BR112018004956B1 - COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND - Google Patents

Abstract

The present invention relates to a compound according to formula (I) wherein R1 is selected from the group consisting of 5- and 6-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, heterocycloalkyl of (4-6) members and phenyl; R2 is selected from (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is selected from phenyl, 5-membered heteroaryl and 6-membered heteroaryl; R4 is selected from hydrogen, halogen, (C1-C4)alkyl and halo(C1-C4)alkyl; X1 is selected from CH, C(Rb) and N, X2 is selected from CH and N; Y is selected from -NH- and -O-; m is 0 or 1; n is 0 or 1; L represents a bond, -O-, -NH- or -N(Rc)-; or pharmaceutically acceptable salts, hydrates or solvates thereof. The invention further relates to intermediates for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases with said compounds and to the use of said compounds in the manufacture of medicaments. .

Description

[01] This invention relates to new non-steroidal compounds that are effective modulators of the glucocorticoid receptor and intermediates for their preparation, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases with said compounds and the use of said compounds in the manufacture of medicines.

BASICS OF THE INVENTION

[02] The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family of transcription factors and a member of the steroid hormone transcription factor family that, when bound to a ligand, promotes or suppresses gene transcription . Glucocorticoid receptor agonists occur naturally or can be prepared synthetically. Glucocorticoids (GC) that interact with GR are potent anti-inflammatory agents and have been used as such to control a wide range of allergic and inflammatory conditions such as asthma, rheumatoid arthritis, eczema and psoriasis. Glucocorticoids have also been used for their immunosuppressive properties and for their antitumor effects.

[03] Glucocorticoids have been applied locally to treat dermatitis, asthma, conjunctivitis and other ophthalmological disorders.

[04] However, the use of glucocorticoids is limited by topical and systemic side effects, these effects include skin and muscle atrophy, osteoporosis, diabetes, wound healing, susceptibility to infection, HPA dysfunction, adrenal atrophy, cataracts, ulcers peptic ulcers, hypertension, metabolic syndrome and electrolyte imbalance [Shacke et al., Pharmacology and Therapeutics (2002), vol. 96 (1), 23-43].

[05] Side effects are generally more serious after systemic rather than topical application. However, even topical therapy can induce systemic adverse effects, as observed after skin therapy for inflammatory dermatitis and pulmonary therapy for asthma. Side effects occur with different prevalence, in different organs and after different durations of therapy. The severity varies from more cosmetic aspects, for example, teleangiectasia and hypertrichosis, to serious disabling and even life-threatening situations (for example, gastric hemorrhage). [Shacke et al., Pharmacology and Therapeutics (2002), vol. 96 (1), 23-43].

[06] The glucocorticoid receptor is activated by the binding of glucocorticoid hormone cortisol and its synthetic derivatives as well as by non-steroidal agonists. Thus, steroid and non-steroid based glucocorticoid analogues are well known in the art.

[07] Document WO2008/076048 describes indazolyl esters and amide derivatives for the treatment of disorders mediated by the glucocorticoid receptor.

[08] WO2009/142571 describes phenyl- and benzodioxinyl-substituted indazole derivatives as glucocorticoid receptor modulators.

[09] Document WO2009/142569 describes phenyl indazole derivatives and pyridinyl derivatives as glucocorticoid receptor modulators.

[010] There is a continued need to develop new non-steroidal glucocorticoid receptor modulators (e.g., agonists, antagonists, partial agonists or partial antagonists). Particularly, the development of nonsteroidal glucocorticoids that retain the anti-inflammatory efficacy of glucocorticoids while minimizing side effects would be of great benefit to a large number of patients with inflammatory diseases. The development of nonsteroidal topical glucocorticoids with high systemic clearance and/or short half-life may provide compounds with reduced side effects while maintaining topical anti-inflammatory efficacy. For topical use, the development of nonsteroidal glucocorticoids with reduced phototoxicity would be beneficial.

SUMMARY OF THE INVENTION

[011] It is an object of the present invention to provide new non-steroidal compounds that are modulators, particularly agonists or partial agonists, of the glucocorticoid receptor and that have potent anti-inflammatory activity and that have advantages in relation to side effects, efficacy, toxicity and/or metabolism.

[012] More particularly, the present invention provides new compounds that are modulators, particularly agonists or partial agonists, of the glucocorticoid receptor; the compounds having an anti-inflammatory effect and a stability profile in biological tissue which imply that only a very low systemic exposure of the compounds will be observed, for example, with topical administration. A specific advantage of some of the compounds of the present invention is that they have high clearance in human liver mycrosomes. Furthermore, some of the compounds of the present invention are rapidly hydrolyzed in human whole blood and some of the compounds of the present invention, at the same time, exhibit stability for enzymatic hydrolysis in human keratinocytes. Furthermore, some compounds of the present invention exhibit reduced phototoxicity.

[013] Thus, the present invention refers to a compound according to formula (I) wherein R1 is selected from the group consisting of 5- and 6-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (4-6) membered heterocycloalkyl and phenyl, wherein said heteroaryl of 5 and 6 members, (C1-C6)alkyl, (C3-C6)cycloalkyl, heterocycloalkyl (4-6) members and phenyl is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4 )alkoxy, halogen, hydroxyl and cyano; R2 is selected from (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is selected from phenyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein said phenyl, 5-membered heteroaryl and 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from R5; R4 is selected from hydrogen, halogen, (C1-C4)alkyl and halo(C1-C4)alkyl; R5 is selected from halogen, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6) )alkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl and -S(O)2Ra, where Ra represents (C1-C4)alkyl; X1 is selected from CH, C(Rb) and N, where Rb represents halogen, (C1-C4)alkyl or halo(C1-C4)alkyl; X2 is selected from CH and N; Y is selected from -NH- and O-; m is 0 or 1; n is 0 or 1; L represents a bond,-O-,-NH- or-N(Rc)-, where Rc represents (C1-C4)alkyl; or pharmaceutically acceptable salts, hydrates or solvates thereof.

[014] Furthermore, the present invention relates to a compound, according to formula (I), for use in therapy.

[015] Furthermore, the present invention relates to a compound, according to formula (I), for use in the prophylaxis, treatment or improvement of inflammatory, allergic or proliferative dermatological diseases or conditions.

BRIEF DESCRIPTION OF FIGURES

[016] Figure 1 is a graph showing the DSC (differential scanning calorimetry) (solid) and TGA (Thermo Gravimetric Analysis) curve (trace) of polymorph F of compound 37.

[017] Figure 2 shows the XRPD (X-ray Powder Diffractogram) pattern of polymorph F of compound 37.

[018] Figure 3 shows the ORTEP drawing of the absolute crystal structure of polymorph F of compound 37. The structure has only one molecule in the asymmetric unit cell

DETAILED DESCRIPTION OF THE INVENTION Definitions

[019] The term "alkyl" is intended to indicate a radical obtained when a hydrogen atom is removed from a branched or linear hydrocarbon. Said alkyl is composed of 1-6, preferably 1-4, as well as 1-3, as well as 2-3 or even 1-2 carbon atoms. The term includes the subclasses normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl.

[020] The term "alkylene" is intended to indicate a divalent saturated aliphatic hydrocarbyl group with, preferably, 1 to 6 and more preferably 1 to 3 carbon atoms that are straight or branched chain. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-) or (-CH(CH3)CH2 -) and the like.

[021] The terms "alkyloxy" and "alkoxy" are intended to indicate a radical of the formula -OR', where R' is alkyl, as indicated in this document, where the alkyl group is attached to the parent molecular unit through of an oxygen atom, for example, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy, isopropoxy, butoxy, tert-butoxy, and the like. Thus, the term "(C1-C4) alkoxy" is intended to indicate a radical of the formula-O (C1-C4) alkyl, for example, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy, isopropoxy, n-butoxy, iso-butoxy or tert-butoxy.

[022] The term "alkylthio" is intended to indicate a radical of the formula-S-R', where R' is alkyl, as indicated in this document, in which the alkyl group is attached to the parent molecular unit through a sulfur atom, for example -S-CH3 (methylthio) or -S-CH2CH3 (ethylthio).

[023] The term "aryl" is intended to indicate a radical of aromatic carbocyclic rings composed of 6-13 carbon atoms, as well as 6-9 carbon atoms, as well as 6 carbon atoms, in particular rings with 5- or 6-membered, including carbocyclic rings fused to at least one aromatic ring. If the aryl group is a fused carbocyclic ring, the point of attachment of the aryl group to the parent molecular moiety may be through an aromatic or through an aliphatic carbon atom within the aryl group. Representative examples of aryl include, but are not limited to, phenyl, naphthyl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl and fluorenyl.

[024] The term "cyano" is intended to indicate a CN-group linked to the parent molecular moiety through the carbon atom.

[025] The term "cycloalkyl" is intended to indicate a saturated cycloalkane hydrocarbon radical, which comprises 3-6 carbon atoms, preferably 3-5 carbon atoms, such as 3-4 carbon atoms, e.g. , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Likewise, the term "(C3-C6) cycloalkyl" is intended to indicate a saturated hydrocarbon radical of cycloalkane, comprising 3-6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[026] The term "haloalkyl" is intended to indicate an alkyl group, as defined herein, substituted with one or more halogen atoms as defined herein, for example fluoro or chloro, such as fluoromethyl, difluoromethyl or trifluoromethyl . Thus, the term "halo(C1-C3)alkyl" is intended to indicate a (C1-C3)alkyl group, as defined herein, substituted with one or more halogen atoms, as defined herein, such as , for example, fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl or fluoropropyl. Likewise, the term "halo (C1-C6) alkyl" is intended to indicate a (C1-C6) alkyl group, as defined herein, substituted with one or more halogen atoms, as defined herein.

[027] The terms "haloalkyloxy" and "haloalkoxy" are intended to indicate a haloalkyl group, as defined herein, that is attached to the parent molecular unit through an oxygen atom, such as difluoromethoxy or trifluoromethoxy. Thus, the term "halo (C1-C6)alkyloxy" is intended to indicate a halo (C1-C6)alkyl group, as defined herein, which is attached to the parent molecular unit through an oxygen atom.

[028] The term "halogen" is intended to indicate a substituent from the 7th main group of the periodic table, such as fluorine, chlorine and bromine.

[029] The term "heteroaryl" is intended to indicate monocyclic heteroaromatic ring radicals comprising a 5- or 6-membered ring containing 1 to 5 carbon atoms and 1-5 heteroatoms selected from oxygen, sulfur and nitrogen, such as 1 -3 carbon atoms and 2-4 heteroatoms selected from O, N and S, such as 2-3 carbon atoms and 2-3 heteroatoms selected from O, N and S, such as 1 carbon atom and 4 heteroatoms selected from O , N and S, such as 2 carbon atoms and 3 heteroatoms selected from O, N and S, such as 3 carbon atoms and 2 heteroatoms selected from O, N and S, such as 4 carbon atoms and 1 heteroatom selected from O, N and S, such as 3 carbon atoms and 3 heteroatoms selected from N, such as 4 carbon atoms and 2 heteroatoms selected from N, such as 5 carbon atoms and 1 heteroatom selected from N. The heteroaryl radical can be bonded to the parent molecular unit through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. Representative examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl.

[030] The term "5-membered heteroaryl" is intended to indicate a heteroaryl, as defined herein, that comprises 5 ring atoms, which contains 1-4 carbon atoms and 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, such as 1-3 carbon atoms and 2-4 heteroatoms selected from O, N and S, such as 2-3 carbon atoms and 2-3 heteroatoms selected from O, N and S, such as 1 carbon atom and 4 heteroatoms selected from O, N and S, such as 2 carbon atoms and 3 heteroatoms selected from O, N and S, such as 3 carbon atoms and 2 heteroatoms selected from O, N and S, such as 4 atoms of carbon and 1 heteroatom selected from O, N and S. Representative examples of 5-membered heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl.

[031] The term "6-membered heteroaryl" is intended to indicate a heteroaryl, as defined herein, which comprises 6 ring atoms, which contains from 1 to 5 carbon atoms and from 1-5 heteroatoms selected from oxygen, sulfur and nitrogen, such as 2-4 carbon atoms and 2-4 heteroatoms selected from O, N and S, such as 2-3 carbon atoms and 3-4 heteroatoms selected from O, N and S, such as 3 carbon atoms and 3 heteroatoms selected from N, such as 4 carbon atoms and 2 heteroatoms selected from N, such as 5 carbon atoms and 1 heteroatom selected from N. Representative examples of heteroaryl groups include, but are not limited to, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl.

[032] The term "heterocycloalkyl" is intended to indicate a cycloalkane radical, as described herein, in which one or more carbon atoms are replaced by heteroatoms, comprising 1-6 carbon atoms, for example 2-5 or 2-4 carbon atoms, further comprising 13 heteroatoms, preferably 1 to 2 heteroatoms, selected from O, N or S. The heterocycloalkyl radical may be linked to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within of the heterocycloalkyl group. Representative examples of heterocycloalkyl groups include, but are not limited to, azepanyl, azetidinyl, aziridinyl, dioxolanyl, dioxolyl, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl.

[033] The term "4-6 membered heterocycloalkyl" is intended to indicate a heterocycloalkyl, as defined herein, that comprises 4-6 ring atoms and comprises 1-5 carbon atoms, for example, 2-5, 3 -5, 4-5 or 2-4 carbon atoms, further comprises 1-5, 1-4 or 1-3 heteroatoms, preferably 1 to 2 heteroatoms, selected from O, N or S. Representative examples of heterocycloalkyl groups with members (46) include azetidinyl, dioxanyl, dioxolanyl, imidazolidinyl, morpholinyl, oxetanil, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, thietanyl.

[034] The term "hydrocarbon radical" is intended to indicate a radical containing only hydrogen and carbon atoms, may contain one or more carbon-carbon double or triple bonds, and may comprise cyclic moieties in combination with linear moieties or branched. Said hydrocarbon comprises 1-6 carbon atoms, and preferably comprises 1-5, for example 1-4, for example 1-3, for example 1-2 carbon atoms. The term includes alkyl, cycloalkyl and aryl, as indicated herein.

[035] The term "hydroxy" or "hydroxyl" is intended to indicate an OH group linked to the parent molecular moiety through the oxygen atom.

[036] The term "hydroxy (C1-C6) alkyl" is intended to indicate a (C1C6) alkyl group, as defined herein, substituted with one or more hydroxyl groups, as defined herein (-OH), such as, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl or dihydroxypropyl.

[037] In some cases, the number of carbon atoms in a hydrocarbon radical (e.g., alkyl, cycloalkyl and aryl) is indicated by the prefix "(Cuma-Cb)", where a is the minimum number and b is the maximum number of carbons in the hydrocarbon radical. Thus, for example (C1-C4) alkyl is intended to indicate an alkyl radical comprising 1 to 4 carbon atoms, (C1-C6)alkyl is intended to indicate an alkyl radical comprising 1 to 6 carbon atoms, and (C3-C6) )cycloalkyl is intended to indicate a cycloalkyl radical comprising 3 to 6 carbon ring atoms.

[038] The term "hydroxyalkyl" is intended to indicate an alkyl group, as defined above, substituted by one or more hydroxy, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl.

[039] The term "oxo" is intended to indicate an oxygen atom that is linked to the parent molecular moiety through a double bond (=O).

[040] The term "thioxo" is intended to indicate a sulfur atom that is linked to the parent molecular unit through a double bond (= S).

[041] The C(O) group is intended to represent a carbonyl group (C=O)

[042] The term "pharmaceutically acceptable salt" is intended to indicate salts prepared by reacting a compound of formula I, comprising a basic moiety, with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric acid. , nitric, phosphoric, formic, acetic, 2,2-dichloroacetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, acetic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D -glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-1,2-disulfonic, 2-hydroxy ethanesulfonic, toluenesulfonic, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula I comprising an acidic moiety may also be prepared by reaction with a suitable base, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines, hydroxy-lower alkylamines, cycloalkylamines, or benzylamines, or L-arginine or L-lysine. Other examples of pharmaceutically acceptable salts are listed in Berge, S.M.; J. Pharm. Sci.; (1977), 66(1), 1-19, which is incorporated herein by reference.

[043] The term "solvate" is intended to indicate a species formed by the interaction between a compound, for example, a compound of formula I, and a solvent, for example, alcohol, glycerol or water, in which said species are in crystalline or non-crystalline form. When water is the solvent, said species is referred to as a hydrate.

[044] The term "treatment" as used herein means the administration and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include slowing the progression of the disease, disorder or condition, reducing, improving or alleviating symptoms and complications, and/or curing or eliminating the disease, disorder or condition. The term may also include prevention of disease, where prevention is to be understood as the administration and treatment of a patient for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of symptoms or complications. However, prophylactic (preventive) and therapeutic (curative) treatments are two distinct aspects.

[045] All references, including publications, patent applications and patents, cited in this document are hereby incorporated by reference in their entirety and to the extent that each reference is individually and specifically indicated to be incorporated by reference, regardless of any incorporation provided separately from specific documents made elsewhere than in this document.

Embodiments of the invention

[046] An embodiment of the present invention provides a compound of formula (I) in which R1 is selected from the group consisting of 5-membered heteroaryl, (C1-C6) alkyl, (C3-C6) cycloalkyl and heterocycloalkyl with (4- 6) members, wherein said 5-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl and (4-6) membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from (C1 -C4) alkyl, (C1-C4)alkoxy, halogen and hydroxyl.

[047] One embodiment of the invention provides a compound of formula (I) in which R2 is methyl.

[048] One embodiment of the invention provides a compound of formula (I) in which R3 is phenyl that is substituted with one or more substituents independently selected from R5.

[049] One embodiment of the invention provides a compound of formula (I) in which R5 is selected from halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl and phenyl.

[050] One embodiment of the invention provides a compound of formula (I) in which R5 is selected from bromine, methyl, ethyl, cyclopropyl and phenyl.

[051] One embodiment of the invention provides a compound of formula (I) in which R4 is hydrogen.

[052] One embodiment of the invention provides a compound of formula (I) in which X1 is selected from CH and N.

[053] One embodiment of the invention provides a compound of formula (I) in which X2 is CH.

[054] One embodiment of the invention provides a compound of formula (I) in which X1 is N, X2 is CH and Y is -NH-.

[055] One embodiment of the invention provides a compound of formula (I) in which X1 is CH, X2 is CH and Y is-O-.

[056] One embodiment of the invention provides a compound of formula (I) in which m is 0 and n is 1.

[057] One embodiment of the invention provides a compound of formula (I) in which L represents a bond, -O- or -NH-.

[058] An embodiment of the invention provides a compound of formula (I), wherein said compound is selected from N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3 -piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, 5-[(1R,2S )-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]- 3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(2,2-difluoropropanoylamino)propoxy]-N-[(3S)-1-[( 3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[ [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isothiazol-3-carboxamide, N-[(1S,2R) -2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3- pyridyl]oxy]ethyl]isothiazol-5-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R )-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1 -methyl-2-[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]thiazol- 4- carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl] -3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]-3-methyl-isoxazol-5-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2- [[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-5-carboxamide, 5-[ (1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-2-hydroxybutanoyl]amino]propoxy]- N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3 -carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-2-hydroxypropanoyl]amino]propoxy]-N- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1- methyl-2-[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazole-5-carboxamide , 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-2-hydroxybutanoyl]amino]propoxy]- N-[(3S)-1-[(3R)-5 -oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methoxyacetyl)amino]propoxy]-N- [(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2- [(2-hydroxy-2-methyl-propanoyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(3-hydroxypropanoylamino)propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]- 3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-hydroxycyclobutanecarbonyl)amino]propoxy]-N-[(3S)-1-[ (3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-hydroxycyclopropanecarbonyl)amino] propoxy]-N-[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4- cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl] oxazol-4-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-1 -[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-hydroxyacetyl) amino]propoxy]-N-[(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-( 4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl ]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran -3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazol-3-carboxamide, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] 2,2-trifluoroacetyl)amino]propoxo]benzoate, 4-[(1R,2S)-1-( [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] 4-cyclopropylphenyl)-2-(1,2,5-thiadiazol-3-carbonylamino)propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methylthiazol-2-carbonyl)amino]propoxy]benzoate -3-carbonyl]-3-piperidyl], [(3S)-1-[( 3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(4-methyl-1,2,5-oxadiazole- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] 3-carbonyl)amino]propoxy]benzoate, 4-[(1R,2S)-1-(4- cyclopropylphenyl)-2-[(5-methylthiazol-4-carbonyl)amino]propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[ [(1R,2S)-1-(4-cyclopropylphenyl)-2-[(4-methylthiazol-5-carbonyl)amino]propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3- carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methyl-1,3,4-oxadiazol-2-carbonyl)amino]propoxy]benzoate of [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(4- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]methylthiadiazol-5-carbonyl)amino]propoxy]benzoate, 4-[(1R,2S)-1-( 4-cyclopropylphenyl)-2-[(4-methyloxazol-5-carbonyl)amino]propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4 -[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methoxyacetyl)amino]propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl] -3-piperidyl], [(3S)-1-[(2-methylpyrazol-3-carbonyl)amino]propoxy]benzoate [(3S)-1-[( 3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methylthiazol-5-carbonyl)amino]propoxy] [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[( 2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl 1-(4-cyclopropylphenyl)-2-[(3-methyltriazol-4-carbonyl)amino]propoxy]benzoate ], [(3S)-1-[(3R)- 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(1,2,4-oxadiazol-3-carbonylamino)propoxy]benzoate 5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylimidazol-2-carbonyl)amino]propoxy]benzoate [ (3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methylisoxazole- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] 5-carbonyl)amino]propoxy]benzoate, 4-[(1R,2S)-1-(4- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-cyclopropylphenyl)-2-[(5-methyl-1,2,4-oxadiazol-3-carbonyl)amino]propoxy]benzoate 3-piperidyl], [(3S)-1-[(3R)4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylimidazol-4-carbonyl)amino]propoxy]benzoate )-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], [(3S) 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isothiazol-3-carbonylamino)propoxy]benzoate -1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methylisoxazol-4-carbonyl [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-amino]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] 2-(thiazol-2-carbonylamino)propoxy]benzoate, 4-[(1R,2S)-1- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl](4-cyclopropylphenyl)-2-(isothiazol-5-carbonylamino)propoxy]benzoate, 4-[(1R [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl] ,2S)-1-(4-cyclopropylphenyl)-2-[(5-methylisothiazol-4-carbonyl)amino]propoxy]benzoate -3-piperidyl], [(3S)-1-[(3R)-5- 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(oxazol-2-carbonylamino)propoxy]benzoate oxotetrahydrofuran-3-carbonyl]-3-piperidyl], [(3S)-1-[4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(oxazol-5-carbonylamino)propoxy]benzoate [(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isoxazol-3-carbonylamino)propoxy]benzoate 3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(thiadiazol-4-carbonylamino) [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[ [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl](5-methylisoxazol-3-carbonyl)amino]propoxy]benzoate, 4-[(1R,2S)- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[ [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3- (1R,2S)-1-(4-cyclopropylphenyl)-2-(thiazol-4-carbonylamino)propoxy]benzoate piperidyl], [(3S) 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methyl-1,2,4-oxadiazol-5-carbonyl)amino]propoxy]benzoate -1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylpyrazol-3-carbonyl [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-amino]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]2-(2,2-difluoropropanoylamino)propoxy]benzoate, N-[(3R)-1-[( 3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy] pyridine-2-carboxamide, N-[(3R)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl) -2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1-[(2S)-5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl] -5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1-[ (2R)-5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy ]pyridine-2-carboxamide, N-[(3S)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1- (p-tolyl )-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[(2S)-5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl ]-5-[(1R,2S)-1- (p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1- [(3R)-5-oxotetrahydrofuran-3-carbonyl]pyrrolidin-3-yl]-5-[(1R,2S)- 1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino ]propoxy]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2 ,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(4-phenylphenyl)-2-[(2,2,2-trifluoroacetyl) amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-4-[(1R,2S)-1- ( p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-4 -[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzaoto, N-[(3S)-1-[[(3S)-5 -oxotetrahydrofuran-3-yl]carbamoyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine- 2-carboxamide, N-[(3S)-1-[[(3R)-5-oxotetrahydrofuran-3-yl]carbamoyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl )-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2 -[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate [(3S)-2-oxotetrahydrofuran-3-yl], (3S)-3-[ [5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate [( 3R)-2-oxotetrahydrofuran-3-yl], (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino ]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate of [(3S)-5-oxotetrahydrofuran-3-yl] or (3S)-3-[[5-[(1R,2S)-1- (p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-[(34)-5-oxotetrahydrofuran-3-yl] carboxylate or pharmaceutically acceptable salts, hydrates or solvates thereof.

[059] Any combination of two or more modalities described in this document is considered within the scope of the present invention.

[060] The present invention includes all embodiments in which R1, R2, R3, R4, R5,X1,X2, Y, m, n and L are combined in any combination, as described elsewhere in this document.

[061] One embodiment of the present invention provides a compound of formula (Ia).

[062] An embodiment of the present invention provides a compound of formula (Ib).

[063] One embodiment of the present invention provides a compound of formula (Ic).

[064] One embodiment of the present invention provides a compound of formula (Id).

[065] One embodiment of the present invention provides a compound of formula (Ie).

[066] An embodiment of the present invention provides a compound of formula (I) in which m is 0 and n is 1.

[067] An embodiment of the present invention provides a compound of formula (Ig) where m is 0 and n is 1.

[068] An embodiment of the present invention provides a compound of formula (Ih),

[069] One embodiment of the invention provides a compound of formula I, said compound being 4-[(1R, 2S)-1-(4-cyclopropylphenyl)-2- [[(2R)-tetrahydrofuran-2- carbonyl] amino] propoxy] [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] benzoate (Compound 37)

[070] One embodiment of the invention provides a compound of formula I, said compound being N-[(1S, 2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S) -1- [(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] carbamoyl]-3-pyridyl] oxy] ethyl] isoxazole-3-carboxamide (Compound 23)

[071] One embodiment of the invention provides a compound of formula I, said compound being N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[( 1R, 2S )-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 1)

[072] An embodiment of the present invention provides a compound of formula (I) in which R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen and X2 is CH.

[073] An embodiment of the present invention provides a compound of formula (I) in which R3 is phenyl that is substituted in the para position with a substituent selected from R5.

[074] An embodiment of the present invention provides a compound of formula (I) in which R1 is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, halogen, hydroxyl and cyano; R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen and X2 is CH.

[075] An embodiment of the present invention provides a compound of formula (I) in which R1 is (C1-C6) alkyl, optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4 ) alkoxy, halogen, hydroxyl and cyano; R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen and X2 is CH.

[076] An embodiment of the present invention provides a compound of formula (I) in which R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen, X2 is CH; m and 0; n is 1 and L represents a bond.

[077] An embodiment of the present invention provides a compound of formula (I) in which R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen; X1 is CH; X2 is CH; Y is-O-; m is 0; n is 1 and L represents a bond.

[078] An embodiment of the present invention provides a compound of formula (I) in which R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen; X1 is N; X2 is CH; Y is -NH-; m is 0; n is 1 and L represents a bond.

[079] The compounds of formula I can be obtained in crystalline form either directly by concentration from an organic solvent or by crystallization or recrystallization from an organic solvent or a mixture of said solvent and a co-solvent that can be organic or inorganic, such as water. The crystals may be isolated in an essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline forms, such as polymorphs and pseudopolymorphs and also mixtures thereof.

[080] Compounds of formula I comprise asymmetrically substituted (chiral) carbon atoms, which generates the existence of isomeric forms, for example, enantiomers and, possibly, diastereomers. The present invention relates to all such isomers, whether in optically pure form or as mixtures thereof (for example, racemic mixtures or partially purified optical mixtures). Pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained by applying procedures known in the art. The various isomeric forms can be separated by physical separation methods such as selective crystallization and chromatographic techniques, for example high pressure liquid chromatography using surgical stationary phases. Enantiomers can be separated from each other by selective crystallization of their diastereomeric salts, which can be formed with optically active amines, such as l-ephedrine, or with optically active acids. The optically purified compounds can subsequently be released from said purified diastereomeric salts. Enantiomers can also be resolved by the formation of diastereomeric derivatives. Alternatively, the enantiomers can be separated by chromatographic techniques using chiral stationary phases. Pure stereoisomeric forms can also be derived from the corresponding pure stereoisomeric forms of appropriate starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific preparation methods. These methods will advantageously employ pure chiral starting materials.

[081] The present invention includes pharmaceutically acceptable isotopically labeled compounds of formula I in which one or more atoms are replaced by atoms with the same atomic number, but an atomic mass or mass number different from the atomic mass number that predominates in nature. Examples of isotopes suitable for inclusion in compounds include hydrogen isotopes such as 2H and 3H, carbon isotopes such as 11C, 13C and 14C, nitrogen isotopes such as 13N and 15N oxygen isotopes such as 15O, 17O and 18O and of fluorine, such as 18F.

[082] One embodiment of the invention provides the intermediates 5-[(1R,2S)-1-(p-Tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, 4-[(1R,2S)- 1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoic acid, 5-[(1R,2S)-1-(4-bromophenyl)-2-[(2, 2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, 4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy] benzoic.

[083] One embodiment of the invention provides the intermediates N-[(3S)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl )amino]propoxy]pyridine-2-carboxamide, N-[(3R)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2- trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[( 3S)-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[ (3S)-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]- N-[(3S)-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)- 3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazol-3-carboxamide, 5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl) amino]propoxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2 -trifluoroacetyl)amino]propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide, N-[(3S)-3-piperidyl]-4-[(1R,2S)-1-(p -tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide, 4-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl [(3S)-3-piperidyl]amino]propoxy]benzoate].

[084] One embodiment of the invention provides the intermediates (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy ]pyridine-2-carbonyl]amino]piperidine-1-tert-butyl carboxylate, (3S)-3-[[5-[(1R,2S)-1-(4-bromophenyl)-2-[(2, tert-butyl 2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[(1R,2S)-1-(4- cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-tert-butyl carboxylate, (3S)-3-[[5-[(1R tert-butyl ,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S )-3-[[5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isoxazol-3-carbonylamino)propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate tert- butyl, (3S)-3-[4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine-1-carboxylate tert-butyl, (3S)-3-[4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine-1- tert-butyl carboxylate, (3R)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2 -carbonyl]amino]pyrrolidine-1- tert-butyl carboxylate, (3S)-3-[[4-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2- tert-butyl trifluoroacetyl)amino]propoxy]benzoyl]amino]piperidine-1-carboxylate and (3S)-3-[4-[(1R,2S)-1-(p-tolyl)-2-[(2, tert-butyl 2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine-1-carboxylate and (3S)-3-[[5-[(1S,2S)-1-(p-tolyl)-2-[ tert-butyl (2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[085] In one or more embodiments of the present invention, the compounds of formula (I) as defined above are useful in therapy and, in particular, useful for the treatment of atopic dermatitis, psoriasis or eczema.

[086] The compounds of the present invention, optionally in combination with other active compounds, would be useful for the treatment of inflammatory, allergic or proliferative dermatological diseases or diseases, in particular for the treatment of atopic dermatitis, psoriasis or eczema.

[087] One embodiment of the invention provides a compound according to general formula (I) for use in the treatment of a disease, disorder or condition, which disease, disorder or condition is sensitive to modulation of the glucocorticoid receptor.

[088] One embodiment of the invention provides the use of a compound according to formula (I) in the manufacture of a medicament for the prophylaxis, treatment or improvement of inflammatory, allergic or proliferative dermatological diseases or conditions.

[089] One embodiment of the invention provides the use of a compound according to general formula (I) in the manufacture of a medicament for the prophylaxis, treatment or improvement of atopic dermatitis, psoriasis or eczema.

[090] An embodiment of the invention provides a method for preventing, treating or ameliorating inflammatory, allergic or proliferative dermatological diseases or diseases, wherein the method comprises administering to a person, suffering from at least one of said diseases or disorders, of an effective amount of one or more compounds according to general formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

[091] An embodiment of the invention provides a method of preventing, treating or ameliorating inflammatory, allergic or proliferative atopic dermatitis, psoriasis or eczema, the method comprising administering to a person suffering from at least one of said diseases or disorders an amount effectiveness of one or more compounds, according to general formula (I).

[092] In addition to being useful for human treatment, the compounds of the present invention can also be useful for the veterinary treatment of animals, including mammals, such as horses, cattle, sheep, pigs, dogs and cats.

Pharmaceutical Compositions of the Invention

[093] For use in therapy, the compounds of the present invention are typically in the form of a pharmaceutical composition. The invention therefore relates to a pharmaceutical composition comprising a compound of formula I, optionally together with one or more other therapeutically active compound(s), together with a pharmaceutically acceptable excipient, carrier or vehicle(s) ( is). The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient.

[094] Conveniently, the active ingredient comprises 0.0001-99.9% by weight of the formulation.

[095] In the form of a dosage unit, the compound can be administered one or more times a day at suitable intervals, always depending, however, on the patient's condition and in accordance with the prescription made by the doctor. Conveniently, a dosage unit of a formulation contains between 0.001 mg and 1000 mg, preferably between 0.01 mg and 100 mg, such as 0.1-50 mg of a compound of formula I.

[096] A suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practicing physician. The compound can be administered orally, parenterally, topically, transdermally or interdermally + other routes, according to different dosing schedules, for example, daily, weekly or at monthly intervals. In general, a single dose will be in the range of 0.001 to 400 mg/kg of body weight. The compound can be administered as a bolus (i.e., the entire daily dose is administered at once) or in divided doses two or more times per day.

[097] In the context of topical treatment, it may be more appropriate to refer to a "unit of use", which denotes that a single dose that is capable of being administered to a patient and that can be readily handled and packaged, remaining a physically and chemically stable unit dose comprising the active material, such as or a mixture thereof with solid, semi-solid or liquid diluents or pharmaceutical carriers.

[098] The term "unit of use" in connection with topical use means a unit dose, that is, single, capable of being administered topically to a patient in one application per square centimeter of the treatment area of 0.001 µg to 1 mg and preferably from 0.05 micrograms to 0.5 mg of the active ingredient in question.

[099] It is also anticipated that, in certain treatment regimens, administration at longer intervals, e.g., every day, every week, or even at longer intervals, may be beneficial.

[0100] If treatment involves administration of another therapeutically active compound, it is recommended to consult Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Ed., JG Hardman and LE Limbird (Eds.), McGraw-Hill 2011, for useful dosages of said compounds.

[0101] The administration of a compound of the present invention with one or more other active compounds can be concomitantly or sequentially.

[0102] Formulations include, for example, those in a form suitable for oral administration (including controlled or sustained release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intra-articular and intravenous), transdermal, intradermal, ophthalmic, topical, nasal, sublingual or buccal.

[0103] The formulations may be conveniently presented in dosage unit form and may be prepared by, but not restricted to, any of the methods well known in the art of pharmacy, for example as described in Remington, The Science and Practice of Pharmacy, 21a ed., 2005. All methods include the step of bringing into association the active ingredient with the carrier that constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately binding the active ingredient in association with a liquid carrier, semisolid carrier, or finely divided solid carrier or combinations thereof and then, if necessary, molding the product into shape. desired formulation.

[0104] The formulations of the present invention suitable for oral and buccal administration may be in the form of discrete units such as capsules, sachets, tablets, chewing gums or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder, granules or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid, such as ethanol or glycerol; or in the form of a gel, a nano or microemulsion, an oil-in-water emulsion, a water-in-oil emulsion or other dispensing systems. The oils may be edible oils, such as, but not restricted to, for example, cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural surfactant agents and viscosifying agents such as, but not restricted to, tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers , polyvinylpyrrolidone, polysorbates, sorbitan fatty acid esters. The active ingredients can also be administered in the form of a bolus, electuary or paste.

[0105] A tablet can be made by compressing, molding or lyophilizing the active ingredient optionally with one or more accessory ingredients. Tablets may be prepared by compressing, in a suitable machine, the active ingredient(s) into a free-flowing form such as a powder or granules, optionally mixed by a binder and/or a filler, such as, for example, lactose, glucose, mannitol starch, gelatin, acacia gum, gum tragacanth, sodium alginate, calcium phosphates, microcrystalline cellulose, carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol, waxes or the like; a lubricant such as, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as, for example, starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, crospovidone or the like or a dispersing agent such as polysorbate 80. Shaped tablets can be made by molding in a suitable machine, a mixture of the powdered active ingredient and a suitable vehicle moistened with an inert liquid diluent. Lyophilized tablets can be formed in a freeze dryer from the drug substance solution. A suitable padding may be included.

[0106] Formulations for rectal administration may be in the form of suppositories in which the compound of the present invention is mixed with low-melting, water-soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycol or esters of fatty acids from polyethylene glycols, while elixirs can be prepared using myristyl palmitate.

[0107] Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the recipient's blood, for example isotonic saline solution, isotonic glucose solution or buffer solution. Furthermore, the formulation may contain co-solvent, solubilizing agent and/or complexing agents. The formulation may be conveniently sterilized by, for example, filtration through a bacteria-retaining filter, addition of sterilizing agent to the formulation, irradiation of the formulation or heating of the formulation. Liposomal formulations, as disclosed in for example Encyclopedia of Pharmaceutical Technology, vol.9, 1994, are also suitable for parenteral administration.

[0108] Alternatively, the compounds of formula I may be presented as a sterile solid preparation, for example a lyophilized powder, which is readily dissolved in a sterile solvent immediately before use.

[0109] Transdermal formulations may be in the form of a plaster, patch, micro needles, liposome or nanoparticle delivery systems or other dermal formulations applied to the skin.

[0110] Suitable ophthalmic administration formulations may be in the form of a sterile aqueous preparation of the active ingredients, which may be in microcrystalline form, for example, in the form of a microcrystalline aqueous suspension. Liposomal formulations or biodegradable polymer systems, as, for example, as described in the Encyclopedia of Pharmaceutical Technology, vol.2, 1989, can also be used to present the active ingredient for ophthalmic administration.

[0111] Formulations suitable for topical administration, such as dermal, intradermal or ophthalmic administration, include liquid or semi-solid preparations, such as liniments, lotions, gels, fillers, sprays, foams, film-forming systems, micro-needles , micro- or nano-emulsions, water-in-oil or oil-in-water emulsions, such as creams, ointments or pastes; or solutions or suspensions such as drops.

[0112] For topical administration, the compound of formula I may typically be present in an amount of 0.001 to 20% by weight of the composition, such as 0.01% to about 10%, such as 0.5% to 5%, but may also be present in an amount of up to about 100% of the composition.

[0113] Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomizers. Such formulations are disclosed in greater detail, for example, in Modern Pharmaceutics, 2nd ed., G.S. Banker and C. T. Rhodes (Eds.), pages 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3rd ed., G.S. Banker and C. T. Rhodes (Eds.), pages 618-619 and 718-721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology, vol. 10, J. Swarbrick and J.C. Boylan (Eds), pages 191-221, Marcel Dekker, New York.

[0114] In addition to the above-mentioned ingredients, formulations of a compound of formula I may include one or more additional ingredients such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, penetration enhancing agents, enhancing agent preservatives. of solubility, for example methyl hydroxybenzoate (including antioxidants), emulsifying agents and the like.

[0115] When the active ingredient is administered in the form of salts with pharmaceutically acceptable non-toxic acids or bases, the preferred salts are, for example, easily soluble in water or slightly soluble in water, so as to obtain a particular absorption rate and appropriate.

Medical use

[0116] Due to their ability to bind to the glucocorticoid receptor, the compounds of the invention are useful as anti-inflammatory agents and may also have anti-allergic, immunosuppressive and anti-proliferative actions. Thus, a compound of formula (I) can be used as a medicament for the treatment or prophylaxis of one or more of the following pathological conditions (disease states) in a mammal:

[0117] Dermatological diseases, which coincide with inflammatory, allergic and/or proliferative processes: Atopic dermatitis, psoriasis, eczema, such as, for example, atopic eczema, seborrheic eczema, nummular eczema or xerotic eczema, exfoliative dermatitis, erythemic diseases, triggered by different noxas, e.g. radiation or chemicals, burns, acid burns, bullous dermatoses, e.g. pemphigus vulgaris or bullous pemphigoid, Diseases of the lichenoid group, Rosacea, Erythema exudativa multiforme, Erythema nodosum, Balanitis, Pruritus, for example, of allergic origin, Manifestation of vascular diseases, Vulvitis, alopecia such as alopecia areata, alopecia totalis or alopecia universalis, discoid lupus, cutaneous T-cell lymphoma, rash of any origin or dermatoses, Pityriasis rubra pilaris.

[0118] Lung diseases, which coincide with inflammatory, allergic and/or proliferative processes: Chronic obstructive lung diseases of any origin, mainly bronchial asthma, chronic obstructive pulmonary disease, bronchitis of different origins, adult respiratory distress syndrome (ARDS), acute respiratory distress syndrome, bronchiectasis, all forms of restrictive lung diseases, mainly allergic alveolitis, all forms of pulmonary edema, mainly toxic pulmonary edema, sarcoidosis and granulomatoses, such as Bock's disease.

[0119] Ophthalmological diseases, which coincide with inflammatory, allergic and/or proliferative processes: allergic rhinitis, as well as chronic forms of keratitis such as adenoviral and Thygeson's keratitis, vernal keratoconjunctivitis, pingueculitis, episcleritis, uveitis, iritis, conjunctivitis, blepharitis, optic neuritis, choroiditis, sympathetic ophthalmia.

[0120] Diseases of the ear-nose and throat area, which coincide with inflammatory, allergic and/or proliferative processes: allergic rhinitis, hay fever, otitis externa, otitis media.

[0121] Allergies, which coincide with inflammatory, allergic and/or proliferative processes: All forms of allergic reactions, for example Quincke's edema, insect bites, contact dermatitis, such as allergic and irritant urticaria.

PREPARATION METHODS

[0122] The compounds of the present invention can be prepared in a variety of forms known to one skilled in the art of synthesis. Compounds of formula I may for example be prepared using the reactions and techniques described below, together with methods known in the art of synthetic organic chemistry or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in solvents appropriate to the reagents and materials used and suitable for the transformations to be carried out. Furthermore, in the synthetic methods described below, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experiment duration, and working procedures, above, are chosen to be standard conditions for this reaction, which should be readily recognized by one skilled in the art. Not all compounds that fall into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions on substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used. The compounds of the present invention or any intermediate may be purified, if necessary, using conventional methods well known to a synthetic organ chemist, for example, methods described in “Purification of Laboratory Chemicals”, 6th ed. 2009, W. Amarego and C. Chai, Butterworth-Heinemann. The starting materials are either known compounds, commercially available, or can be prepared by routine synthetic methods well known to those skilled in the art.

Synthetic routes

[0123] The following schemes illustrate the preparation of compounds of formula (I), wherein X1,X2, R1, R2, R3, R4, Y, L, men are as previously defined:

[0124] When L is a bond, then: Suitable acids for use as compound (III) are commercially available, are known in the literature or can be prepared as outlined in scheme 5.1

[0125] Step (a): The acid (III) is reacted with amine (II) to give the compound of formula (I). This reaction is carried out by standard methods.

[0126] Coupling can be carried out using (i) Hydrochloric acid derived from acid (III) + amine (II), with an excess of base in a suitable solvent, or (ii) Acid (III) with a coupling agent conventional + amine (II), optionally in the presence of a catalyst, with an excess of base in a suitable solvent.

[0127] Typically, the conditions are as follows: acid (III) acid chloride (generated in situ), an excess of amine (II), optionally with an excess of 3rd amine such as Et3N, Hünig's base or NMM , in DCM or THF, without heating for 1 to 24 hours, or (ii) acid (III), WSCDI/DCC and HOBT/HOAT, an excess of amine (II), with an excess of NMM, Et3N, Hünig's base in THF, DCM or EtOAc, at room temperature for 4 to 48 hours; or, acid (III), PYBOP®/ PyBrOP®/ Mukaiyama reagent, an excess of amine (II), with an excess of NMM, Et3N, Hünig's base in THF, DCM or EtOAc, at room temperature for 4 to 24 hours.

[0128] The preferred conditions are: 1.5 eq. of acid(III) acid chloride (generated in situ), 1 eq. of amine (II), in DCM at room temperature for 16 hours or 1.5 carboxylic acid (III), 1 eq HOBt, 1 eq. WSCDI, 1 eq. of amine (II) in dichloromethane at room temperature for 18 hours.

[0129] When L is NH, N (Rc) or O, then:

[0130] Compound (I) can be prepared as described in scheme 1.1 Scheme 1.1

[0131] Amines and alcohols suitable for use as compound (IV) are commercially available or are known in the literature.

[0132] LG represents a leaving group, typically chlorine, compounds suitable for use as compound (V) are known in the literature or commercially available.

[0133] Step (b): The amine or alcohol (IV) is transformed in situ to the reactive intermediate (IV '), if LG is Chlorine, then (IV') is an isocyanate, carbamoyl chloride or carbonchloroimidate.

[0134] Typical conditions are,

[0135] (i) The amine or alcohol (IV) in a suitable aprotic solvent with phosgene, triphosgene, diphosgene or CDI in the presence of a tertiary base, without heating for 1 to 24 hours.

[0136] The preferred conditions are: The amine or alcohol (IV) in DCM with triphosgene (0.4 eq) with Hunig's base (2 eq.), without heating for 2 hours.

[0137] Step (c): the reactive intermediate (IV ') is reacted with amine (II). Typical conditions are,

[0138] (i) The reactive intermediate (IV') in a suitable aprotic solvent with amine (II) in the presence of a tertiary base such as NMM, Hunig's base, triethylamine without heating for 1 to 24 hours.

[0139] The preferred conditions are: The reactive intermediate (IV') (2 eq.) with amine (II) with triethylamine (3 eq) in DMF at room temperature for 1 hour.

[0140] Alternatively, when L is NH, N (Rc) or O, then:

[0141] Compound (I) can be prepared as described in scheme 1.2

Scheme 1.2

[0142] Amines and alcohols suitable for use as compound (IV) are commercially available or are known in the literature.

[0143] LG represents a leaving group, for example chlorine, compounds suitable for use as compound (V) are known in the literature or commercially available or can be prepared as described in scheme 6.1.

[0144] Step (b): The amine (II) is transformed in situ to the reactive intermediate (II'), if LG is Chlorine then (IV') is a carbamoyl chloride.

[0145] Typical conditions are, The amine (II) in a suitable aprotic solvent with phosgene, triphosgene, diphosgene or CDI in the presence of a tertiary base, without heating for 1 to 24 hours.

[0146] The preferred conditions are: Amine (II) in DCM with triphosgene (0.4 eq) with Hunig's base (2 eq.), without heating for 2 hours.

[0147] Step (c): The reactive intermediate (II') is reacted with amine or alcohol (IV). Typical conditions are,

[0148] The reactive intermediate (II') in a suitable aprotic solvent with amine or alcohol (II) in the presence of a tertiary base such as NMM, Hunig's base, triethylamine or strong base such as sodium hydride with heating for 1 to 24 hours.

[0149] The preferred conditions are: The reactive intermediate (II') with amine or alcohol (IV) (2 eq) with triethylamine (3 eq) in DMF at 50 oC for 5 hours.

[0150] Compounds suitable for use as compounds (II) can be prepared as shown in schemes 2.1 and 2.2.

Scheme 2.1

[0151] PROT * represents a suitable protecting group for nitrogen. Standard methodology for nitrogen protecting groups is used, such as that found in textbooks (e.g., “Protecting Groups in Organic Synthesis” by TW Greene and P. Wutz).

[0152] Compounds suitable for use as compound (VII) are commercially available or known in the literature.

[0153] Step (d*): Deprotection of compound (V) is carried out using standard methodology, as described in “Protecting Groups in Organic Synthesis” by TW Greene and P. Wutz.

[0154] When PROT* is Boc, the preferred method is hydrogen chloride in a suitable solvent such as 1,4-dioxane at room temperature for 1-16 hours, or a solution of trifluoroacetic acid in dichloromethane for 1-2 hours.

[0155] When PROT * is CBz, the preferred method is hydrogenolysis using a suitable palladium catalyst in a solvent such as ethanol.

[0156] When PROT* is an allyl carbamate, the preferred conditions are thiobenzoic acid and a suitable palladium catalyst such as Pd2(dba)3 with a suitable phosphine additive such as 1,4-bis (diphenylphosphine) butane in tetrahydrofuran for 20 minutes.

[0157] Step (a): Acid (VI) is reacted with amine or alcohol (VII) to give the compound of formula (V). This reaction is carried out by standard methods.

[0158] Coupling can be carried out using (i) Hydrochloric acid derived from acid (VI) + amine or alcohol (VII), with an excess of base in a suitable solvent, or (ii) Acid (VI) with an agent conventional coupling + amine or alcohol (VII), optionally in the presence of a catalyst, with an excess of base in a suitable solvent.

[0159] Typically, the conditions are as follows: acid (VI) acid chloride (generated in situ), an excess of amine or alcohol (VII), optionally with an excess of 3° amine such as Et3N, Hünig base or NMM, in DCM or THF, without heating for 1 to 24 hours, or when Y is NH, acid (VI), WSCDI/DCC and HOBT/HOAT, an excess of amine (VII), with an excess of NMM, Et3N , Hünig's base in THF, DCM or EtOAc, at room temperature for 4 to 48 hours; or, acid (VI), PYBOP®/ PyBrOP®/ Mukaiyama reagent, an excess of amine (VII), with an excess of NMM, Et3N, Hünig's base in THF, DCM. DMF or EtOAc, at room temperature for 4 to 24 hours. or when Y is O acid (VI), EDC an excess of alcohol (VII) in DCM, THF or DMF with DMAP at room temperature for 1 to 24 hours.

[0160] The preferred conditions are: 1.5 eq. of acid(III) acid chloride (generated in situ), 1 eq. of amine or alcohol (VII), in DCM at room temperature for 16 hours or 1 eq carboxylic acid (VI), 1 eq HOBt, 1 eq. WSCDI, 1.5 eq. amine (VII) in DMF at room temperature for 18 hours or or o 1.2 eq carboxylic acid (VI), EDC, 1 eq alcohol (VII) with DMAP (2.5 eq) in DMF at room temperature for 18 hours .

Scheme 2.2

[0161] PROT and PROT* represent orthogonal protecting groups suitable for nitrogen that, by definition, can be unprotected independently of each other. Standard methodology for nitrogen protecting groups is used, such as that found in textbooks (e.g., “Protecting Groups in Organic Synthesis” by TW Greene and P. Wutz).

[0162] Compounds suitable for use as compound (X) are commercially available or known in the literature.

[0163] Compounds (V') can be prepared in a manner analogous to Compound (V) as outlined in scheme 2.1

[0164] Typically, PROT is TFA, FMOC and PROT * is BOC, CBz, but those skilled in the art would understand that PROT could be BOC, CBz and PROT* TFA, FMOC.

[0165] When PROT is TFA and PROT* is BOC

[0166] Step (d): Compound (IX) in protic solvent such as ethanol, methanol or aqueous miscible solvents such as dioxane, THF, DMF, DMSO with sodium hydroxide, lithium hydroxide or potassium hydroxide.

[0167] Preferably,

[0168] Compound (IX) in dioxane with 1.2 eq of lithium hydroxide at room temperature for 20 hours.

[0169] Compounds (VI) can be prepared as described in Scheme 3.1

Scheme 3.1

[0170] Nitriles suitable for use as compounds (XVI) are commercially available, known in the literature or can be prepared from commercially available intermediates using methods described in, among others, Kondolff, Tetrahedron 60(17), 3813 (2004) , Mormino et al., Organic letters, 16(6), 1744-47, 2014, Maillard PCT 2004024081 and Tet. Letters 2002, 43, 6987-6990.

[0171] Step (e): Amino alcohol (XV) with a strong base such as metal hydride or metal hexamethyldisilazide in a suitable aprotic solvent with nitrile (XVI), at 0oC to 70oC for 1 to 6 hours.

[0172] When X1 is N

[0173] Preferably, the amino alcohol (XV) with 1.5 eq. NaH in THF at 50 oC for 1 hour, cooled to 0oC and 1.2 eq of nitrile (XVI) added, kept at 0oC for 4 to 8 hours.

[0174] When X1 is CH, C (Rb)

[0175] Preferably, the amino alcohol (XV) with 1.5 eq. NaH in THF at 50 oC for 1 h, 1.2 eq of nitrile (XVI) was added, heated at 50 oC for 1 to 4 hours.

[0176] Step (f): The amino nitrile (XIV) in protic solvent such as ethanol, methanol or aqueous miscible solvents such as dioxane, THF, DMF, DMSO with sodium hydroxide, lithium hydroxide or potassium hydroxide, with heating for 1 hour to 48 hours.

[0177] Preferably, when X1 is N,

[0178] Compound (XIV) in ethanol and water with 5 eq of sodium hydroxide at 85 oC for 2 hours.

[0179] When X1 is CH, C (Rb),

[0180] Compound (XIV) in ethanol and water with 5 eq of sodium hydroxide at 85 oC for 16 to 48 hrs.

[0181] Step (g): The amino acid (XIII) in methanol with a strong acid catalyst, with heating.

[0182] Typically, the amino acid (XIII) in anhydrous methanol with 0.2 eq. 98% sulfuric acid at 85 oC for 16 hours to 48 hours.

[0183] Step (h): the amino acid (XIII) in a suitable solvent such as diethyl ether, THF, dioxane, acetonitrile, DCM with excess acid chloride or acid anhydride (X) optionally in the presence of a 3rd base, triethylamine, NMM, pyridine or aqueous inorganic base, optionally with heating for 1 to 6 hours.

[0184] Typically, the amino acid (XIII) in DCM with excess acid acid chloride (X) in the presence of aqueous sodium hydroxide in excess aqueous for 1 to 6 hours.

[0185] Or if R1 is CF3, the amino acid (XIII) in acetonitrile pyridine with excess TFAA in the presence of excess pyridine at 0 oC for 1 to 4 hours.

[0186] Step (i): The amino ester (XI) in protic solvent such as ethanol, methanol or aqueous miscible solvents such as dioxane, THF, DMF, DMSO with sodium hydroxide, lithium hydroxide or potassium hydroxide, optionally with heating during 1 hour to 48 hours.

[0187] When X1 is N and R1 is CF3

[0188] Typically, the amino ester (XI) in methanol with 1.5 eq. sodium hydroxide at room temperature for 6 hours,

[0189] When X1 is CH, C (Rb) and R1 is not CF3

[0190] Typically, the amino ester (XI) in methanol with 1.5 eq. sodium hydroxide with heating to 60oC for 2 hours.

[0191] Amino acids suitable for use as compound (XV) are commercially available or known in the literature or can be prepared using methods described in scheme 4.1 and specifically in schemes 7.1 and 7.2.

Scheme 4.1

[0192] Compounds suitable for use as amide (XIX) are known in the literature or are commercially available.

[0193]

[0194]

[0195] such as THF, diethyl ether, dioxin with organometallic acid (XX) at low temperature for 1 hour to 24 hours.

[0196] Typically, amide (XIX) with 2.5 eq. Grignard (XX) (Met is Mg) in THF at 0oC at room temperature for 6 h to 18 h.

[0197] Step (m): Ketone (XVIII) in a suitable solvent with a reducing agent.

[0198] Typically, (i) Ketone (XVIII) in aqueous alcohol, methanol, ethanol or IPA with sodium/lithium/potassium borohydride at room temperature for 1 to 4 hours. (ii) Ketone (XVIII) in toluene and IPA with catalytic aluminum isopropoxide with heating for 6 to 24 hours. (iii) Ketone (XVIII) in aprotic solvent such as THF, diethyl ether or dioxane at low temperature with Dibal.

[0199] Preferably, the ketone (XVIII) in toluene and IPA with 0.5 eq. aluminum isopropoxide at 60oC for 8 hours. Scheme 5.1

[0200] Compounds (XXI) are known in the literature.

[0201] Step (n): Alkene (XXI) in a suitable solvent under oxidative cleavage conditions.

[0202] Typically, alkene (XXI) in acetonitrile, carbon tetrachloride and water with 5% ruthenium (III) chloride and excess sodium periodate.

[0203] Compounds suitable for use as boronic acid (or ester) (XXII) are commercially available or are known in the literature-

[0204] Hal represents an Iodine, bromine or chlorine halide.

[0205] Step (p): Halide (V') in a suitable solvent with boronic acid (or ester) (XXII) in the presence of a palladium catalyst and phosphine ligand, in the presence of a base with heating for 1 to 48 hours .

[0206] Typically, the Halide (V') with 0.05 eq. palladium(II) acetate, 0.15 eq. Tricylohexylphosphine, 3 eq. potassium acetate, 1.5 eq boronic acid (XXII) in toluene/water heated in an inert atmosphere (nitrogen or argon) at 100°C for 6 hours.

[0207] It will be appreciated by those skilled in the art that, where appropriate, the order in which the steps are performed may be changed, but may require additional protection/deprotection steps for the sensitive functionality. Standard methodology for nitrogen protecting groups is used, such as that found in textbooks (e.g., “Protecting Groups in Organic Synthesis” by TW Greene and P. Wutz). GENERAL PROCEDURES, PREPARATIONS AND EXAMPLES The following abbreviations were used:

[0208] 1H nuclear magnetic resonance (NMR) spectra were recorded at 300 MHz unless otherwise indicated. Chemical shift values (d, in ppm) are quoted relative to internal tetramethylsilane standards (d = 0.00). The value of a multiplet, whether doublet (d), triplet (t), quartet (q)) or not (m) defined at the approximate midpoint is given unless a range is included. (br) indicates a broad peak, while (s) indicates a simple one. All NMR spectra are recorded in DMSO-d6 unless another solvent is declared.

[0209] The organic solvents used were generally anhydrous. Solvent ratios indicated refer to v:v unless otherwise stated. UPLC-MS Method 1. Column: Waters Aquity UPLC HSS T3 1.8µm, 2.1 x 50 mm. Column temperature: 60oC. UV: PDA 210-400 nm. Injection volume: 2µl. Eluents: A: 10 mM ammonium acetate with 0.1% formic acid. MS: Electrospray switching between positive and negative ionization. Instruments: Waters Aquity UPLC, Waters SQD UPLC-MS Method 2: Column: Acquity UPLC HSS T3 1.8 µm; 2.1 x 50mm Flow: 0.7 ml/min Column temperature: 40°C Mobile phases: A: 10 mM ammonium acetate + 0.1% formic acid B: 100% acetonitrile + 0.1% formic acid UV: 240-400 nm UPLC (input method): XE Metode 7 CM MS Method: PosNeg_50_1000 4.8 99% A 1% B Instruments: Acquity Waters UPLC, Waters LCT Premier PANalytical's X'pert PRO MPD conventional diffractometer configured with transmission geometry and equipped with a PIXcel detector. A continuous scan interval of 2? of 3-30° was used with a CuKa X radiation = 1.5418 Â source and a generating power of 40KV and 45 mA. Was it using a step size of 2? of 0.0070°/step with a step time of 148.92 s. Instrument calibration was performed using a silicon reference standard. The sample was gently flattened into a well in a 96-well plate for transmission measurements. The well plate was moved back and forth in the x direction and the experiment was carried out at room temperature.

[0210] Differential Scanning Calorimetry (DSC): The DSC experiment was performed using a Perkin Elmer DSC8500 system. About 1.7 mg of sample was used for the measurement. An aluminum pan was used for the analysis and was sealed by applying pressure by hand and pushing each part of the pan. The temperature increased from -60 to 250°C at 20°C/min. Dry nitrogen was used as purge gas at a flow rate of 20 mL/min.

[0211] Thermogravimetric Analysis (TGA): The TGA experiment was conducted using a Perkin Elmer Pyris 1 TGA instrument. About 1.4 mg of sample was loaded into a ceramic pan for measurement. The sample temperature was increased from 25 to 500°C at 10°C/min. Dry nitrogen was used as purge gas at a flow rate of 40 mL/min.

[0212] Single crystal X-ray diffraction data was collected using a SuperNova dual diffractometer with Atlas CCD area detector (Temperature: 120(2) K; Cu Ka Radiation ). More details can be found in table 3. Program(s) used to solve the structure: CrysAlisPro, Agilent Technologies, Version 1.171.37.34 (22-05-2014 edition CrysAlis171.NET), ShelXL (Sheldrick, 2008) used to refine structure and Olex2 (Dolomanov et al., 2009) for ORTEP designs.

[0213] The error ranges given in this application for spectroscopic characteristics, including those in the claims, may be greater or lesser depending on factors well known to those skilled in the art of spectroscopy and may, for example, depend on sample preparation, such as particle size distribution, or if the crystal form is part of a formulation, the composition of the formulation, as well as instrumental fluctuations and other factors. PREPARATIONS Scheme 7.1 Preparation 1: (S)-tert-butyl-(1-methoxy(methyl)amino)-1-oxopropan-2-yl) carbamate

[0214] N-(3-dimethylaminopropyl)-N'-ethylcarboimide hydrochloride (455 g, 2378.4 mmol), 1-hydroxybenzotriazole (214.3 g, 1585.6 mmol) and triethylamine (571.9) were added. mL, 3964 mmol) to a stirred solution of (2S)-2-(tert-butoxycarbonylamino)propanoic acid (300 g, 1585.6 mmol) in dichloromethane (3 L) at 0°C, followed by N hydrochloride hydrochloride , O-dimethylhydroxylamine (185.6 g, 1902.7 mmol). The reaction mixture was left at room temperature for 16 h. Upon completion, the reaction was concentrated under reduced pressure. Water (1 L) was added to the resulting crude product and the mixture was stirred for 0.5 h, filtered and dried to give the title compound as a white solid (290 g, 78.8%). TLC system: 30% ethyl acetate in petroleum ether, Rf: 0.2. 1H NMR (400MHz, CDCl3) d = 5.25 (br d, J=6.1 Hz, 1H), 4.68 (br s, 1H), 3.77 (s, 3H), 3.21 (s, 3H), 1.44 (s, 9H), 1.31 (d, J=6.7 Hz, 3H). Preparation 2: (S)-tert-Butyl(1-oxo-1-(p-tolyl)propan-2-yl) carbamate

[0215] 4-Methylphenylmagnesium bromide (3 eq, 646 mmol) [freshly prepared from 4-bromotoluene (106 mL, 619.7 mmol) using magnesium coils (22.3 g, 929 mmol), Iodine ( cat) and 1,2-dibromoethane (0.5 mL) in tetrahydrofuran (1 L) at room temperature] was added slowly, over 1 h, to a stirred amide solution from Preparation 1 (50 g, 215.5 mmol) in tetrahydrofuran (1 L) at 0°C. After addition, the reaction mixture was allowed to stir at room temperature for 16 h. Upon completion, the reaction mixture was cooled to 5 oC and quenched with saturated aqueous ammonium chloride solution (1 L) and extracted with ethyl acetate (2x 1 L). The combined ethyl acetate layers were washed with water (1 L), brine (250 mL), dried over sodium sulfate and evaporated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (100-200 mesh) eluting with a gradient of ethyl acetate (3-10%) in petroleum ether to generate the title compound as a white solid (31 g, 53%, white solid). TLC system: 10% ethyl acetate in petroleum ether, Rf: 0.5. 1H NMR (300MHz, CDCl3) d = 7.87 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.58 (br d, J=6.3 Hz, 1H), 5.27 (td, J=7.1, 14.3 Hz, 1H), 2.42 (s, 3H), 1.46 (s, 9H), 1.39 (d, J=7.1 Hz, 3H). Preparation 3: tert-butyl ((1R,2S)-1-hydroxy-1-(p-tolyl)propan-2-yl)carbamate

[0216] Aluminum isopropoxide (32.9 g, 161.5 mmol) and isopropanol (255 mL) were added to a stirred solution of ketone from Preparation 2 (85 g, 323.2 mmol) in toluene (425 mL) at room temperature. The reaction mixture was stirred at 60°C for 16 h. Upon completion, the reaction mixture was cooled to 5 oC and quenched with 1 N hydrochloric acid (300 mL) and extracted with ethyl acetate (2 x 500 mL). The combined ethyl acetate layers were washed with water (300 ml), brine (200 ml), dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was triturated with 1 mixture (1:1) of n-pentane and diethyl ether (2 x 150 mL) and dried to give the title compound as a white solid (80 g, 93.43%). TLC system: 20% ethyl acetate in petroleum ether, Rf: 0.4 1H NMR (300MHz, CDCl3) d = 7.25-7.20 (m, 2H), 7.19-7.11 (m, 2H), 4.82 (t, J=3.5 Hz, 1H), 4.60 (br s, 1H), 3.99 (br s, 1H), 3.10 (br s, 1H), 2.34 (s, 3H), 1.46 (s, 9H), 0.99 (d, J=7.0Hz, 3H). HPLC purity: 97% Preparation 4: (1R,2S)-2-Amino-1-(p-tolyl)propan-1-ol

[0217] 1,1,1-Trifluoroacetic acid (2 L, 18113 mmol) was slowly added to a stirred solution of carbamate from Preparation 3 (80 g, 301.8 mmol) in dichloromethane (600 mL) and water (600 mL) at 0°C over 1.5 h. The reaction mixture was warmed to room temperature and stirred for 4 min. The dichloromethane layer was separated and the aqueous 1,1,1-trifluoroacetic acid layer was concentrated to a small volume under reduced pressure. The resulting aqueous solution was then cooled in an ice bath before being made basic with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (2 x 1 L). The combined dichloromethane layers were washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (40 g, 80.3%). TLC system: 10% methanol in dichloromethane, Rf: 0.1 1H NMR (400MHz, DMSO-d6) d = 7.20-7.16 (m, 2H), 7.13-7.09 (m, 2H), 5.05 (br s, 1H ), 4.26 (d, J=4.9 Hz, 1H), 2.94-2.74 (m, 1H), 2.28 (s, 3H), 1.23 (br s, 2H), 0.84 (d, J=6.7 Hz, 3H) Scheme 7.2 Preparation 5: (S)-tert-Butyl-(1-(4-bromophenyl)-1-oxopropan-2-yl)carbamate

[0218] Using a similar procedure to that described for Preparation 2, but using 4-bromophenylmagnesium bromide, the title compound was prepared as a white solid (30 g, 42.6%). TLC system: 10% ethyl acetate in petroleum ether, Rf: 0.5 1H NMR (400MHz, CDCl3) d = 7.84 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H ), 5.48 (br d, J=6.7 Hz, 1H), 5.23 (br t, J=7.2 Hz, 1H), 1.45 (s, 9H), 1.38 (d, J=7.3 Hz, 3H). Preparation 6: tert-Butyl-((1R, 2S)-1-(4-bromophenyl)-1-hydroxypropan-2-yl)carbamate

[0219] Using a similar procedure to that described for Preparation 3, but using the compound from Preparation 5, the title compound was prepared as a white solid (78 g, 96.9%). TLC system: 20% ethyl acetate in petroleum ether, Rf: 0.45 1H NMR (400MHz, CDCl3) d = 7.53-7.40 (m, 2H), 7.22 (d, J=8.2 Hz, 2H), 4.81 (d, J=2.4 Hz, 1H), 4.55 (br s, 1H), 3.98 (br s, 1H), 3.42 (br s, 1H), 1.46 (s, 9H), 0.98 (d, J=7.0 Hz , 3H). Preparation 7: (1R,2S)-2-amino-1-(4-bromophenyl)propan-1-ol

[0220] Using a similar procedure to that described for Preparation 4, but using the compound described in Preparation 6, the title compound was prepared as a white solid (20 g, 71.8%). TLC system: 10% methanol in dichloromethane, Rf: 0.1 1H NMR (400MHz, DMSO-d6) d = 7.52-7.47 (m, 2H), 7.26 (d, J=8.2 Hz, 2H), 5.25 (br s, 1H), 4.30 (d, J=4.9 Hz, 1H), 2.86 (m, 1H), 1.53-1.08 (m, 2H), 0.83 (d, J=6.7 Hz, 3H). Preparation 8: tert-Butyl N-[(1S)-2-(4-ethylphenyl)-1-methyl-2-oxo-ethyl]carbamate

[0221] Using a similar procedure to that described for Preparation 2, but using 4-ethylphenylmagnesium bromide, the title compound was prepared as a white solid (25 g, 69%). TLC system: 20% ethyl acetate in petroleum ether, Rf = 0.5 1H NMR (300MHz, CDCl3) d = 7.90 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H ), 5.58 (br d, J=6.9 Hz, 1H), 5.27 (br t, J=7.1 Hz, 1H), 2.72 (q, J=7.7 Hz, 2H), 1.46 (s, 9H), 1.40 (d , J=6.9 Hz, 3H), 1.26 (t, J=7.7 Hz, 3H). LCMS: 97.9%, Mass (M+H) = 278.4. Preparation 9: tert-Butyl N-[(1S,2R)-2-(4-ethylphenyl)-2-hydroxy-1-methyl-ethyl]carbamate

[0222] Using a similar procedure to that described for Preparation 3, but using the compound from Preparation 8, the title compound was prepared as a white solid (20 g, 80.3%). TLC system: 20% ethyl acetate in petroleum ether, Rf = 0.4 1H NMR (300MHz, CDCl3) d = 7.26-7.22 (m, 2H), 7.20-7.14 (m, 2H), 4.82 (t, J=3.4 Hz, 1H), 4.61 (br s, 1H), 3.99 (br s, 1H), 3.05 (br s, 1H), 2.64 (q, J=7.6 Hz, 2H), 1.46 (s, 9H) , 1.23 (t, J=7.7 Hz, 3H), 1.00 (d, J=6.9 Hz, 3H), LCMS: 99.7%, Mass (M+H)=280.4. Preparation 10: (1R,2S)-2-Amino-1- (4-ethylphenyl)propan-1-ol

[0223] Using a similar procedure to that described for Preparation 4, but using the compound described in Preparation 9, the title compound was prepared as a white solid (23 g, 81.4%). TLC system: 10% methanol in dichloromethane, Rf: 0.2. 1H NMR (400MHz, CDCl3) d = 7.26-7.23 (m, 2H), 7.20-7.16 (m, 2H), 4.49 (d, J=4.9 Hz, 1H), 3.26-3.10 (m, 1H), 2.65 ( q, J=7.4 Hz, 2H), 1.68-1.39 (m, 2H), 1.24 (t, J=7.6 Hz, 3H), 0.99 (d, J=6.4 Hz, 3H) Preparation 11: 5-[(1R,2S)-2-Amino-1-(p-tolyl)propoxy]pyridine-2-carbonitrile

[0224] Sodium hydride (60% w/w in mineral oil, 2.99 g, 74.6 mmol) was added in small portions to a solution of the amino alcohol from Preparation 4 (10 g, 57.4 mmol) in tetrahydrofuran (200 mL). The reaction was stirred at 50oC for 1 hour before being cooled to -25oC. 5-fluoropyridine-2-carbonitrile (7.93 g, 64.9 mmol) was dissolved in tetrahydrofuran (100 mL) and added over 15 min to the cooled reaction mixture. The reaction mixture was allowed to warm to 0°C and was stirred for 3 h before being quenched by pouring into an ice-cold, aqueous, saturated solution of ammonium chloride (500 mL). The product was extracted with ethyl acetate (4 x 250 mL). The combined organics were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (100-200 mesh) eluting with a 2:1 mixture of ethyl acetate:heptane until high current impurities were eluted followed by 90:10:1 ethyl acetate. ethyl:methanol:aqueous ammonia 0.880. The cleaned fractions evaporated under reduced pressure to give the title compound as an oil (10.04 g, 65%). 1H NMR (300 MHz, CDCl3) d 8.35 (dd, J = 2.9, 0.6 Hz, 1H), 7.47 (dd, J = 8.6, 0.6 Hz, 1H), 7.25 - 7.14 (m, 4H), 7.09 (dd, J = 8.7, 2.9 Hz, 1H), 4.93 (d, J = 5.4 Hz, 1H), 3.38 (qd, J = 6.5, 5.3 Hz, 1H), 2.33 (s, 3H), 1.19 (d, J = 6.5 Hz, 3H). Preparation 12: Methyl 5-[(1R, 2S)-2-amino-1-(p-tolyl)propoxy]pyridine-2-carboxylate

[0225] Sodium hydroxide (32% by weight in water, 27 g, 216 mmol) was added to a solution of the nitrile from Preparation 11 (10.0 g, 37.4 mmol) in ethanol (100 mL) and the resulting mixture was heated to 85oC for 2 hours. The solvent was removed by evaporation under reduced pressure followed by azeotropic distillation with toluene (3 x 150 mL). The resulting solid was suspended in methanol (300 mL) and conc. sulfuric acid. 98% (12 mL, 224 mmol) was added for 0.05 h. The reaction mixture was heated at 85oC for 18 hours. The mixture was cooled and concentrated, by evaporation, under reduced pressure, to a small volume. The resulting residue was poured into a mixture of ice-cold saturated sodium hydrogen carbonate (300 mL) and ethyl acetate (300 mL). The aqueous layer was extracted three more times with ethyl acetate (3 x 200 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and evaporated to give the title compound as an oil (8.82 g, 78%). 1H NMR (300 MHz, CDCl3) d = 8.37 (dt, J=2.9, 0.6, 1H), 7.94 (dt, J=8.7, 0.6, 1H), 7.22 - 7.09 (m, 5H), 5.01 (d, J =5.2, 1H), 3.92 (d, J=0.6, 3H), 3.46 - 3.31 (m, 1H), 2.32 (s, 3H), 1.20 (dd, J=6.6, 0.6, 3H). Preparation 13: Methyl 5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylate

[0226] Trifluoroacetic anhydride (4.5 mL, 32 mmol) was added to a solution of the aminoester form of Preparation 12 (7.4 g, 25 mmol) and triethylamine dissolved in dichloromethane (74 mL). The mixture was stirred at room temperature for 0.5 h. The reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate (75 mL) and extracted with dichloromethane (3 x 75 mL). The organic dichloromethane layers were dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (100-200 mesh) eluting with a gradient of ethyl acetate (25-100%) in heptane to give the title compound as an oil (7.90 g, 81%). 1H NMR (300 MHz, DMSO-d6) d = 9.50 (d, J=8.4, 1H), 8.35 (d, J=3.0, 1H), 7.92 (d, J=8.7, 1H), 7.33 (dd, J =8.8, 2.9, 1H), 7.25 (d, J=8.1, 2H), 7.16 (d, J=8.0, 2H), 5.43 (d, J=6.0, 1H), 4.25 (dt, J=14.1, 6.9 , 1H), 3.80 (s, 3H), 2.26 (s, 3H), 1.29 (d, J=6.8, 3H). Preparation 14: 5-[(1R,2S)-1-(p-Tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid

[0227] Sodium hydroxide (0.866 g, 21.6 mmol) was dissolved in water (19.7 mL) and added to an ester solution from Preparation 13 (7.8 g, 19.7 mmol) dissolved in methanol ( 80 mL).The mixture was stirred at 50°C for 8 h. Methanol was removed by evaporation under reduced pressure and the residue was lyophilized. The dry residue was dissolved in a small amount of methanol (10 mL) and water (40 mL) was added. The mixture was made slightly acidic with 4M aqueous hydrochloric acid (pH = 4) and extracted with ethyl acetate (3 x 150 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered and evaporated to give the title compound as a pink solid (6.71 g, 89.2%). 1H NMR (300 MHz, CDCl3) d = 8.22 (dd, J=2.8, 0.6, 1H), 8.04 (dd, J=8.7, 0.7, 1H), 7.23 - 7.16 (m, 5H), 6.44 (d, J =8.8, 1H), 5.43 (d, J=3.2, 1H), 4.50 (s, 1H), 2.35 (s, 3H), 1.29 (d, J=6.8, 3H). Preparation 15: (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl] amino]piperidine-1- tert-butyl carboxylate

[0228] O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.53 g, 22.4 mmol) was added to an acid solution of Preparation 14 ( 5.72 g, 15.0 mmol), tert-butyl (3S)-3-aminopiperidine-1-carboxylate (4.49 g, 22.4 mmol) and triethylamine (6.06 g, 60 mmol) in N ,N-dimethylformamide (150 mL). The reaction was stirred overnight at room temperature. The mixture evaporated under reduced pressure and the resulting residue was dissolved in diethyl ether (500 mL). This diethyl ether solution was washed with 10% aqueous citric acid solution (3 x 50 mL) followed by 10% aqueous ammonia, saturated brine solution and dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (100-200 mesh) eluting with 50% ethyl acetate in heptane to give the title compound as an amorphous solid (7.2 g, 86%). 1H NMR (300 MHz, DMSO-d6) d = 9.47 (d, J=8.4, 1H), 8.27 (d, J=8.1, 1H), 8.21 (dd, J=2.9, 0.6, 1H), 7.89 (dd , J=8.7, 0.6, 1H), 7.39 (dd, J=8.8, 2.9, 1H), 7.25 (d, J=8.2, 2H), 7.15 (d, J=7.8, 2H), 5.41 (d, J =6.1, 1H), 4.27 (h, J=6.8, 1H), 3.55 (s, 3H), 2.97 (s, 2H), 2.26 (s, 3H), 1.77 (s, 1H), 1.62 (s, 2H ), 1.50 - 1.24 (m, 13H). UPLC-MS Method 2: Ion mass 564.26 (M+), Rt = 2.63 min. Preparation 16: N-[(3S)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine- 2-carboxamide

[0229] Trifluoroacetic acid (50 mL, 653 mmol) was added to a carbamate solution from Preparation 15 (7.2 g, 12.8 mmol) dissolved in dichloromethane (100 mL). The reaction was stirred at room temperature for 20 min. The reaction mixture evaporated, partitioned between diethyl ether and 10% aqueous ammonia solution. The diethyl ether layer was washed with 10% aqueous citric acid (5 x 100 mL) and then the combined citrus layers were washed again with a small volume of diethyl ether (50 mL). The combined aqueous citrus layers were then basiced with ammonia and extracted with diethyl ether (3 x 200 mL). These diethyl ether layers were combined and washed with a small volume of brine and then dried over magnesium sulfate, filtered and evaporated to give the title compound as an off-white foam (5.86 g, 99%). 1H NMR (300 MHz, CDCl3) d = 8.15 (dd, J=2.9, 0.6, 1H), 8.09 - 7.95 (m, 2H), 7.21 - 7.11 (m, 5H), 6.61 (d, J=8.8, 1H ), 5.37 (d, J=3.3, 1H), 4.47 (s, 1H), 4.03 (tq, J=7.5, 3.7, 1H), 3.11 (dd, J=11.9, 3.4, 1H), 2.86 (m, 1H), 2.81 - 2.60 (m, 2H), 2.33 (s, 3H), 1.89 (td, J=7.6, 3.7, 1H), 1.73 (m, 1H), 1.60 - 1.48 (m, 2H), 1.27 ( d, J=6.9, 3H). UPLC-MS Method 2: Ion mass 464.2 (M+), Rt = 2.02 min. Preparation 17: N-[(3R)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine- 2-carboxamide

[0230] Using a similar procedure to that described for Preparation 15, but using (3R)-3-aminopiperidine-1-carboxylate, followed by a similar procedure to that described in Preparation 16, the title compound was prepared as an off-white foam ( 0.156 g, 64%). 1H NMR (300 MHz, DMSO-d6) d = 9.49 (d, J=8.4, 1H), 8.38 (d, J=8.6, 1H), 8.24 (d, J=2.8, 1H), 7.88 (d, J =8.7, 1H), 7.38 (dd, J=8.7, 2.9, 1H), 7.25 (d, J=8.0, 2H), 7.15 (d, J=7.9, 2H), 5.40 (d, J=6.2, 1H ), 4.27 (q, J=7.1, 1H), 3.99 - 3.81 (m, 1H), 2.95 (dd, J=11.8, 3.7, 1H), 2.88 - 2.77 (m, 1H), 2.61 (dd, J= 11.6, 8.4, 2H), 2.26 (s, 3H), 1.78 - 1.40 (m, 4H), 1.30 (d, J=6.8, 3H). UPLC-MS Method 2: Ion mass 464.2 (M+), Rt = 2.01 min. Preparation 18: 5-[(1R,2S)-2-Amino-1-(4-ethylphenyl)propoxy]pyridine-2-carbonitrile

[0231] Using a similar procedure to that described for Preparation 11, but using the amino alcohol described in Preparation 10, the title compound was prepared as a brown oil (0.55 g, 70%). 1H NMR (300 MHz, CDCl3) d = 8.35 (dd, J=2.9, 0.6, 1H), 7.48 (dd, J=8.6, 0.6, 1H), 7.20 (m, 4H), 7.09 (dd, J=8.7 , 2.9, 1H), 4.93 (d, J=5.4, 1H), 3.45 - 3.24 (m, 1H), 2.63 (q, J=7.6, 2H), 1.25 - 1.18 (m, 6H). Preparation 19: 5-[(1R,2S)-2-Amino-1-(4-ethylphenyl)propoxy]pyridine-2-methyl carboxylate

[0232] Using a similar procedure to that described for Preparation 12, but using the compound described in Preparation 18, the title compound was prepared as a brown solid (0.48 g, 79%). 1H NMR (300 MHz, CDCl3) d = 8.37 (d, J=2.7, 1H), 7.95 (dd, J=8.7, 0.6, 1H), 7.25 - 7.11 (m, 5H), 5.01 (d, J=5.2 , 1H), 3.93 (s, 3H), 3.48 - 3.24 (m, 1H), 2.62 (q, J=7.6, 2H), 1.24 - 1.17 (m, 6H). Preparation 20: 5-[(1R,2S)-1-(4-Ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid

[0233] Using a similar procedure to that described for Preparation 13, but using the compound described in Preparation 19, followed by a similar procedure to that used in Preparation 14 the title compound was prepared as an oil (0.089 g, 71%). 1H NMR (300 MHz, DMSO-d6) d = 9.50 (d, J=8.4, 1H), 8.33 (d, J=2.9, 1H), 7.91 (d, J=8.8, 1H), 7.33 (dd, J =8.8, 2.9, 1H), 7.30 - 7.17 (m, 4H), 5.44 (d, J=5.9, 1H), 4.46 - 4.09 (m, 1H), 2.56 (q, J=7.6, 2H), 1.29 ( d, J=6.8, 3H), 1.14 (t, J=7.6, 3H). Preparation 21: 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-3-piperidyl]pyridine- 2-carboxamide

[0234] Using a similar procedure to that described for Preparation 15, but using the compound from Preparation 20, followed by a similar procedure to that described in Preparation 16, the title compound was prepared as an oil (0.066 g, 54%). 1H NMR (300 MHz, CDCI3) d = 8.35 - 8.22 (m, 2H), 8.18 (d, J=2.7, 1H), 7.94 (d, J=8.7, 1H), 7.20 (s, 4H), 7.09 ( dd, J=8.7, 2.8, 1H), 6.67 (d, J=8.7, 1H), 5.39 (d, J=3.2, 1H), 4.60 - 4.42 (m, 1H), 4.37 - 4.14 (m, 1H) , 3.31 (dd, J=12.9, 3.9, 1H), 3.19 - 2.94 (m, 3H), 2.63 (q, J=8.0, 2H), 2.09 - 1.91 (m, 2H), 1.89 - 1.63 (m, 2H) ), 1.28 (d, J=6.9, 3H), 1.22 (t, J=7.6, 3H). Preparation 22: 5-[(1R,2S)-2-Amino-1-(4-bromophenyl)propoxy]pyridine-2-carbonitrile

[0235] Using a similar procedure to that described for Preparation 11, but using the amino alcohol described in Preparation 7, the title compound was prepared as a brown oil (2 g, 85%). 1H NMR (300 MHz, DMSO-d6) d = 8.44 (dd, J=3.0, 0.7, 1H), 7.89 (dd, J=8.7, 0.6, 1H), 7.61 - 7.52 (m, 2H), 7.42 (dd , J=8.7, 2.9, 1H), 7.38 - 7.33 (m, 2H), 5.34 (d, J=5.1, 1H), 3.28 - 3.20 (m, 1H), 1.03 (d, J=6.5, 3H). Preparation 23: Methyl 5-[(1R,2S)-1-(p-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylate

[0236] Using a procedure similar to that described for Preparation 12, but using the compound described in Preparation 22, followed by a procedure similar to that described in Preparation 13, the title compound was prepared as an amorphous solid (1.73 g, 62 .3%). 1H NMR (300 MHz, DMSO-d6) d = 9.51 (d, J=8.5, 1H), 8.38 (dd, J=3.0, 0.6, 1H), 7.94 (dd, J=8.8, 0.6, 1H), 7.67 - 7.51 (m, 2H), 7.44 - 7.27 (m, 3H), 5.48 (d, J=6.0, 1H), 4.30 (h, J=6.7, 1H), 3.81 (s, 3H), 1.30 (d, J=6.8, 3H). Preparation 24: (3S)-3-[[5-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl] amino]piperidine-1- tert-butyl carboxylate

[0237] Using a similar procedure to that described for Preparation 14, but using the compound described in Preparation 23 and using 2 M aqueous sodium hydroxide (2.5 equiv.) in N,N-dimethylformamide (10 mL/g) to obtain the intermediate acid, 5-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, followed by a similar procedure to Preparation 15 but using O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate instead of O-(7-Azabenzotriazol-1-yl)-N,N,N hexafluorophosphate ',N'-tetramethyluronium, the title compound was prepared as an off-white amorphous solid (1.08 g, 54%). 1H NMR (300 MHz, DMSO-d6) d = 9.50 (d, J=8.4, 1H), 8.29 (d, J=8.1, 1H), 8.23 (d, J=2.8, 1H), 7.91 (d, J =8.7, 1H), 7.56 (d, 2H), 7.42 (dd, J=8.7, 2.9, 1H), 7.33 (d, 2H), 5.45 (d, J=6.2, 1H), 4.30 (h, J= 6.8, 1H), 3.91 - 3.39 (m, 3H), 3.27 - 2.71 (m, 2H), 1.78 (s, 1H), 1.72 - 1.56 (m, 2H), 1.51 - 1.29 (m, 13H). Preparation 25: (3S)-3-[[5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl] amino]piperidine-1- Tert-butyl carboxylate

[0238] Palladium (II) acetate (0.015 g, 0.06910 mmol) was added to a bromide solution from Preparation 24 (0.87 g, 1.382 mmol), cyclopropyl boronic acid (0.154 g, 1.797 mmol), tricyclohexylphosphine (0.038 g, 0.1382 mmol) and potassium phosphate (1.03 g, 4.837 mmol) in toluene:water 20:1 (5.5 mL). After washing the flask with argon, it was sealed and the reaction was heated at 100°C for 2 h. The reaction was left to cool and was diluted with ethyl acetate (50 mL) and washed with 10% citric acid solution (2 x 20 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (100-200 mesh) eluting with a gradient of ethyl acetate in heptane (50% to 100%) to generate the title compound as an almost white foam (0.762 g , 93%). 1H NMR (600 MHz, DMSO-d6) d = 9.55 (d, J=8.3, 1H), 8.48 - 8.26 (m, 1H), 8.21 (d, J=2.8, 1H), 7.89 (d, J=8.7 , 1H), 7.39 (dd, J=8.7, 2.8, 1H), 7.22 (d, 2H), 7.04 (d, 2H), 5.41 (d, J=6.0, 1H), 4.25 (dt, J=8.3, 6.4, 1H), 3.94 - 3.43 (m, 3H), 3.23 - 2.69 (m, 2H), 1.86 (tt, J=8.4, 5.1, 1H), 1.80 - 1.72 (m, 1H), 1.72 - 1.55 (m , 2H), 1.53 - 1.16 (m, 13H), 0.97 - 0.87 (m, 2H), 0.69 - 0.54 (m, 2H). Preparation 26: tert-butyl (3S)-3-[[5-[(1R,2S)-2-amino-1-(4-cyclopropylphenyl)propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[0239] Aqueous lithium hydroxide solution (1 M, 54 mL, 54 mmol) was added to a solution of Preparation 25 (3.2 g, 5.4 mmol) in 1,4-dioxane (250 mL). The reaction mixture was heated at 50oC for 2 hours. Upon completion, the mixture was cooled and evaporated under reduced pressure to remove 1,4-dioxane. The residue was extracted with dichloromethane (4 x 150 mL) and the combined organics dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white foam (2.7 g, 100%). UPLC-MS Method 1: Ion mass 495 (MH+), Rt = 0.67 min Preparation 27: (3S)-3-[[5-[(1R,2S)-1-(4-cyclopropylphenyl)-2 tert-butyl -[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[0240] Oxalyl chloride (4.2 mL, 50 mmol) was added to a solution of (2R)-tetrahydrofuran-2-carboxylic acid (0.580 g, 5 mmol) in dichloromethane (20 mL), followed by catalytic DMF ( 0.02 mL). The reaction mixture was stirred at room temperature for 1 h and then evaporated under reduced pressure to generate a yellow gum. This gum was dissolved in toluene (20 mL) and evaporated under reduced pressure, the process was repeated to remove excess oxalyl chloride. (2R)-Tetrahydrofuran-2-carboxylic acid chloride was added to a solution of amine from Preparation 26 (1.3 g, 2.7 mmol) and 4-methylmorpholine (1.5 mL, 14 mmol). in dichloromethane (30 mL) at 5oC. The reaction was stirred at 5°C for 0.5 h and then evaporated under reduced pressure. The residue was partitioned between tert-butylmethyl ether (200 ml) and 5% aqueous citric acid solution (2 x 50 ml). The combined aqueous layers were extracted again with tert-butyl methyl ether (2 x 50 mL) and the ether layers were combined and washed with 5% aqueous ammonia solution (2 x 50 mL), saturated brine (30 mL) and dried. over magnesium sulfate, they were filtered and evaporated to generate a brown foam. This brown foam was purified by column chromatography on silica (120 g) eluting with a gradient of ethyl acetate in heptane (0% to 100%) to give the title compound as an amorphous solid (1.24 g, 77% ). UPLC-MS Method 1: Ion mass 593 (MH+), Rt = 0.88 min Preparation 28: (3S)-3-[[5-[(1R,2S)-1-(4-cyclopropylphenyl)-2 tert-butyl -(isoxazol-3-carbonylamino)propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[0241] Using a similar procedure to that described for Preparation 27, but using isoxazole-3-carboxylic acid instead of (2R)-tetrahydrofuran-2-carboxylic acid, the title compound was prepared as an amorphous solid (1, 46 g, 90%). UPLC-MS Method 1: Mass 590 ion (MH+), Rt = 0.90 min Preparation 29: 4-[(1R,2S)-2-amino-1-(4-bromophenyl)propoxy]benzonitrile hydrochloride

[0242] Sodium hydride (60% w/w in mineral oil, 2.9 g, 73 mmol) was added in small portions to an amino alcohol solution of Preparation 7 (15.3 g, 66.5 mmol) in N -methylpyrrolidin-2-one (46 mL). The highlight was stirred at 60°C for 0.5 h before adding 4-flurobenzonitrile (9.66 g, 79.8 mmol) and heating for a further 0.5 h. The reaction mixture evaporated under reduced pressure (3.2 mbar) at 70oC. The residue was diluted with ethyl acetate (200 mL) and washed with 10% aqueous citric acid solution (50 mL) followed by saturated aqueous sodium hydrocarbonate solution (2 x 25 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and the filtrate was treated with 1 M ethereal hydrogen chloride. The resulting mixture evaporated under reduced pressure to give an off-white solid. This solid was triturated with a small volume of cold ethyl acetate to give the title compound as a white solid (19.8 g, 81%). 1H NMR (300 MHz, DMSO-d6) d = 8.52 (s, 3H), 7.74 (d, 2H), 7.62 (d, 2H), 7.34 (d, 2H), 7.06 (d, 2H), 5.86 (d , J=3.1, 1H), 3.91 - 3.47 (m, 1H), 1.18 (d, J=7.1, 3H). Preparation 30: (3S)-3-[4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine-1-carboxylate tert-butyl

[0243] Aqueous sodium hydroxide solution (32% w/w, 8.6 mL, 93 mmol) was added to a solution of the compound from Preparation 29 (3.2 g, 5.4 mmol) in 1.4 -dioxane (250 mL). (6.85 g, 18.6 mmol) dissolved in ethanol (44 mL). The resulting solution was heated to 85°C for 20 h and then cooled and evaporated under reduced pressure. The residue was quenched with 4M aqueous hydrochloric acid (25 mL). The resulting mixture evaporated under reduced pressure and the residue was suspended in toluene (3 x 100 mL) and evaporated under reduced pressure to generate the intermediate amino acid hydrochloride salt. This salt was suspended in a mixture of acetonitrile (75 mL) and pyridine (75 mL) and then cooled before adding trifluoroacetic anhydride (10 mL). The mixture was stirred at room temperature for 1h, before evaporating under reduced pressure. The resulting residue was partitioned between dichloromethane (250 mL) and 10% aqueous citric acid solution (3 x 50 mL). The dichloromethane layer was then washed with saturated aqueous sodium hydrogen carbonate solution (25 mL) before drying over magnesium sulfate and filtering. The filtrate evaporated under reduced pressure to give intermediate trifluoroacetamide, 4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoic acid, as an oil brown (8.3 g). This oil was dissolved in dichloromethane (300 mL) before adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.14 g, 37.2 mmol), N,N-dimethylaminopyridine (6.8 g , 55.8 mmol) and tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (4.12 g, 20.5 mmol). The resulting mixture was stirred at room temperature for 5 hours before washing with 10% aqueous citric acid solution (2 x 50 mL), saturated sodium hydrogen carbonate (2 x 25 mL) and drying over magnesium sulfate. The mixture was filtered and evaporated under reduced pressure. This resulting residue was purified by column chromatography on silica (220 g) eluting with a gradient of ethyl acetate in heptane (0% to 100%) to give the title compound as an off-white amorphous solid (6.08 g, 52%). UPLC-MS Method 1: ion mass 573, 575 (MH+ [79Br]-tBu, MH+ 81 + 79 + 81 [ Br]-tBu), 529, 531 (MH [ Br]-BOC, MH [ Br]- BOC) Rt = 0.97 min Preparation 31: (3S)-3-[4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy tert-butyl ]benzoyl]oxypiperidine-1-carboxylate

[0244] Using a similar procedure to that described for Preparation 25, but using the bromide described in Preparation 30, the title compound was prepared as an amorphous solid (4.6 g, 97%). UPLC-MS Method 1: Ion mass 535 (MH+-tBu), 491 (MH+-BOC, MH+) Rt = 0.98 min Preparation 32: (3R)-3-[[5-[(1R,2S) tert-butyl -1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[0245] Using a procedure similar to that described for Preparation 15, but using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate instead of tert-butyl (3S)-3-aminopiperidine-1-carboxylate, the compound of the title was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 550.24 (M+), Rt = 2.53 min Preparation 33: (3R)-5-oxotetrahydrofuran-3-carboxylic acid

[0246] Sodium periodate (114 g, 533 mmol) was carefully added in small portions to a rapidly stirred mixture of (4S)-4-vinyl-tetrahydrofuran-2-one (15 g, 133 mmol) and ruthenium trichloride (1.39 g, 6.7 mmol) dissolved in a mixture of tetrachloromethane (150 mL), acetonitrile (150 mL) and water (225 mL). The reaction is very exothermic and the reaction mixture was allowed to reach 50 oC during the addition of sodium periodate. After all the sodium periodate had been added, the mixture was stirred for another 1 hour. Sodium chloride (200 g) was added to the reaction mixture along with ethyl acetate (250 mL) and then stirred quickly for 5 minutes. The ethyl acetate decanted and was replaced with fresh ethyl acetate (250 mL) and was quickly stirred again and decanted, the process was repeated with 4 more batches of ethyl acetate. The ethyl acetate extracts were combined and dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a dark brown oil. The oil was stored in the freezer overnight, at which point it turned black. This black material was dissolved in dichloromethane (200 mL) and filtered through a small plug of silica to remove the black impurity. The filtrate evaporated to give the title compound as a white crystalline solid (12.2 g, 70%). 1H NMR (300 MHz, CDCl3d) d = 10.81 (s, 1H), 4.69 - 4.39 (m, 2H), 3.53 (dddd, J=9.6, 8.0, 6.9, 6.3, 1H), 3.05 - 2.67 (m, 2H ). Preparation 34: (3S)-5-oxotetrahydrofuran-3-carboxylic acid

[0247] Using a similar procedure to that described for Preparation 33, but using (4R)-4-vinyltetrahydrofuran-2-one instead of (4S)-4-vinyltetrahydrofuran-2-one, the title compound was prepared as a waxy brown solid. 1H NMR (300 MHz, CDCl3d) d = 10.81 (s, 1H), 4.69 - 4.39 (m, 2H), 3.53 (dddd, J=9.6, 8.0, 6.9, 6.3, 1H), 3.05 - 2.67 (m, 2H ). Preparation 35: 4-[(1R,2S)-2-amino-1-(p-tolyl)propoxy]benzonitrile

[0248] Sodium hydride (60% w/w in mineral oil, 0.67 g, 17 mmol) was added in small portions to an amino alcohol solution from Preparation 4 (2.5 g, 15 mmol) in N-methylpyrrolidin -2-one (30 mL). The reaction was stirred at 60oC for 0.5 h before adding 4-flurobenzonitrile (2.2 g, 18 mmol) and heating for a further 0.5 h. The reaction mixture was cooled and carefully poured into a mixture of diethyl ether (300 mL) and 4M aqueous hydrochloric acid (150 mL). The diethyl ether layer was extracted again with 4M aqueous hydrochloric acid (100 mL). The combined aqueous layers were then extracted again with heptane (100 mL) and then basified with 32% aqueous sodium hydroxide solution and extracted with diethyl ether (2 x 100 mL). The diethyl ether layers were washed with water (2 x 30 mL), saturated brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting oil was purified by column chromatography on silica (80 g) eluting with a gradient of methanol:triethylamine (1:1) in ethyl acetate (0% to 10%) to give the title compound as a colorless oil ( 1.38 g, 34%). 1H NMR (300 MHz, CDCl3-d) d = 7.56 - 7.40 (m, 1H), 7.22 - 7.04 (m, 1H), 7.01 - 6.69 (m, 1H), 4.91 (d, J=5.3, 0H), 3.40 - 3.24 (m, 0H), 2.33 (s, 1H), 1.16 (d, J=6.6, 1H). Preparation 36: 4-[(1R,2S)-2-amino-1-(p-tolyl)propoxy]benzoic acid

[0249] 2M aqueous sodium hydroxide (62 mL, 124 mmol) was added to a solution of the nitrile from Preparation 35 (1.38 g, 5.1 mmol) in methanol (12 mL) and the resulting mixture was heated at 85oC for 3 hours. The mixture was concentrated under reduced pressure to a small volume (20 ml) and neutralized (pH 7) with 4M aqueous hydrochloric acid. The mixture was further reduced in volume (20 mL) under reduced pressure and the resulting filtered off-white solid was washed with a small volume of cold water to give the title compound (1.16 g, 79%). 1H NMR (300 MHz, DMSO-d6) d = 7.78 (d, J=8.8, 2H), 7.37 - 7.07 (m, 4H), 6.93 (d, J=8.8, 2H), 5.30 (d, J=4.6 , 1H), 3.46 - 3.16 (m, 1H), 2.27 (s, 3H), 1.07 (d, J=6.5, 3H). Preparation 37: 4-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoic acid

[0250] Trifluoroacetic anhydride (1.13 mL, 8.13 mmol) was added to an amino acid suspension from Preparation 36 in dichloromethane (50 mL), acetonitrile (20 mL) and triethylamine (5.66 mL, 40 mmol). The mixture was stirred for 1 hour before filtering. The filtrate evaporated under reduced pressure and was purified by column chromatography on silica (80 g) eluting with a gradient of ethyl acetate in heptane (0% to 30%) to give the title compound as an amorphous solid (0.93 g, 60%). 1H NMR (300 MHz, CDCl3-d) d = 7.95 (d, J=8.9, 2H), 7.18 (s, 4H), 6.87 (d, J=9.0, 2H), 6.47 (d, J=8.9, 1H ), 5.40 (d, J=3.1, 1H), 4.62 - 4.39 (m, 1H), 2.34 (s, 3H), 1.25 (d, J=7.0, 3H). Preparation 38: (3S)-3-[[4-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]amino]piperidine- tert-butyl 1-carboxylate

[0251] Using a similar procedure to that described for Preparation 15, but using the acid from Preparation 37, the title compound was prepared as an amorphous solid (63 mg, 85%). UPLC-MS Method 1: Ion mass 508 (MH+-tBu), 464 (MH+-BOC), Rt = 0.89 min Preparation 39: (3S)-3-[4-[(1R,2S)-1 tert-butyl -(p-tolyl)-2-[(2,2,2-trifluoroaceyl)amino]propoxy]benzoyl]oxypiperidine-1-carboxylate

[0252] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.131 mmol) was added to an acid solution of Preparation 37 (25 mg, 0.066 mmol), N,N-dimethylaminopyridine (16 mg , 0.131 mmol) and tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (20 mg, 0.098 mmol) in N,N-dimethylformamide (3 mL). The resulting mixture was stirred at room temperature for 20 hours before diluting with ethyl acetate (10 mL) and washing with 1M aqueous hydrochloric acid solution (2 x 3 mL), saturated sodium hydrogen carbonate (2 x 2 mL) and Drying over magnesium sulfate to give the title compound as an oil (30 mg, 80%). UPLC-MS Method 1: Ion mass 563.3 (MH+) Rt = 0.98 min Preparation 40: (3S)-3-[4-[(1R,2S)-2-amino-1-( hydrochloride tert-butyl 4-cyclopropylphenyl)propoxy]benzoyl]oxypiperidine-1-carboxylate

[0253] 1M Aqueous lithium hydroxide (68 mL, 69.8 mmol) was added to a solution of the trifluoroacetamide from Preparation 31 (33 g, 55.88 mmol) in tetrahydrofuran (330 mL) and the resulting mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure and the resulting residue was diluted with water (100 ml) and extracted with ethyl acetate (4x 250 ml). The combined ethyl acetate layers were washed with 2M aqueous hydrochloric acid (100 mL), saturated brine and dried over magnesium sulfate. The mixture was filtered and the magnesium sulfate filter cake was washed with 20% methanol in ethyl acetate (5x 100 mL). The combined ethyl acetate filtrates evaporated under reduced pressure to give a yellow solid. The yellow solid was suspended with tert-butyl methyl ether (3 x 100 mL), filtered and dried at 70°C to give the title compound as a very pale yellow solid (23.4 g, 79%). UPLC-MS Method 1: Ion mass 439 (MH+-tBu), 495 (MH+) Rt = 0.74 min Preparation 41: (3S)-3-[4-[(1R,2S)-1-(4 tert-butyl-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoyl]oxypiperidine-1-carboxylate

[0254] Oxalyl chloride (36 mL, 0.425 mol) was added to a solution of (2R)-tetrahydrofuran-2-carboxylic acid (9.87 g, 85 mmol) in dichloromethane (300 mL). Dimethylformamide (50 µL, cat.) was added and the resulting mixture was stirred for 2 h before evaporation under reduced pressure. The residue was redissolved in dichloromethane (200 mL) and evaporated under reduced pressure, this process was repeated twice more to generate the intermediate (2R)-tetrahydrofuran-2-carbonyl chloride. (2R)-Tetrahydrofuran-2-carbonyl chloride (7.5 g, 52.4 mmol) was dissolved in dichloromethane (50 mL) and added dropwise to an ice-cooled solution of the amine of preparation 40 (22.8 g, 42.9 mmol) and 4-methylmorpholine (14 mL, 129 mmol) in dichloromethane (400 mL). The resulting mixture was stirred at 5 oC for 20 minutes and then evaporated under reduced pressure. The resulting residue was resuspended with ethyl acetate (500 ml) and washed with 1 M hydrochloric acid (3 x 100 ml) followed by saturated aqueous sodium hydrocarbonate (2 x 50 ml). The ethyl acetate solution was dried over sodium sulfate, filtered through a small plug of silica and evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 x 200 mL) and evaporated to give the title compound as a light yellow foam (23.5 g, 92%). UPLC-MS Method 1: Ion mass 537 (MH+-tBu), Rt = 0.95 min Preparation 42: (3S)-3-[4-[(1R,2S)-1-(4-cyclopropylphenyl)- tert-butyl 2-[[(2S)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoyl]oxypiperidine-1-carboxylate

[0255] EDAC (1520 mg, 7.9 mmol) was added to an amine solution of preparation 40 (3.0 g, 5.65 mmol), (2S)-tetrahydrofuran-2-carboxylic acid (787 mg , 6.78 mmol) and Oxyma® (ethyl 2-cyano-2-hydroxyimino-acetate) (321 mg, 2.26 mmol) in acetonitrile (30 mL). To the resulting mixture was added triethylamine (1.97 mL, 14 mmol) and the mixture was stirred at room temperature for 20 hours.

[0256] The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 ml) and washed with 1 M hydrochloric acid (2 x 100) followed by saturated aqueous sodium hydrocarbonate. The ethyl acetate solution was coevaporated with toluene (2 x 200 mL) to give the title compound as a clear yellow oil (3.36 g, 100%). UPLC-MS Method 1: Ion mass 537 (MH+-tBu), Rt = 0.954 min Preparation 43: 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R) hydrochloride [(3S)-3-piperidyl]-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate

[0257] Hydrochloric acid (4M in 1,4-dioxane, 60 mL) was added to a solution of carbamate from Preparation 41 (23 g, 38.8 mmol) in dichloromethane (100 mL). The reaction mixture was stirred rapidly at room temperature for 0.33 h and then evaporated under reduced pressure to generate the title compound as a white foam. (20.5 g, 100%) UPLC-MS Method 1: Ion mass 493 (MH+), Rt 0.60 min. Preparation 44: [(3S)-3 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate hydrochloride -piperidyl]

[0258] Using a similar procedure to that described for Preparation 43, but using the carbamate from Preparation 42, the title compound was prepared as an amorphous solid. UPLC-MS Method 1: Ion mass 493 (MH+), Rt 0.62 min. Preparation 45: [(1S,2S)-2-(tert-butoxycarbonylamino)-1-(p-tolyl)propyl] 4-nitrobenzoate

[0259] To a stirred solution of the alcohol from Preparation 3 (5 g, 18.867 mmol), triphenylphosphine (14.83 g, 56.6 mmol) and 4-nitro-benzoic acid (3.78 g, 22.640 mmol) in tetra -hydrofuran (100 mL, 20 vol) was added diethylazodicarboxylate (9.85 g, 56.6 mmol) at 0°C for 5 min. The reaction was stirred at room temperature for 16 h. Upon completion, the reaction was diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (30-40% ethyl acetate in pet ether as eluent) to give the title compound as a colorless gum (2.3 g, 33%). 1H NMR (CDCl3, 400 MHz): d = 8.26 (s, 4H), 7.33 (m, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 5.74 - 5.72 (m, 1H) , 4.53 - 4.49 (m, 1H), 4.34 - 4.30 (m, 1H), 2.34 (s, 3H), 1.32 (s, 9H), 1.07 (m, J = 6.8 Hz, 3H). Preparation 46: tert-butyl N-[(1S,2S)-2-hydroxy-1-methyl-2-(p-tolyl) ethyl]carbamate

[0260] To a stirred solution of carbamate from Preparation 45 (2 g) in methanol (20 mL, 10 vol) was added potassium carbonate (1 g, 7.246 mmol) at room temperature. The reaction was stirred at room temperature for 3 h. Upon completion, the reaction mixture was filtered and washed with methanol and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (20% ethyl acetate as eluent) to give the title compound as an off-white solid (1.1 g, 85 g). 1H NMR (CDCl3, 400 MHz): d = 7.20-7.24 (m, 2H), 7.13-7.19 (m, 2H), 4.83-4.80 (m, 1H), 4.62-4.59 (m, 1H), 4.00-3.98 (m, 1H), 3.09-3.07 (m, 1H), 2.28-2.39 (m, 3H), 1.37-1.52 (m, 9H), 0.99 (d, J = 6.8 Hz, 3H). LCMS (ESI): m/z 266 [M+H]+; RT = 2.65 min; (KINETEX-1.7u XB-C18 column, 0.05% formic acid in water with acetonitrile). Preparation 47: (1S,2S)-2-amino-1-(p-tolyl)propan-1-ol

[0261] Using a similar procedure to that described for Preparation 4, but using the carbamate from Preparation 46, the title compound was prepared as a light brown solid. 1H NMR (CDCl3, 400MHz): d = 7.21-7.24 (m, 2H), 7.12-7.17 (m, 2H), 4.21 (d, J = 6.8 Hz, 1H), 3.09-3.07 (m, 2H), 2.34 (s, 3H), 1.80 (m, 2H), 1.03 (d, J = 6.4 Hz, 3H) LCMS (ESI): m/z 166 [M+H]+; 85%; RT = 1.43 min; (KINETEX-1.7u XB-C18 column, 0.05% formic acid in water with acetonitrile). Preparation 48: 5-[(1S,2S)-2-Amino-1-(p-tolyl)propoxy]pyridine-2-Carbonitrile

[0262] Using a similar procedure to that described for Preparation 11, but using the amino alcohol from Preparation 47, the title compound was prepared as a light yellow oil, (600 mg, 74%). 1H NMR (CDCl3, 300MHz): d = 8.37 (d, J = 2.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.10-7.20 (m, 5H), 4.84 (d, J = 6.6 Hz, 1H), 3.32-3.35 (m, 1H), 2.33 (s, 3H), 1.04 (d, J = 6.6 Hz, 3H). LCMS (ESI): m/z 268 [M+H]+; 97.85%; RT = 1.97 min (KINETEX-1.7u XB-C18 column, 0.05% formic acid in acetronyl water) Preparation 49: 5-[(1S,2S)-2-amino-1-(p-tolyl )propoxy] Methyl pyridine-2-carboxylate

[0263] Using a similar procedure to that described for Preparation 12, but using anitrile from Preparation 48, the title compound was prepared as an off-white solid, (500 mg, 74%). 1H NMR (CDCl3, 300MHz): d = 8.37 (d, J = 2.9 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.12-7.21 (m, 5H), 4.86 (d, J = 7.0 Hz, 1H), 3.93 (s, 3H), 3.31-3.38 (m, 1H), 2.31 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H) LCMS (ESI): m/z 301 [M +H]+; 94%; RT = 2.02 min (KINETEX-1.7u XB-C18 column, 0.05% formic acid in acetronyl water) Preparation 50: 5-[(1S,2S)-1-(p-tolyl)-2- Methyl [(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylate

[0264] Using a similar procedure to that described for Preparation 13, but using the amine from Preparation 49, the title compound was prepared as a yellow liquid, (800 mg, 75%). 1H NMR (CDCl3, 400MHz): d = 8.37 (d, J = 2.4 Hz, 1H), 7.98-7.95 (m, 1H), 7.06-7.20 (m, 5H), 6.31-6.54 (m, 1H), 5.25 -5.43 (m, 1H), 4.43-4.60 (m, 1H), 3.94 (s, 3H), 2.31 (s, 3H), 1.23-1.38 (m, 3H) LCMS (ESI): m/z 397 [M +H]+ ; 38.45%; RT = 1.24 min + 59.63%; ; RT = 2.84 min (KINETEX-1.7u XB-C18 column, 0.05% formic acid in acetronyl water) Preparation 51: 5-[(1S,2S)-1-(p-tolyl)-2 acid -[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid

[0265] Using a similar procedure to that described for Preparation 14, but using the ester from Preparation 50, the title compound was prepared as an off-white solid (600 mg, 89%). 1H NMR (CDCl3, 400MHz): d = 8.25-8.23 (m, 1H), 8.03-8.05 (d, J = 8.8 Hz, 1H), 7.15-7.17 (m, 5H), 6.29-6.30 (m, 1H) , 5.30 (d, J = 4.4 Hz, 1H), 4.50-4.55 (m, 1H), 2.35 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). LCMS (ESI): m/z 383 [M+H]+; 82.16%; RT = 2.43 min (KINETEX-1.7u XB-C18 column, 0.05% formic acid in acetronyl water) Preparation 52: (3S)-3-[[5-[(1S,2S)-1- tert-butyl (p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[0266] Using a similar procedure as described for Preparation 15, but using the acid from Preparation 51, except that the crude material was purified by SFC purification (column: Chiralpak LuxCellulose- 2 (4.6*250) mm, 5u, %CO2:80%, %cosolvent: 20% (100% methanol), total flow: 100 g/min, back pressure: 100 bar, UV: 246 nm, stack time: 3.2 min, charge: 10 mg) to give the title compound as an off-white solid (400 mg). 1H NMR (CDCl3, 400MHz): d = 8.14-8.12 (m, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.89-7.93 (m, 1H), 7.12-7.20 (m, 5H), 6.30 -6.34 (m, 1H), 5.23 (d, J = 4.4 Hz, 1H), 4.53 (m, 1H), 4.07 (m, 1H), 3.59 (m, 1H), 3.49 (d, J = 5.4 Hz, 1H), 3.40 (m, 2H), 2.33 (s, 3H), 1.88 (m, 1H), 1.67-1.75 (m, 2H), 1.42 (s, 7H), 1.36 (d, J = 6.8 Hz, 3H ). LCMS (ESI): m/z 565 [M+H]+; 98%; RT = 3.11 min (KINETEX-1.7u XB-C18 column, 0.05% formic acid in water with acetonitrile) and chiral HPLC ~ 99.7%, Rt = 3.41 min [SFC METHOD: Injection volume : 10, solvent: 0.5% DEA in methanol Column: Chiralpak LuxCellulose-2 (4.6*250) mm, 5u, Well Location: 16D, Column Temperature: 29.9, Flow: 3, Pressure: 100, RT: 3.41 min peak1 and RT: 4.54 min peak2]. Preparation 53: (3S)-3-[[5-[(1S,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl] amino]piperidine-1- tert-butyl carboxylate

[0267] Using a similar procedure as described for Preparation 15, but using the acid from Preparation 51, to generate the title compound as a light green solid (300 mg, 93%). 1H NMR (DMSO, 300MHz): d = 9.50-9.54 (m, 1H), 8.63-8.67 (m, 1H), 8.25 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H ), 7.37-7.41 (m, 1H), 7.22-7.28 (m, 2H), 7.137.19 (m, 2H), 5.43 (d, J = 6.2 Hz, 1H), 4.25-4.29 (m, 1H), 4.12-4.16 (m, 1H), 3.07-3.23 (m, 2H), 2.84-2.94 (m, 1H), 2.71-2.75 (m, 1H), 2.26 (s, 3H), 1.801.84 (m, 2H ), 1.60-1.71 (m, 2H), 1.30 (d, J=6.6 Hz, 3H). LCMS (ESI): m/z 465 [M+H]+ ; 99%; RT = 1.24 min. (KINETEX-1.7u XB-C18 column, 0.05% formic acid in water with acetonitrile) and chiral HPLC~99%; SFC METHOD: Injection volume: 10, Solvent: 0.5% DEA in Methanol, Column: Chiralpak LuxCellulose 2 (4.6 * 250) mm, 5u, Column Temperature: 29.9, Flow: 3, pressure: 100, RT: 4.17 min. EXAMPLES Example 1: N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl) -2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 1)

[0268] 2M oxalyl chloride (40 mL, 80 mmol) in dichloromethane was added to a lactone solution from Preparation 33 (1.9 g, 14.6 mmol) in dichloromethane (80 mL) followed by the catalytic DMF ( 0.02 mL). The reaction mixture was stirred at room temperature for 1 h and then evaporated under reduced pressure to generate a yellow gum. This gum was dissolved in toluene (50 mL) and evaporated under reduced pressure, the process was repeated to remove excess oxalyl chloride. The resulting acid chloride was dissolved in dichloromethane (20 mL) and added to a solution of amine from Preparation 16 (5.52 g, 11.9 mmol) and 4-methylmorpholine (3 mL, 27.3 mmol) in dichloromethane ( 150 mL) at 5oC. The reaction was stirred at 5°C for 0.5 h and then evaporated under reduced pressure. The residue was dissolved in dichloromethane and purified by column chromatography on silica (400 g) eluting with 100% ethyl acetate to give a white foam (6.7 g). The white foam was dissolved in ethyl acetate (25 mL) and diethyl ether was added slowly (200 mL). The resulting white viscous solid was stirred for 2 h and then removed by filtration. The resulting white powder was dissolved in refluxing ethyl acetate (250 mL) and the resulting solution was concentrated under reduced pressure to approximately 50 mL and seeded with a small amount of seed crystals (white powder above). This mixture was stored in the freezer overnight and the resulting white crystals were filtered and dried under vacuum to give the title compound (4.8 g, 70%). Mpt: 207.5 oC. UPLC-MS Method 1: Ion of mass 577 (MH+), Rt = 0.74 min UPLC-MS Method 2: Ion of mass 576.22 (M+), Rt = 2.3 minutes 1H NMR (600 MHz, DMSO-d6) Mixture of rotamers d = 9.52 (s, 1H), 8.43 (dd, J=26.8, 8.3, 1H), 8.24 (dd, J=11.9, 2.8, 1H), 7.90 (dd, J=14.4, 8.7, 1H), 7.39 (td, J=8.8, 2.9, 1H), 7.25 (d, J=7.9, 2H), 7.16 (d, J=7.9, 2H), 5.41 (dd, J=7.9, 6.0, 1H), 4.60 (t, J=8.5, 0.53H), 4.44 (t, J=8.4, 0.47H), 4.27 (ddd, J=8.4, 5.7, 2.5, 2H), 4.21 (dd, J=12.5, 4.1, 0.47H), 4.16 - 4.10 (m, 0.53H), 3.86 - 3.69 (m, 3H), 3.09 - 2.96 (m, 1H), 2.82 - 2.55 (m, 3H), 2.26 (s, 3H), 1.84 (m, J=11.8, 11.0, 3.4, 1H), 1.77 - 1.61 (m, 2H), 1.55 - 1.36 (m, 1H), 1.30 (dd, J=6.9, 1.2, 3H). Example 2: 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R) -5- oxotetrahydrofuran-3-carbonyl]-3- piperidyl]pyridine-2-carboxamide (Compound 2)

[0269] Trifluoroacetic acid (4 mL) was added to a solution of the carbamate from Preparation 25 (0.752 g, 1.275 mmol) in acetonitrile (4 mL) and the resulting solution was stirred at room temperature for 0.2 h. The reaction mixture evaporated under reduced pressure. The resulting residue was dissolved in 2 M acetic acid in methanol and purified by ion exchange chromatography (10 g SCX cartridge) eluting with 100% methanol followed by 2 M ammonia in methanol. The ammonia methanol eluent was evaporated under reduced pressure to generate the crude amine intermediate (5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy ]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide). This crude amine intermediate was dissolved in N,N-dimethylformamide (30 mL) together with the acid from preparation 33 (0.248 g, 1.9 mmol) and diisopropylethylamine (0.89 mL, 5.1 mmol) and, finally, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl) hexafluorophosphate (0.965 g, 2.55 mmol). The resulting mixture was stirred at room temperature for 1h, before evaporating under reduced pressure. The residue obtained was dissolved in ethyl acetate (150 mL) and washed with 10% aqueous citric acid solution (2 x 20 mL) followed by saturated aqueous sodium hydrocarbonate solution (1 x 50 mL). The solution was dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica eluting with a gradient of ethyl acetate in heptane (0% to 100%) to give the title compound as a white amorphous solid (0.55 g, 72%). UPLC-MS Method 2: Ion mass 602.24 (M+), Rt = 2.36 min. 1H NMR (300 MHz, DMSO-d6) rotamer mixture, d = 9.48 (d, J=8.5, 1H), 8.40 (dd, J=13.9, 8.1, 1H), 8.23 (dd, J=5.4, 2.8, 1H), 7.95 - 7.75 (m, 1H), 7.38 (ddd, J=7.8, 4.5, 2.9, 1H), 7.23 (d, J=8.1, 2H), 7.04 (d, J=8.2, 2H), 5.41 (t, J=5.1, 1H), 4.59 (t, J=8.5, 0.55H), 4.44 (t, J=8.4, 0.45H), 4.39 - 4.00 (m, 3H), 3.78 (m, 3H), 3.03 (m, 1H), 2.86 - 2.57 (m, 3H), 1.97 - 1.60 (m, 4H), 1.60 - 1.35 (m, 1H), 1.29 (d, J=6.8, 3H), 0.92 (dd, J =8.3, 2.4, 2H), 0.79 - 0.50 (m, 2H). Example 3: 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(2,2-difluoropropanoylamino)propoxy]-N-[(3S)-1-[(3R)-5-oxo- tetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide (Compound 3)

[0270] An aqueous solution of lithium hydroxide (1 M, 2 mL, 2 mmol) was added to a solution of the compound of Example 2 (100 mg, 0.166 mmol) and the resulting solution was heated to 70 oC for 1.5 hour. The reaction mixture evaporated under reduced pressure and the resulting residue was suspended in toluene (2 x 50 mL) and evaporated to remove any residual water to generate the unprotected ring open intermediate. This intermediate (0.018 mmol), 2,2-difluoropropanoic acid (3 mg, 0.027 mmol) and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl) uronium hexafluorophosphate (17 mg , 0.045 mmol) were dissolved in N,N-dimethylformamide (0.5 mL) and finally diisopropylethylamine (0.013 mL, 0.072 mmol) was added. The resulting mixture was heated to 40°C and then purified by preparative reverse phase HLPC using a gradient of acetonitrile in 0.1% aqueous formic acid (10% to 100%) to generate the title compound as a amorphous solid. UPLC-MS Method 2: Ion mass 598.26 (M+), Rt = 2.32 min.

Example 4-21:

[0271] The compounds of the following tabulated examples (Table 1) of the general formula: were prepared by a similar method to example 3 using the appropriate acid in place of 2,2-difluoropropanoic acid.

[0272] Table 1. UPLC-MS Method 2 used. 2. Compound 19: 1H NMR (600 MHz, DMSO-d6) d = 8.57 (dd, J=2.0, 1.0, 1H), 8.50 (dd, J=2.2, 1.0, 1H), 8.45 (d, J=7.9 , 0.5H), 8.40 (d, J=8.6, 0.5H), 8.25 (dd, J=11.0, 2.8, 1H), 8.12 (dd, J=8.9, 1.7, 1H), 7.89 (dd, J=14.9 , 8.7, 1H), 7.38 (ddd, J=8.8, 7.7, 2.9, 1H), 7.26 (d, J=7.9, 2H), 7.07 - 6.97 (m, 2H), 5.57 (t, J=6.1, 1H ), 4.68 - 4.36 (m, 2H), 4.31 - 4.09 (m, 2H), 3.78 (m, 3H), 3.11 - 2.97 (m, 1H), 2.82 - 2.55 (m, 3H), 1.84 (m, 2H ), 1.80 - 1.57 (m, 2H), 1.28 (dd, J=6.8, 2.1, 3H), 0.90 (dt, J=8.4, 1.7, 2H), 0.72 - 0.46 (m, 2H). Example 22: 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-1-[( 3R) 5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide (Compound 22)

[0273] Hydrochloric acid (4M in dioxane, 40 mL) was added to a solution of carbamate from Preparation 27 (1.25 g, 2.11 mmol) in dichloromethane (20 mL). The reaction mixture was briefly stirred at room temperature for 0.33 h and then evaporated under reduced pressure to generate the deprotected amine intermediate (5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[ [(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide) (UPLC-MS method 1: Ion mass 493 (MH+ ), Rt 0.56 min). Simultaneously, 2M oxalyl chloride (40 mL, 80 mmol) in dichloromethane was added to a lactone solution from Preparation 33 (0.468 g, 3.6 mmol) in dichloromethane (20 mL) followed by the catalytic DMF (0.01 mL). The reaction mixture was stirred at room temperature for 1 h and then evaporated under reduced pressure to generate a yellow gum. This gum was dissolved in toluene (50 mL) and evaporated under reduced pressure, the process was repeated to remove excess oxalyl chloride. The resulting acid chloride was dissolved in dichloromethane (20 mL) and added to a solution of the intermediate amine (2.11 mmol) in dichloromethane (50 mL) and 4-methylmorpholine (2.6 mL, 24 mmol). This reaction mixture was stirred at 5 oC for 0.5 h before evaporating under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with 5% aqueous citric acid solution (2 x 50 mL), saturated aqueous sodium hydrogen carbonate (1 x 50 mL), saturated brine (50 mL) and dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give a brown amorphous solid (1.25 g). This solid was purified by column chromatography on silica gel (40 g) eluting with 100% ethyl acetate, then a gradient of acetonitrile in ethyl acetate (0% to 70%). The resulting amorphous solid was dissolved in acetonitrile (50 mL) and enough water was added to give a slightly cloudy solution (80 mL) and then acetonitrile (2 mL) was added to give a clear solution. This solution was frozen and then lyophilized for 70 h to give the title compound as a white amorphous solid (0.88 g, 70%). UPLC-MS Method 1: Ion of mass 605 (MH+), Rt = 0.70 min UPLC-MS Method 2: Ion of mass 604.29 (M+), Rt = 2.21 min 1H NMR (600 MHz, DMSO-d6), Rotamer mixture, d = 8.45 (d, J=8.0, 1H), 8.24 (dd, J=10.5, 2.8, 1H), 7.90 (dd, J=14.6, 8.7, 1H), 7.62 ( d, J=9.4, 1H), 7.38 (ddd, J=9.6, 7.1, 2.9, 1H), 7.24 (d, J=8.0, 2H), 7.02 (d, J=8.0, 2H), 5.39 (t, J=6.2, 1H), 4.60 (t, J=8.5, 0.53H), 4.44 (t, J=8.4, 0.47H), 4.34 - 4.06 (m, 4H), 3.89 - 3.65 (m, 5H), 3.11 - 2.96 (m, 1H), 2.83 - 2.55 (m, 3H), 1.87 (m, 3H), 1.78 - 1.57 (m, 3H), 1.54 - 1.38 (m, 1H), 1.32 (m, 2H), 1.23 (m, 3H), 0.91 (m, 2H), 0.67 - 0.53 (m, 2H). Example 23: N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3 -carbonyl]-3-piperidyl] carbamoyl]-3-pyridyl]oxy]ethyl] isoxazol-3-carboxamide (Compound 23)

[0274] Using a similar procedure to that described for Example 22, but using the carbamate from Preparation 28 (1.4 g, 2.4 mmol) through the amine intermediate N-[(1S,2R)-2-(4-cyclopropylphenyl )-1-methyl-2- [[6-[[(3S)-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazol-3-carboxamide, the title compound was prepared as a white amorphous solid (0.85 g, 60%). UPLC-MS Method 1: Ion of mass 602 (MH+), Rt = 0.73 min UPLC-MS Method 2: Ion of mass 601.25 (M+), Rt = 2.29 min 1H NMR (600 MHz, DMSO-d6): Mixture of rotamers, d = 9.05 (s, 1H), 8.80 (d, J=8.5, 1H), 8.45 (d, J=8.0, 1H), 8.24 (dd, J=11.8, 2.9, 1H), 7.89 (dd, J=14.7, 8.7, 1H), 7.37 (td, J=8.3, 2.9, 1H), 7.26 (d, J=8.0, 2H), 7.03 (d, J=8.1, 2H) , 6.80 (s, 1H), 5.51 (t, J=6.4, 1H), 4.60 (t, J=8.5, 0.5H), 4.51 - 4.37 (m, 1.5H), 4.33 - 4.10 (m, 2H), 3.92 - 3.68 (m, 3H), 3.09 - 2.95 (m, 1H), 2.81 - 2.55 (m, 3H), 1.85 (ddd, J=10.3, 8.4, 5.1, 2H), 1.79 - 1.59 (m, 2H) , 1.55 - 1.36 (m, 1H), 1.35 - 1.23 (m, 3H), 0.90 (dd, J=8.5, 2.5, 2H), 0.66 - 0.56 (m, 2H). Example 24: 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoate [(3S)-1-[(3R)-5 -oxotetrahydrofuran-3-carbonyl]-3-piperidyl] (Compound 24)

[0275] Using a similar procedure to that described for Example 2, but using the carbamate from Preparation 31 (4.6 g, 7.79 mmol), the title compound was prepared as a white amorphous solid (3.32 g, 90 %). UPLC-MS Method 2: Ion mass 602.22 (M+), Rt = 2.51 minutes 1H NMR (600 MHz, DMSO-do): Mixture of rotamers, d = 9.73 - 9.31 (m, 1H), 7.90 - 7.66 (m, 2H), 7.21 (dd, J=8.3, 2.0, 2H), 7.06 - 7.01 (m, 2H), 7.00 - 6.96 (m, 1H), 6.95 - 6.92 (m, 1H), 5.34 ( dd, J=11.6, 6.1, 1H), 4.93 (m, 1H), 4.45 (ddd, J=10.4, 8.8, 7.9, 1H), 4.27 - 4.14 (m, 2H), 3.89 - 3.80 (m, 1H) , 3.77 - 3.70 (m, 1H), 3.68 - 3.50 (m, 2H), 3.38 (m, 0.5H), 3.29 (m, 0.5H), 2.75 - 2.63 (m, 1H), 2.58 (dd, J= 17.2, 6.0, 0.5H), 2.47 (dd, J=17.2, 9.0, 0.5H), 1.97 - 1.63 (m, 4H), 1.57 (m, 0.5H), 1.50 (m, 0.5H), 1.32 - 1.23 (m, 3H), 0.97 - 0.86 (m, 2H), 0.68 - 0.56 (m, 2H).

Examples 25 to 58:

[0276] The compounds of the following tabulated examples (Table 2) of the general formula: were prepared as a parallel array using the method described below.

[0277] Di-tert-butyl dicarbonate (0.426 g, 1.96 mmol) was added to a solution of the compound of Example 24 (0.59 g, 0.98 mmol) and N,N-dimethylpyridine (12 mg, 0.098 mmol) in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 18 h before being diluted with dichloromethane (100 mL) and washed with 10% aqueous citric acid solution (2 x 20 mL), saturated aqueous sodium hydrogen carbonate (1 x 25 mL) and then dried over magnesium sulfate, filtered and evaporated under reduced pressure to generate an amorphous solid. This solid was dissolved in tetrahydrofuran (100 mL) and a 10% aqueous sodium carbonate solution (5 mL) was added. The resulting solution was stirred at room temperature for 70 h. The mixture evaporated under reduced pressure and the resulting residue was diluted with dichloromethane (70 mL) and washed with 10% aqueous citric acid solution (2 x 25 mL), saturated aqueous sodium hydrogen carbonate (1 x 25 mL) and then , dried over magnesium sulfate, filtered and evaporated. The resulting gum was purified by column chromatography on silica (120 g) eluting with a gradient of ethyl acetate in heptane (0% to 100%) to generate the carbamate intermediate. This carbamate intermediate was dissolved in 4M hydrochloric acid in dioxane (5 mL) and stirred at room temperature for 0.5 h. This mixture was concentrated, by evaporation under reduced pressure, in a small volume. The resulting mixture was filtered to give the intermediate amine salt as a white solid. This intermediate amine salt (0.015 mmol) was dissolved in N,N-dimethylformamide (0.15 mL) and the appropriate acid (0.023 mmol) was added followed by a solution of N,N,N',N'-tetramethyl- Uronium O-(1H-benzotriazol-1-yl)hexafluorophosphate (0.03 mmol) and diisopropylethylamine in N,N-dimethylformamide (0.15 mL). The resulting mixtures were stirred at room temperature for 1 h and then purified by preparative reversed-phase HLPC using a gradient of acetronyl in 0.1% aqueous formic acid (10% to 100%) to generate the title compound. as amorphous solids.

[0278] Table 2 UPLC-MS method1 used. 2 Compound 31: 1H NMR (300 MHz, DMSO-d6), rotamer mixture, d = 9.22 (d, J=8.7, 1H), 7.77 (dd, J=8.9, 7.7, 2H), 7.24 (d, J =8.1, 2H), 7.05 - 6.84 (m, 4H), 5.53 - 5.38 (m, 1H), 5.06 - 4.78 (m, 1H), 4.50 - 4.30 (m, 2H), 4.20 (ddd, J=14.7, 8.7, 5.4, 1H), 3.94 - 3.47 (m, 5H), 2.80 - 2.52 (m, 5H), 2.02 - 1.39 (m, 5H), 1.29 (d, J=6.7, 3H), 0.89 (dd, J =8.5, 2.4, 2H), 0.69 - 0.47 (m, 2H). 3 Compound 34: 1H NMR (300 MHz, DMSO-d6) Mixture of rotamers, d = 7.82 - 7.72 (m, 2H), 7.69 (d, J=8.7, 1H), 7.21 (d, J=8.1, 2H) , 7.08 - 7.00 (m, 2H), 7.00 - 6.88 (m, 2H), 5.40 (t, J=5.0, 1H), 4.99 - 4.83 (m, 0H), 4.45 (td, J=8.4, 5.1, 1H ), 4.20 (ddd, J=15.4, 8.8, 5.5, 2H), 3.92 - 3.41 (m, 7H), 3.18 (s, 3H), 2.78 - 2.54 (m, 1H), 2.07 (s, 2H), 1.99 - 1.38 (m, 5H), 1.16 (d, J=6.8, 3H), 1.01 - 0.77 (m, 2H), 0.62 (t, J=5.7, 2H). 4 Compound 37 can be crystallized from ethyl acetate followed by slurry in heptane at 60°C for 4 days to generate a fully crystalline solid Mpt 146°C. 1H NMR (300 MHz, DMSO-d6) Mixture of rotamers, d = 7.84 - 7.65 (m, 2H), 7.58 (d, J=9.3, 1H), 7.22 (d, J=8.1, 2H), 7.08 - 6.88 (m, 4H), 5.34 (dd, J=7.1, 3.8, 1H), 5.09 - 4.83 (m, 1H), 4.45 (td, J=8.3, 6.2, 1H), 4.20 (ddd, J=16.0, 8.7 , 5.3, 2H), 4.13 - 4.04 (m, 1H), 3.85 (dt, J=13.3, 7.0, 1H), 3.79 - 3.46 (m, 5H), 3.31 (s, 1H), 2.83 - 2.39 (m, 2H), 2.00 - 1.43 (m, 7H), 1.34 (q, J=3.4, 2H), 1.19 (d, J=6.7, 3H), 0.90 (dq, J=8.4, 1.3, 2H), 0.61 (td , J=10.0, 8.8, 5.5, 2H). 5 Compound 42: 1H NMR (300 MHz, DMSO-d6) Mixture of rotamers, d = 8.88 (d, J=8.7, 1H), 7.83 - 7.69 (m, 2H), 7.24 (d, J=8.2, 2H) , 7.11 - 6.79 (m, 4H), 5.47 (dd, J=6.2, 4.1, 1H), 5.12 - 4.75 (m, 1H), 4.53 - 4.31 (m, 2H), 4.20 (ddd, J=14.5, 8.8 , 5.4, 1H), 3.92 - 3.51 (m, 4H), 3.49 - 3.37 (m, 1H), 2.80 - 2.52 (m, 5H), 2.01 - 1.40 (m, 2H), 1.27 (d, J=6.7, 3H), 1.01 - 0.79 (m, 2H), 0.73 - 0.51 (m, 2H). Example 37 Alternative method: 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2- [[(2R)tetrahydrofuran-2-carbonyl]amino]propoxy] [(3S)-1- benzoate [(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl](compound 37)

[0279] lactone solution from Preparation 33 (7.38 g, 56.7 mmol) in dichloromethane (250 mL) followed by catalytic DMF (0.09 mL). The reaction mixture was stirred at room temperature for 1.5 h and then evaporated under reduced pressure to generate a yellow gum. This gum was dissolved in toluene (2 x 200 mL) and evaporated under reduced pressure, the process was repeated to remove excess oxalyl chloride to generate the intermediate (3R)-5-oxotetrahydrofuran-3-carbonyl chloride (8 .4 g, 100%).

[0280] The intermediate (3R)-5-oxotetrahydrofuran-3-carbonyl hydrochloride (8.4 g, 56.7 mmol) was dissolved in dichloromethane (100 mL) and added to an ice-cooled amine solution of Preparation 43 (20.0 g, 37.8 mmol) in dichloromethane (400 mL) and 4-methylmorpholine (19.3 mL, 151 mmol). This reaction mixture was stirred at 5 oC for 2.5 h before evaporating under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and washed with 2M aqueous citric acid solution (3 x 100 mL), saturated aqueous sodium hydrogen carbonate (1 x 50 mL), saturated brine (50 mL) and dried. over magnesium sulfate, it was filtered and the filtrate evaporated under reduced pressure to give a brown amorphous solid (25 g). This solid was purified by column chromatography on silica gel (250 g) eluting with 100% ethyl acetate. The resulting cream-colored solid was recrystallized twice from hot ethyl acetate to a white crystalline solid (15.5 g). This solid was suspended in heptane and heated to 90°C for 5 hours and then filtered and dried to constant weight in vacuum at 7 mmHg and 80°C to give the title compound. 1H NMR (300 MHz, DMSO-d6) Mixture of rotamers, d = 7.84 - 7.65 (m, 2H), 7.58 (d, J=9.3, 1H), 7.22 (d, J=8.1, 2H), 7.08 - 6.88 (m, 4H), 5.34 (dd, J=7.1, 3.8, 1H), 5.09 - 4.83 (m, 1H), 4.45 (td, J=8.3, 6.2, 1H), 4.20 (ddd, J=16.0, 8.7 , 5.3, 2H), 4.13 - 4.04 (m, 1H), 3.85 (dt, J=13.3, 7.0, 1H), 3.79 - 3.46 (m, 5H), 3.31 (s, 1H), 2.83 - 2.39 (m, 2H), 2.00 - 1.43 (m, 7H), 1.34 (q, J=3.4, 2H), 1.19 (d, J=6.7, 3H), 0.90 (dq, J=8.4, 1.3, 2H), 0.61 (td , J=10.0, 8.8, 5.5, 2H). UPLC-MS Method 1: Ion mass 604.29 (M+), Rt = 0.755 min UPLC-MS Method 2: Ion mass 604.29 (M+), Rt = 2.21 min Characterization of Polymorph F of compound 37

DSC

[0281] Polymorph F of compound 37 has a differential scanning calorimetry (DSC) curve comprising an endothermic event beginning at about 144°C (± 2°C) and no weight loss associated with the melting process; see Figure 1.

XRPD

[0282] Polymorph F of compound 37 has an essentially similar XRPD pattern, as shown in Figure 2. Polymorph F of compound 37 is characterized by an XRPD pattern that exhibits one or more reflection peaks at approximately 2? = 6.3, 8.2, 14.8, 17.2, 17.4, 21.1 and/or 21.3 (± 0.1 degree), respectively (primary in bold). X-ray crystallography

[0283] Polymorph F of compound 37 is characterized by having single crystal parameters that are substantially the same as those presented in Table 3. Polymorph F of compound 37 has a structure obtained by single crystal X-ray crystallography (XRC ) as shown in Figure 3Figure 3.

[0284] Table 3. The crystal parameters of determining the structure of a single crystal.

[00285] Compound 37 is a single enantiomer, the absolute configuration of the molecule can be determined by analyzing the anomalous X-ray scattering by the crystal. The differences in anomalous scattering intensities are then compared with the scattering intensities calculated for each enantiomer. These measured and calculated intensities can then be fitted to a parameter, for example, the Flack factor (see Flack, HD; Bernardinelli, G. Acta Cryst. 1999, A55, 908; Flack, HD; Bernardinelli, G. Reporting and evaluating absolute -structure and absolute-configuration determinations, J. Appl. Cryst. 2000, 33, 1143). The Flack factor (absolute structure parameter), x(u) should be close to 0 if the resolved structure configuration is correct, within statistical fluctuations, generally |x|<2u or x will be close to 1 if the inverse model is correct. The Flack factor measured for the F-form structure of compound 37 shown in Table 3 is 0.1 with a standard uncertainty of 0.3. This structure contains 5 chiral centers located at C4, C6, C8, C25 and C31, which were designated as R, S, R, S and R configuration, respectively. This is consistent with the proposed configuration of the molecule. Coordinate polymorph F from compound 37 data. Example 59: N-[(3R)-1 [(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2 -[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 59)

[0286] O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate (15 mg, 0.038 mmol) was added to a solution of the acid from Preparation 33 (6 mg, 0.039 mmol ), the amine from Preparation 17 (9 mg, 0.019 mmol) and triethylamine (20 µL, 0.095 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred for 0.25 h at room temperature and purified by reversed-phase preparative HPLC using a gradient of acetonitrile in 50 mM aqueous ammonium bicarbonate solution (5% to 95%) to generate the title compound as a amorphous solid. UPLC-MS Method 2: Ion mass 576.22 (M+), Rt = 2.30 minutes Example 60: N-[(3R)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl] -3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 60)

[0287] Using a similar procedure to that described for Example 59, but using the acid from Preparation 34, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 576.22 (M+), Rt = 2.30 minutes Example 61: N-[(3R)-1-[(2S)-5-oxotetrahydrofuran-2-carbonyl] -3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 61)

[0288] Using a similar procedure to that described for Example 59, but using (2R)-5-oxotetrahydrofuran-2-carboxylic acid instead of the acid of Preparation 33, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 576.22 (M+), Rt = 2.29 minutes Example 62: N-[(3R)-1-[(2R)-5-oxotetrahydrofuran-2-carbonyl] -3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 62)

[0289] Using a similar procedure to that described for Example 59, but using (2S)-5-oxotetrahydrofuran-2-carboxylic acid instead of the acid from Preparation 33, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 576.22 (M+), Rt = 2.29 minutes Example 63: N-[(3S)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl] -3-piperidyl]- 5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 63)

[0290] Using a similar procedure to that described for Example 59, but using the acid from Preparation 34 and the amine from Preparation 16, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 576.22 (M+), Rt = 2.30 minutes Example 64: N-[(3S)-1-[(2S)-5-oxotetrahydrofuran-2-carbonyl] -3-piperidyl]- 5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 64)

[0291] Using a similar procedure to that described for Example 59, but using (2S)-5-oxotetrahydrofuran-2-carboxylic acid and the amine from Preparation 16, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 576.22 (M+), Rt = 2.29 minutes Example 65: N-[(3R)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl] pyrrolidin-3-yl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 65)

[0292] Using a similar procedure to that described for Example 2, but using the carbamate from Preparation 32 instead of that from Preparation 25, via intermediate amine 5-[(1R,2S)-1-(p-tolyl)-2- [ (2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-pyrrolidin-3-yl]pyridine-2-carboxamide, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 562.20 (M+), Rt = 2.21 min Example 66: 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2.2 ,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide (Compound 66)

[0293] Using a similar procedure to that described for Example 59, but using the amine from Preparation 21 instead of that from Preparation 17, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 590.24 (M+), Rt = 2.38 min Example 67: 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2, 2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide (Compound 67)

[0294] Using a similar procedure to that described for Example 2, but using the carbamate from Preparation 24 instead of that from Preparation 25, to prepare intermediate amine 5-[(1R,2S)-1-(4-bromophenyl)-2- [(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-piperidyl]pyridine-2-carboxamide, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 640.11 (M+), Rt = 2.34 min 1H NMR (600 MHz, DMSO-d6) mixture of rotamers, d = 9.57 (d, J=8.5, 1H), 8.49 (dd, J=25.5, 8.4, 1H), 8.26 (dd, J=10.3, 2.9, 1H), 7.91 (dd, J=14.8, 8.7, 1H), 7.62 - 7.52 (m, 2H), 7.42 ( ddd, J=10.5, 8.8, 2.9, 1H), 7.37 - 7.29 (m, 2H), 5.46 (dd, J=9.5, 6.2, 1H), 4.61 (t, J=8.5, 0.55H), 4.45 (dd , J=8.8, 8.0, 0.45H), 4.34 - 4.10 (m, 3H), 3.91 - 3.67 (m, 3H), 3.08 - 2.94 (m, 1H), 2.82 - 2.54 (m, 3H), 1.83 (s , 1H), 1.70 (dddd, J=27.2, 17.8, 13.0, 5.5, 2H), 1.56 - 1.34 (m, 0H), 1.54 - 1.34 (m, 1H), 1.30 (dd, J=6.8, 1.6, 3H ). Example 68: N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(4-phenylphenyl)-2- [(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 68)

[0295] [1,1'-Bis(diphenylphosphine)ferrocene]dichloropalladium (II) (1.7 mg, 0.002 mmol) was added to a solution of the bromide from Preparation 24 (24 mg, 0.0413 mmol), phenyl acid -boronic acid (5.5 mg, 0.045 mmol) and aqueous sodium carbonate (2M, 50 µL, 0.1 mmol) in toluene:ethanol 4:1 (250 µL). After washing the flask with argon, it was sealed and the reaction was heated to 90°C for 2 h. The reaction was allowed to cool and was diluted with ethyl acetate (50 mL) and washed with 10% citric acid solution (2 x 20 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting carbamate intermediate was subjected to a procedure similar to that described in Example 2 to generate the title compound as an amorphous solid. UPLC-MS Method 2: Ion mass 638.24 (M+), Rt = 2.43 min Example 69: N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3 - piperidyl]-4-[(1R, 2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide (Compound 69)

[0296] Using a procedure similar to that described in Example 2, but using the carbamate from Preparation 38 instead of that from Preparation 25 to prepare the amine intermediate N-[(3S)-3-piperidyl]-4-[(1R, 2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 575.22 (M+), Rt = 2.30 minutes Example 70: 4-[(1R,2S)-1-(p-tolyl)-2-[(2.2 [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] ,2-trifluoroacetyl)amino]propoxy]benzoate (Compound 70)

[0297] Using a procedure similar to that described in Example 2, but using the carbamate from Preparation 39 instead of that from Preparation 25 to prepare the amine intermediate [(3S)-3-piperidyl]-4-[(1R, 2S) -1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoate, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 576.21 (M+), Rt = 2.45 minutes Example 71: N-[(3S)-1-[[(3S)-5-oxotetrahydrofuran-3-yl]carbamoyl ]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 71)

[0298] A solution of triethylamine (0.420 mL, 3.0 mmol) and (4S)-4-amino-tetrahydrofuran-2-one (206 mg, 1.5 mmol) in dichloromethane (3 mL) was added dropwise to a solution of triphosgene (200 mg, 0.675 mmol) in dichloromethane (5 mL) cooled to 0 oC. The reaction mixture was stirred at room temperature for 1 hour and then filtered and the filtrate evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate (10 mL) and stirred for 0.2 h before filtration. The filtrate was evaporated under reduced pressure to generate the crude intermediate isocyanate. This crude (4S)-4-isocyanatotetrahydrofuran-2-one (14 mg, 0.053 mmol) was added to a solution of the amine from Preparation 16 (10 mg, 0.0215 mmol) and triethylamine (7.5 µL, 0.053 mmol) in N,N-dimethylformamide (0.3 mL) and the resulting mixture was stirred at room temperature for 0.3 h. The crude reaction mixture was purified by reversed-phase HPLC using a gradient of acetonitrile in 50 mM aqueous ammonium bicarbonate solution (5% to 95%) to generate the title compound as an amorphous solid (8 mg, 63%) . UPLC-MS Method 2: Ion mass 591.23 (M+), Rt = 2.26 min Example 72: N-[(3S)-1-[[(3R)-5-oxotetrahydrofuran-3-yl]carbamoyl ]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 72)

[0299] Using a similar procedure to that described in Example 71, but using (4R)-4-amino-tetrahydrofuran-2-one instead of (4S)-4-amino-tetrahydrofuran-2-one, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 591.23 (M+), Rt = 2.26 min Example 73: (3S)-3-[[5-[(1R, 2S)-1-(p-tolyl) [(3S)-2-oxotetrahydrofuran-3-yl]-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (Compound 73)

[0300] A solution of pyridine (0.192 mL, 2.4 mmol) and triphosgene (267 mg, 0.9 mmol) in dichloromethane (5 mL) was added dropwise to a solution of (3S)-3-hydroxy- tetrahydrofuran-2-one (204 mg, 2 mmol) in dichloromethane (5 mL) cooled to 0 oC. The reaction mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The resulting residue was dissolved in ethyl acetate (10 mL) and stirred for 0.2 h before filtration. The filtrate was evaporated under reduced pressure to generate the crude intermediate carbon chloride. This crude [(3S)-2-oxotetrahydrofuran-3-yl] carbon chloride (11 mg, 0.064 mmol) was added to a solution of the amine from Preparation 16 (12 mg, 0.026 mmol) and triethylamine (11 ? L, 0.078 mmol) in N,N-dimethylformamide (0.5 mL) and the resulting mixture was stirred at room temperature for 0.3 hour. The crude reaction mixture was purified by reversed-phase HPLC using a gradient of acetonitrile in aqueous solution of 50 mM ammonium bicarbonate (5% to 95%) to generate the title compound as an amorphous solid (10 mg, 52%). UPLC-MS Method 2: Ion mass 592.21 (M+), Rt = 2.39 minutes Example 74: (3R)-3-[[5-[(1R, 2S)-1-(p-tolyl) [(3S)-2-oxotetrahydrofuran-3-yl]-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (Compound 74)

[0301] Using a similar procedure to that described in Example 73, but using (3R)-3-hydroxy-tetrahydrofuran-2-one instead of (3S)-3-hydroxy-tetrahydrofuran-2-one, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 592.21 (M+), Rt = 2.39 minutes Example 75: (3S)-3-[[5-[(1R, 2S)-1-(p-tolyl) [(3S)-5-oxotetrahydrofuran-3-yl]-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (Compound 75)

[0302] Using a similar procedure to that described in Example 73, but using (4S)-4-hydroxy-tetrahydrofuran-2-one instead of (3S)-3-hydroxy-tetrahydrofuran-2-one, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 592.21 (M+), Rt = 2.37 minutes 1H NMR (300 MHz, DMSO-d6) d = 9.50 (d, J=8.4, 1H), 8.34 (d, J=8.0, 1H), 8.23 (d, J=2.8, 1H), 7.88 (d, J=8.7, 1H), 7.38 (dd, J=8.8, 2.8, 1H), 7.25 (d, J=7.9, 2H), 7.15 (d, J=7.8, 2H), 5.41 (d, J=6.1, 1H), 5.24 (d, J=6.3, 1H), 4.48 (dd, J=10.7, 4.6, 1H), 4.27 (dd, J=13.5, 8.6, 2H), 3.93 - 3.61 (m, 3H), 3.14 - 2.80 (m, 3H), 2.25 (s, 3H), 1.79 (s, 1H), 1.64 (s, 2H) , 1.44 (d, J=11.2, 1H), 1.30 (d, J=6.8, 3H). Example 76: (3S)-3-[[5-[(1R, 2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl] [(34)-5-oxotetrahydrofuran-3-yl] amino]piperidine-1-carboxylate (Compound 76)

[0303] Using a similar procedure to that described in Example 73, but using (4R)-4-hydroxy-tetrahydrofuran-2-one instead of (3S)-3-hydroxy-tetrahydrofuran-2-one, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 592.21 (M+), Rt = 2.37 minutes Example 77: 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R) [(3S)-1-[3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate (Compound 77)

[0304] EDAC (253 mg, 1.32 mmol) was added to a solution of the amine from Preparation 43 (500 mg, 0.94 mmol), the acid from Preparation 34 (147 mg, 1.13 mmol) and Oxyma ® (ethyl-2-cyano-2-hydroxyimino-acetate) (53 mg, 0.37 mmol) in ethyl acetate (5 mL). Triethylamine (0.32 mL, 2.2681 mmol) was added to the resulting mixture and the mixture was stirred at room temperature for 4 hours.

[0305] The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (20 mL) and washed with 1M aqueous hydrochloric acid (2x 10 mL), followed by saturated aqueous sodium hydrocarbonate (1x 10 mL). The ethyl acetate solution was evaporated under reduced pressure to give the title compound as a white amorphous solid (0.54 g, 95%). UPLC-MS Method 1: Ion mass 604.29 (MH+), Rt = 0.764 min Example 78: 4-[(1R, 2S)-1-(4-cyclopropylphenyl)-2-[[(2S)tetrahydrofuran- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] 2-carbonyl]amino]propoxy]benzoate (Compound 78)

[0306] Using a similar procedure to that described in Example 77, but using the amine from Preparation 44 instead of that from Preparation 33, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: Ion mass 604.29 (MH+), Rt = 0.775 min Example 79: 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-2-carbonyl]amino]propoxy]benzoate (Compound 79)

[0307] Using a similar procedure to that described in Example 77, but using the amine from Preparation 44, the title compound was prepared as an amorphous solid. UPLC-MS Method 2: ion mass 604.29 (MH+), Rt = 0.774 min Example 80: N-[(3S)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3 - piperidyl]-5-[(1S,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 80)

[0308] Using a similar procedure to that described for Example 77, but using the amine from Preparation 53, the title compound was prepared as an amorphous solid (35 mg, 29%). 1H NMR (DMSO, 400MHz): d = 9.11 (br s, 1H), 8.20 (d, J = 2.9 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.8 Hz , 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 5.41 (d, J = 6.4 Hz, 1H ), 4.38-4.42 (m, 1H), 4.20-4.30 (m, 2H), 3.80-3.92 (m, 2H), 3.70-3.80 (m, 2H), 3.02-3.19 (m, 2H), 2.50-2.60 (m, 2H), 2.26 (s, 3H), 1.80-1.90 (m, 2H), 1.60-1.70 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H) LCMS (ESI): m/z 565 [M+H]+ ; 99.6%; RT = 2.7 min (KINETEX-1.7u XB-C18 column, 0.05% FA in water with ACN) and chiral HPLC ~ 96.9% SFC METHOD: Injection volume: 10, solvent: 0.5% DEA in methanol, column: Chiralpak LuxCellulose-2 (4.6*250)mm, 5u, Column temperature: 30, Flow: 4, Pressure: 100, RT: 2.9 min. Example 81: N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]- 5-[(1S,2S)-1-(p-tolyl)-2- [(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide (Compound 81)

[0309] Using a similar procedure to that described in Example 77, but using the amine from Preparation 53 and the acid from Preparation 33, the title compound was prepared as an amorphous solid (35 mg, 29%). 1H NMR (DMSO, 400MHz): d = 9.11 (m, 1H), 8.20 (d, J = 2.9 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 5.41 (d, J = 6.4 Hz, 1H) , 4.50 (s, 1H), 4.20-4.30 (m, 2H), 3.80-3.92 (m, 2H), 3.70-3.80 (m, 2H), 3.02-3.19 (m, 2H), 2.55-2.60 (m, 2H), 2.26 (s, 3H), 1.80-1.90 (m, 2H), 1.60-1.70 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H) LCMS (ESI): m/z 565 [M +H]+ ; 98%; RT = 3.11 min (KINETEX-1.7u XB-C18 column, 0.05% FA in water with ACN) and chiral HPLC ~ 93% SFC METHOD: Injection volume: 10, solvent: 0.5% DEA in methanol , column: Chiralpak LuxCellulose-2 (4.6*250)mm, 5u, Column temperature: 30, Flow: 4, Pressure: 100, RT: 2.67 min.

Glucocorticoid receptor binding assay

[0310] GR binding was measured using a commercial kit (A-15897, Life Technologies) with a fluorescence polarization readout. The 4nM full-length recombinant receptor protein was incubated with increasing concentrations of GR ligand, 2.5nM fluorescently labeled tracer (Fluormone GS1, Kd = 0.75nM +/- 0.25nM) and 100uM stabilizing peptide for 2 hours at room temperature. Test compounds were diluted in DMSO by seven orders of magnitude, further diluted in assay buffer, and distributed into 384-well plates. The sensitivity limit of this assay was 2-4 nM. Label displacement by 10 µM dexamethasone was used to define the assay window.

[0311] The data was processed by sigmoidal curve fitting.

[0312] Absolute IC50 (Abs) and Emax were determined from the curve fits.

[0313] IC50 Abs Glucocorticoid Receptor Binding Assay Varies

The results are shown in Table 4. Inhibition of TNF alpha release from human PBMCs

[0314] PBMCs were isolated from fresh buffy coats by density centrifugation using lymphoprep tubes (Medinor AB, cat no. 1019818). Isolated PBMC were washed in assay medium (RPMI1640 with 25 mM HEPES, 1% pen/strep, 200 mM L glutamine and 10% fetal calf serum). Surplus PBMCs were frozen in medium containing 10% extra fetal calf serum and 5% DMSO. On the day of the assay, fresh cells or cells cryopreserved after thawing were washed in serum-free medium (RPMI1640 with 25 mM HEPES, 1% pen/strep, 200 mM L glutamine and 0.5% serum albumin). human) and counted, to determine the fraction of living cells (generally > 95%).

[0315] Test compounds were diluted in DMSO by seven orders of magnitude, diluted in serum-free medium and distributed into wells of 384-well tissue culture plates. LPS was added to a final concentration of 1 µg/ml into the cells. Immediately afterwards, the titled test compounds were added and incubated for 18 hours at 37 oC.

[0316] The level of TNF-a in the culture supernatant was quantified by AlphaLISA (Perkin Elmer). 2-(3,5-dichloro-4-pyridinyl)-1-(7-methoxyspiro[1,3-benzodioxole-2,1'-cyclopentan]-4-yl)-ethanone (CAS 18540634-2) at 100 x IC50 was used to define the assay window.

[0317] The data was processed by sigmoidal curve fitting. EC50 and Emax were determined from curve fits.

[0318] Inhibition of TNF alpha release; EC50 varies from

The results are shown in Table 4. Human Liver Microsomal (HLM) Assay

[0319] Incubations of test compounds in DMSO, diluted with phosphate buffer, pH 7.4 at 0.5 µM were carried out with human liver microsomes (0.5 mg/mL). The percentage of organic solvent in the incubations was 1%. The human liver microsomal suspension in phosphate buffer was mixed with NADPH (1 mM) and preheated to 37°C before the test compound was added. Aliquots were taken at 0, 5, 10, 20 and 30 minutes and reactions were completed by addition of methanol containing the analytical internal standard (IS).

[0320] The results were expressed as apparent clearance (Clapp) (mL/min/kg) and hepatic extraction ratio (Eh) (%) calculated from the rate constant (k) (min-1) of compound depletion of test. shown in Table 4.

Human Whole Blood Stability Assay

[0321] Incubations of test compounds in DMSO, diluted with phosphate buffer, pH 7.4, at 0.1 uM were carried out with human whole blood stabilized with fresh sodium heparin. The percentage of organic solvent in the incubations was 1%. Incubations were carried out at 37°C with aliquots taken at 0, 15, 30, 60 and 120 minutes, and reactions were completed by addition of acetonitrile containing analytical internal standard (IS). Depletion of the test compound was determined using a compound-specific LC/MS/MS method.

[0322] The results were expressed as half-life (T/) in minutes calculated from the rate constant (k) (min-1) of depletion of test compounds.

[0323] Some compounds of the present invention were tested in the human whole blood stability assay.

Keratinocyte stability assay

[0324] Incubations of test compounds in DMSO, diluted with growth medium (EpiLife keratinocyte medium, Cascade Biologics Cat. No. M-EPI-500-CA, without growth supplements or antibiotics), pH ~ 7.4 , at 1 uM were performed with coated human keratinocytes. The percentage of organic solvent in the incubations was 0.01%. Incubations were performed at 37°C with aliquots taken at 0, 1, 3, 6 hours, and reactions were completed by addition of acetonitrile containing analytical internal standard (IS).

[0325] The results were expressed as half-life (T/) in minutes calculated from the observed rate constant (k) (min-1) of depletion of test compounds.

[0326] Some compounds of the present invention were tested in the keratinocyte stability assay.

[0327] Table 4 Additional embodiments of the invention are presented below:

[0328] Embodiment 1. A compound according to formula (I) wherein R1 is selected from the group consisting of 5- and 6-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (4-6) membered heterocycloalkyl and phenyl, wherein said heteroaryl of 5 and 6 members, (C1-C6)alkyl, (C3-C6)cycloalkyl, heterocycloalkyl (4-6) members and phenyl is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4 )alkoxy, halogen, hydroxyl and cyano; R2 is selected from (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is selected from phenyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein said phenyl, 5-membered heteroaryl and 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from R5; R4 is selected from hydrogen, halogen, (C1-C4)alkyl and halo(C1-C4)alkyl; R5 is selected from halogen, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6) )alkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl and -S(O)2Ra, where Ra represents (C1-C4)alkyl; X1 is selected from CH, C(Rb) and N, where Rb represents halogen, (C1-C4)alkyl or halo(C1-C4)alkyl; X2 is selected from CH and N; Y is selected from -NH- and O-; m is 0 or 1; n is 0 or 1; L represents a bond,-O-,-NH- or-N(Rc)-, where Rc represents (C1-C4)alkyl; or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0329] Modality 2. The compound according to modality 1 of general formula (Ia). wherein R1, R2, R3, R4, R5,X1,X2, Y, L, m, n and L are as indicated in embodiment 1, or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0330] Modality 3. The compound according to any of modalities 1 to 2 of general formula (Ib) wherein R1, R2, R3, R4, R5,X1,X2, Y, L, m, n and L are as indicated in embodiment 1, or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0331] Modality 4. The compound according to any one of modalities 1 to 3 of general formula (Ic) wherein R1, R2, R3, R4, R5,X1,X2, Y, L, m, n and L are as indicated in embodiment 1, or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0332] Modality 5. The compound according to any one of modalities 1 to 3 of general formula (Id) wherein R1, R2, R3, R4, R5,X1,X2, Y, L, m, n and L are as indicated in embodiment 1, or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0333] Modality 6. The compound according to any one of modalities 1 to 5 of general formula (Ie). wherein R1, R2, R3, R4, R5,X1,X2, Y, L, m, n and L are as indicated in embodiment 1, or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0334] Modality 7. The compound according to any one of modalities 1 to 6 of general formula (Ih), wherein R1, R2, R3, R4, R5,X1,X2, Y, L, m, n and L are as indicated in embodiment 1, or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0335] Embodiment 8. The compound according to any one of embodiments 1 to 7, wherein R1 is selected from the group consisting of 5-membered heteroaryl, (C1-C6) alkyl, (C3-C6) cycloalkyl and heterocycloalkyl in metamorphosis (4-6), wherein said 5-membered heteroaryl, (C1-C6) alkyl, (C3-C6) cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from ( C1-C4) alkyl, (C1-C4) alkoxy, halogen and hydroxyl.

[0336] Embodiment 9. The compound according to any one of embodiments 1 to 7 wherein R1 is 5-membered heteroaryl optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, halogen, hydroxyl and cyano; R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen and X2 is CH.

[0337] Embodiment 10. The compound according to any one of embodiments 1 to 7 wherein R1 is (C1-C6) alkyl, optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4 ) alkoxy, halogen, hydroxyl and cyano; R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen and X2 is CH.

[0338] Embodiment 11. The compound according to any one of embodiments 1 to 7, wherein R1 is 4 to 6 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1 -C4) alkoxy, halogen, hydroxyl and cyano; R2 is methyl; R3 is phenyl wherein said phenyl is substituted with one or more substituents independently selected from R5; R4 is hydrogen and X2 is CH.

[0339] Embodiment 12. The compound according to any one of embodiments 1 to 7, wherein R1 is selected from the group consisting of imidazolyl, thiadiazolyl, thiazolyl, oxadiazolyl, pyrazolyl, tetrahydrofuranyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl, wherein said imidazolyl, thiadiazolyl, thiazolyl, oxadiazolyl, pyrazolyl, tetrahydrofuranyl, triazolyl, oxazolyl, isoxazolyl, isothiazolyl, methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclobutyl is optionally substituted with one or more substituents independently selected from methyl, methoxyl, hydroxyl and fluoro.

[0340] Embodiment 13. The compound according to any one of embodiments 1 to 8, wherein R2 is (C1-C3) alkyl.

[0341] Embodiment 14. The compound according to any one of embodiments 1 to 13, wherein R2 is methyl.

[0342] Embodiment 15. The compound according to any one of embodiments 1 to 14, wherein R3 is phenyl, which is substituted with one or more substituents independently selected from R5.

[0343] Embodiment 16. The compound according to any one of embodiments 1 to 15, wherein R3 is phenyl, which is substituted with one or more independently selected halogen substituents, (C1-C6) alkyl, (C3-C6) cycloalkyl and phenyl.

[0344] Embodiment 17. The compound according to any one of embodiments 1 to 16, wherein R5 is selected from halogen, (C1-C6) alkyl, (C3-C6) cycloalkyl and phenyl.

[0345] Embodiment 18. The compound according to any one of embodiments 1 to 17, wherein R5 is selected from bromine, methyl, ethyl, cyclopropyl and phenyl.

[0346] Embodiment 19. The compound according to any one of embodiments 1 to 18, wherein R4 is hydrogen.

[0347] Embodiment 20. The compound according to any one of embodiments 1 to 19, wherein X1 is selected from CH and N.

[0348] Embodiment 21. The compound according to any one of embodiments 1 to 20, wherein X1 is CH.

[0349] Embodiment 22. The compound according to any one of embodiments 1 to 20, wherein X1 is N.

[0350] Embodiment 23. The compound according to any one of embodiments 1 to 22, wherein X2 is CH.

[0351] Embodiment 24. The compound according to any one of embodiments 1 to 23, wherein X1 is N, X2 is CH and Y is -NH-.

[0352] Embodiment 25. The compound according to any one of embodiments 1 to 23, wherein X1 is CH, X2 is CH and Y is-O-.

[0353] Embodiment 26. The compound according to any one of embodiments 1 to 25, wherein m is 0 and n is 1.

[0354] Embodiment 27. The compound according to any one of embodiments 1 to 26, wherein L represents a bond, -O- or -NH-.

[0355] Embodiment 28. The compound according to any one of embodiments 1 to 27, wherein L represents a bond.

[0356] Modality 29. The compound according to any one of fmodalities 1 to 28, wherein X1 is CH, X2 is CH, Y is-O-, m is 0, n is 1 and L represents a bond.

[0357] Embodiment 30. The compound according to any one of embodiments 1 to 28, wherein X1 is CH, X2 is CH, Y is NH, m is 0, n is 1 and L represents a bond.

[0358] Embodiment 31. The compound according to any one of embodiments 1 to 28, wherein X1 is CH, X2 is CH, Y is NH, m is 0, n is 1 and L represents a bond.

[0359] Embodiment 32. The compound according to any one of embodiments 1 to 31 selected from N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]- 5-[(1R,2S)-1- (p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, 5-[(1R,2S)-1- (4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(2,2-difluoropropanoylamino)propoxy]-N-[(3S)-1-[(3R)-5 -oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S) -1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isothiazol-3-carboxamide, N-[(1S,2R)-2-( 4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy] ethyl]isothiazol-5-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2 -[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]thiazol-4-carboxamide, N- [(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl ]carbamoyl]-3-pyridyl]oxy]ethyl]-3-methyl-isoxazol-5-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6- [[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-5-carboxamide, 5-[(1R,2S )-1-(4-cyclopropylphenyl)-2-[[(2S)-2-hydroxybutanoyl]amino]propoxy]- N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]- 3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-2-hydroxypropanoyl]amino]propoxy]-N-[(3S) -1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2- [[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazole-5-carboxamide, 5-[ (1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-2-hydroxybutanoyl]amino]propoxy]- N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3 -carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methoxyacetyl)amino]propoxy]-N-[(3S) - 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2- hydroxy-2-methyl-propanoyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[( 1R,2S)-1-(4-cyclopropylphenyl)-2-(3-hydroxypropanoylamino)propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-hydroxycyclobutanecarbonyl)amino]propoxy]-N-[(3S)-1-[(3R)- 5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-hydroxycyclopropanecarbonyl)amino]propoxy]-N -[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1 -methyl-2-[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-4- carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-1-[(3R )-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-hydroxyacetyl)amino]propoxy] -N-[(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl) -2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2 -carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl ]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazol-3-carboxamide, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]propoxo]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl) [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-2-(1,2,5-thiadiazol-3-carbonylamino)propoxy]benzoate], 4-[( [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl 1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methylthiazol-2-carbonyl)amino]propoxy]benzoate ]-3-piperidyl], [(3S)-1-[(3R)-5 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(thiazol-5-carbonylamino)propoxy]benzoate -oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(4-methyl-1,2,5-oxadiazol-3-carbonyl) [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]amino]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2 [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-[(5-methylthiazol-4-carbonyl)amino]propoxy]benzoate, 4-[(1R,2S [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3 )-1-(4-cyclopropylphenyl)-2-[(4-methylthiazol-5-carbonyl)amino]propoxy]benzoate -piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methyl-1,3,4-oxadiazol-2-carbonyl)amino]propoxy]benzoate [(3S )-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(4-methylthiadiazol-5- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbonyl)amino]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl) [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-2-[(4-methyloxazol-5-carbonyl)amino]propoxy]benzoate], 4-[(1R [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl ,2S)-1-(4-cyclopropylphenyl)-2-[(2-methoxyacetyl)amino]propoxy]benzoate ], [(3S)-1-[(3R)-5 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methylpyrazol-3-carbonyl)amino]propoxy]benzoate -oxotetrahydrofuran-3-carbonyl]-3-piperidyl], [( 3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-2-carbonyl]amino]propoxy]benzoate, 4-[(1R,2S)-1-(4 -cyclopropylphenyl)-2-[(3-methyltriazol-4-carbonyl)amino]propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4- [(1R,2S)-1-(4-cyclopropylphenyl)-2-(1,2,4-oxadiazol-3-carbonylamino)propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran- 3-carbonyl]-3-piperidyl], [(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methylisoxazol-5-carbonyl) [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]amino]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2 [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-[(5-methyl-1,2,4-oxadiazol-3-carbonyl)amino]propoxy]benzoate , [(3S)-1-[(3R)-5- 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylimidazol-4-carbonyl)amino]propoxy]benzoate oxotetrahydrofuran-3-carbonyl]-3-piperidyl], [(3S)-1-[4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isothiazol-3-carbonylamino)propoxy]benzoate (3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methylisoxazol-4-carbonyl)amino]propoxy [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(thiazole [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-2-carbonylamino)propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] )-2-(isothiazol-5-carbonylamino)propoxy]benzoate, 4-[(1R,2S)- [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl 1-(4-cyclopropylphenyl)-2-[(5-methylisothiazol-4-carbonyl)amino]propoxy]benzoate ], [(3S)-1-[(3R)-5-oxotetrahydrofuran-3- 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(oxazol-2-carbonylamino)propoxy]benzoate carbonyl]-3-piperidyl], [(3S)-1-[(3R)- 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(oxazol-5-carbonylamino)propoxy]benzoate 5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], [(3S)-1 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isoxazol-3-carbonylamino)propoxy]benzoate -[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(thiadiazol-4-carbonylamino)propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methylisoxazole [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-3-carbonyl)amino]propoxy]benzoate, 4-[(1R,2S)-1-(4 [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-cyclopropylphenyl)-2-(isoxazol-5-carbonylamino)propoxy]benzoate, 4-[(1R,2S [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] )-1-(4-cyclopropylphenyl)-2-(thiazol-4-carbonylamino)propoxy]benzoate], 4 -[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methyl-1,2,4-oxadiazol-5-carbonyl)amino]propoxy]benzoate [(3S)-1-[ (3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylpyrazol-3-carbonyl)amino]propoxy ][(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(2 [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] ,2-difluoropropanoylamino)propoxy]benzoate, N-[(3R)-1-[(3R)-5 -oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2- carboxamide, N-[(3R)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[ (2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1-[(2S)-5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl]-5-[ (1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1-[(2R)- 5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2 -carboxamide, N-[(3S)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2- [(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[(2S)-5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl]-5- [(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1-[(3R) -5-oxotetrahydrofuran-3-carbonyl]pyrrolidin-3-yl]-5-[(1R,2S)- 1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine -2-carboxamide, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[( 3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl )amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(3S)-1-[( 3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(4-phenylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy] pyridine-2-carboxamide, N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-4-[(1R,2S)-1-(p-tolyl) -2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-4-[(1R ,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoate, N-[(3S)-1-[[(3S)-5-oxotetrahydrofuran-3 -yl]carbamoyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[[(3R)-5-oxotetrahydrofuran-3-yl]carbamoyl]-3-piperidyl]-5- [(1R,2S)-1-(p-tolyl)-2- [(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2 ,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate [(3S)-2-oxotetrahydrofuran-3-yl], (3S)-3-[[5-[ (1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-[(3R)-2 carboxylate -oxotetrahydrofuran-3-yl], (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine [(3S)-5-oxotetrahydrofuran-3-yl]-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[(1R,2S)-1-(p-tolyl )-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate [(34)-5-oxotetrahydrofuran-3-yl], 4-[( 1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate [(3S)-1-[(3S)-5-oxotetrahydrofuran-3 -carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate [(3S) -1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl], 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2 - [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbonyl]amino]propoxy]benzoate, N-[(3S)-1-[(3S)-5 -oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1S,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2- carboxamide or N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1S,2S)-1-(p-tolyl)-2-[ (2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0360] Modality 33. A compound according to any one of modalities 1 to 32 for use in therapy.

[0361] Modality 34. A compound according to any one of modalities 1 to 32 for use in the prophylaxis, treatment or improvement of inflammatory, allergic or proliferative dermatological diseases or conditions.

[0362] Modality 35. The compound according to modality 34 for use in the prophylaxis, treatment or improvement of atopic dermatitis, psoriasis or eczema.

[0363] Embodiment 36. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 32, together with a pharmaceutically acceptable vehicle or pharmaceutically acceptable carrier(s).

[0364] Modality 37. The pharmaceutical composition according to modality 36, together with one or more other therapeutically active compounds.

[0365] Modality 38. The use of a compound according to modalities 1 to 32, in the manufacture of a medicine for the prophylaxis, treatment or improvement of inflammatory, allergic or proliferative dermatological diseases or conditions.

[0366] Embodiment 39. A method for preventing, treating or ameliorating inflammatory, allergic or proliferative dermatological diseases or conditions, the method comprising administering to a person suffering from at least one of said diseases or disorders an effective amount of one or more compounds, according to any one of embodiments 1 to 32, optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

[0367] Embodiment 40. A compound according to any one of embodiments 1 to 32 for use in treating a disease, disorder or condition, in which the disease, disorder or condition is responsive to glucocorticoid receptor modulation.

[0368] Embodiment 41. A compound according to general formula (VI) wherein R1 is selected from the group consisting of 5- and 6-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (4-6) membered heterocycloalkyl and phenyl, wherein said heteroaryl of 5 and 6 members, (C1-C6)alkyl, (C3-C6)cycloalkyl, heterocycloalkyl (4-6) members and phenyl is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4 )alkoxy, halogen, hydroxyl and cyano; R2 is selected from (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is selected from phenyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein said phenyl, 5-membered heteroaryl and 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from R5; R4 is selected from hydrogen, halogen, (C1-C4)alkyl and halo(C1-C4)alkyl; R5 is selected from halogen, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6) )alkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl and -S(O)2Ra, where Ra represents (C1-C4)alkyl; X1 is selected from CH, C(Rb) and N, where Rb represents halogen, (C1-C4)alkyl or halo(C1-C4)alkyl; X2 is selected from CH and N.

[0369] Modality 42. The compound according to modality 41, selected from 5-[(1R,2S)-1-(p-Tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy acid ]pyridine-2-carboxylic acid, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, 4- [(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoic acid, 5-[(1R,2S)-1-(4-bromophenyl) -2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, 4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2 - trifluoroacetyl)amino]propoxy]benzoic acid, 5-[(1S,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino] propoxy]pyridine-2-carboxylic acid.

[0370] Modality43. A compound according to general formula (II) wherein R1 is selected from the group consisting of 5- and 6-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (4-6) membered heterocycloalkyl and phenyl, wherein said heteroaryl of 5 and 6 members, (C1-C6)alkyl, (C3-C6)cycloalkyl, heterocycloalkyl (4-6) members and phenyl is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4 )alkoxy, halogen, hydroxyl and cyano; R2 is selected from (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is selected from phenyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein said phenyl, 5-membered heteroaryl and 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from R5; R4 is selected from hydrogen, halogen, (C1-C4)alkyl and halo(C1-C4)alkyl; R5 is selected from halogen, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6) )alkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl and -S(O)2Ra, where Ra represents (C1-C4)alkyl; X1 is selected from CH, C(Rb) and N, where Rb represents halogen, (C1-C4)alkyl or halo(C1-C4)alkyl; X2 is selected from CH and N; Y is selected from -NH- and O-; m is 0 or 1; n is 0 or 1, or a pharmaceutically acceptable salt thereof.

[0371] Modality 44. The compound according to modality 43, selected from N-[(3S)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[( 2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[ (2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino] propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino ]propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2- carbonyl]amino]propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6 -[[(3S)-3-piperidyl]carbamoyl]- 3-pyridyl]oxy]ethyl]isoxazol-3-carboxamide, 5-[(1R,2S)-1-(p-tolyl)-2-[(2 ,2,2-trifluoroacetyl)amino]propoxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-bromophenyl)-2- [(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide, N-[(3S)-3-piperidyl]-4-[(1R, 2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide, 4-[(1R,2S)-1-(p-tolyl)-2-[( [(3S)-3-piperidyl]2,2,2-trifluoroacetyl)amino]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S) Hydrochloride [(3S)-3-piperidyl]-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate, (3S)-3-[[5-[(1S,2S)-1-(p-tolyl)-2- tert-butyl [(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate.

[0372] Embodiment 45. A compound according to the general formula (Va) wherein R1 is selected from the group consisting of 5- and 6-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (4-6) membered heterocycloalkyl and phenyl, wherein said heteroaryl of 5 and 6 members, (C1-C6)alkyl, (C3-C6)cycloalkyl, heterocycloalkyl (4-6) members and phenyl is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4 )alkoxy, halogen, hydroxyl and cyano; R2 is selected from (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is selected from phenyl, 5-membered heteroaryl and 6-membered heteroaryl, wherein said phenyl, 5-membered heteroaryl and 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from R5; R4 is selected from hydrogen, halogen, (C1-C4)alkyl and halo(C1-C4)alkyl; R5 is selected from halogen, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6) )alkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl and -S(O)2Ra, where Ra represents (C1-C4)alkyl; X1 is selected from CH, C(Rb) and N, where Rb represents halogen, (C1-C4)alkyl or halo(C1-C4)alkyl; X2 is selected from CH and N; Y is selected from -NH- and O-; m is 0 or 1; n is 0 or 1.

[0373] Modality 46. The compound according to modality 45 selected from (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2 - tert-butyl trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[(1R,2S)-1-(4-bromophenyl)- tert-butyl 2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[(1R,2S) tert-butyl -1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[ [5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate tert-butyl, (3S)-3-[[5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isoxazol-3-carbonylamino)propoxy]pyridine-2-carbonyl]amino]piperidine- tert-Butyl 1-carboxylate, (3S)-3-[4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl] tert-butyl oxypiperidine-1-carboxylate, (3S)-3-[4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy] tert-butyl benzoyl]oxypiperidine-1-carboxylate, (3R)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino ]propoxy]pyridine-2-carbonyl]amino]tert-butylpyrrolidine-1-carboxylate, (3S)-3-[[4-[(1R,2S)-1-(p-tolyl)-2-[( tert-butyl 2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]amino]piperidine-1-carboxylate and (3S)-3-[4-[(1R,2S)-1-(p-tolyl)- tert-butyl 2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine-1-carboxylate, (3S)-3-[[5-[(1S,2S)-1-(p- tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-tert-butyl carboxylate.

Claims (13)

1. Compound, characterized by the fact that it is in accordance with formula (I) wherein R1 is selected from the group consisting of 5- and 6-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (4-6) membered heterocycloalkyl and phenyl, wherein said heteroaryl of 5 and 6 members, (C1-C6)alkyl, (C3-C6)cycloalkyl, heterocycloalkyl (4-6) members and phenyl is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, (C1-C4 )alkoxy, halogen, hydroxyl and cyano; R2 is selected from (C1-C3)alkyl and halo(C1-C3)alkyl; R3 is R3 is phenyl, which is substituted with one or more substituents independently selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl and phenyl; R4 is selected from hydrogen, halogen, (C1-C4)alkyl and halo(C1-C4)alkyl; R5 is selected from halogen, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6) )alkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl and -S(O)2Ra, where Ra represents (C1-C4)alkyl; X1 is selected from CH, C(Rb) and N, where Rb represents halogen, (C1-C4)alkyl or halo(C1-C4)alkyl; X2 is selected from CH and N; Y is selected from -NH- and -O-; m is 0 or 1; n is 0 or 1; L represents a bond, -O-, -NH- or -N(Rc)-, where Rc represents (C1-C4)alkyl; or pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, characterized by the fact that R1 is selected from the group consisting of 5-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl and (4-6)heterocycloalkyl ) members, wherein said 5-membered heteroaryl, (C1-C6)alkyl, (C3-C6)cycloalkyl and (4-6) membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4)alkoxy, halogen and hydroxyl. 3. Compound according to any one of claims 1 to 2, characterized by the fact that R2 is (C1-C3)alkyl. 4. Compound according to any one of claims 1 to 3, characterized by the fact that R4 is hydrogen. 5. Compound according to any one of claims 1 to 4, characterized in that X1 is selected from CH and N. 6. Compound according to any one of claims 1 to 5, characterized by the fact that X2 is CH. 7. Compound according to any one of claims 1 to 6, characterized in that it is selected from 1. N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl] -5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, 5-[(1R,2S)-1 -(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl ]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(2,2-difluoropropanoylamino)propoxy]-N-[(3S)-1-[(3R)- 5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S )-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isothiazol-3-carboxamide, N-[(1S,2R)-2- (4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy ]ethyl]isothiazol-5-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5 - oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl- 2-[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]thiazol-4-carboxamide, N -[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3- piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]-3-methyl-isoxazol-5-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6 -[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-5-carboxamide, 5-[(1R, 2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-2-hydroxybutanoyl]amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl] -3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-2-hydroxypropanoyl]amino]propoxy]-N-[(3S )-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2 -[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazole-5-carboxamide, 5- [(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-2-hydroxybutanoyl]amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran- 3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methoxyacetyl)amino]propoxy]-N-[(3S )-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2 -hydroxy-2-methyl-propanoyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[ (1R,2S)-1-(4-cyclopropylphenyl)-2-(3-hydroxypropanoylamino)propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl ]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-hydroxycyclobutanecarbonyl)amino]propoxy]-N-[(3S)-1-[(3R) -5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-hydroxycyclopropanecarbonyl)amino]propoxy]- N-[(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)- 1-methyl-2-[[6-[[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]oxazol-4 - carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-1-[( 3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-hydroxyacetyl)amino]propoxy ]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl )-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine- 2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[(3S)-1-[(3R)-5- oxotetrahydrofuran-3- carbonyl]-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazol-3-carboxamide, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4 - [(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran- 3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(1,2,5-thiadiazol-3-carbonylamino)propoxy]benzoate, [(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methylthiazol-2-carbonyl)amino ]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-( thiazol-5-carbonylamino)propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl )-2-[(4-methyl-1,2,5-oxadiazol-3-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3 -piperidyl]4- [(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methylthiazol-4-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)- 5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(4-methylthiazol-5-carbonyl)amino]propoxy]benzoate, [( 3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methyl-1, 3,4-oxadiazol-2-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4- [(1R,2S)- 1-(4-cyclopropylphenyl)-2-[(4-methylthiadiazol-5-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl ]4- [(1R,2S)-1-(4-cyclopropylphenyl)-2-[(4-methyloxazol-5-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methoxyacetyl)amino]propoxy]benzoate, [(3S)-1-[ (3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2-methylpyrazol-3-carbonyl)amino]propoxy] benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2- methylthiazol-5-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4 -cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4 - [(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methyltriazol-4-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran- 3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(1,2,4-oxadiazol-3-carbonylamino)propoxy]benzoate, [(3S)- 1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylimidazol-2-carbonyl)amino ]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[ (3-methylisoxazol-5-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1 -(4-cyclopropylphenyl)-2-[(5-methyl-1,2,4-oxadiazol-3-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3 -carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylimidazol-4-carbonyl)amino]propoxy]benzoate, [(3S)-1- [(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isothiazol-3-carbonylamino)propoxy]benzoate, [( 3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(3-methylisoxazol-4- carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)- 2-(thiazol-2-carbonylamino)propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-( 4-cyclopropylphenyl)-2-(isothiazol-5-carbonylamino)propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S )-1-(4-cyclopropylphenyl)-2-[(5-methylisothiazol-4-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3 -piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(oxazol-2-carbonylamino)propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3 -carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(oxazol-5-carbonylamino)propoxy]benzoate, [(3S)-1-[(3R)- 5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isoxazol-3-carbonylamino)propoxy]benzoate, [(3S)-1- [(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(thiadiazol-4-carbonylamino)propoxy]benzoate, [( 3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(5-methylisoxazol-3- carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl],4-[(1R,2S)-1-(4-cyclopropylphenyl) -2-(isoxazol-5-carbonylamino)propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-( 4-cyclopropylphenyl)-2-(thiazol-4-carbonylamino)propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S )-1-(4-cyclopropylphenyl)-2-[(3-methyl-1,2,4-oxadiazol-5-carbonyl)amino]propoxy]benzoate, [(3S)-1-[(3R)-5- oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(1-methylpyrazol-3-carbonyl)amino]propoxy]benzoate, [(3S) -1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(2,2-difluoropropanoylamino)propoxy]benzoate , N-[(3R)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[( 2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[( 1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-1-[(2S)-5 -oxotetrahydrofuran-2-carbonyl]-3-piperidyl]-5- [(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2- carboxamide, N-[(3R)-1-[(2R)-5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[ (2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[ (1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[(2S)- 5-oxotetrahydrofuran-2-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2 - carboxamide, N-[(3R)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]pyrrolidin-3-yl]- 5-[(1R,2S)-1-(p-tolyl)-2 -[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl) amino]propoxy]- N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-( 4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]pyridine -2-carboxamide, N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1R,2S)-1-(4-phenylphenyl)- 2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]- 4-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide, [(3S)-1-[(3R)-5-oxotetrahydrofuran -3-carbonyl]-3-piperidyl]4-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoate, N-[(3S )-1-[[(3S)-5-oxotetrahydrofuran-3-yl]carbamoyl]-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2 ,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3S)-1-[[(3R)-5-oxotetrahydrofuran-3-yl]carbamoyl]-3-piperidyl]-5-[( 1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, (3S)-3-[[5-[(1R,2S [(3S)-2-oxotetrahydrofuran-3 )-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate -yl], (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl [(3R)-2-oxotetrahydrofuran-3-yl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2- [(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate [(3S)-5-oxotetrahydrofuran-3-yl], (3S)-3-[[ [(34) )-5-oxotetrahydrofuran-3-yl], [(3S)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]4- [(1R,2S)-1-(4- cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate, [(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl],4 - [(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate [(3S)-1-[(3R)-5-oxotetrahydrofuran -3-carbonyl]-3-piperidyl],4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate N-[ (3S)-1-[(3S)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1S,2S)-1-(p-tolyl)-2-[(2,2, 2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide and N-[(3S)-1-[(3R)-5-oxotetrahydrofuran-3-carbonyl]-3-piperidyl]-5-[(1S,2S) -1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide or pharmaceutically acceptable salts thereof. 8. Compound according to any one of claims 1 to 7, characterized in that the compound is [(3S)-1-[(3R)-5-oxo-tetrahydrofuran-3-carbonyl]-3-piperidyl]4-[ (1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]benzoate. 9. Compound according to any one of claims 1 to 8, characterized by the fact that it has the formula 10. Pharmaceutical composition, characterized by the fact that it comprises a compound as defined in any one of claims 1 to 10, together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s). 11. Use of a compound as defined in any one of claims 1 to 9, characterized in that it is for the manufacture of a medicament for the treatment of a disease, disorder or condition that is responsive to modulation of the glucocorticoid receptor. 12. Compound, characterized by the fact that it is selected from 5-[(1R,2S)-1-(p-Tolyl)-2-[(2,2,2-trifluoroacetyl)amino] propoxy]pyridine-2 acid -carboxylic acid, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl) amino]propoxy]pyridine-2-carboxylic acid, 4-[(1R, 2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino] propoxy]benzoic acid, 5-[(1R,2S)-1-(4-bromophenyl)-2-[ (2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxylic acid, 4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl) amino acid ]propoxy]benzoic acid and 5-[(1S,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino] propoxy]pyridine-2-carboxylic acid. 13. Compound, characterized by the fact that it is selected from N-[(3S)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2, 2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, N-[(3R)-3-piperidyl]-5-[(1R,2S)-1-(p-tolyl)-2-[(2,2 ,2-trifluoroacetyl)amino]propoxy]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-ethylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]- N -[(3S)-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]- N-[(3S)-3-piperidyl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino] propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide, N-[(1S,2R)-2-(4-cyclopropylphenyl)-1-methyl-2-[[6-[[( 3S)-3-piperidyl]carbamoyl]-3-pyridyl]oxy]ethyl]isoxazol-3-carboxamide, 5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2 -trifluoroacetyl)amino]propoxy]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide, 5-[(1R,2S)-1-(4-bromophenyl)-2-[(2, 2,2-trifluoroacetyl)amino]propoxy]-N-[(3S)-3-piperidyl]pyridine-2-carboxamide, N-[(3S)-3-piperidyl]-4-[(1R,2S)-1 -(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzamide [(3S)-3-piperidyl]4-[(1R,2S)-1-(p-tolyl)- 2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoate, 4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2S)-tetrahydrofuran-2-carbonyl hydrochloride [(3S)-3-piperidyl]amino]propoxy]benzoate and (3S)-3-[[5-[(1S,2S)-1-(p-tolyl)-2-[(2,2, tert-butyl 2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate. 14 Compound, characterized by the fact that it is selected from (3S)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino tert-butyl]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[(1R,2S)-1-(4-bromophenyl)-2-[( tert-butyl 2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[(1R,2S)-1-( tert-butyl 4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate, (3S)-3-[[5-[ (1R,2S)-1-(4-cyclopropylphenyl)-2-[[(2R)-tetrahydrofuran-2-carbonyl]amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-tert-butyl carboxylate, (3S)-3-[[5-[(1R,2S)-1-(4-cyclopropylphenyl)-2-(isoxazol-3-carbonylamino)propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate tert-butyl, (3S)-3-[4-[(1R,2S)-1-(4-bromophenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine-1- tert-butyl carboxylate, (3S)-3-[4-[(1R,2S)-1-(4-cyclopropylphenyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine- tert-butyl 1-carboxylate, (3R)-3-[[5-[(1R,2S)-1-(p-tolyl)-2-[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine tert-butyl -2-carbonyl]amino]pyrrolidine-1-carboxylate, (3S)-3-[[4-[(1R,2S)-1-(p-tolyl)-2-[(2,2, tert-butyl 2-trifluoroacetyl)amino]propoxy]benzoyl]amino]piperidine-1-carboxylate, (3S)-3-[4-[(1R,2S)-1-(p-tolyl)-2-[( tert-butyl 2,2,2-trifluoroacetyl)amino]propoxy]benzoyl]oxypiperidine-1-carboxylate and (3S)-3-[[5-[(1S,2S)-1-(p-tolyl)-2 tert-butyl -[(2,2,2-trifluoroacetyl)amino]propoxy]pyridine-2-carbonyl]amino]piperidine-1-carboxylate.