groups, which may optionally be 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 halogen, especially -F, OR a where R a represents -H or -(C1-C4)-alkyl especially H or Me, or is 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 groups or -(C1-C4)-alkyl-Ar’, where Ar’ is aryl or heteroaryl, especially furyl;

[0081] ο-(C1-C6)-alkyl-Y-Z groups, especially -(CH2) l-Y-Z, where l ranges from 1 to 6, l is more particularly 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl groups, the saturated heterocyclic groups being in particular morpholinyl, tetrahydropyranyl, imidazolidinyl, the saturated heterocyclic groups being optionally substituted by at least one =O group and representing for example imidazolidine-2,4-dione; the heteroaryl being in particular tetrazolyl;

[0082] ο aryl or heteroaryl group, in particular pyrazolyl or tetrazolyl, the aryl or heteroaryl group being optionally substituted by at least one R selected from -(C1-C6)-alkyl and -NH2 groups c group;

[0083] ο-(C0-C6)-alkyl-C(=O)OR d , where R d is H or -(C1-C6)-alkyl group, in particular H, -(C0-C6)-alkyl-C(=O)NR d R d ’, R d and R d ’ are independently H or -(C1-C6)-alkyl group, in particular H, -(C0-C6)-alkyl-S(=O)2OR d , R d is H or -(C1-C6)-alkyl group, in particular H, or -(C0-C6)-alkyl-S(=O)2NR d R d ’ group, R d and R d ’ are independently H, -(C1-C6)-alkyl group, in particular H, or -NH-C(=O)-C1-C6-alkyl group, in particular -NH-C(=O)-Me group, more particularly -COOH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2 or –(CH2)2-S(=O)2NH2 group;

[0084] ο-NHC(=O)-(C1-C6)-alkyl, in particular-NHC(=O)-Me;

[0085] The -O-(C1-C4)-alkyl-Ar group is for example one of the following formulas:

[0086]

[0087] -halogen, in particular -F;

[0088] --CF3;

[0089] Alternatively, R is -F and the hydrogen geminal thereto is substituted by -F, and R, the carbon atom C to which it is bonded, and the hydrogen geminal to it substituted by -F form a CF2 residue; or an enantiomer, diastereomer, and / or pharmaceutically acceptable salt or solvate thereof.

[0090] The group -F2 as used in the present invention means two -F atoms bonded to the same carbon atom C.

[0091] In certain embodiments, R is selected from the group consisting of -O-(C1-C4)-alkyl-Ar groups, particularly -O-(CH2) j -Ar, where j ranges from 1 to 4, j is more particularly 1, and Ar is an aryl group which is optionally substituted by at least one R'' group as defined above.

[0092] In a specific embodiment, the Ar group is substituted by an R'' group as defined above.

[0093] In another specific embodiment, the Ar group is substituted by two independently selected R'' groups as defined above.

[0094] In a specific embodiment, the Ar group is substituted by an -OH group and an R'' group as defined above.

[0095] In a more specific embodiment, the Ar group is selected from:

[0096] R'' is as defined above,

[0097] Two R'' groups are independently selected as described above, The R'' group is independently selected as described above,

[0098]

[0099] In certain embodiments, R is selected from:

[0100] Two R'' groups are independently selected as described above, The R'' group is independently selected as described above,

[0101]

[0102] For the purposes of the present invention, the term "pharmaceutically acceptable" is intended to mean a substance useful in the preparation of pharmaceutical compositions and which is generally safe and non-toxic for pharmaceutical use.

[0103] 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 and which has the pharmacological activity of the corresponding compound.

[0104] Pharmaceutically acceptable salts include:

[0105] (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, trifluoroacetic acid, etc.), and

[0106] (2) Base addition salts formed when the acidic proton present in the compound is replaced by a metal ion (such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or coordinated 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.

[0107] Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates, such as those formed during 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 called hydrates) or ethanol.

[0108] 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 diastereoisomers and enantiomers. These compounds are generally prepared as racemates and can be used conveniently as such, but the individual enantiomers can be separated or synthesized by conventional techniques if desired. Such racemates and individual enantiomers and their mixtures form part of the present invention.

[0109] How to prepare and isolate such optically active forms is well known in the art. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. 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.

[0110] In a specific embodiment, the present invention relates to a compound of formula (I) as defined above:

[0111]

[0112] wherein,

[0113] X is selected from -H, halogen, -(C1-C6)-alkyl group, -O-(C1-C6)-alkyl group, and -O-CF3, particularly -Me or -Cl, more particularly -Me;

[0114] R is selected from the group consisting of:

[0115] --O-(C1-C4)-alkyl group, particularly -OMe;

[0116] --O-(C2-C4)-alkyl-OH group, particularly -O-(CH2) i -OH, where i ranges from 2 to 4, and i is more particularly 2;

[0117] --O(-(C2-C4)-alkyl-O) n -H group, particularly -O(-CH2-CH2) n -OH, where n ranges from 2 to 4, and n is more particularly 2;

[0118] --O-(C2-C4)-alkyl-O-(C1-C4)-alkyl group, particularly -O-(CH2) i -OMe, where i ranges from 2 to 4, and i is more particularly 2;

[0119] --O(-(C2-C4)-alkyl-O)m -(C1-C4)-alkyl, especially -O(-CH2-CH2-O) m -Me or -O(-CH2-CH2-O) m -Et, where m ranges from 2 to 4, m is more especially 2;

[0120] --O-(C1-C4)-alkyl-Ar, especially -O-(CH2) j -Ar, where j ranges from 1 to 4, j is more especially 1, and Ar is an aryl group optionally substituted by at least one R” group, especially at least one -OH group, and the -O-(C1-C4)-alkyl-Ar group is for example of the following formula:

[0121]

[0122] R” is selected from the following group:

[0123] ο-OH;

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

[0125] ο-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0126] ο-(C1-C6)-alkyl-W group, especially -(CH2) k -W group, which 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 OR a where R a represents -H or -(C1-C4)-alkyl especially H or Me, or a PEG group especially of the following 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 an aryl or heteroaryl group, especially furyl;

[0127] ο-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l-Y-Z, where l ranges from 1 to 6, l is more particularly 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl groups, the saturated heterocyclic groups being in particular morpholinyl, tetrahydropyranyl, imidazolidinyl, the saturated heterocyclic groups being optionally substituted by at least one =O group and representing for example imidazolidine-2,4-dione; the heteroaryl being in particular tetrazolyl;

[0128] an aryl or heteroaryl group, in particular pyrazolyl, the aryl or heteroaryl group being optionally substituted by at least one R selected from -(C1-C6)-alkyl and -NH2 groups c groups;

[0129] a -(C0-C6)-alkyl-C(=O)NH2 or -(C0-C6)-alkyl-S(=O)2NH2 group, in particular a -C(=O)NH2 or –(CH2)2-S(=O)2NH2 group;

[0130] -halogen, in particular -F.

[0131] In a specific embodiment, the present invention relates to a compound of formula (I) as defined above:

[0132]

[0133] wherein,

[0134] X is selected from -H, halogen, -(C1-C6)-alkyl groups, -O-(C1-C6)-alkyl groups and -O-CF3, in particular -Me or -Cl, more particularly -Me;

[0135] R is selected from the group consisting of:

[0136] --O-(C1-C4)-alkyl groups, in particular -OMe;

[0137] --O-(C2-C4)-alkyl-OH groups, in particular -O-(CH2) i -OH, where i ranges from 2 to 4, i being more particularly 2;

[0138] --O-(C2-C4)-alkyl-O-(C1-C4)-alkyl groups, in particular -O-(CH2) i -OMe, where i ranges from 2 to 4, i being more particularly 2;

[0139] --O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl, in particular -O(-CH2-CH2-O) m -Me or -O(-CH2-CH2-O)m -Et, where m ranges from 2 to 4, and m is more particularly 2;

[0140] --O-(C1-C6)-alkyl-V and -S-(C1-C6)-alkyl-V groups, especially -CH2-CH2-V; V is a group selected from the group consisting of:

[0141] ο-cyclo-(C3-C6)-alkyl group, which is optionally substituted by at least one group selected from the group consisting of -(C1-C6)-alkyl and =O group;

[0142] ο-heterocyclo-(C3-C6)-alkyl group, which is optionally substituted by at least one group selected from the group consisting of -(C1-C6)-alkyl and =O group, such as imidazolidine-2,4-dione group;

[0143] The O-(C1-C6)-alkyl-V group is, for example, of the following formula:

[0144]

[0145] --O-(C1-C4)-alkyl-Ar, especially -O-(CH2) j -Ar, where j ranges from 1 to 4, j is more particularly 1, and Ar is an aryl group optionally substituted by at least one R” group, especially at least one -OH group, and the -O-(C1-C4)-alkyl-Ar group is, for example, of the following formula:

[0146]

[0147] -O-(CH2)-Ar, where Ar is a heteroaryl such as indolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and the Ar group is optionally substituted by at least one R” group, especially at least one -OH group,

[0148] R” is selected from the following group:

[0149] ο-OH;

[0150] ο-O-(C1-C6)-alkyl or -O-cyclo-(C3-C6)-alkyl, especially -O-cyclopropyl;

[0151] ο-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0152] ο-(C1-C6)-alkyl-W group, especially -(CH2) k-W group, said group is optionally further substituted by at least one -W' group, where k ranges from 1 to 6, k is more particularly 1 or 2, and W and W' are independently OR a , where R a represents -H or -(C1-C4)-alkyl, especially H or Me; or W and W' are NR b H, where R b represents -H, -(C1-C4)-alkyl group or -(C1-C4)-alkyl-Ar', where Ar' is an aryl or heteroaryl group, especially furyl;

[0153] ο-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, l is more particularly 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl groups, said saturated heterocyclic groups are especially morpholinyl, tetrahydropyranyl, imidazolidinyl, said saturated heterocyclic groups are optionally substituted by at least one =O group and represent, for example, imidazolidine-2,4-dione; said heteroaryl is especially tetrazolyl;

[0154] ο-(C0-C6)-alkyl-S(=O)2NH2 group, especially –(CH2)2-S(=O)2NH2 group; said Ar group is not substituted by only one -OH group, or not substituted by two -O-(C1-C6)-alkyl or -O-cyclo-(C3-C6)-alkyl;

[0155] -halogen, especially -F;

[0156] In another specific embodiment, the present invention relates to a compound of formula (I) as defined above:

[0157]

[0158] wherein,

[0159] X is selected from -H, halogen, -(C1-C6)-alkyl group, -O-(C1-C6)-alkyl group and -O-CF3, especially -Me or -Cl, more especially -Me;

[0160] R is selected from -O-(C1-C4)-alkyl-Ar group, especially -O-(CH2) j -Ar, where j ranges from 1 to 4, more especially j is 1, and Ar is optionally an aryl group substituted by at least one R'' group, especially at least one -OH group, said -O-(C1-C4)-alkyl-Ar group has, for example, the following formula:

[0161]

[0162] R” is selected from the following group:

[0163] ο-OH;

[0164] ο-O-(C1-C6)-alkyl or -O-cyclo-(C3-C6)-alkyl, especially -O-cyclopropyl;

[0165] ο-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl;

[0166] ο-(C1-C6)-alkyl-W group, especially -(CH2) k -W group, which 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 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 group or -(C1-C4)-alkyl-Ar’, where Ar’ is an aryl or heteroaryl group, especially furyl;

[0167] ο-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, l is more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl groups, the saturated heterocyclic groups especially morpholinyl, tetrahydropyranyl, imidazolidinyl, the saturated heterocyclic groups being optionally substituted by at least one =O group, representing for example imidazolidine-2,4-dione; the heteroaryl especially tetrazolyl;

[0168] ο aryl or heteroaryl group, especially pyrazolyl, the aryl or heteroaryl group being optionally substituted by at least one R selected from -(C1-C6)-alkyl and -NH2 groups c groups;

[0169] ο-(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.

[0170] In a specific embodiment, the present invention relates to a compound as defined above, which has one of the following formulas:

[0171]

[0172]

[0173] Wherein X and R are as defined above.

[0174] In a specific embodiment, X is Me.

[0175] In another specific embodiment, X is Cl.

[0176] In a particular embodiment, R is not an -O-(C1-C4)-alkyl group, and in particular is not -OMe.

[0177] In a specific embodiment, the present invention relates to a compound as defined above, wherein R is selected from:

[0178] -F,

[0179] In a specific embodiment, the present invention relates to a compound as defined above, wherein R is selected from:

[0180]

[0181]

[0182] 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.

[0183] All of the above embodiments related to the compounds of the present invention apply equally herein, either individually or in any combination.

[0184] The compounds or pharmaceutical compositions of the present invention can be administered by any route in the form of conventional pharmaceutical compositions, including oral, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, intraventricular, and by injection into joints, particularly oral, intravenous, or intranasal administration.

[0185] 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 in determining the individual treatment regimen and dose level most suitable for a particular patient.

[0186] For preparing the pharmaceutical composition from the compounds of the present invention, the inert, pharmaceutically acceptable vehicle can be solid or liquid. Preparations in solid form include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

[0187] The solid carrier can be one or more substances, which can also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrants; they can also be encapsulating materials.

[0188] Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

[0189] Compositions in liquid form include solutions, suspensions and emulsions. For example, a sterile aqueous or propylene glycol solution of the active compound can be a liquid preparation suitable for parenteral administration. Liquid compositions can also be formulated as aqueous polyethylene glycol solutions.

[0190] An aqueous solution for oral administration can be prepared by dissolving the active ingredient in water and adding suitable coloring agents, flavoring agents, stabilizers and thickening agents as required. An aqueous solution for oral administration can be prepared by dispersing the subdivided active ingredient in water together with a viscous material such as natural and synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspending agents known in the art of pharmaceutical formulations.

[0191] Compositions comprising microspheres based on polymers such as hyaluronic acid, dextran and / or starch can be used, for example, for intranasal administration.

[0192] Depending on the mode of administration, according to one embodiment of the invention, the pharmaceutical composition will comprise from 0.05% to 99% by weight (weight percentage) of the compound of the invention, and according to an alternative embodiment, the pharmaceutical composition will comprise from 0.10 to 50% by weight of the compound of the invention, all weight percentages being based on the total composition. One of ordinary skill in the art can determine a therapeutically effective amount for the practice of the invention by using known criteria including the age, weight and response of the individual patient and interpreting it in the context of the disease being treated or prevented.

[0193] In another aspect, the invention also relates to a dermatological and / or cosmetic composition comprising a compound as defined above mixed with at least one pharmaceutically acceptable excipient.

[0194] All of the above embodiments related to the compounds of the invention apply equally herein, either individually or in any combination.

[0195] The dermatological and / or cosmetic composition of the invention can be administered by any route (including oral administration, topical administration, especially topical administration) in the form of a conventional dermatological and / or cosmetic composition.

[0196] The dosage will depend on the route of administration, the severity of the disease, disorder or condition, the age and weight of the patient, and other factors that a treating physician or practitioner typically considers in determining the individual treatment regimen and dosage level most suitable for a particular patient.

[0197] For the preparation of dermatological and / or cosmetic compositions from the compounds of the invention, the inert, pharmaceutically acceptable vehicle can be solid or liquid.

[0198] The dermatological and / or cosmetic composition can be in any suitable form commonly used in cosmetics. In a particular embodiment, the composition is selected from solutions, suspensions, creams, lotions, pastes, emulsions, gels, foundations, serums and ointments.

[0199] Depending on the mode of administration, according to one embodiment of the invention, the dermatological and / or cosmetic composition will comprise from 0.05% to 99% by weight (weight percent) of the compound of the invention, and according to an alternative embodiment, from 0.10 to 50% by weight of the compound of the invention, all weight percents being based on the total composition.

[0200] In another aspect, the invention also relates to the use of the compounds as defined above for the prevention and / or treatment of a disease, disorder or condition, which is: autism, autism spectrum disorder, in particular for the treatment of social interaction impairment in 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; paraphilic behavior; skin, muscle, bone aging; erectile dysfunction; and any disease for which oxytocin is known to have a beneficial effect.

[0201] All of the above embodiments related to the compounds of the invention apply equally here, either alone or in any combination.

[0202] In a particular embodiment, the invention relates to the use of the compounds as defined above for the prevention and / or treatment of a disease, disorder or condition, which is autism, autism spectrum disorder, in particular for the treatment of social interaction impairment in autism spectrum disorder.

[0203] In another aspect, the invention also relates to the use of the compounds as defined above for relieving or alleviating pain. All of the above embodiments related to the compounds of the invention apply equally here, either alone or in any combination.

[0204] In another aspect, the invention also relates to the use of the compounds as defined above for slowing down the aging of skin, muscle, bone, in particular skin.

[0205] All of the embodiments described above in connection with the compounds of the present invention apply equally herein, either singly or in any combination.

[0206] In another aspect, the present invention also relates to the use of a compound as defined above for promoting erection, lactation, parturition, breast-feeding and / or the post-partum period.

[0207] All of the embodiments described above in connection with the compounds of the present invention apply equally herein, either singly or in any combination.

[0208] In another aspect, the present invention also relates to a method for preventing and / or treating a disease, disorder or condition, which is: autism, autism spectrum disorder, in particular for treating social interaction impairment in autism spectrum disorder; pain; drug and / or alcohol addiction; depression; post-traumatic stress disorder; anxiety disorder; eating disorder, in particular anorexia, bulimia and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorder; social interaction disorder; paraphilia; skin, muscle, bone aging; erectile dysfunction; and any disease for which oxytocin is known to have a beneficial effect, the method comprising administering to a subject in need thereof a compound as defined above.

[0209] In another aspect, the present invention also relates to a method for slowing down skin, muscle, bone (in particular skin) aging or promoting erection, lactation, parturition, breast-feeding and / or the post-partum period, comprising administering to a subject in need thereof a compound as defined above.

[0210] On the other hand, the present invention also relates to a composition comprising at least one compound as defined above and a diuretic (e.g., urea or its salts), or a V2r antagonist, particularly vaptan (such as tolvaptan, lixivaptan or satavaptan) as a combination product for simultaneous, separate or dispersed therapeutic use for the prevention and / or treatment of diseases, disorders or conditions which are: 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; borderline behavior; skin, muscle, bone aging; erectile dysfunction; and any disease for which oxytocin is known to have a beneficial effect. On the other hand, the present invention also relates to a composition comprising at least one compound as defined above and a diuretic (e.g., urea or its salts) or a V2r antagonist, particularly vaptan (such as tolvaptan, lixivaptan or satavaptan) as a combination product for simultaneous, separate or dispersed therapeutic use to slow down the aging of skin, muscle, bone (particularly skin) or to promote erection, lactation, parturition, breast-feeding and / or the post-partum period.

[0211] Definitions

[0212] The following terms and expressions included herein are defined as follows:

[0213] As used herein, a value range in the form of "x - y" or "x to y" or "x through y" includes the integers x, y and the integers therebetween. For example, the phrase "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 sub-combination of the integers. For example, preferred integers for "1 - 6" may include 1, 2, 3, 4, 5, 6, 1 - 2, 1 - 3, 1 - 4, 1 - 5, 2 - 3, 2 - 4, 2 - 5, 2 - 6, etc.

[0214] As used in the present invention, the term "-(C1 - C6)alkyl" 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.

[0215] As used in the present invention, the term "aryl" (which may be abbreviated as "Ar") specifically refers to an aromatic hydrocarbon group, preferably including 6 to 10 carbon atoms and including one or more (particularly 1 or 2) fused rings, such as, for example, a phenyl or naphthyl group. Advantageously, it will be a phenyl group.

[0216] As used in the present invention, the term "-(C1-C4)-alkyl-aryl" refers to an aryl group as defined above bonded to a molecule via an (C1-C4) alkyl group as defined above.

[0217] As used in the present invention, the term "-(C3-C6)-cycloalkyl" refers to a saturated hydrocarbon monocyclic ring having 3 to 6 carbon atoms.

[0218] As used in the present invention, the term "saturated heterocyclic group" specifically refers to a saturated hydrocarbon monocyclic or polycyclic ring (including fused rings, bridged rings or spiro rings) (such as, bicyclic rings), wherein one or more, preferably 1 to 4, more preferably 1 or 2 carbon atoms are each replaced by a heteroatom selected from nitrogen, oxygen and sulfur atoms (especially nitrogen atoms). Preferably, the heterocyclic ring includes 5 to 15, especially 5 to 10 atoms in one or more rings. One or more rings of the heterocyclic ring preferably have 5 or 6 members.

[0219] 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 are each replaced by a nitrogen or oxygen atom, especially a nitrogen atom.

[0220] As used in the present invention, the term "heteroaryl" specifically refers to an aromatic hydrocarbon monocyclic or bicyclic ring (i.e., including fused rings), each ring having 5 or 6 members, especially 6 members, and 1 to 4, especially 1 or 2 carbon atoms are each replaced by a nitrogen or oxygen atom, especially a nitrogen atom.

[0221] Heteroaryl may especially be thiophene, furan, pyrrole, imidazole, pyrazole, azole, iso azole, thiazole, isothiazole, triazole (1,2,3-triazole and 1,2,4-triazole), benzofuran, indole, benzothiophene, benzimidazole, indazole, benzo azole, benzoiso azole, benzothiazole, benzisothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, etc.

[0222] As used in the present invention, the term "-(C1-C4)alkyl-heteroaryl" refers to a heteroaryl group as defined above bonded to a molecule via an (C1-C4) alkyl group as defined above.

[0223] As used in the present invention, the term "halogen" refers to a fluorine, bromine, chlorine or iodine atom.

[0224] Synthesis

[0225] 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, these methods can be found in R.C. Larock, Comprehensive Organic Transformations, Wiley-VCH Publishers, 2018 [R.C. Larock, Comprehensive Organic Transformations, Wiley-VCH Publishers, 2018].

[0226] All methods 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.

[0227] 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, diastereoisomeric, racemic, and isomeric forms of the structure are contemplated. 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 salt formation, and recrystallization, etc., or by chiral synthesis from chiral starting materials or by intentional synthesis targeting chiral centers.

[0228] The compounds of the present invention can be prepared by a variety of synthetic routes. The 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.

[0229] 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 desired in the final product), to avoid their unnecessary participation in the reaction. Conventional protecting groups can be used according to standard practice, for example, see 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.

[0230] The reagents and starting materials are commercially available or can be readily synthesized by those of ordinary skill in the art by well-known techniques.

[0231] Specifically, the compounds defined above are obtained according to the following steps:

[0232]

[0233] wherein X and R are as described above or are protected by an ad hoc protecting group in situ. Examples

[0234] Example 1 Synthesis of the compound of the present invention

[0235] The compound of the present invention is obtained by the following method:

[0236]

[0237] wherein X and R are as described above or are protected by an in situ ad hoc protecting group.

[0238] Step (i):

[0239] 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, stirred 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 to a solution of compound B (1 equivalent) and triethylamine (2 equivalents) in anhydrous CH2Cl2 at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes and then stirred 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 mixture of CHCl3 / PrOH 8 / 2 v / v. The combined organic phases were washed with saturated NaHCO3, dried over Na2SO4, and evaporated under reduced pressure. Purification by silica gel chromatography (CH2Cl2 / MeOH, 95 / 5 v / v) gave product C.

[0240] Step (ii):

[0241] 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 precipitate formed 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 with diethyl ether again. The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give compound D.

[0242] Step (iii):

[0243] A solution of compound D (1 equivalent), 1,1'-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.

[0244] The following analytical data were obtained:

[0245]

[0246]

[0247] Synthesis of (2S,4R)-2-(dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (LIT-003_Int1)

[0248]

[0249] Step 1. Synthesis of (2S,4R)-2-(dimethylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0250] (2S,4R)-1-[(tert-Butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (80 g, 346.15 mmol) was dissolved in DCM and cooled to 0 °C. (3-[(Ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (86 g, 449.99 mmol) was added at 0 °C and then ethyldi(propan-2-yl)amine (134 g, 1.04 mol, 180.75 ml, 3.0 eq) and 1H-1,2,3-benzotriazol-1-ol (61 g, 449.99 mmol) were added, and the mixture was stirred at room temperature for 4 h. After 4 h, dimethylamine hydrochloride (36 g, 449.99 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. After 16 h, the mixture was poured into water, and the organic layer was washed with NaHSO4 solution and brine, dried over Na2SO4 and evaporated to obtain 60 g of the product with a purity of 60%. The crude product was purified by FC (system MeOH / MTBE) to give tert-butyl (2S,4R)-2-(dimethylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (41.0 g, 90.0% purity, 142.85 mmol, 41.3% yield).

[0251] Step 2. Synthesis of tert-butyl (2S,4R)-4-(acetyloxy)-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate

[0252] (2S,4R)-2-(dimethylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (10.0 g, 38.74 mmol), ethyldi(propan-2-yl)amine (10.01 g, 77.47 mmol) and N,N-dimethylpyridin-4-amine (473 mg, 3.87 mmol) were dissolved in DCM. Acetyl acetate (4.74 g, 46.48 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for an additional 10 min. After 10 min, the mixture was allowed to warm to room temperature and stirred at room temperature for 16 h. The mixture was diluted with water, and the organic layer was washed with 10% K2CO3 solution and saturated NaHSO4 solution, dried over Na2SO4 and evaporated to give tert-butyl (2S,4R)-4-(acetyloxy)-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (8.4 g, 74.0% purity, 20.7 mmol, 53.4% yield).

[0253] Step 3. Synthesis of tert-butyl (2S,4R)-4-(acetyloxy)-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate

[0254] Dissolve tert-butyl (2S,4R)-4-(acetyloxy)-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (52.0 g, 173.13 mmol) and [(disulfanylidene-lambda5-phosphanyl)sulfanyl]-lambda5-phosphanedithione (30.72 g, 138.5 mmol) in di ane and stir at 105 °C for 1 hour. After 1 hour, allow the reaction mixture to cool to room temperature, concentrate and purify the residue by FC (ACN / CHCl3 system) to obtain tert-butyl (2S,4R)-4-(acetyloxy)-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate (10.2 g, purity 90.0%, 29.01 mmol, yield 16.8%).

[0255] Step 4. Synthesis of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylate

[0256] Mix tert-butyl (2S,4R)-4-(acetyloxy)-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate (10.2 g, 32.24 mmol) and potassium carbonate (11.11 g, 80.59 mmol) in MeOH and stir at room temperature for 16 hours. After 16 hours, concentrate the mixture and dilute with CHCl3. Wash the organic phase with water, dry over Na2SO4 and evaporate to obtain tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylate, LIT-003_Int1. Yield: 6.0 g, 66.5%.

[0257] 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)methanamine hydrochloride (LIT-003_Int2)

[0258]

[0259] Step 1. Synthesis of ethyl 1-methyl-5-[(2-nitrophenyl)amino]-1H-pyrazole-4-carboxylate

[0260] Sodium hydride (32.64 g, 1.36 mol) was added portionwise to a stirred THF solution of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (100.0 g, 591.42 mmol) at 0 °C, and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 h. After 4 h, 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 h. After 16 h, 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, purity 95.0%, 376.37 mmol, yield 63.6%).

[0261] Step 2. Synthesis of ethyl 5-[(2-aminophenyl)amino]-1-methyl-1H-pyrazole-4-carboxylate

[0262] 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 gas atmosphere for 16 h. After 16 h, 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, purity 96.0%, 313.49 mmol, yield 79.1%).

[0263] 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

[0264] 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, yield 44.3%).

[0265] 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

[0266] 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-pentaen-8-one (27.0 g, 126.12 mmol) was added portionwise to a stirred suspension of lithium(1+) aluminium hydride (19.18 g, 504.48 mmol) in THF at room temperature, and the resulting mixture was heated to reflux for 16 h. After 16 h, the mixture was allowed to cool to room temperature, another portion of lithium(1+) aluminium hydride (19.18 g, 504.48 mmol) was added portionwise at room temperature, and the mixture was heated to reflux again 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, yield 32.1%).

[0267] 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-pentaen-9-carbonyl)phenyl)methyl]carbamate

[0268] 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 from the reaction mixture showed a purity of 88%. The resulting mixture was purified by FC (gradient CHCl3 / AcN) to afford 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, purity 95.0%, 5.52 mmol, yield 69%).

[0269] Step 6. 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-pentaene-9-carbonylphenyl)methanamine hydrochloride

[0270] 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) 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 afford 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-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 calculated for C 31 H 37 N 11 O3S: 644.31; Observed: 644.4 [M+H] + .

[0271] Synthesis of (2S,4R)-2-(dimethylthiocarbamoyl)-4-(3-hydroxypropoxy)-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-carbonyl)phenyl)methyl]pyrrolidine-1-carboxamide (LIT-003-01)

[0272]

[0273] Step 1. Synthesis of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-[3-( prop-2-yloxy)propoxy]pyrrolidine-1-carboxylate

[0274] At 0 °C, sodium hydride (197 mg, 8.2 mmol) was added to a stirred suspension of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (1) (900 mg, 3.28 mmol) in DMF (10 ml), and the mixture was stirred at 0 °C for 2 h, then 2-(3-bromopropoxy) propane (2) (728 mg, 3.28 mmol) was added and the reaction mixture was stirred at 0 °C for an additional 2 h. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. LCMS of the reaction mixture showed the desired product was present at 59%. The reaction mixture was concentrated and purified by FC (system ACN / CHCl3) to give tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-[3-( prop-2-yloxy)propoxy]pyrrolidine-1-carboxylate (3) (300 mg, purity 93.0%, 69.75 μmol, yield 20.4%).

[0275] Step 2. Synthesis of (2S,4R)-4-(3-hydroxypropoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride

[0276] (2S,4R)-2-(dimethylthiocarbamoyl)-4-[3-( prop-2-yloxy)propoxy]pyrrolidine-1-carboxylate (3) (300 mg, 720.16 μmol) was dissolved in 4 M di in an alkane-hydrochloric acid solution (15 ml) and stirred at 60 °C for 16 hours. LCMS from the reaction mixture showed that the content of the desired product was 90%. The reaction mixture was concentrated to give (2S,4R)-4-(3-hydroxypropoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (4) (160 mg, purity 90.0%, 535.71 μmol, yield 86.2%).

[0277] Step 3. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-(3-hydroxypropoxy)-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

[0278] 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)methanamine (5) (148 mg, 425.92 μmol), 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole (138 mg, 851.83 μmol) and ethyldi(isopropyl)amine (550 mg, 4.26 mmol, 740.0 μl, 10.0 eq) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 hours. (2S,4R)-4-(3-Hydroxypropoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (4) (160 mg, 595.23 μmol) was added to the mixture and the mixture was stirred at room temperature for 16 hours. LCMS from the reaction mixture showed that the content of the desired product was 71%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 8 - 15 - 30% H2O / ACN, 30 ml\min (loading pump 4 ml ACN), target mass 605 column: CHROMATOREX C18 100*19 mm, 5 microM) to give (2S,4R)-2-(dimethylcarbamothioyl)-4-(3-hydroxypropoxy)-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, LIT-003-01. Yield: 162 mg, 62.8%; Appearance: yellow solid; HPLC purity: 100%; LCMS calculated for C 31 H 39 N7O4S: 606.32; Observed: 606.2 [M + H] + .

[0279] Synthesis of (2S,4R)-2-(dimethylthiocarbamoyl)-4-(4-hydroxybutoxy)-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-003-02)

[0280]

[0281] Step 1. 2-(4-Bromobutoxy) Synthesis of alkane

[0282] 3,4-Dihydro-2H-pyran (1) (3.96 g, 47.06 mmol, 4.29 ml, 1.3 eq) was added dropwise to a solution of 4-bromobutan-1-ol (5.5 g, 36.19 mmol) and 4-methylbenzene-1-sulfonic acid hydrate (69 mg, 361.95 μmol) in DCM (50 ml), and the mixture was stirred at room temperature for 16 h. After removal of the solvent, the residue was purified by FC (system MTBE - hexane) to give 2-(4-bromobutoxy) alkane (2.9 g, purity 95.0%, 11.62 mmol, yield 32.1%).

[0283] Step 2. Synthesis of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-[4-( alkane-2-yloxy)butoxy]pyrrolidine-1-carboxylate

[0284] At 0 °C, sodium hydride (219 mg, 9.11 mmol) was added to a stirred suspension of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (1.0 g, 3.64 mmol) in DMF (10 ml), and the mixture was stirred at 0 °C for 2 h, then 2-(4-bromobutoxy) alkane (860 mg, 3.64 mmol) was added, and the reaction mixture was stirred at 0 °C for another 2 h, allowed to warm to room temperature and stirred for 16 h. LCMS of the reaction mixture showed that the desired product content was 59%. The reaction mixture was concentrated and purified by FC (system ACN / CHCl3) to give tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-[4-( alkane-2-yloxy)butoxy]pyrrolidine-1-carboxylate (580 mg, purity 98.0%, 1.32 mmol, yield 36.2%).

[0285] Step 3. Synthesis of (2S,4R)-4-(4-hydroxybutoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride

[0286] (2S,4R)-2-(Dimethylcarbamothioyl)-4-[4-( (tert-butoxy)butoxy]pyrrolidine-1-carboxylic acid tert-butyl ester (580 mg, 1.35 mmol) was dissolved in 4 M dioxane-hydrochloric acid solution and stirred at 60 °C for 16 h. LCMS from the reaction mixture showed that the desired product was present at 65%. The reaction mixture was concentrated to afford (2S,4R)-4-(4-hydroxybutoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (380 mg, purity 65.0%, 873.31 μmol, yield 64.8%).

[0287] Step 4. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-(4-hydroxybutoxy)-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

[0288] ​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 (114 mg, 327.54 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (106 mg, 655.07 μmol), and ethyldi(isopropyl)amine (423 mg, 3.27 mmol, 570.0 μl, 10.0 equiv) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-4-(4-Hydroxybutoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (130 mg, 458.55 μmol) was added to the mixture and stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 71%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 27 - 35 - 100% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 619 column: CHROMATOREX C18 SMB100 - 5T 100*19 mm, 5 microM) to give only 85% purity. The material was repurified by SFC (Viridis 2 - EP (150x4.6 mm, 5mkm)--01233120816103--13 mobile phase: hexane - [IPA:MeOH], [50:50] 10 - 60! 32 flow rate: 1.0 ml / min) to afford (2S,4R)-2-(dimethylcarbamothioyl)-4-(4-hydroxybutoxy)-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-003-02. Yield: 10.0 mg, 4.9%; Appearance: Beige solid; HPLC purity: 100%; For C 32 H 41 Calculated LCMS for C28H36N7O4S: 620.34; Observed: 620.2 [M+H] + 。

[0289] (2S,4R)-2-(Dimethylcarbamothioyl)-4-[2-(2-hydroxyethoxy)ethoxy]-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-003-03) Synthesis

[0290]

[0291] Step 1.2 - [2-(2-Bromoethoxy)ethoxy] Synthesis of alkane

[0292] 3,4-Dihydro-2H-pyran (1) (3.9 g, 46.43 mmol, 4.23 ml, 1.5 eq) was added dropwise to a solution of 2-(2-bromoethoxy)ethan-1-ol (5.2 g, 30.96 mmol) and 4-methylbenzene-1-sulfonic acid hydrate (59 mg, 309.56 μmol) in DCM (100 ml), and the mixture was stirred at room temperature for 16 h. After removal of the solvent, the residue was purified by FC (system MTBE - hexane) to give 2-[2-(2-bromoethoxy)ethoxy] alkane (2) (4.0 g, purity 95.0%, 15.01 mmol, yield 48.5%).

[0293] Step 2. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-2-[2-( alkane-2-yloxy)ethoxy]ethoxypyrrolidine-1-carboxylate

[0294] At 0 °C, sodium hydride (175 mg, 7.29 mmol) was added to a stirred suspension of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate (3) (800 mg, 2.92 mmol) in DMF (10 ml), and the mixture was stirred at 0 °C for 2 h, then 2-[2-(2-bromoethoxy)ethoxy] alkane (2) (735 mg, 2.92 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h, allowed to warm to room temperature and stirred for 16 h. LCMS of the reaction mixture showed the desired product was present at 40%. The reaction mixture was concentrated and purified by FC (system ACN / CHCl3) to give tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-2-[2-( alkane-2-yloxy)ethoxy]ethoxypyrrolidine-1-carboxylate (4) (200 mg, purity 91.0%, 407.52 μmol, yield 14%)

[0295] Step 3. Synthesis of (2S,4R)-4-[2-(2-hydroxyethoxy)ethoxy]-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride

[0296] (2S,4R)-2-(dimethylcarbamothioyl)-4-2-[2-( tert-Butyl (2S,4R)-4-[[2-(2-(2-methoxyethoxy)ethoxy)ethoxy]pyrrolidine-1-carboxylate (4) (200 mg, 447.83 μmol) was dissolved in 4 M diethyl ether-hydrochloric acid solution and stirred at 70 °C for 16 h. LCMS from the reaction mixture showed that the desired product was present at 78%. The reaction mixture was concentrated to afford (2S,4R)-4-[2-(2-hydroxyethoxy)ethoxy]-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (5) (130 mg, purity 78.0%, 339.32, yield 75.7%).

[0297] Step 4. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[2-(2-hydroxyethoxy)ethoxy]-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

[0298] ​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)methanamine (6) (108 mg, 311.43 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (101 mg, 622.86 μmol) and ethyldi(propan-2-yl)amine (402 mg, 3.11 mmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-4-[2-(2-Hydroxyethoxy)ethoxy]-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (5) (130 mg, 435.03 μmol) was added to the mixture and the mixture was stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 70%. The reaction mixture was purified by HPLC (system 0-2-8 min 7-15-30% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 635 column: CHROMATOREXC18 SMB100-5T 100*19 mm, 5 microM) to afford (2S,4R)-2-(dimethylcarbamothioyl)-4-[2-(2-hydroxyethoxy)ethoxy]-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, LIT-003-03. Yield: 17.0 mg, 8.5%; Appearance: colorless solid; HPLC purity: 98.60%; For C 32 H 41 Calculated LCMS for C25H33N7O5S: 636.33; Observed: 636.2 [M+H] + 。

[0299] Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-methoxy-4-methylbenzenesulfonamide (LIT-003-04)

[0300]

[0301] Step 1. Synthesis of tert-butyl (2S,4R)-4-[(3,5-dimethoxyphenyl)methoxy]-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate

[0302] At 0 °C, sodium hydride (1.12 g, 46.48 mmol) was added to a stirred solution of (2S,4R)-tert-butyl 2-(dimethylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (2) (3.0 g, 11.62 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h. Then 1-(bromomethyl)-3,5-dimethoxybenzene (1) (2.67 g, 11.62 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h. It was allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product was present at 47%. The reaction mixture was concentrated and purified by FC (ACN / CHCl3) to afford (2S,4R)-tert-butyl 4-[(3,5-dimethoxyphenyl)methoxy]-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (3) (500 mg, purity 70.0%, 856.82 μmol, yield 7.4%).

[0303] Step 2. Synthesis of (2S,4R)-tert-butyl 4-[(3,5-dimethoxyphenyl)methoxy]-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate

[0304] (2S,4R)-tert-butyl 4-[(3,5-dimethoxyphenyl)methoxy]-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate (3) (500 mg, 1.22 mmol) and [(dithiocarboxy-λ5-phosphanyl)thio]-λ5-phosphanedithione (217 mg, 979.85 μmol) were dissolved in di ane, and the mixture was stirred at 100 °C for 1 h. After 1 h, the reaction mixture was allowed to cool to room temperature, concentrated, and the residue was purified by HPLC (system 23 - 30 - 90 0 - 2 - 9 min H2O / ACN flow rate 30 ml / min (loading pump 4 ml ACN), target mass 424 column: XBRIDGE 100*19 mm, 5 microM) to afford (2S,4R)-tert-butyl 4-[(3,5-dimethoxyphenyl)methoxy]-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate (4) (130 mg, purity 80.0%, 244.96 μmol, yield 20%).

[0305] Step 3. Synthesis of (2S,4R)-4-[(3,5-dimethoxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-thiocarboxamide

[0306] (2S,4R)-tert-Butyl 4-[(3,5-dimethoxyphenyl)methoxy]-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate (4) (130 mg, 306.2 μmol) was dissolved in DCM (2 ml), and TFA (1 ml) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 12 h. LCMS from the reaction mixture showed the content of the desired product was 75%. The mixture was concentrated to give (2S,4R)-4-[(3,5-dimethoxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (5) as the TFA salt (120 mg, purity 75.0%, 277.4 μmol, yield 90.6%).

[0307] Step 4. Synthesis of (2S,4R)-4-[(3,5-dimethoxyphenyl)methoxy]-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-carbonylphenyl)methyl]pyrrolidine-1-carboxamide

[0308] 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 (6) (92 mg, 263.67 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (86 mg, 527.34 μmol) and ethyldi(propan-2-yl)amine (341 mg, 2.64 mmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-4-[(3,5-Dimethoxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (5) (120 mg, 369.87 μmol) was added to the mixture and stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product to be 49%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 23 - 30 - 50% H2O / ACN, 30 ml\min (loading pump 4 ml ACN), target mass 697 column: Chromatorex C18 SMB100 - 5T 100*19 mm, 5 microM) to afford (2S,4R)-4-[(3,5-dimethoxyphenyl)methoxy]-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-003-04. Yield: 32.6 mg, 17.7%; Appearance: Beige solid; HPLC purity: 100%; For C 37 H 43 Calculated LCMS for C29H36N7O5S: 698.35; Observed: 698.2 [M+H] + 。

[0309] Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-hydroxyphenyl)methoxy]-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-003-05)

[0310]

[0311] Step 1. Synthesis of [3-(bromomethyl)phenoxy](tert-butyl)dimethylsilane obtained

[0312] At 0 °C, triphenylphosphane (2.86 g, 10.92 mmol) and carbon tetrabromide (3.58 g, 10.92 mmol) were added portionwise to a stirred solution of 3-[(tert-butyldimethylsilyl)oxy]benzyl alcohol (1) (2.0 g, 8.4 mmol) in DCM. The resulting mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by FC (system MTBE / hexane) to afford [3-(bromomethyl)phenoxy](tert-butyl)dimethylsilane (2) (1.3 g, purity 95.0%, 4.1 mmol, yield 48.8%).

[0313] Step 2. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-hydroxyphenyl)methoxy]pyrrolidine-1-carboxylate

[0314] At 0 °C, sodium hydride (140 mg, 5.83 mmol) was added to a suspension of (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl ester (3) (400 mg, 1.46 mmol) in DMF and the mixture was stirred at 0 °C for 2 h, then [3-(bromomethyl)phenoxy](tert-butyl)dimethylsilane (2) (438 mg, 1.46 mmol) was added and the reaction mixture was stirred at 0 °C for an additional 2 h, allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product at 21%. The reaction mixture was concentrated and purified by HPLC (system 0-2-8 min 27-35-100% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 380 column: CHROMATOREX C18 SMB100-5T100*19 mm, 5 microM) to afford tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-hydroxyphenyl)methoxy]pyrrolidine-1-carboxylate (4) (36 mg, purity 84.0%, 79.47 μmol, yield 5.4%).

[0315] Step 3. Synthesis of (2S,4R)-4-[(3-hydroxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide

[0316] (2S,4R)-tert-Butyl 2-(dimethylcarbamothioyl)-4-[(3-hydroxyphenyl)methoxy]pyrrolidine-1-carboxylate (4) (36 mg, 94.61 μmol) was dissolved in DCM (2 ml), and TFA (1 ml) was added to the mixture at 0 °C. LCMS from the reaction mixture showed the desired product was present at 76%. The resulting mixture was stirred at room temperature for 1 h. The cyclized product was concentrated to afford (2S,4R)-4-[(3-hydroxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (5) as the TFA salt (30 mg, purity 76.0%, 81.32 μmol, 86% yield).

[0317] Step 4. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-hydroxyphenyl)methoxy]-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

[0318] 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)methanamine (6) (26 mg, 76.48 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (24.79 mg, 153 μmol) and ethyldi(propan-2-yl)amine (99 mg, 764.77 μmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-4-[(3-Hydroxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (5) (30 mg, 107.0 μmol) was added to the mixture and the mixture was stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 86%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 18 - 25 - 50% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 653 column: CHROMATOREX C18 SMB100 - 5T 100*19 mm, 5 microM) to afford (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-hydroxyphenyl)methoxy]-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, LIT-003-05, yield: 30.0 mg, 57.6%; appearance: brown solid; HPLC purity: 97.94%; for C 35 H 39 Calculated LCMS for C29H33N7O4S: 653.28; observed: 653 [M+H] + 。

[0319] (2S,4R)-2-(Dimethylcarbamothioyl)-4-[(4-hydroxyphenyl)methoxy]-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 (LIT-003-07) synthesis

[0320]

[0321] Step 1. Synthesis of [4-(bromomethyl)phenoxy](tert-butyl)dimethylsilane

[0322] At 0 °C, triphenylphosphine (2.86 g, 10.92 mmol, 1.3 eq) and carbon tetrabromide (3.58 g, 10.92 mmol) were added portionwise to a stirred solution of 4-[(tert-butyldimethylsilyl)oxy]benzyl alcohol (1) (2.0 g, 8.4 mmol) in DCM. The resulting mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by FC (system MTBE / hexane) to afford [4-(bromomethyl)phenoxy](tert-butyl)dimethylsilane (2) (600 mg, 95.0% purity, 1.89 mmol, 22.5% yield).

[0323] Step 2. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(4-hydroxyphenyl)methoxy]pyrrolidine-1-carboxylate

[0324] At 0 °C, sodium hydride (224 mg, 9.34 mmol) was added to a stirred suspension of (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl ester (3) (640 mg, 2.33 mmol) in DMF (10 ml), and the mixture was stirred at 0 °C for 2 h, then [4-(bromomethyl)phenoxy](tert-butyl)dimethylsilane (2) (700 mg, 2.33 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h and allowed to warm to room temperature and stirred for 16 h. LCMS of the reaction mixture showed the desired product was present at 56%. The reaction 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 380 column: CHROMATOREX C18 100*19 mm, 5 microM) to afford tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(4-hydroxyphenyl)methoxy]pyrrolidine-1-carboxylate (4) (130.0 mg, 97.0% purity, 331.4 μmol, 14.2% yield).

[0325] Step 3. Synthesis of (2S,4R)-4-[(4-hydroxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide

[0326] (2S,4R)-tert-Butyl 2-(dimethylcarbamothioyl)-4-[(4-hydroxyphenyl)methoxy]pyrrolidine-1-carboxylate (4) (72 mg, 189.22 μmol) and zinc dibromide (420 mg, 1.89 mmol) were dissolved in acetonitrile (ACN) and stirred at 82 °C for 32 h. LCMS from the reaction mixture showed the desired product to be present at 43%. The mixture was concentrated and the residue was purified by HPLC (system 0 - 2 - 8 min 13 - 20 - 40% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 380 column: CHROMATOREX C18 100*19 mm, 5 microM) to afford (2S,4R)-4-[(4-hydroxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (5) (8.0 mg, 94.0% purity, 26.82 μmol, 14.2% yield).

[0327] Step 3. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[(4-hydroxyphenyl)methoxy]-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

[0328] 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)methanamine (6) (5.3 mg, 15.28 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (4.95 mg, 30.56 μmol) and ethyldi(propan-2-yl)amine (20 mg, 152.8 μmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-4-[(4-Hydroxyphenyl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (5) (6 mg, 21.4 μmol) was added to the mixture and the mixture was stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 66%. The reaction 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 653 column: Chromatorex C18 SMB100-5T 100*19 mm, 5 microM) to afford (2S,4R)-2-(dimethylcarbamothioyl)-4-[(4-hydroxyphenyl)methoxy]-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, LIT-003-07. Yield: 5.0 mg, 50.1%; Appearance: brown solid; HPLC purity: 100%; For C 35 H 39 Calculated LCMS for C27H32N7O4S: 654.32; Observed: 654.4 [M+H] + 。

[0329] (2S,4R)-4-[(3-Carbamoylphenyl)methoxy]-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-carbonylphenyl)methyl]pyrrolidine-1-carboxamide (LIT-003-08) Synthesis

[0330]

[0331] Step 1. Synthesis of (2S,4R)-4-[(3-Carbamoylphenyl)methoxy]-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0332] At 0 °C, sodium hydride (210 mg, 8.75 mmol) was added to a stirred suspension of (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1) (600 mg, 2.19 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h. Then 3-(chloromethyl)benzamide (2) (370 mg, 2.19 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h. The mixture was allowed to warm to room temperature and stirred for 16 h. LCMS of the reaction mixture showed that the desired product was present at 38%. The reaction mixture was concentrated and purified by HPLC (system 0 - 2 - 8 min 23 - 30 - 60% H2O / MEOH / , 30 ml\min (loading pump 4 ml MeOH), target mass 407 column: Chromatorex 100*19 mm, 5 microM) to afford (2S,4R)-4-[(3-carbamoylphenyl)methoxy]-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3) (200 mg, purity 98.0%, 480.95 μmol, 22% yield).

[0333] Step 2. Synthesis of 3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzamide hydrochloride

[0334] (2S,4R)-4-[(3-carbamoylphenyl)methoxy]-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3) (200 mg, 490.77 μmol) was dissolved in 4 M di ane-hydrochloric acid (10 ml), and the resulting mixture was stirred at room temperature for 16 h. LCMS of the reaction mixture showed that the desired product was present at 71%. The reaction mixture was concentrated to afford 3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzamide hydrochloride (4) (140 mg, purity 71.0%, 289.06 μmol, 58.8% yield).

[0335] Step 3. Synthesis of (2S,4R)-4-[(3-carbamoylphenyl)methoxy]-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

[0336] 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)methanamine (5) (101 mg, 290.83 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (94 mg, 581.65 μmol) and ethyldi(propan-2-yl)amine (375.61 mg, 2.91 mmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. 3-([(3R,5S)-5-(Dimethylthiocarbamoyl)pyrrolidin-3-yl]oxymethyl)benzamide hydrochloride (4) (140 mg, 407.13 μmol) was added to the mixture and the mixture was stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was 88% in content. The reaction mixture was purified by HPLC (system 0-2-8 min 7-15-100% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 680 column: XBRIDGE BEH C18 SMB100-5T 100*19 mm, 5 microM) to afford (2S,4R)-4-[(3-carbamoylphenyl)methoxy]-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, LIT-003-08. Yield: 141 mg, 71.2%; Appearance: yellow oil; HPLC purity: 100%; For C 36 H 40 Calculated LCMS for C29H36N8O4S: 681.33; Observed: 681.2 [M+H] + 。

[0337] (2S,4R)-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]-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-1-carboxamide (LIT-003-09) synthesis

[0338]

[0339] Step 1. Synthesis of 3-(bromomethyl)benzene-1-sulfonamide

[0340] 3-(Hydroxymethyl)benzene-1-sulfonamide (1) (2.0 g, 10.69 mmol) was dissolved in DCM, and phosphorus tribromide (3.44 g, 12.83 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 16 h. Water was carefully added and the organic phase was separated, washed with brine, dried over sodium sulfate and concentrated to give 3-(bromomethyl)benzene-1-sulfonamide (2) (750 mg, purity 94.0%, 2.82 mmol, yield 26.4%).

[0341] Step 2. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-1-carboxylate

[0342] At 0 °C, sodium hydride (161 mg, 6.71 mmol) was added to a stirred solution of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate (3) (460 mg, 1.68 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h, then 3-(bromomethyl)benzene-1-sulfonamide (2) (418 mg, 1.68 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h, allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product was present at 31%. The reaction mixture was concentrated and purified by HPLC (system 0 - 2 - 8 min 0 - 0 - 25% H2O / ACN / 0.1% NH4OH 30 ml / min (loading pump 4 ml ACN), target mass 443 column: XBRIDGE BEH C18 SMB100 - 5T 100*19 mm, 5 microM) to give tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-1-carboxylate (4) (52.0 mg, purity 96.0%, 112.54 μmol, yield 6.7%).

[0343] Step 3. Synthesis of (2S,4R)-N,N-dimethyl-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-2-carbothioamide

[0344] (2S,4R)-tert-Butyl 2-(dimethylcarbamothioyl)-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-1-carboxylate (4) (52 mg, 117.23 μmol) was dissolved in DCM (2 ml), and TFA (1 ml) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 2 h. LCMS from the reaction mixture showed the content of the desired product was 84%. The mixture was concentrated to afford (2S,4R)-N,N-dimethyl-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-2-carbothioamide (5) as the TFA salt (40 mg, purity 84.0%, 97.83 μmol, yield 83.4%).

[0345] Step 4. Synthesis of (2S,4R)-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-carbonylphenyl)methyl]-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-1-carboxamide

[0346] Dissolve 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)methanamine (6) (29 mg, 83.14 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (27 mg, 166.28 μmol) and ethyldi(propan-2-yl)amine (107 mg, 831.39 μmol) in DMF (5 ml) and stir at 15 °C for 3 h. Add (2S,4R)-N,N-dimethyl-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-2-carbothioamide (5) (40 mg, 116.46 μmol) to the mixture and stir the mixture at room temperature for 16 h. LCMS from the reaction mixture showed the content of the desired product was 89%. The reaction mixture was purified by HPLC (system 0-2-8 min 7-15-40% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 716 column: CHROMATOREX C18 SMB100-5T 100*19 mm, 5 microM) to give (2S,4R)-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-carbonylphenyl)methyl]-4-[(3-sulfamoylphenyl)methoxy]pyrrolidine-1-carboxamide, LIT-003-09. Yield: 32.0 mg, 53.7%; Appearance: brown solid; HPLC purity: 100%; For C 34 H 39 Calculated LCMS for C18H25N8O5S2: 717.29; Observed: 717.0 [M+H] + 。

[0347] Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-methoxy-4-methylbenzene-1-sulfonamide (LIT-003-10)

[0348]

[0349] Step 1. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(5-methoxy-5-oxopentyl)oxy]pyrrolidine-1-carboxylate

[0350] At 0 °C, sodium hydride (262 mg, 10.94 mmol) was added to a stirred solution of (2S,4R)-tert-butyl 2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate (1) (600 mg, 2.19 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h. Then methyl 5-bromovalerate (2) (424 mg, 2.19 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h. The mixture was allowed to warm to room temperature and stirred for 16 h. LCMS of the reaction mixture showed that the desired product was present at 37%. The reaction mixture was concentrated and purified by HPLC (system 0 - 2 - 8 min 27 - 35 - 45% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 388 column: CHROMATOREX C18 100*19 mm, 5 microM, 130 A) to give (2S,4R)-tert-butyl 2-(dimethylcarbamothioyl)-4-[(5-methoxy-5-oxopentyl)oxy]pyrrolidine-1-carboxylate (3) (190 mg, purity 96.0%, 469.47 μmol, yield 21.5%).

[0351] Step 2. Synthesis of 5-[(3R,5S)-1-[(tert-butoxy)carbonyl]-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxypentanoic acid (2S,4R)-tert-butyl 2-(dimethylcarbamothioyl)-4-[(5-methoxy-5-oxopentyl)oxy]pyrrolidine-1-carboxylate (3) (80.0 mg, 205.91 μmol) and lithium hydroxide (1+) ion hydrate (17.31 mg, 411.75 μmol) were combined in a THF-H2O solution and stirred at 40 °C for 16 h. LCMS of the reaction mixture showed that the desired product was present at 99%. The mixture was concentrated, diluted with water, acidified with NaHSO4 solution and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give 5-[(3R,5S)-1-[(tert-butoxy)carbonyl]-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxypentanoic acid (4) (60.0 mg, purity 99.0%, 158.61 μmol, yield 77%).

[0352] Step 3. Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-methoxy-4-methylbenzenesulfonamide

[0353] 5-[(3R,5S)-1-[(tert-Butoxy)carbonyl]-5-(dimethylthiocarbamoyl)pyrrolidin-3-yl]oxypentanoic acid (4) (60 mg, 160.35 μmol) and 1-(1H-imidazol-1-carbonyl)-1H-imidazole (31 mg, 192.44 μmol) were mixed in acetonitrile and stirred at room temperature for 1 hour. After 1 hour, amine hydrate (17 mg, 481.11 μmol) was added and the mixture was stirred at room temperature for 16 hours. LCMS from the reaction mixture showed that the desired product was present at 99%. The mixture was concentrated, the residue was dissolved in DCM, washed with NaHSO4, dried over Na2SO4 and evaporated to give tert-butyl (2S,4R)-4-(4-carbamoylbutoxy)-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate (5) (40.0 mg, purity 99.0%, 106.02 μmol, yield 66.1%).

[0354] Step 4. Synthesis of 5-[(3R,5S)-5-(dimethylthiocarbamoyl)pyrrolidin-3-yl]oxypentanamide

[0355] tert-Butyl (2S,4R)-4-(4-carbamoylbutoxy)-2-(dimethylthiocarbamoyl)pyrrolidine-1-carboxylate (5) (40.0 mg, 107.09 μmol) was dissolved in DCM (2 ml) and TFA (1 ml) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. LCMS from the reaction mixture showed that the desired product was present at 100%. The mixture was concentrated to give 5-[(3R,5S)-5-(dimethylthiocarbamoyl)pyrrolidin-3-yl]oxypentanamide (6) as the TFA salt (30.0 mg, 109.73 μmol, yield 102.4%).

[0356] Step 5. Synthesis of the obtained (2S,4R)-4-(4-carbamoylbutoxy)-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

[0357] 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)methanamine (7) (27.21 mg, 78.39 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (25.41 mg, 156.77 μmol) and ethyldi(isopropyl)amine (101.24 mg, 783.86 μmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. 5-[(3R,5S)-5-(Dimethylthiocarbamoyl)pyrrolidin-3-yl]oxypentanamide (6) (30.0 mg, 109.73 μmol) was added to the mixture and the mixture was stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was 84% by content. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 7 - 15 - 55% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 646 column: Chromatorex C18SMB100 - 5T 100*19 mm, 5 microM) to afford (2S,4R)-4-(4-carbamoylbutoxy)-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, LIT-003-10. Yield: 15.6 mg, 30.2%; Appearance: white solid; HPLC purity: 98.78%; LCMS calculated for C 33 H 42 N8O4S: 647.35; Observed: 647.2 [M+H] + 。

[0358] Synthesis of (2S,4R)-2-(Dimethylthiocarbamoyl)-4-(3-[2-(2-hydroxyethoxy)ethoxy]phenylmethoxy)-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 (LIT-003-11)

[0359]

[0360] Step 1. Synthesis of 3-2-[2-( ethan-2-yloxy)ethoxy]ethoxybenzaldehyde

[0361] 2-[2-(2-Bromoethoxy)ethoxy] Alkane (1) (800 mg, 3.17 mmol), 3-hydroxybenzaldehyde (2) (352 mg, 2.88 mmol) and potassium carbonate (597 mg, 4.33 mmol) were dissolved in DMF and stirred at 80 °C for 16 h. LCMS from the reaction mixture showed the desired product was 93% in content. The mixture was poured into water, extracted with EtOAc, the organic layer was washed with water and brine, dried over Na2SO4 and evaporated to give 3-2-[2-( Alkane-2-yloxy)ethoxy]ethoxybenzaldehyde (3) (840 mg, purity 93.0%, 2.65 mmol, yield 92%).

[0362] Step 2. Synthesis of (3-2-[2-( Alkane-2-yloxy)ethoxy]ethoxyphenyl)methanol

[0363] At 10 °C, sodium borohydride (271 mg, 7.14 mmol) was added portionwise to a stirred solution of 3-2-[2-( Alkane-2-yloxy)ethoxy]ethoxybenzaldehyde (3) (840 mg, 2.85 mmol) in MeOH and the mixture was stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was 94% in content. The mixture was poured into saturated NH4Cl solution, extracted with EtOAc, the organic layer was washed with water and brine, dried over Na2SO4 and evaporated to give (3-2-[2-( Alkane-2-yloxy)ethoxy]ethoxyphenyl)methanol (4) (830 mg, purity 94.0%, 2.63 mmol, yield 92.2%).

[0364] Step 3. Synthesis of 2-(2-2-[3-(Bromomethyl)phenoxy]ethoxyethoxy) Alkane

[0365] At 0 °C, phosphorus tribromide (825 mg, 3.08 mmol, 290.0 μl, 1.1 eq) was added dropwise to a stirred solution of (3-2-[2-( Alkane-2-yloxy)ethoxy]ethoxyphenyl)methanol (4) (830 mg, 2.8 mmol) in DCM and the mixture was stirred at room temperature for 2 h. After 2 h, the mixture was poured into water, the organic layer was washed with saturated NaHCO3 solution, dried over Na2SO4 and evaporated to give 2-(2-2-[3-(bromomethyl)phenoxy]ethoxyethoxy) Alkane (5) (800 mg, purity 80.0%, 1.78 mmol, yield 63.6%). The NMR purity of the product was 80%.

[0366] Step 4. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-2-[2-( (2-((2-((2-(3-(bromomethyl)phenoxy)ethoxy)ethoxy)ethoxy)phenyl)methoxy)pyrrolidine-1-carboxylate

[0367] At 0 °C, sodium hydride (214 mg, 8.91 mmol) was added to a stirred solution of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate (6) (611 mg, 2.23 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h, then 2-(2-2-[3-(bromomethyl)phenoxy]ethoxyethoxy) alkane (7) (800 mg, 2.23 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h, allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product was present at 24%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 33 - 40 - 60% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 468 column: CHROMATOREX C18 100*19 mm, 5 microM, 130 A) to give tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-2-[2-( (2-((2-((2-(3-(bromomethyl)phenoxy)ethoxy)ethoxy)ethoxy)phenyl)methoxy)pyrrolidine-1-carboxylate (7) (93 mg, purity 99.0%, 166.58 μmol, yield 7.5%).

[0368] Step 5. Synthesis of (2S,4R)-4-(3-[2-(2-hydroxyethoxy)ethoxy]phenylmethoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride

[0369] tert-Butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-2-[2-( (2-((2-((2-(3-(bromomethyl)phenoxy)ethoxy)ethoxy)ethoxy)phenyl)methoxy)pyrrolidine-1-carboxylate (7) (60 mg, 108.55 μmol) was dissolved in 4 M di ane-hydrochloric acid solution and stirred at 50 °C for 12 h. LCMS from the reaction mixture showed the desired product was present at 79%. The mixture was concentrated to give (2S,4R)-4-(3-[2-(2-hydroxyethoxy)ethoxy]phenylmethoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (8) (40 mg, purity 79.0%, 78.03 μmol, yield 71.8%).

[0370] Step 6. Synthesis of (2S,4R)-2-(dimethylthiocarbamoyl)-4-(3-[2-(2-hydroxyethoxy)ethoxy]phenylmethoxy)-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

[0371] Dissolve 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)methanamine (9) (24 mg, 70.49 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (23 mg, 140.99 μmol) and ethyldi(propan-2-yl)amine (91 mg, 704.95 μmol) in DMF (5 ml) and stir at 15 °C for 3 h. Add (2S,4R)-4-(3-[2-(2-hydroxyethoxy)ethoxy]phenylmethoxy)-N,N-dimethylpyrrolidine-2-carbothioamide hydrochloride (8) (40 mg, 98.78 μmol) to the mixture and stir the mixture at room temperature for 16 h. LCMS from the reaction mixture shows the desired product is present at 61%. The reaction mixture is purified by HPLC (system 0 - 3 min 13 - 20 - 40% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 741 column: Chromatorex C18 SMB100 - 5T 100*19 mm, 5 microM) to give (2S,4R)-2-(dimethylthiocarbamoyl)-4-(3-[2-(2-hydroxyethoxy)ethoxy]phenylmethoxy)-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, LIT-003-11. Yield: 29 mg, 55.4%; Appearance: Beige solid; HPLC purity: 100%; LCMS calculated for C 39 H 47 N7O6S: 742.38; Observed: 743.2 [M + H] + 。

[0372] (2S,4R)-2-(Dimethylthiocarbamoyl)-4-[(1H-indol-6-yl)methoxy]-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-003-12) Synthesis

[0373]

[0374] Step 1. Synthesis of Methyl 1-(4-methylbenzenesulfonyl)-1H-indole-6-carboxylate

[0375] At 0 °C, sodium hydride (491 mg, 20.45 mmol) was added to a stirred solution of methyl 1H-indole-6-carboxylate (1) (1.79 g, 10.22 mmol), and the mixture was stirred at 0 °C for 1 hour. After 1 hour, 4-methylbenzene-1-sulfonyl chloride (2.53 g, 13.29 mmol) was added and the mixture was allowed to warm to room temperature and stirred at room temperature for 3 hours. After 3 hours, the mixture was poured into water, extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4 and evaporated to give methyl 1-(4-methylbenzenesulfonyl)-1H-indole-6-carboxylate (2) (3.4 g, purity 80.0%, 8.26 mmol, yield 80.8%).

[0376] Step 2. Synthesis of [1-(4-methylbenzenesulfonyl)-1H-indol-6-yl]methanol

[0377] At 10 °C, lithium(1+) borohydride (454 mg, 20.61 mmol) was added in portions to a stirred solution of methyl 1-(4-methylbenzenesulfonyl)-1H-indole-6-carboxylate (2) (3.39 g, 10.3 mmol) and the reaction mixture was allowed to warm to room temperature and heated to reflux for 16 hours. After 16 hours, the mixture was cooled to room temperature, poured into saturated NH4Cl solution, extracted with EtOAc, the combined organic phases were washed with brine, dried over Na2SO4 and evaporated to give [1-(4-methylbenzenesulfonyl)-1H-indol-6-yl]methanol (3) (2.6 g, purity 86.0%, 7.42 mmol, yield 72%).

[0378] Step 3. Synthesis of 6-(Bromomethyl)-1-(4-methylbenzenesulfonyl)-1H-indole

[0379] At 0 °C, triphenylphosphine (3.13 g, 11.96 mmol) was added to a stirred solution of [1-(4-methylbenzenesulfonyl)-1H-indol-6-yl]methanol (3) (2.4 g, 7.97 mmol) in DCM, and the mixture was stirred at 0 °C for 10 minutes. After 10 minutes, carbon tetrabromide (3.92 g, 11.96 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After 16 hours, the mixture was concentrated, and the resulting residue was purified by FC (system: EtOAc - hexane) to give 6-(bromomethyl)-1-(4-methylbenzenesulfonyl)-1H-indole (4) (2.0 g, purity 95.0%, 5.22 mmol, yield 65.4%).

[0380] Step 4. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(1H-indol-6-yl)methoxy]pyrrolidine-1-carboxylate

[0381] At 0 °C, sodium hydride (263 mg, 10.97 mmol) was added to a stirred solution of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate (5) (753 mg, 2.74 mmol) in DMF, and the mixture was stirred at 0 °C for 2 hours. Then 6-(bromomethyl)-1-(4-methylbenzenesulfonyl)-1H-indole (4) (999 mg, 2.74 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 hours, allowed to warm to room temperature and stirred for 16 hours. LCMS from the reaction mixture showed the desired product was present at 25%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 13 - 20 - 65% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 403 column: XBRIDGE BEH C18 SMB100 - 5T 100*19 mm, 5 microM) to give tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(1H-indol-6-yl)methoxy]pyrrolidine-1-carboxylate (6) (87 mg, purity 98.0%, 211.28 μmol, yield 7.7%).

[0382] Step 5. Synthesis of (2S,4R)-4-[(1H-indol-6-yl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide

[0383] (2S,4R)-tert-Butyl 2-(dimethylcarbamothioyl)-4-[(1H-indol-6-yl)methoxy]pyrrolidine-1-carboxylate (6) (87 mg, 215.59 μmol) and zinc dibromide (239 mg, 1.08 mmol) were mixed in acetonitrile and stirred at 82 °C for 16 h. After 16 h, the mixture was filtered and the mother liquor was evaporated to give (2S,4R)-4-[(1H-indol-6-yl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (7) (60 mg, purity 47.0%, 92.94 μmol, yield 43.1%).

[0384] Step 6. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[(1H-indol-6-yl)methoxy]-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

[0385] 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)methanamine (8) (49 mg, 141.25 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (46 mg, 282.49 μmol) and ethyldi(propan-2-yl)amine (182 mg, 1.41 mmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-4-[(1H-Indol-6-yl)methoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (7) (60 mg, 197.74 μmol) was added to the mixture and stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 10%. The reaction mixture was purified by HPLC (System 7-15-35% 0-2-8 min H2O / ACN, flow 30 ml / min (loading pump 4 ml ACN) target mass 676 column: XBridge BEH C18 100*19 mm, 5 microM) to give a 5.4 mg sample of 68% purity which was further purified by micro-HPLC (System (modified after loading) Sample information: 15 mM NH4HCO3-ACN 30-50% ACN 0.5-6 min 5 ml / min, Chromatorex Phenyl 7.8*75 mm, 5 mkm) to give (2S,4R)-2-(dimethylcarbamothioyl)-4-[(1H-indol-6-yl)methoxy]-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, LIT-003-12. Yield: 800 mg, 8%; Appearance: yellow solid; HPLC purity: 97.11%; For C 37 H 40 Calculated LCMS for C29H35N8O3S: 677.34; Observed: 677.4 [M+H] + 。

[0386] Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-methoxy-4-methylbenzene-1-sulfonamide (LIT-003-13)

[0387]

[0388] Step 1. Synthesis of N-[3-(hydroxymethyl)phenyl]acetamide

[0389] At 0 °C, acetyl chloride (3.17 g, 40.63 mmol) was added dropwise to a stirred THF solution of (3-aminophenyl)methanol (1) (5.0 g, 40.63 mmol) and sodium bicarbonate (10.24 g, 121.88 mmol), and the mixture was stirred at room temperature for 16 h. After 16 h, the mixture was poured into water, the precipitate was filtered, washed with water, and dried under reduced pressure to give N-[3-(hydroxymethyl)phenyl]acetamide (2) (4.8 g, purity 95.0%, 27.6 mmol, yield 67.9%).

[0390] Step 2. Synthesis of N-[3-(bromomethyl)phenyl]acetamide

[0391] N-[3-(Hydroxymethyl)phenyl]acetamide (2) (600 mg, 3.63 mmol) and triphenylphosphine (1.43 g, 5.45 mmol) were dissolved in DCM, and a solution of carbon tetrabromide (1.79 g, 5.45 mmol) in ACN was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 16 h and concentrated. The residue was purified by FC (system ACN / CHCl3) to give N-[3-(bromomethyl)phenyl]acetamide (3) (240 mg, purity 95.0%, 999.62 μmol, yield 27.5%).

[0392] Step 3. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-acetamidophenyl)methoxy]pyrrolidine-1-carboxylate

[0393] At 0 °C, sodium hydride (101 mg, 4.21 mmol) was added to a stirred DMF solution of (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl ester (4) (289 mg, 1.05 mmol), and the mixture was stirred at 0 °C for 2 h, then N-[3-(bromomethyl)phenyl]acetamide (3) (239 mg, 1.05 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h, allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product was present at 18%. The reaction mixture was purified by HPLC (system 0-2-8 min 8-15-100% H2O / ACN, 30 ml\min (loading pump 4 ml ACN), target mass 421 column: Chromatorex 100*19 mm, 5 microM) to give tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-acetamidophenyl)methoxy]pyrrolidine-1-carboxylate (5) (43 mg, 102.0 μmol, yield 9.7%).

[0394] Step 4. Synthesis of N-[3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)phenyl]acetamide

[0395] Dissolve tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-acetamidophenyl)methoxy]pyrrolidine-1-carboxylate (5) (43 mg, 102.0 μmol) in DCM (2 ml), and add TFA (1 ml) to the mixture at 0 °C. Stir the resulting mixture at room temperature for 2 h. LCMS from the reaction mixture shows the content of the desired product to be 78%. Concentrate the mixture to give N-[3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)phenyl]acetamide (6) as the TFA salt (35 mg, 78.0% purity, 84.93 μmol, 83.2% yield).

[0396] Step 5. Synthesis of (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-acetamidophenyl)methoxy]-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

[0397] 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)methanamine (7) (27 mg, 77.72 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (25 mg, 155.43 μmol), and ethyldi(isopropyl)amine (100 mg, 777.15 μmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. N-[3-([(3R,5S)-5-(Dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)phenyl]acetamide (6) (35 mg, 108.89 μmol) was added to the mixture and stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 91%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 7 - 15 - 40% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 694 column: XBRIDGE BEH C18 SMB100 - 5T 100*19 mm, 5 microM) to afford (2S,4R)-2-(dimethylcarbamothioyl)-4-[(3-acetamidophenyl)methoxy]-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, LIT-003-13. Yield: 34.1 mg, 63.1%; Appearance: beige solid; HPLC purity: 100%; Calculated LCMS for C 37 H 42 N8O4S: 695.35; Observed: 694.4 [M + H] + 。

[0398] (2S,4R)-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-carbonylphenyl)methyl]-4-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]methoxypyrrolidine-1-carboxamide (LIT-003-14) Synthesis

[0399]

[0400] Step 1. Synthesis of 3-[1-( 2-yl)-1H-1,2,3,4-tetrazol-5-yl]benzaldehyde

[0401] Mix 3-(1H-1,2,3,4-tetrazol-5-yl)benzaldehyde (1) (2.0 g, 11.49 mmol), 3,4-dihydro-2H-pyran (1.45 g, 17.24 mmol) and 4-methylbenzenesulfonic acid hydrate (21.84 mg, 114.92 μmol) in acetone and stir at 45 °C for 16 h. Concentrate the reaction mixture and purify the residue by FC (system ACN / CHCl3) to obtain 3-[1-( Alkan-2-yl)-1H-1,2,3,4-tetrazol-5-yl]benzaldehyde (2) (2.8 g, 90.0% purity, 9.76 mmol, 84.9% yield).

[0402] Step 2. Synthesis of 3-[1-( Alkan-2-yl)-1H-1,2,3,4-tetrazol-5-yl]phenylmethanol

[0403] Dissolve 3-[1-( Alkan-2-yl)-1H-1,2,3,4-tetrazol-5-yl]benzaldehyde (2) (2.0 g, 7.75 mmol) in MeOH and add sodium borohydride (442 mg, 11.62 mmol) portionwise at room temperature. Stir the mixture at room temperature for 16 h. LCMS from the reaction mixture shows the desired product content is 84%. Pour the mixture into water and extract with EtOAc. Wash the organic phase with brine, dry over Na2SO4 and concentrate to obtain 3-[1-( Alkan-2-yl)-1H-1,2,3,4-tetrazol-5-yl]phenylmethanol (3) (1.38 g, 84.0% purity, 4.45 mmol, 57.5% yield).

[0404] Step 3. Synthesis of 5-[3-(bromomethyl)phenyl]-1-( Alkan-2-yl)-1H-1,2,3,4-tetrazole

[0405] At 0 °C, add triphenylphosphine (2.39 g, 9.11 mmol) to a stirred DCM solution of 3-[1-( Alkan-2-yl)-1H-1,2,3,4-tetrazol-5-yl]phenylmethanol (3) (1.58 g, 6.07 mmol), then add 1-bromopyrrolidine-2,5-dione (1.61 g, 9.11 mmol) and stir the resulting mixture at room temperature for 16 h. Concentrate the mixture and purify the residue by FC (system ACN / CHCl3) to obtain 5-[3-(bromomethyl)phenyl]-1-( (2S,4R)-2-(Dimethylthiocarbamoyl)-4-(3-[1-(alkyl-2-yl)-1H-1,2,3,4-tetrazol-5-yl]phenylmethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (6) (280 mg, purity 93.0%, 504.01 μmol, yield 29.6%).

[0406] Step 4. Synthesis of (2S,4R)-2-(Dimethylthiocarbamoyl)-4-(3-[1-( (alkyl-2-yl)-1H-1,2,3,4-tetrazol-5-yl]phenylmethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0407] To a stirred solution of (2S,4R)-2-(Dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (5) (467 mg, 1.7 mmol) in DMF at 0 °C was added sodium hydride (163 mg, 6.81 mmol), and the mixture was stirred at 0 °C for 2 h, then 5-[3-(Bromomethyl)phenyl]-1-( (alkyl-2-yl)-1H-1,2,3,4-tetrazole (4) (550 mg, 1.7 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h, allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product was present at 67%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 38 - 45 - 60 H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 516 column: XBridge BEH C18 100*19 mm, 5 microM) to afford (2S,4R)-2-(Dimethylthiocarbamoyl)-4-(3-[1-( (alkyl-2-yl)-1H-1,2,3,4-tetrazol-5-yl]phenylmethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (6) (280 mg, purity 93.0%, 504.01 μmol, yield 29.6%).

[0408] Step 5. Synthesis of (2S,4R)-N,N-Dimethyl-4-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]methoxypyrrolidine-2-thiocarboxamide hydrochloride

[0409] (2S,4R)-2-(Dimethylthiocarbamoyl)-4-(3-[1-( (alkyl-2-yl)-1H-1,2,3,4-tetrazol-5-yl]phenylmethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (6) (63 mg, 121.94 μmol) was dissolved in 4 M di in an alkane-hydrochloric acid solution (10 ml) and stirred at 70 °C for 6 hours. LCMS from the reaction mixture showed that the content of the desired product was 58%. The reaction mixture was concentrated to give (2S,4R)-N,N-dimethyl-4-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]methoxypyrrolidine-2-carbothioamide hydrochloride (7) (40 mg, purity 58.0%, 62.89 μmol, yield 51.6%).

[0410] Step 6. Synthesis of (2S,4R)-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-carbonylphenyl)methyl]-4-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]methoxypyrrolidine-1-carboxamide

[0411] 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)methanamine (8) (27 mg, 77.5 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (25 mg, 154.99 μmol) and ethyldi(isopropyl)amine (100 mg, 774.97 μmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 hours. (2S,4R)-N,N-Dimethyl-4-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]methoxypyrrolidine-2-carbothioamide hydrochloride (7) (40 mg, 108.43 μmol) was added to the mixture and stirred at room temperature for 16 hours. LCMS from the reaction mixture showed that the content of the desired product was 68%. The reaction mixture was purified by HPLC (system 0-2-8 min 0-0-35% H2O / ACN / 0.1% NH4OH 30 ml\min (loading pump 4 ml ACN), target mass 705 column: XBRIDGE BEH C18 100*19 mm, 5 microM) to give (2S,4R)-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-carbonylphenyl)methyl]-4-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]methoxypyrrolidine-1-carboxamide, LIT-003-14. Yield: 35.3 mg, 64.5%; Appearance: beige solid; HPLC purity: 100%; for C 36H 39 N 11 LCMS calculated for O3S: 706.33; Observed: 706.2 [M+H] + 。

[0412] (2S,4R)-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]-4-[(1H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-1-carboxamide (LIT-003-15) Synthesis

[0413]

[0414] Step 1. Synthesis of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-[(2H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-1-carboxylate

[0415] At 0 °C, sodium hydride (175 mg, 7.29 mmol) was added to a stirred solution of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (1) (500 mg, 1.82 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h, then (1H-1,2,3,4-tetrazol-5-yl)methanol (2) (182 mg, 1.82 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h and allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product was present at 35%. The reaction mixture was purified by HPLC (System 0-2-80-2-8 min 3-10-40% H2O / ACN / 0.1% FA 30 ml / min (loading pump 4 ml ACN), target mass 356 Column: CHROMATOREX C18 SMB100-5T 100*19 mm, 5 microM) to afford tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-[(2H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-1-carboxylate (3) (115 mg, purity 98.0%, 316.18 μmol, yield 17.3%).

[0416] Step 2. Synthesis of (2S,4R)-N,N-dimethyl-4-[(2H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-2-carbothioamide (2S,4R)-tert-Butyl 2-(dimethylcarbamothioyl)-4-[(2H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-1-carboxylate (3) (55 mg, 154.3 μmol) was dissolved in DCM (2 ml), and TFA (1 ml) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 1 h. LCMS from the reaction mixture showed that the content of the desired product was 37%. The mixture was concentrated to give (2S,4R)-N,N-dimethyl-4-[(2H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-2-carbothioamide (4) as the TFA salt (40 mg, purity 37.0%, 57.74 μmol, yield 37.4%).

[0417] Step 3. Synthesis of (2S,4R)-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]-4-[(1H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-1-carboxamide

[0418] 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)methanamine (5) (39 mg, 111.48 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (36 mg, 222.95 μmol), and ethyldi(isopropyl)amine (144 mg, 1.11 mmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-N,N-Dimethyl-4-[(2H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-2-carbothioamide (4) (40 mg, 156.05 μmol) was added to the mixture and stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 42%. The reaction mixture was purified by HPLC (system 0-2-8 min 0-5-45% H2O / MEOH / 0.1% NH4OH 30 ml\min (loading pump 4 ml MEOH), target mass 629 column: XBRIDGE BEHC18 SMB100-5T 100*19 mm, 5 microM) to give (2S,4R)-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-carbonylphenyl)methyl]-4-[(1H-1,2,3,4-tetrazol-5-yl)methoxy]pyrrolidine-1-carboxamide, LIT-003-15. Yield: 25.0 mg, 33.8%; Appearance: white solid; HPLC purity: 97.34%; LCMS calculated for C 30 H 35 N 11 O3S: 630.29; Observed: 630.4 [M+H] + 。

[0419] Synthesis of 5-chloro-N-(3-chloro-5-cyclopropylphenyl)-2-methoxy-4-methylbenzenesulfonamide (LIT-003-16)

[0420]

[0421] Step 1. Synthesis of tert-butyl (2S,4R)-4-(2-cyanoethoxy)-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate

[0422] At 0 °C, sodium hydride (175 mg, 7.29 mmol) was added to a stirred solution of (2S,4R)-tert-butyl 2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate (1) (500 mg, 1.82 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h. Then acrylonitrile (2) (961 mg, 1.82 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h and allowed to warm to room temperature and stirred for 16 h. LCMS from the reaction mixture showed the desired product was present at 57%. The reaction 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 327 column: Chromatorex C18SMB100 - 5T 100*19 mm, 5 microM) to give (2S,4R)-tert-butyl 4-(2-cyanoethoxy)-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate (3) (160 mg, 488.64 μmol, 26.8% yield).

[0423] Step 2. Synthesis of (2S,4R)-tert-butyl 2-(dimethylcarbamothioyl)-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-1-carboxylate

[0424] (2S,4R)-tert-Butyl 4-(2-cyanoethoxy)-2-(dimethylcarbamothioyl)pyrrolidine-1-carboxylate (3) (160 mg, 488.64 μmol), sodium azide (95 mg, 1.47 mmol) and ammonium chloride (52 mg, 977.14 μmol) were dissolved in DMF and stirred at 100 °C for 80 h. LCMS from the reaction mixture showed the desired product was present at 79%. The mixture was concentrated to give (2S,4R)-tert-butyl 2-(dimethylcarbamothioyl)-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-1-carboxylate (4) (60 mg, 79.0% purity, 127.95 μmol, 26.2% yield).

[0425] Step 3. Synthesis of (2S,4R)-N,N-dimethyl-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-2-thiocarboxamide

[0426] (2S,4R)-tert-Butyl 2-(dimethylcarbamothioyl)-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-1-carboxylate (4) (60 mg, 161.96 μmol) was dissolved in DCM (2 ml), and TFA (1 ml) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 h. LCMS from the reaction mixture showed the desired product was present at 63%. The mixture was concentrated to afford (2S,4R)-N,N-dimethyl-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-2-carbothioamide (5) as the TFA salt (40 mg, purity 63.0%, 93.21 μmol, yield 57.5%).

[0427] Step 4. Synthesis of (2S,4R)-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-carbonylphenyl)methyl]-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-1-carboxamide

[0428] 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)methanamine (6) (37 mg, 105.63 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (34 mg, 211.26 μmol), and ethyldi(isopropyl)amine (136 mg, 1.06 mmol) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. (2S,4R)-N,N-Dimethyl-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-2-carbothioamide (5) (40 mg, 147.95 μmol) was added to the mixture and stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 43%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 23 - 30 - 55% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 643 column: Chromatorex C18SMB100 - 5T100*19 mm, 5 microM) to afford (2S,4R)-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-carbonylphenyl)methyl]-4-[2-(1H-1,2,3,4-tetrazol-5-yl)ethoxy]pyrrolidine-1-carboxamide, LIT-003-16. Yield: 18.0 mg, 25.7%; Appearance: white solid; HPLC purity: 100%; For C 31 H 37 N 11 LCMS calculated for C: 644.31; Observed: 644.4 [M+H] + 。

[0429] (2S,4R)-2-(Dimethylcarbamothioyl)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]-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 (LIT-003-17) synthesis

[0430]

[0431] Step 1. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]pyrrolidine-1-carboxylate

[0432] At 0 °C, sodium hydride (175 mg, 7.29 mmol) was added to a stirred solution of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylate (1) (500 mg, 1.82 mmol) in DMF, and the mixture was stirred at 0 °C for 2 h. Then 5-(2-bromoethyl)imidazolidine-2,4-dione (2) (375 mg, 1.82 mmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h. The mixture was allowed to warm to room temperature and stirred for 16 h. LCMS of the reaction mixture showed that the desired product was present at 18%. The reaction mixture was purified by HPLC (system 0 - 2 - 8 min 13 - 20 - 100% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 400 column: CHROMATOREX C18 100*19 mm, 5 microM) to give tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]pyrrolidine-1-carboxylate (3) (37 mg, purity 90.0%, 83.15 μmol, yield 4.6%).

[0433] Step 2. Synthesis of (2S,4R)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]-N,N-dimethylpyrrolidine-2-carbothioamide

[0434] (2S,4R)-2-(dimethylcarbamothioyl)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]pyrrolidine-1-carboxylate (3) (37 mg, 92.39 μmol) was dissolved in DCM (2 ml), and TFA (1 ml) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. LCMS of the reaction mixture showed that the desired product was present at 88%. The mixture was concentrated to give (2S,4R)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (4) as the TFA salt (30 mg, purity 88.0%, 87.89 μmol, yield 95%).

[0435] Step 3. Synthesis of (2S,4R)-2-(dimethylthiocarbamoyl)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]-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

[0436] Dissolve 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)methanamine (5) (25 mg, 71.39 μmol), 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole (23 mg, 142.78 μmol) and ethyldi(propan-2-yl)amine (92 mg, 713.88 μmol, 120.0 μl, 10.0 eq) in DMF (5 ml) and stir at 15 °C for 3 h. Add (2S,4R)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]-N,N-dimethylpyrrolidine-2-carbothioamide (4) (30 mg, 99.87 μmol) to the mixture and stir at room temperature for 16 h. LCMS from the reaction mixture shows the desired product content to be 56%. The reaction mixture is purified by HPLC (system 0-2-8 min 13-20-40% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 673 column: Chromatorex C18 100*19 mm, 5 microM) to give (2S,4R)-2-(dimethylthiocarbamoyl)-4-[2-(2,5-dioxoimidazolidin-4-yl)ethoxy]-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, LIT-003-17. Yield: 11.5 mg, 23.4%; Appearance: Beige solid; HPLC purity: 100%; Calculated LCMS for C 33 H 39 N9O5S: 674.31; Observed: 674.4 [M+H] + 。

[0437] Synthesis of 3-([(3R,5S)-5-(dimethylthiocarbamoyl)-1-[(2-methyl-4-methyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradec-1(14),3(7),5,10,12-pentaen-9-carbonylphenyl)methyl]carbamoylpyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid (LIT-003-18)

[0438]

[0439] Step 1. Synthesis of 3-(chloromethyl)benzene-1-sulfonic acid

[0440] 3-(Bromomethyl)benzene-1-sulfonyl chloride (1) (200 mg, 746.56 μmol) was dissolved in distilled water. The mixture was added to 1-[4-(chloromethyl)benzene-1-sulfonic acid)-2-nitropropene (10 ml) and HCl (10 ml) and stirred at 40°C for 16 hours. The reaction mixture was concentrated. Water and CHCl3 were added to the residue, and the aqueous layer was separated and evaporated to give 3-(chloromethyl)benzene-1-sulfonic acid (2) (130 mg, purity 87.0%, 547.31 μmol, yield 60.5%).

[0441] Step 2. Synthesis of 3-([(3R,5S)-1-[(tert-butoxy)carbonyl]-5-(dimethylthiocarbamoyl)pyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid

[0442] To a stirred solution of tert-butyl (2S,4R)-2-(dimethylthiocarbamoyl)-4-hydroxypyrrolidine-1-carboxylate (3) (130 mg, 473.8 μmol) in DMF at 0°C was added sodium hydride (46 mg, 1.9 mmol), and the mixture was stirred at 0°C for 2 hours. 3-(Chloromethyl)benzene-1-sulfonic acid (2) (98 mg, 474.62 μmol) was then added, and the reaction mixture was stirred at 0°C for an additional 2 hours, allowed to warm to room temperature, and stirred for 16 hours. LCMS from the reaction mixture showed 47% of the desired product. The reaction mixture was purified by HPLC (system 0-2-8 min 13-20-25% H2O / ACN 30 ml\min (loading pump 4 ml ACN), target mass 444 column: CHROMATOREX C18 100*19 mm, 5 microM) to give 3-([(3R,5S)-1-[(tert-butoxy)carbonyl]-5-(dimethylthiocarbamoyl)pyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid (4) (67 mg, purity 98.0%, 147.69 μmol, yield 31.1%).

[0443] Synthesis of 3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid

[0444] Dissolve 3-([(3R,5S)-1-[(tert-butoxy)carbonyl]-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid (4) (67 mg, 150.71 μmol) in DCM (2 ml), and add TFA (1 ml) to the mixture at 0 °C. Stir the resulting mixture at room temperature for 2 hours. LCMS from the reaction mixture showed that the content of the desired product was 90%. Concentrate the mixture to obtain 3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid (5) (50 mg, purity 90.0%, 130.64 μmol, yield 86.7%) as the TFA salt.

[0445] Synthesis of 3-([(3R,5S)-5-(dimethylcarbamothioyl)-1-[(2-methyl-4,4-dimethyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaen-9-carbonylphenyl)methyl]carbamoylpyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid

[0446] Dissolve 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)methanamine (6) (36 mg, 103.64 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (34 mg, 207.28 μmol) and ethyldi(propan-2-yl)amine (134 mg, 1.04 mmol) in DMF (5 ml) and stir at 15 °C for 3 h. Add 3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzene-1-sulfonic acid (5) (50 mg, 145.16 μmol) to the mixture and stir at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was 90% in content. The reaction mixture was purified by HPLC (system 0 - 5 - 35% 0 - 2 - 8 min H2O / ACN / 0.034% HCl, flow rate 30 ml / min (loading pump 4 ml ACN) target mass 717 column): Chromatorex C18 SMB100 - 5T 100*19 mm, 5 microM) to give 3-([(3R,5S)-5-(dimethylcarbamothioyl)-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)methyl]carbamoylpyrrolidin-3-yl]oxymethyl)benzene-1-sulfonate, LIT-003-18. Yield: 18.0 mg, 23.7%; Appearance: white solid; HPLC purity: 98.71%; Calculated LCMS for C 35 H 39 N7O6S2: 718.27; Observed: 718.2 [M+H] + .

[0447] Synthesis of methyl 3-([(3R,5S)-5-(dimethylcarbamothioyl)-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)methyl]carbamoylpyrrolidin-3-yl]oxymethyl)benzoate (LIT-003-19)

[0448]

[0449] Step 1. Synthesis of tert-butyl (2S,4R)-2-(dimethylcarbamothioyl)-4-[3-(methoxycarbonyl)phenyl]methoxypyrrolidine-1-carboxylate

[0450] At 0 °C, sodium hydride (87 mg, 3.64 mmol) was added to a stirred solution of (2S,4R)-2-(dimethylcarbamothioyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1) (250 mg, 911.15 μmol) in DMF, and the mixture was stirred at 0 °C for 2 h. Then methyl 3-(bromomethyl)benzoate (2) (208 mg, 910.62 μmol) was added, and the reaction mixture was stirred at 0 °C for an additional 2 h. The mixture was allowed to warm to room temperature and stirred for 16 h. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. LCMS from the reaction mixture showed that the desired product was present at 62%. The reaction mixture was purified by HPLC (system 0 - 0.2 - 3 min 0 - 0 - 20% H2O / ACN 30 ml / min (loading pump 4 ml ACN), target mass 408 column: Chromatorex C18 SMB100 - 5T 100*19 mm, 5 microM) to afford 3-([(3R,5S)-1-[(tert-butoxy)carbonyl]-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzoic acid (3) (160 mg, 391.67 μmol, 43% yield).

[0451] Step 2. Synthesis of methyl 3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzoate

[0452] 3-([(3R,5S)-1-[(tert-butoxy)carbonyl]-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzoic acid (3) (160 mg, 391.99 μmol) was dissolved in DCM (2 ml), and TFA (1 ml) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 2 h. LCMS from the reaction mixture showed that the desired product was present at 60%. The mixture was concentrated to afford 3-([(3R,5S)-5-(dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzoic acid (4) as the TFA salt (120 mg, purity 60.0%, 233.47 μmol, 59.5% yield).

[0453] Step 3. Synthesis of methyl 3-([(3R,5S)-5-(dimethylcarbamothioyl)-1-[(2-methyl-4,4-dimethyl-2,4,5,9-tetraazatricyclo[8.4.0.0,3,7]tetradeca-1(14),3(7),5,10,12-pentaen-9-carbonylphenyl)methyl]carbamoyl]pyrrolidin-3-yl]oxymethyl)benzoate

[0454] 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 (5) (96 mg, 277.21 μmol), 1-(1H-imidazol-1-carbonyl)-1H-imidazole (90 mg, 554.41 μmol), and ethyldi(isopropyl)amine (358 mg, 2.77 mmol, 480.0 μl, 10.0 equiv) were dissolved in DMF (5 ml) and stirred at 15 °C for 3 h. 3-([(3R,5S)-5-(Dimethylcarbamothioyl)pyrrolidin-3-yl]oxymethyl)benzoic acid (4) (120 mg, 389.11 μmol) was added to the mixture and stirred at room temperature for 16 h. LCMS from the reaction mixture showed the desired product was present at 57%. The reaction mixture was purified by HPLC (system 0-2-8 min 43-50-75% H2O / ACN / 0.037% HCl 30 ml / min (loading pump 4 ml ACN), target mass 681 column: Chromatorex C18 SMB100-5T 100*19 mm, 5 microM) to afford 3-([(3R,5S)-5-(Dimethylcarbamothioyl)-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)methyl]carbamoyl pyrrolidin-3-yl]oxymethyl)benzoic acid hydrochloride, LIT-003-19. Yield: 6.4 mg, 3.4%; Appearance: yellow solid; HPLC purity: 100%; For C 36 H 40 Calculated LCMS for ClN7O5S: 682.31; Observed: 682.2 [M+H] + 。

[0455] Example 2 Bioassay

[0456] The activation constant (EC 50 , in nM) was measured in a CHO cell line expressing the oxytocin receptor by the IP-One IP1 accumulation assay.

[0457] These values are the mean ± SEM of at least three independent experiments.

[0458]

[0459]

[0460] Example 3 V1A / OT Selectivity Assay

[0461] The efficacy comparison has been carried out as an OT receptor agonist (measured as described in Example 2) or as a V1A receptor antagonist (measured as calcium signal, as shown below).

[0462]

Claims

1. A compound of the following formula (I): Wherein, X is selected from -H, halogen, -(C1-C6)-alkyl group, -O-(C1-C6)-alkyl group, -S-(C1-C6)-alkyl group, and -O-CF3, -S-CF3, especially -Me or -Cl, more especially -Me; R is selected from the groups including the following: --(C1-C6)-alkyl group, especially -Me; --(C1-C6)-alkyl-V group, especially -CH2-CH2--V, where V is halogen, especially -F; --O-(C1-C4)-alkyl group, especially -OMe; --S-(C1-C4)-alkyl group, especially -SMe; --O-(C2-C4)-alkyl-OH and -S-(C2-C4)-alkyl-OH groups, especially -O-(CH2) i -OH, where i ranges from 2 to 4, and i is more particularly 2, 3 or 4; --O(-(C2-C4)-alkyl-O) n -H and -S(-(C2-C4)-alkyl-O) n -H group, especially -O(-CH2-CH2-O) n -H, where n ranges from 2 to 4, and n is more especially 2; --O-(C2-C4)-alkyl -O-(C1-C4)-alkyl, -S-(C2-C4)-alkyl -O-(C1-C4)-alkyl, -O-(C2-C4)-alkyl -S-(C1-C4)-alkyl and -S-(C2-C4)-alkyl -S-(C1-C4)-alkyl groups, especially -O-(CH2) i -OMe, where i ranges from 2 to 4 and i is more particularly 2; --O-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -S-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -O-(C2-C4)-alkyl -S-(C1-C4)-alkyl-W” and -S-(C2-C4)-alkyl-S-(C1-C4)-alkyl-W” groups, where W” is halogen, especially -F, such as –O-CH2-CH2-O-(CH2)2-F; --O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl and -S(-(C2-C4)-alkyl-O) m -(C1-C4)-, especially -O(-CH2-CH2-O) m -Me or -O(-CH2-CH2-O) m -Et, where m ranges from 2 to 4, m being more particularly 2; --O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W”-S(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W” group, where W” is a halogen, especially -F, for example –O(-CH2-CH2-O)2-(CH2)2-F; --O-(C1-C6)-alkyl-V and -S-(C1-C6)-alkyl-V groups, especially -CH2-CH2-V; V is selected from the groups including the following: o-C(=O)NR d R d ’, R d and R d ’ are independently H or a -(C1-C6) alkyl group, especially H; o-S(=O)2NR d R d ’, R d and R d ’ are independently H or a -(C1-C6)-alkyl group, especially H; -C(=O)OR d , where R d is H or a -(C1-C6)-alkyl group; o-S(=O)2OH; o halogen, especially -F; o-cyclo-(C3-C6)-alkyl group, which may be optionally substituted by at least one group selected from -(C1-C6)-alkyl and =O groups; o-heterocyclo-(C3-C6)-alkyl group, which may be optionally substituted by at least one group selected from -(C1-C6)-alkyl and =O groups, such as imidazolidine-2,4-dione group; The O-(C1-C6)-alkyl-V group is for example of the following formula: -O-(C1-C4)-alkyl-Ar, especially -O-(CH2) j -Ar, where j ranges from 1 to 4, j is especially 1 or 2, and Ar is an aryl group such as phenyl, or a heteroaryl group such as indolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and the aryl or heteroaryl group is optionally substituted by at least one R'' group, especially at least one -OH group, and R'' is selected from the following group: o-OH; o halogen, especially -F; o-O-(C1-C6)-alkyl and -S-(C1-C6)-alkyl, especially -OMe, or -O-cyclo-(C3-C6)-alkyl, especially -O-cyclopropyl; o-O-(C2-C4)-alkyl-OH and -S-(C2-C4)-alkyl-OH groups, in particular -O-(CH2) i -OH, where i ranges from 2 to 4, and i is more particularly 2, 3 or 4; o-O(-(C2-C4)-alkyl-O) n -H and -S(-(C2-C4)-alkyl-O) n -H groups, especially -O(-CH2-CH2-O) n -H, where n ranges from 2 to 4, and n is more especially 2; o-O-(C2-C4)-alkyl-O-(C1-C4)-alkyl, -S-(C2-C4)-alkyl-O-(C1-C4)-alkyl, -O-(C2-C4)-alkyl -S-(C1-C4)-alkyl and -S-(C2-C4)-alkyl-S-(C1-C4)-alkyl groups, in particular -O-(CH2) i -OMe, where i ranges from 2 to 4 and i is more particularly 2; o-O-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -S-(C2-C4)-alkyl-O-(C1-C4)-alkyl-W”, -O-(C2-C4)-alkyl-S-(C1-C4)-alkyl-W” and -S-(C2-C4)-alkyl-S-(C1-C4)-alkyl-W” groups, where W” is a halogen, especially -F, for example –O-CH2-CH2-O-(CH2)2-F; -O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl groups, especially -O(-CH2-CH2-O) m -Me or -O(-CH2-CH2-O) m -Et, where m ranges from 2 to 4, m is especially 2; o-O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W” and -S(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl-W” group where W” is halogen, especially -F, such as –O(-CH2-CH2-O)2-(CH2)2-F; o-(C1-C6)-alkyl or -cyclo-(C3-C6)-alkyl, especially cyclopropyl; o-(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 being more especially 1 or 2, and W and W' are halogen, especially -F, OR a , where R a represents -H or -(C1-C4)-alkyl especially H or Me, or is 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 group or -(C1-C4)-alkyl-Ar', where Ar' is aryl or heteroaryl, especially furyl; o-(C1-C6)-alkyl-Y-Z group, especially -(CH2) l -Y-Z, where l ranges from 1 to 6, l is more especially 1 or 2, Y is -O-, -NH- or absent, and Z is selected from saturated heterocyclic groups and heteroaryl groups, the saturated heterocyclic groups especially being morpholinyl, tetrahydropyranyl, imidazolidinyl, the saturated heterocyclic groups optionally being substituted by at least one =O group and representing for example imidazolidine-2,4-dione, the heteroaryl group especially being tetrazolyl; o an aryl or heteroaryl group, in particular a pyrazolyl or tetrazolyl group, the aryl or heteroaryl group being optionally substituted by at least one R group selected from -(C1-C6)-alkyl and -NH2 groups c groups; o-(C0-C6)-alkyl-C(=O)OR d , where R d is H or a -(C1-C6)-alkyl group, especially H, -(C0-C6)-alkyl -C(=O)NR d R d ’, R d and R d ’ are independently H or a -(C1-C6)-alkyl group, especially H, -(C0-C6)-alkyl -S(=O)2OR d ,R d is H or a -(C1-C6)-alkyl group, especially H, or -(C0-C6)-alkyl-S(=O)2NR d R d ’ Group, R d and R d ’ are independently H, a -(C1-C6)-alkyl group, especially H, or -NH-C(=O)-C1-C6-alkyl groups, especially -NH-C(=O)-Me group, more especially -COOH, -C(=O)NH2, -S(=O)2OH, -S(=O)2NH2 or –(CH2)2-S(=O)2NH2 groups; -NHC(=O)-(C1-C6)-alkyl group, especially -NHC(=O)-Me; The -O-(C1-C4)-alkyl-Ar group is for example one of the following formulas: - halogen, especially -F; --CF3; or R is -F and the hydrogen geminal thereto is replaced by -F, and R together with the carbon atom C to which it is bonded and the hydrogen geminal thereto replaced by -F forms a CF2 residue; or an enantiomer, diastereomer and / or pharmaceutically acceptable salt or solvate thereof.

2. The compound according to claim 1, wherein the compound has the following formula (I): wherein, X is -Me or -Cl, especially -Me; R is selected from the group consisting of: --O-(C1-C4)-alkyl group, especially -OMe; --O-(C2-C4)-alkyl-OH group, especially -O-(CH2) i -OH, where i ranges from 2 to 4, and i is more particularly 2; --O(-(C2-C4)-alkyl-O) n -H group, especially -O(-CH2-CH2) n -OH, where n ranges from 2 to 4, and n is more especially 2; --O-(C2-C4)-alkyl-O-(C1-C4)-alkyl group, especially -O-(CH2) i -OMe, where i ranges from 2 to 4, and i is more especially 2; --O(-(C2-C4)-alkyl-O) m -(C1-C4)-alkyl, especially -O(-CH2-CH2-O) m -Me or -O(-CH2-CH2-O) m -Et, wherein m ranges from 2 to 4, and m is more especially 2; --O-(C1-C4)-alkyl-Ar, especially -O-(CH2) j -Ar, where j ranges from 1 to 4, j is more particularly 1, and Ar is an aryl group optionally substituted by at least one R'' group as defined in claim 1, especially at least one -OH group, The -O-(C1-C4)-alkyl-Ar group has, for example, the following formula: -halogen, especially -F.

3. The compound according to claim 1, wherein the compound has the following formula (I): wherein, X is -Me or -Cl, especially -Me; R is selected from -O-(C1-C4)-alkyl-Ar group, especially -O-(CH2) j -Ar, where j ranges from 1 to 4, j is more particularly 1, and Ar is an aryl group optionally substituted by at least one R'' group as defined in claim 1, especially at least one -OH group, and the -O-(C1-C4)-alkyl-Ar group has, for example, the following formula:

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

5. The compound according to any one of claims 1 to 4, wherein, X is Me.

6. The compound according to any one of claims 1 to 4, wherein, X is Cl.

7. The compound according to any one of claims 1 to 6, wherein, R is selected from:

8. A pharmaceutical, dermatological or cosmetic composition, comprising the compound according to any one of claims 1 to 7, mixed with at least one pharmaceutically acceptable excipient.

9. The compound according to any one of claims 1 to 7, wherein the compound is used for preventing and / or treating diseases, disorders or conditions, which are: 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 disorders, especially anorexia, bulimia and Prader-Willi syndrome; schizophrenia; neurodevelopmental disorders; social interaction disorders; paraphilic behavior; skin, muscle, bone aging; and any disease in which oxytocin is known to have a beneficial effect.

10. A composition, the composition comprising at least one compound according to any one of claims 1 to 7 and a diuretic such as urea or its salts or a V2r antagonist, the composition being for simultaneous, separate or dispersed therapeutic use as a combined product for preventing and / or treating a disease, disorder or condition, said disease, disorder or condition being: autism, autism spectrum disorder, in particular for treating social interaction impairment in 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; Paraphilic behavior; Skin, muscle, bone aging; and any disease in which oxytocin is known to have a beneficial effect.

Images