Imidazotriazine derivatives as IL-17 modulators

Abstract

The series of substituted imidazo[1,2-b][1,2,4]triazine derivatives of formula (I) defined herein are potent modulators of human IL-17 activity and are therefore useful in the treatment and / or prevention of a wide range of human diseases, including inflammatory and autoimmune disorders.

Description

[Technical Field]

[0001] The present invention relates to heterocyclic compounds and their use in therapy. More particularly, the present invention relates to pharmacologically active substituted imidazo[1,2-b][1,2,4]triazine derivatives. These compounds act as modulators of IL-17 activity and are therefore useful as pharmaceuticals for the treatment and / or prevention of pathological conditions, including deleterious inflammatory and autoimmune disorders. [Background technology]

[0002] IL-17A (originally named CTLA-8 and also known as IL-17) is a pro-inflammatory cytokine and the founding member of the IL-17 family (Rouvier et al., J. Immunol., 1993, vol. 150, pp. 5445-5456). Five additional members of the IL-17 family (IL-17B to IL-17F) have since been identified, including the most closely related IL-17F (ML-1), which shares approximately 55% amino acid sequence identity with IL-17A (Moseley et al., Cytokine Growth Factor Rev., 2003, vol. 14, pp. 155-174). IL-17A and IL-17F are expressed by Th17, a recently defined autoimmune-associated subset of T helper cells that also expresses the characteristic cytokines related to IL-21 and IL-22 (Korn et al., Ann. Rev. Immunol., 2009, vol. 27, pp. 485-517). IL-17A and IL-17F are expressed as homodimers but can also be expressed as IL-17A / F heterodimers (Wright et al., J. Immunol., 2008, vol. 181, pp. 2799-2805). IL-17A and IL-17F signal through the receptors IL-17R, IL-17RC, or the IL-17RA / RC receptor complex (Gaffen, Cytokine, 2008, vol. 43, pp. 402-407). Both IL-17A and IL-17F are associated with many autoimmune diseases.

[0003] The compounds according to the invention are potent modulators of human IL-17 activity and are therefore useful in the treatment and / or prevention of a wide range of human diseases, including inflammatory and autoimmune disorders.

[0004] Furthermore, the compounds of the present invention may be useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacologically active substances. Thus, the compounds of the present invention may be useful as radioligands in assays for detecting pharmacologically active compounds.

[0005] WO2013 / 116682 and WO2014 / 066726 relate to separate classes of compounds that modulate the activity of IL-17 and are shown to be useful in the treatment of medical conditions, including inflammatory diseases.

[0006] WO2018 / 229079 and WO2020 / 011731 describe spirocyclic molecules that act as modulators of IL-17 activity and are therefore shown to be beneficial in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders.

[0007] WO2019 / 138017, WO2020 / 260425, WO2020 / 260426, WO2020 / 261141, WO2021 / 170627, WO2021 / 170631, WO2021 / 204800, WO2021 / 204801, WO2022 / 096411, WO2022 / 096412 and WO2022 / 128584 describe various classes of fused bicyclic imidazole derivatives which act as modulators of IL-17 activity and are therefore shown to be beneficial in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders. Fused bicyclic imidazole derivatives that act as modulators of IL-17 activity are also described in co-pending International Patent Application Publication PCT / EP2022 / 068165 (published January 5, 2023 as WO2023 / 275301).

[0008] WO2020 / 120140 and WO2020 / 120141 describe distinct classes of compounds that act as modulators of IL-17 activity and are therefore shown to be beneficial in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders.

[0009] Heterocyclic compounds that inhibit IL-17A and are indicated to be useful as immunomodulators are described in WO2019 / 223718, WO2021 / 027721, WO2021 / 027722, WO2021 / 027724, WO2021 / 027729 and WO2021 / 098844.

[0010] Heterocyclic compounds shown to be capable of modulating IL-17 activity are also described in WO2020 / 127685, WO2020 / 146194 and WO2020 / 182666. Summary of the Invention [Problem to be solved by the invention]

[0011] However, none of the prior art available to date discloses or suggests the precise structural class of substituted imidazo[1,2-b][1,2,4]triazine derivatives as provided by the present invention.

[0012] In addition to being potent modulators of human IL-17 activity, the compounds of the present invention also have other notable advantages. In particular, the compounds of the present invention exhibit valuable metabolic stability as analyzed in microsomal or hepatocyte incubations. The compounds of the present invention also exhibit valuable permeability as determined by standard assays, such as the Caco-2 permeability assay. [Means for solving the problem]

[0013] The present invention relates to a compound of formula (I): [ka] [In the formula, E is of formula (Ea), (Eb), (Ec), (Ed) or (Ee): [ka] represents a group of asterisk( * ) represents the point of attachment to the rest of the molecule; The A ring is C 3~7 Cycloalkyl or C 3~7 heterocycloalkyl, either group of which may be optionally substituted by one or more substituents; R 1 represents hydrogen, fluoro, chloro, methyl, difluoromethyl or trifluoromethyl; R 6 -OR 6a or -NR 6b R 6c or R 6 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) Alkyl, C 3~7 Heterocycloalkyl, C 3~7 Heterocycloalkyl-(C 1~6 ) alkyl, heteroaryl or heteroaryl (C 1~6 ) alkyl, either of which groups may be optionally substituted by one or more substituents; R 6a is C 1~6 represents alkyl; or R 6a is C 3~9 Cycloalkyl or C 3~7 heterocycloalkyl, either group of which may be optionally substituted by one or more substituents; R 6b is hydrogen or C 1~6 represents alkyl; R 6c is hydrogen or C 1~6represents alkyl; or R 6b and R 6c taken together with the nitrogen atom to which they are attached represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents. or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0014] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0015] The present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0016] The present invention also provides a compound of formula (I) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of disorders in which the administration of a modulator that regulates the function of IL-17 is indicated.

[0017] The present invention also provides the use of a compound of formula (I) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of disorders in which the administration of a modulator that regulates the function of IL-17 is indicated.

[0018] The present invention also provides a method for the treatment and / or prevention of disorders in which the administration of a modulator that regulates the function of IL-17 is indicated, which method comprises the step of administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0019] When any of the groups in the compound of formula (I) above is shown to be optionally substituted, this group may be unsubstituted or substituted with one or more substituents. Generally, such groups are unsubstituted or substituted with 1, 2, 3 or 4 substituents. Usually, such groups are unsubstituted or substituted with 1, 2 or 3 substituents. Suitably, such groups are unsubstituted or substituted with 1 or 2 substituents. DETAILED DESCRIPTION OF THE INVENTION

[0020] For use in medicine, the salts of the compound of formula (I) are pharmaceutically acceptable salts. However, other salts are useful in the preparation of the compound of formula (I) or its pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", edited by P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compound of formula (I) include acid addition salts, which can be formed, for example, by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0021] The present invention also includes within its scope co-crystals of compounds of formula (I) above. The term "co-crystal" is used to describe a situation in which neutral molecular components exist in a crystalline compound in a well-defined stoichiometric ratio. The preparation of pharmaceutical co-crystals allows for modification of the crystalline form of an active pharmaceutical ingredient, thereby altering its physicochemical properties without impairing its intended biological activity (see "Pharmaceutical Salts and Co-crystals," edited by J. Wouters & L. Quere, RSC Publishing, 2012).

[0022] Suitable alkyl groups that may be present on the compounds for use in the present invention include straight and branched C 1~6 Alkyl groups, such as C 1~4 alkyl groups. Typical examples include methyl and ethyl groups, as well as straight-chain or branched propyl, butyl, and pentyl groups. Specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, and 3-methylbutyl. "C 1~6 Alkoxy," "C 1~6 alkylthio", "C 1~6 Alkylsulfonyl" and "C 1~6 Derived expressions such as "alkylamino" are to be construed accordingly.

[0023] As used herein, the term "C 3~9 "Cycloalkyl" refers to a monovalent group of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, including its benzo-fused analogs. 3~9 Cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononanyl.

[0024] As used herein, the term "aryl" refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or from multiple fused aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

[0025] Suitable aryl (C 1~6 ) Alkyl groups include benzyl, phenylethyl, phenylpropyl, and naphthylmethyl.

[0026] As used herein, the term "C 3~7"Heterocycloalkyl" refers to a saturated monocyclic ring containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur, and nitrogen, and can include benzo-fused analogs thereof. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydro-thiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[1,2,5]thiadiazolo[2,3-a]-pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl, and azocanyl.

[0027] As used herein, the term "heteroaryl" refers to a monovalent aromatic group containing at least five atoms from a single ring or multiple fused rings, in which one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen.Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b]-[1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl. indyl group, pyrazolo[3,4-d]pyrimidinyl group, pyrazolo[1,5-a]pyrazinyl group, indazolyl group, 4,5,6,7-tetrahydroindazolyl group, oxazolyl group, benzoxazolyl group, isoxazolyl group, thiazolyl group, benzothiazolyl group, isothiazolyl group, imidazolyl group, benzimidazolyl group, imidazo[2,1-b]thiazolyl group, imidazo[1,2-a]pyridinyl group, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl group, imidazo- [4,5-b]pyridinyl, imidazo[1,2-b]pyridazinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]-triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro[1,2,4 ]triazolo[4,3-a]pyridinyl group, [1,2,4]triazolo[1,5-a]pyrimidinyl group, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl group, benzotriazolyl group, tetrazolyl group, pyridinyl group, quinolinyl group, isoquinolinyl group, naphthyridinyl group, pyridazinyl group, cinnolinyl group, phthalazinyl group, pyrimidinyl group, quinazolinyl group, pyrazinyl group, quinoxalinyl group, pteridinyl group, triazinyl group, and chromenyl group.

[0028] As used herein, the term "halogen" is intended to include fluorine, chlorine, bromine and iodine atoms, and is typically a fluorine, chlorine or bromine atom.

[0029] When a compound of formula (I) has one or more asymmetric centers, the compound of formula (I) may accordingly exist as an enantiomer. When the compounds according to the invention have two or more asymmetric centers, they may further exist as diastereomers. It is understood that the present invention extends to the use of all such enantiomers and diastereomers, as well as mixtures thereof in any proportion, including racemates. Formula (I) and the formulae set forth below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise stated or indicated. Furthermore, compounds of formula (I) may exist as tautomers, such as keto (CHC=O)⇔enol (CH=CHOH) tautomers or amide (NHC=O)⇔hydroxyimine (N=COH) tautomers. Formula (I) and the formulae set forth below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or indicated.

[0030] It will be understood that each individual atom present in formula (I), or in the formulae set out below, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae set out below, may be: 1 H, 2 H (deuterium) or 3 It may be present as a H (tritium) atom, preferably 1 H. Similarly, by way of example, each individual carbon atom present in formula (I) or in the formulae shown below is 12 C. 13 C or 14 It may be present as a C atom, preferably 12 It is C.

[0031] In a first embodiment, E represents a group of formula (Ea). In a second embodiment, E represents a group of formula (Eb). In a third embodiment, E represents a group of formula (Ec). In a fourth embodiment, E represents a group of formula (Ed). In a fifth embodiment, E represents a group of formula (Ee).

[0032] Suitably, E represents a group of formula (Ea) or (Ed), in particular a group of formula (Ea).

[0033] In general, the present invention provides a compound of formula (IA-1), (IA-2), (IA-3), (IA-4) or (IA-5): [ka] [ka] [ka] [In the formula, A, R 1 and R 6 is as defined above] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0034] Generally, the present invention provides a compound of formula (IA-1) or (IA-4) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0035] Suitably, the present invention provides a compound of formula (IA-1) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0036] Generally, the A ring is C 3~7 Cycloalkyl or C 3~7 Suitably, the A ring represents a heterocycloalkyl, either of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. 3~6 Cycloalkyl or C4~6 It may represent heterocycloalkyl, either group of which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0037] In a first embodiment, the A ring is suitably C 3~7

[0023] Ring A may suitably represent cycloalkyl, which may be unsubstituted or substituted with one or more substituents, usually one or two. As a general example of this embodiment, ring A may suitably represent cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, either of which may be unsubstituted or substituted with one or more substituents, usually one or two. As a specific example of this embodiment, ring A may suitably represent cyclopropyl or cyclobutyl, either of which may be unsubstituted or substituted with one or more substituents, usually one or two. In a first aspect of this embodiment, ring A may suitably represent a cyclopropyl ring, which may be unsubstituted or substituted with one or more substituents, usually one or two. In a second aspect of this embodiment, ring A may suitably represent a cyclobutyl ring, which may be unsubstituted or substituted with one or more substituents, usually one or two. In a third aspect of this embodiment, the A ring may suitably represent a cyclopentyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a fourth aspect of this embodiment, the A ring may suitably represent a cyclohexyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0038] In a second embodiment, the A ring is suitably C 3~7Heterocycloalkyl may represent, and this group may be unsubstituted or substituted with one or more substituents, usually one or two substituents. As a representative example of this embodiment, ring A may suitably represent oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of which groups may be unsubstituted or substituted with one or more substituents, usually one or two substituents. As a general example of this embodiment, ring A may suitably represent oxetanyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of which groups may be unsubstituted or substituted with one or more substituents, usually one or two substituents. As a preferred example of this embodiment, ring A may suitably represent oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl, any of which groups may be unsubstituted or substituted with one or more substituents, usually one or two substituents. In certain specific examples of this embodiment, ring A may suitably represent tetrahydropyranyl or piperidinyl, either of which groups may be unsubstituted or substituted with one or more substituents, usually one or two. In a first aspect of this embodiment, ring A may suitably represent an oxetanyl ring, which may be unsubstituted or substituted with one or more substituents, usually one or two. In a second aspect of this embodiment, ring A may suitably represent a tetrahydrofuranyl ring, which may be unsubstituted or substituted with one or more substituents, usually one or two. In a third aspect of this embodiment, ring A may suitably represent a pyrrolidinyl ring, which may be unsubstituted or substituted with one or more substituents, usually one or two. In a fourth aspect of this embodiment, ring A may suitably represent a tetrahydropyranyl ring, which may be unsubstituted or substituted with one or more substituents, usually one or two.In a fifth aspect of this embodiment, the A ring may suitably represent a piperidinyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0039] Generally, the A ring can represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of which groups can be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0040] Typically, the A ring can represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of which groups can be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0041] Under preferred conditions, the A ring may represent cyclopropyl, cyclobutyl, oxetanyl, tetrahydro-furanyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0042] Suitably, the A ring may represent cyclopropyl, cyclobutyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0043] Typical examples of optional substituents on the A ring are halogen, cyano, C 1~6 Alkyl, Fluoro(C 1~6 ) alkyl, difluoro(C 1~6 ) alkyl, trifluoro(C 1~6 ) Alkyl, Hydroxy, C 1~6 Alkoxy, C1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, C 2~6 Alkyl carbonyl, C 2~6 Alkoxycarbonyl, Amino, C 1~6 Alkylamino and di(C 1~6 ) alkylamino.

[0044] Suitable examples of optional substituents on the A ring include halogen, C 1~6 Alkyl, Fluoro(C 1~6 ) alkyl, difluoro-(C 1~6 ) alkyl and C 2~6 The alkyl group may have 1, 2, or 3 substituents independently selected from alkoxycarbonyl.

[0045] Suitable examples of optional substituents on the A ring include halogen and C 2~6 The alkyl group may have 1, 2, or 3 substituents independently selected from alkoxycarbonyl.

[0046] Typical examples of certain substituents on the A ring include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, methyl, fluoro-isobutyl, difluoropropyl, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy-carbonyl, amino, methylamino and dimethylamino.

[0047] Suitable examples of certain substituents on the A ring include 1, 2 or 3 substituents independently selected from fluoro, methyl, fluoroisobutyl, difluoropropyl and tert-butoxycarbonyl.

[0048] Suitable examples of certain substituents on the A ring include 1, 2 or 3 substituents independently selected from fluoro and tert-butoxycarbonyl.

[0049] Typical examples of the A ring include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonylpyrrolidinyl, tetrahydropyranyl, piperidinyl, methoxycarbonylpiperidinyl, and tert-butoxycarbonylpiperidinyl. Further examples include tetrahydrofuranyl, methylpiperidinyl, fluoroisobutylpiperidinyl, and difluoropropylpiperidinyl.

[0050] Preferred examples of the A ring include cyclopropyl, difluorocyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, methylpiperidinyl, fluoroisobutyl-piperidinyl, difluoropropylpiperidinyl and tert-butoxycarbonylpiperidinyl.

[0051] Suitable examples of the A ring include cyclopropyl, difluorocyclobutyl, tetrahydropyranyl, piperidinyl and tert-butoxycarbonylpiperidinyl.

[0052] In the first embodiment, R 1 represents hydrogen. In a second embodiment, R 1 represents fluoro. In a third embodiment, R 1 represents chloro. In a fourth embodiment, R 1 represents methyl. In a fifth embodiment, R 1 represents difluoromethyl. In a sixth embodiment, R 1 represents trifluoromethyl.

[0053] Usually, R 1 represents hydrogen, fluoro, chloro or methyl.

[0054] In general, R 1 represents hydrogen or fluoro.

[0055] Appropriately, R 1 represents hydrogen.

[0056] Usually, R 6 -OR 6a or -NR 6b R 6c or R 6 is C 1~6 Alkyl, C 3~9 Cycloalkyl, C 3~9 Cycloalkyl(C 1~6 ) Alkyl, aryl, aryl (C 1~6 ) alkyl, heteroaryl or heteroaryl-(C 1~6 ) alkyl, either of which groups may be optionally substituted by one or more substituents.

[0057] Appropriately, R 6 -OR 6a or -NR 6b R 6c or R 6 is C 3~9 It represents a cycloalkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.

[0058] Appropriately, R 6 -OR 6a or R 6 represents heteroaryl, which may be optionally substituted by one or more substituents.

[0059] In the first embodiment, R 6 is sometimes replaced by C 1~6 In a second embodiment, R 6 is sometimes replaced by C 3~9 In a third embodiment, R 6 is sometimes replaced by C 3~9 Cycloalkyl(C 1~6 ) alkyl. In a fourth embodiment, R 6 represents an optionally substituted aryl. In a fifth embodiment, R 6 is optionally substituted aryl (C 1~6) alkyl. In a sixth embodiment, R 6 is sometimes replaced by C 3~7 In a seventh embodiment, R represents heterocycloalkyl. 6 is sometimes replaced by C 3~7 Heterocycloalkyl(C 1~6 ) alkyl. In an eighth embodiment, R 6 represents an optionally substituted heteroaryl. In a ninth embodiment, R 6 is an optionally substituted heteroaryl (C 1~6 ) alkyl. In a tenth embodiment, R 6 HA-OR 6a In an eleventh embodiment, R 6 is -NR 6a R 6b Represents.

[0060] R 6 A typical example of this is -OR 6a or -NR 6a R 6b and methyl, ethyl, propyl, 2-methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, triazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.

[0061] R 6 A typical example is -OR 6a or -NR 6a R 6b and cyclopropyl, pyrazolyl, oxadiazolyl or triazolyl, any of which groups may be optionally substituted by one or more substituents.

[0062] R 6 A specific example of this is -OR 6aand pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl, any of which groups may be optionally substituted by one or more substituents.

[0063] R 6 Suitable examples of include pyrazolyl, isoxazolyl, oxadiazolyl and triazolyl, any of which groups may be optionally substituted by one or more substituents.

[0064] R 6 Suitable examples of include pyrazolyl, oxadiazolyl and triazolyl, any of which groups may be optionally substituted by one or more substituents.

[0065] R 6 One particular example of the above is oxadiazolyl, which may be optionally substituted by one or more substituents.

[0066] R 6 Typical examples of the above optional substituents are halogen, cyano, nitro, C 1~6 Alkyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, fluorophenyl, hydroxy, hydroxy(C 1~6 ) Alkyl, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C 2~6 Alkylcarbonylamino, C 2~6 Alkylcarbonyl-amino(C 1~6 ) Alkyl, C 2~6 Alkoxycarbonylamino, C 1~6Alkyl sulfonyl amino, formyl, C 2~6 Alkyl-carbonyl, carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, di(C 1~6 ) Alkylaminocarbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 ) alkylamino-sulfonyl and di(C 1~6 ) alkylsulfoximinyl.

[0067] R 6 Suitable examples of the above optional substituents include C 1~6 The group may have 1, 2, or 3 substituents independently selected from alkyl.

[0068] R 6 Typical examples of certain of the above substituents include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydro-pyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonyl-amino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximinyl.

[0069] R 6Suitable examples of certain of the above substituents include 1, 2 or 3 substituents independently selected from methyl.

[0070] R 6Examples of certain values of methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxyethyl, difluoropropyl, 2-methylpropyl, butyl, fluorocyclopropyl, cyanocyclopropyl, methyl-cyclopropyl, ethylcyclopropyl, dimethylcyclopropyl, difluoromethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxy-cyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chlorophenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethylsulfoximinylphenyl, benzyl, fluoro-benzyl, difluorobenzyl, chlorobenzyl, (chloro)(fluoro)benzyl, dichlorobenzyl, (chloro)-(difluoro)benzyl, bromobenzyl, cyanobenzyl, diethylbenzyl, methylbenzyl, dimethylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, hydroxymethylbenzyl, benzoyl, methoxybenzyl, dimethoxybenzyl, trifluoromethoxybenzyl, methylsulfonylbenzyl, aminomethylbenzyl, aminoethylbenzyl, dimethylaminobenzyl, pyrrolidinylbenzyl, (dimethyl)-(pyrrolidinyl)benzyl, morpholinylbenzyl, (dimethyl)(morpholinyl)benzyl, piperazinylbenzyl, acetylaminoethylbenzyl, phenylethyl, chlorophenylethyl, methylpyrazolyl, ethylpyrazolyl, isopropylpyrazolyl, (methyl)(tetrahydropyranyl)pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl, isopropyltriazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, pyridinylmethyl, and aminopyridinylmethyl.

[0071] R 6Preferred values of include fluorocyclopropyl, difluoromethylcyclopropyl, trifluoromethylcyclopropyl, methylpyrazolyl, ethylpyrazolyl, isopropylpyrazolyl, methyl-isoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl and isopropyltriazolyl.

[0072] R 6 Typical values of include fluorocyclopropyl, difluoromethylcyclopropyl, trifluoromethylcyclopropyl, isopropylpyrazolyl, methyloxadiazolyl, cyclopropyl-oxadiazolyl and isopropyltriazolyl.

[0073] R 6 Suitable values of include isopropylpyrazolyl, methyloxadiazolyl, cyclopropyloxadiazolyl and isopropyltriazolyl.

[0074] R 6 A preferred value of is methyloxadiazolyl.

[0075] In general, R 6a is C 1~6 represents alkyl; or R 6a is C 3~9 represents a cycloalkyl, which may be optionally substituted by one or more substituents.

[0076] In the first embodiment, R 6a is C 1~6 In a second embodiment, R 6a is sometimes replaced by C 3~9 In a third embodiment, R 6a is sometimes replaced by C 3~7 represents heterocycloalkyl;

[0077] Appropriately, R 6a is C 1~6 represents alkyl; or R 6arepresents cyclobutyl or oxetanyl, either of which groups may be optionally substituted by one or more substituents.

[0078] Usually, R 6a is C 1~6 represents alkyl; or R 6a represents cyclobutyl, which may be optionally substituted by one or more substituents.

[0079] R 6a Typical examples of the above optional substituents are halogen, cyano, nitro, C 1~6 Alkyl, trifluoromethyl, hydroxy, hydroxy(C 1~6 ) Alkyl, oxo, C 1~6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1~6 Alkylthio, C 1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, amino, amino(C 1~6 ) Alkyl, C 1~6 Alkylamino, di(C 1~6 ) Alkylamino, C 2~6 Alkylcarbonylamino, C 2~6 Alkoxycarbonylamino, C 1~6 Alkyl sulfonyl amino, formyl, C 2~6 Alkylcarbonyl, carboxy, C 2~6 Alkoxycarbonyl, aminocarbonyl, C 1~6 Alkylaminocarbonyl, di(C 1~6 ) Alkylaminocarbonyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 ) alkylaminosulfonyl.

[0080] R 6a Suitable examples of the above optional substituents include 1, 2 or 3 substituents independently selected from halogen.

[0081] R 6aTypical examples of certain of the above substituents include 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethyl-aminosulfonyl.

[0082] R 6a Suitable examples of certain of the above substituents include 1, 2 or 3 substituents independently selected from fluoro.

[0083] R 6a Representative examples of certain values of include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, difluorocyclobutyl, and oxetanyl.

[0084] R 6a Particular examples of values for include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl and difluorocyclobutyl.

[0085] Usually, R 6a represents cyclobutyl.

[0086] Usually, R 6b represents hydrogen or methyl.

[0087] In the first embodiment, R 6b represents hydrogen. In a second embodiment, R 6b is C 1~6It stands for alkyl, especially methyl.

[0088] Usually, R 6c represents hydrogen or methyl.

[0089] In the first embodiment, R 6c represents hydrogen. In a second embodiment, R 6c is C 1~6 It stands for alkyl, especially methyl.

[0090] Or, -NR 6b R 6c The moiety suitably represents azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may optionally be substituted by one or more substituents.

[0091] Heterocyclic moiety -NR 6b R 6c Examples of suitable substituents include C 1~6 Alkyl, C 1~6 Alkyl sulfonyl, hydroxy, hydroxy(C 1~6 ) alkyl, amino (C 1~6 ) Alkyl, cyano, oxo, C 2~6 Alkylcarbonyl, carboxy, C 2~6 Alkoxycarbonyl, Amino, C 2~6 Alkylcarbonyl-amino, C 2~6 Alkylcarbonylamino (C 1~6 ) Alkyl, C 2~6 Alkoxycarbonylamino, C 1~6 Alkylsulfonyl-amino and aminocarbonyl are included.

[0092] Heterocyclic moiety -NR 6b R 6cSelected examples of certain of the above substituents include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy-carbonylamino, methylsulfonylamino, and aminocarbonyl.

[0093] Some subclasses of compounds according to the present invention are represented by formula (IIA): [ka] [In the formula, X represents CH or N; R 16 represents methyl, ethyl, isopropyl, difluoromethyl or cyclopropyl; A is as defined above] and its N-oxides, and pharmaceutically acceptable salts thereof.

[0094] In a first embodiment, X represents CH. In a second embodiment, X represents N.

[0095] In the first embodiment, R 16 represents methyl. In a second embodiment, R 16 represents ethyl. In a third embodiment, R 16 represents isopropyl. In a fourth embodiment, R 16 represents difluoromethyl. In a fifth embodiment, R 16 represents cyclopropyl.

[0096] Appropriately, R 16 represents methyl, isopropyl or cyclopropyl, especially methyl.

[0097] Certain novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.

[0098] The compounds according to the present invention are useful in the treatment and / or prevention of a wide range of human ailments, including inflammatory and autoimmune disorders.

[0099] The compounds according to the invention are useful for the treatment and / or prevention of pathological disorders mediated by the pro-inflammatory IL-17 cytokine or associated with increased levels of the pro-inflammatory IL-17 cytokine. Generally, pathological conditions include infections (viral, bacterial, fungal and parasitic infections), endotoxic shock associated with infections, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman's disease, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathy, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, pilonidal disease, and the like. disease), peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, type 1 diabetes, Lyme arthritis, meningoencephalitis, immune-mediated inflammatory diseases of the central and peripheral nervous system, other autoimmune disorders such as multiple sclerosis and Guillain-Barré syndrome, pancreatitis, physical trauma (due to surgery), graft-versus-host disease, graft rejection, fibrosing disorders including pulmonary fibrosis, liver fibrosis, kidney fibrosis, scleroderma or systemic sclerosis disorders), cancer (solid tumors, e.g., melanoma, hepatoblastoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, both ovarian cancer and hematological malignancies, in particular acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), heart diseases, including ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydia and pain (in particular pain associated with inflammation).

[0100] WO 2009 / 089036 discloses that modulators of IL-17 activity can be administered to suppress or reduce the severity of ocular inflammatory disorders, particularly ocular surface inflammatory disorders, including dry eye syndrome (DES). Consequently, the compounds of the present invention are useful for treating and / or preventing IL-17-mediated ocular inflammatory disorders, particularly IL-17-mediated ocular surface inflammatory disorders, including dry eye syndrome. Ocular surface inflammatory disorders include dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial-thickness grafting, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal ocular surface inflammatory conditions, conjunctival scarring conditions, ocular autoimmune conditions, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis. Certain categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjogren's syndrome, Sjogren's syndrome-associated keratoconjunctivitis sicca, non-Sjogren's syndrome-associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction, and evaporative loss, among others.

[0101] Illustratively, the compounds of the invention may be useful in the treatment and / or prevention of pathological disorders selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airways disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer, and pain (particularly pain associated with inflammation).

[0102] Suitably, the compounds of the present invention are useful for the treatment and / or prevention of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis or ankylosing spondylitis.

[0103] The present invention also provides pharmaceutical compositions comprising a compound according to the invention, as described above, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.

[0104] Pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or in a form suitable for administration by inhalation or insufflation.

[0105] For oral administration, the pharmaceutical compositions may take the form of tablets, troches, or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form, for example, of solutions, syrups, or suspensions, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional methods with pharmaceutically acceptable excipients such as suspending agents, emulsifying agents, non-aqueous vehicles, or preservatives. The preparations may also contain buffer salts, flavoring agents, coloring agents, or sweetening agents, as appropriate.

[0106] Preparations for oral administration can be suitably formulated to give controlled release of the active compound.

[0107] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0108] The compounds according to the present invention can be formulated for parenteral administration by injection, for example, bolus injection or infusion. The formulations for injection can be presented in unit dosage form, for example, in glass ampoules or in the form of multi-dose containers, for example, glass vials. The compositions for injection can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, such as suspending agents, stabilizers, preservatives, and / or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0109] In addition to the formulations described above, the compounds of the present invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or intramuscular injection.

[0110] For nasal administration or administration by inhalation, the compounds according to the invention can conveniently be delivered in the form of a supply as an aerosol spray for a pressurized pack or a nebulizer, with the use of a suitable propellant, for example dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

[0111] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispenser device may be accompanied by instructions for administration.

[0112] For topical administration, the compounds according to the present invention can be conveniently formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, and water. Alternatively, the compounds according to the present invention can be formulated into a suitable lotion containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol, and water.

[0113] For ophthalmic administration, the compounds according to the invention can be conveniently formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, with or without preservatives such as bactericides or fungicides, e.g., phenylmercuric nitrate, benzylalkonium chloride, or chlorhexidine acetate. Alternatively, for ophthalmic administration, the compounds according to the invention can be formulated in an ointment such as petrolatum.

[0114] For rectal administration, the compounds according to the invention can be conveniently formulated as suppositories. These can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the active ingredient. Such materials include, for example, cocoa butter, beeswax, and polyethylene glycols.

[0115] The amount of a compound according to the present invention required for the prevention or treatment of a particular condition will vary depending on the compound selected and the condition of the patient being treated. However, in general, the daily dosage may be in the range of about 10 ng to 1000 mg per kg of body weight for oral or buccal administration, usually 100 ng to 100 mg per kg of body weight, for example, about 0.01 mg to 40 mg per kg of body weight, about 10 ng to 50 mg per kg of body weight for parenteral administration, and about 0.05 mg to about 1000 mg, for example, about 0.5 mg to about 1000 mg for intranasal administration or administration by inhalation or pneumoperitoneum.

[0116] If desired, the compounds according to the invention can be co-administered with another pharmaceutically active agent, for example, an anti-inflammatory molecule.

[0117] The compounds of formula (I) above have the formula R 6 -COH carboxylic acid or its salt, for example its alkali metal salt such as lithium salt, of formula (III): [ka] [In the formula, E, A, R 1 and R 6 is as defined above] The compound of formula (I) can be prepared by a process comprising the step of reacting a compound of formula (I) with a compound of formula (II).

[0118] The reaction is conveniently carried out in the presence of a coupling agent and a base. Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU); and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. Suitable bases include organic amines, such as trialkylamines such as N,N-diisopropylethylamine, or pyridine. The reaction is conveniently carried out in a suitable solvent, such as a cyclic ether such as tetrahydrofuran; a dipolar aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide; a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate, at ambient or elevated temperature. Alternatively, the reaction may conveniently be effected in the presence of a coupling agent such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). The reaction is suitably carried out at a suitable temperature, for example in the region of 0°C, in a suitable solvent, for example an organic nitrile solvent such as acetonitrile.

[0119] R 6 C 1~6 When alkyl, e.g. methyl, is represented, the compound of formula (I) above may be of formula R 6 It can be prepared by a method comprising reacting a compound of -COCl, such as acetyl chloride, with a compound of formula (III) as defined above. The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, for example, trialkylamines such as N,N-diisopropylethylamine. The reaction is conveniently carried out in a suitable solvent, for example, a cyclic ether such as tetrahydrofuran, at ambient temperature.

[0120] R 6 -OR 6a When the compound of formula (I) represents 6aIt can be prepared by a two-step process comprising reacting the compound of -OH with N,N'-disuccinimidyl carbonate, ideally in the presence of a base, for example an organic amine such as triethylamine; and (ii) reacting the resulting material with a compound of formula (III) as defined above. Steps (i) and (ii) are conveniently carried out in a suitable solvent, for example a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile, at ambient temperature.

[0121] The intermediate of formula (III) above can be converted to a compound of formula (IV): [ka] [Wherein E, A and R 1 is as defined above, and R p represents an N-protecting group] from the compound of formula (I) to form the N-protecting group R p It can be prepared by removing

[0122] N-protecting group R p is suitably tert-butoxycarbonyl (BOC), in which case removal of the protecting group is conveniently effected by treatment with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

[0123] Alternatively, an N-protecting group R p may be benzyloxycarbonyl, in which case its removal is conveniently effected by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of, for example, palladium on charcoal or palladium hydroxide on charcoal. p When is benzyloxycarbonyl, its removal can be achieved by treatment with boron tribromide; or with hydrogen bromide and acetic acid.

[0124] In another procedure, the compound of formula (I) above is reacted with (i) reacting 2-(trifluoromethyl)acrylic acid with formula (V): [ka] [In the formula, E, A, R 1 and R 6 is as defined above; (ii) treating the resulting material with diphenylphosphoryl azide; It can be prepared by a two-step process including:

[0125] Similarly, the intermediate of formula (IV) above is (i) reacting 2-(trifluoromethyl)acrylic acid with formula (VI): [ka] [In the formula, E, A, R 1 and R p is as defined above; (ii) treating the resulting material with diphenylphosphoryl azide; It can be prepared by a two-step process including:

[0126] Step (i) is generally carried out in the presence of a base. Suitable bases include alkali metal bicarbonates, such as sodium bicarbonate. The reaction is carried out in a suitable solvent, such as C12, such as methanol. 1~4 It is conveniently carried out in an alkanol or a cyclic ether such as 1,4-dioxane at ambient or elevated temperature.

[0127] Step (ii) is generally carried out in the presence of a base. Suitable bases include alkali metal tert-butoxides, such as sodium tert-butoxide. The reaction is conveniently carried out in a suitable solvent, such as a cyclic ether such as 1,4-dioxane, at elevated temperature.

[0128] In another procedure, the compound of formula (I) can be prepared by converting a compound of formula (VII) to a compound of formula (VIII): [ka] [In the formula, E, A, R 1 and R 6 is as defined above] The compound of formula (I) can be prepared by a process comprising the step of reacting a compound of formula (I) with a compound of formula (II).

[0129] Suitable transition metal catalysts for the reaction include [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis-{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C}iridium(III) hexafluorophosphate. The reaction is typically carried out by exposing the reactants to a bright light source. Suitable bright light sources typically include the "integrated photoreactor" described in ACS Cent. Sci., 2017, Vol. 3, pp. 647-653. The reaction is conveniently carried out at ambient temperature in a suitable solvent, e.g., a dipolar aprotic solvent such as N,N-dimethylformamide; or an organic sulfoxide such as dimethyl sulfoxide.

[0130] The intermediate of formula (VII) is (i) Formula (IX): [ka] wherein A is as defined above and Alk 1 is C 1~4 represents alkyl, for example methyl, ethyl or tert-butyl; (ii) reacting the resulting carboxylic acid derivative with N-hydroxyphthalimide; It can be prepared by a two-step process comprising:

[0131] Alk 1 When represents methyl or ethyl, the saponification reaction in step (i) is generally carried out by treatment with a base. Suitable bases include inorganic hydroxides, for example alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. The saponification reaction is carried out in water and a suitable organic solvent, for example a cyclic ether such as tetrahydrofuran, or a C 2 -isotope such as methanol. 1~4 The reaction is conveniently carried out in an alkanol at ambient or elevated temperature.

[0132] Or Alk 1 When represents tert-butyl, the saponification reaction in step (i) can generally be carried out by treatment with an acid, for example an organic acid such as trifluoroacetic acid. The reaction is conveniently carried out in a suitable organic solvent, for example a chlorinated solvent such as dichloromethane, at ambient temperature.

[0133] Step (ii) is generally carried out in the presence of a coupling agent. Typical coupling agents include N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl); and N,N'-dicyclohexylcarbodiimide (DCC), suitably in the presence of 4-(dimethylamino)pyridine (DMAP). The reaction is conveniently carried out in a suitable solvent, for example, a chlorinated solvent such as dichloromethane, or a cyclic ether such as tetrahydrofuran, at ambient temperature.

[0134] The intermediate of the above formula (IX) is (i) reacting 2-(trifluoromethyl)acrylic acid with a compound of formula (X): [ka] wherein A and Alk 1 is as defined above; (ii) treating the material thereby obtained with diphenylphosphoryl azide under conditions similar to those described above; It can be prepared by a two-step process including:

[0135] The intermediate of the above formula (V) is (i) reacting a compound of formula (VIII) as defined above with a compound of formula (XI): [ka] wherein A is as defined above and R q represents an N-protecting group; (ii) N-protecting group R q and removing It can be prepared by a two-step process including:

[0136] Similarly, the intermediate of formula (VI) above is (i) reacting a compound of formula (XI) as defined above with a compound of formula (XII): [ka] [In the formula, E, R 1 and R p is as defined above; (ii) N-protecting group R q and removing It can be prepared by a two-step process including:

[0137] N-protecting group R q is suitably tert-butoxycarbonyl (BOC), in which case its removal in step (ii) may conveniently be effected by treatment with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

[0138] The intermediate of formula (XI) can be converted to a compound of formula (XIII) under conditions similar to those described above for the reaction between N-hydroxyphthalimide and the carboxylic acid derivative obtained from the saponification of compound (IX): [ka] [Wherein A and R q is as defined above] with N-hydroxyphthalimide.

[0139] The intermediate of the above formula (VIII) is (i) Removal of the N-protecting group R from a compound of formula (XII) as defined above under conditions similar to those described above p removing the (ii) Compound (III) and Formula R 6 The resulting compound can be reacted with a compound of formula R under conditions similar to those described above for the reaction of —COH with a carboxylic acid or salt thereof. 6 reacting —COH with a carboxylic acid or a salt thereof, an alkali metal salt thereof, such as a lithium salt thereof; It can be prepared by a two-step process including:

[0140] The intermediate of formula (XII) above can be prepared by converting a compound of formula (XIV) into a compound of formula (XV): [ka] [In the formula, E, R 1 and R p is as defined above, and L 1 represents a suitable leaving group].

[0141] Leaving group L 1 is usually a halogen atom, for example bromo.

[0142] The reaction is generally carried out in the presence of a base. Suitably, the base may be an inorganic base, for example, a bicarbonate such as sodium bicarbonate; or an organic base such as pyridine. The reaction is carried out in a suitable solvent, for example, a C 2 O 4 solution such as ethanol or isopropanol. 1~4 It is conveniently carried out in an alkanol or a cyclic ether such as 1,4-dioxane at elevated temperature.

[0143] If not commercially available, starting materials of formula (X), (XIII), (XIV) and (XV) can be prepared by methods analogous to those described in the accompanying examples or by standard methods well known in the art.

[0144] It will be appreciated that any compound of formula (I) initially obtained from any of the above methods can, where appropriate, be subsequently expanded to further compounds of formula (I) by techniques known in the art. By way of example, a compound containing an N-BOC moiety (BOC stands for tert-butoxycarbonyl) can be converted to the corresponding compound containing an NH moiety by treatment with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

[0145] Compounds containing an NH function can be alkylated, e.g., methylated, by treatment with an appropriate alkyl halide, e.g., iodomethane, or with an appropriate alkyl trifluoromethanesulfonate, usually in the presence of a base, e.g., an inorganic carbonate such as sodium carbonate or potassium carbonate.

[0146] Compounds containing an NH function can be acylated, e.g., acetylated, typically by treatment with a suitable acyl halide, e.g., acetyl chloride, in the presence of a base, e.g., an organic base such as N,N-diisopropylethylamine or triethylamine. Similarly, compounds containing an NH function can be acylated, e.g., acetylated, typically by treatment with a suitable acyl anhydride, e.g., acetic anhydride, in the presence of a base, e.g., an organic base such as triethylamine.

[0147] Similarly, compounds containing an NH functional group can be reacted with the appropriate C 1~4 Treatment with an alkylsulfonyl chloride reagent, such as methylsulfonyl chloride, affords NS(O)Alk 1 (In the formula, Alk 1 is as defined above) functional group.

[0148] Similarly, compounds containing an NH functionality can be converted to the corresponding compounds containing a carbamate or urea moiety by treatment with an appropriate chloroformate or carbamoyl chloride reagent, respectively, typically in the presence of a base, such as triethylamine or an organic base such as N,N-diisopropylethylamine. Alternatively, compounds containing an NH functionality can be converted to the corresponding compounds containing a urea moiety by treatment with an appropriate amine-substituted (3-methylimidazol-3-ium-1-yl)methanone iodide derivative, typically in the presence of a base, such as triethylamine. Alternatively, compounds containing an NH functionality can be converted to the corresponding compounds containing a urea moiety by treatment with an appropriate isocyanate derivative, Alk, typically in the presence of a base, such as triethylamine. 1 -N=C=O to form the urea moiety NC(O)N(H)Alk 1 (In the formula, Alk 1 is as defined above).

[0149] Compounds containing an NH functionality can be converted to the corresponding compounds containing an NC(H) functionality by treatment with an appropriate aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride.

[0150] C 1~4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1(wherein R is as defined above) can be converted to the corresponding compound containing a carboxylic acid (—COH) moiety by treatment with a base, for example, an alkali metal hydroxide salt such as lithium hydroxide. Alternatively, a compound containing a tert-butoxy-carbonyl moiety can be converted to the corresponding compound containing a carboxylic acid (—COH) moiety by treatment with trifluoroacetic acid.

[0151] Compounds containing a carboxylic acid (-COH) moiety can be prepared by reacting compound (III) with the compound of formula R 6 They can be converted to the corresponding compounds containing an amide moiety by treatment with an appropriate amine under conditions similar to those described above for the reaction of -CO2H with a carboxylic acid.

[0152] C 1~4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1 is defined above) can be converted to the corresponding compound containing a hydroxymethyl (—CHOH) moiety by treatment with a reducing agent such as lithium aluminum hydride.

[0153] C 1~4 Alkylcarbonyloxy moiety -OC(O)Alk 1 (In the formula, Alk 1 is defined above), e.g., acetoxy, can be converted to the corresponding compound containing a hydroxy (—OH) moiety by treatment with a base, e.g., an alkali metal hydroxide salt such as sodium hydroxide.

[0154] Compounds containing halogen atoms, such as bromo, can be converted to the corresponding compounds containing an optionally substituted aryl, heterocycloalkenyl, or heteroaryl moiety by treatment with an appropriately substituted aryl, heterocycloalkenyl, or heteroaryl boronic acid or its cyclic ester formed with an organic diol, such as pinacol, 1,3-propanediol, or neopentyl glycol. This reaction is typically carried out in the presence of a transition metal catalyst and a base. The transition metal catalyst may be [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Alternatively, the transition metal catalyst may be tris(dibenzylideneacetone)dipalladium(0), which may be advantageously used in combination with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). Suitably, the base may be an inorganic base, such as sodium carbonate or potassium carbonate.

[0155] Compounds containing a halogen atom, e.g., bromo, can be converted to the corresponding compounds containing an optionally substituted aryl or heteroaryl moiety via a two-step procedure comprising (i) reacting with bis(pinacolato)diboron; and (ii) reacting the resulting compound with an appropriately substituted bromoaryl or bromoheteroaryl derivative. Step (i) is conveniently carried out in the presence of a transition metal catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and potassium acetate. Step (ii) is conveniently carried out in the presence of a transition metal catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and a base, e.g., an inorganic base such as sodium carbonate or potassium carbonate.

[0156] Compounds containing a cyano (-CN) moiety can be converted to the corresponding compounds containing a 1-aminoethyl moiety by a two-step process involving (i) reaction with methylmagnesium chloride, ideally in the presence of titanium(IV) isopropoxide, and (ii) treatment of the resulting material with a reducing agent such as sodium borohydride. If excess methylmagnesium chloride is used in step (i), the corresponding compound containing a 1-amino-1-methylethyl moiety can be obtained.

[0157] Compounds containing an -S- moiety can be converted to the corresponding compounds containing an -S(O)(NH)- moiety by treatment with (diacetoxyiodo)benzene and ammonium carbamate.

[0158] Compounds containing a C=C double bond can be converted to the corresponding compounds containing a CH-CH single bond by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst, such as palladium on charcoal.

[0159] Compounds containing an aromatic nitrogen atom can be converted to the corresponding compounds containing an N-oxide moiety by treatment with a suitable oxidizing agent, such as 3-chloroperbenzoic acid.

[0160] When a mixture of products is obtained from any of the above-described processes for preparing compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods, such as, for example, preparative HPLC; or column chromatography, for example, utilizing silica and / or alumina, in combination with a suitable solvent system.

[0161] If the above-described method for preparing the compound according to the present invention results in a mixture of stereoisomers, these isomers can be separated by conventional techniques. In particular, if it is desired to obtain a specific enantiomer of a compound of formula (I), it can be produced from the corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g., salts, can be produced by reacting a mixture of an enantiomer of formula (I), e.g., a racemate, with an appropriate chiral compound, e.g., a chiral base. The diastereomers can then be separated by any convenient means, e.g., crystallization, and the desired enantiomer can be recovered, e.g., if the diastereomer is a salt, by treatment with an acid. In another resolution process, the racemate of formula (I) can be separated using chiral HPLC. Furthermore, if desired, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer can be obtained by enantiospecific biodegradation, e.g., ester hydrolysis using an esterase, followed by purification of the enantiomerically pure hydrolyzed acid from the unreacted ester antipode. Chromatography, recrystallization, and other conventional separation procedures can also be used with intermediates or final products when it is desired to obtain a particular geometric isomer of the present invention.

[0162] During any of the above synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by convenient protecting groups such as those described in "Greene's Protective Groups in Organic Synthesis", P.G.M.Wuts (ed.), John Wiley & Sons, 5th Edition, 2014. The protecting groups may be removed at any convenient subsequent stage using methods known in the art.

[0163] Compounds according to the present invention potently inhibit IL-17-induced IL-6 release from human dermal fibroblasts. Thus, when tested in the HDF cell line assay described below, compounds of the present invention exhibit pIC 50 A value of 5.0 or greater, generally 6.0 or greater, usually 7.0 or greater, typically 7.2 or greater, suitably 7.5 or greater, ideally 7.8 or greater, and preferably 8.0 or greater (pIC 50 ha-log 10 [I C 50 ], and IC 50 is expressed as a molar concentration, so those skilled in the art can 50 (Understanding that a higher value indicates a more active compound).

[0164] Inhibition of IL-17A-induced IL-6 release from a skin fibroblast cell line The purpose of this assay is to test the neutralizing ability of IL-17 protein in a human primary cell system. Stimulation of normal human dermal fibroblasts (HDFs) with IL-17 alone produces a very weak signal, but when combined with several other cytokines, such as TNFα, it can show a synergistic effect on the production of inflammatory cytokines, namely IL-6.

[0165] HDFs were stimulated with IL-17A (50 pM) in combination with TNF-α (25 pM). The resulting IL-6 response was then measured using a homogeneous time-resolved FRET kit from Cisbio. The kit utilizes two monoclonal antibodies: one labeled with Eu-cryptate (donor) and the other labeled with d2 or XL665 (acceptor). The signal intensity is proportional to the concentration of IL-6 present in the sample (the ratio is calculated as 665 / 620 × 10).

[0166] This assay measures the ability of compounds to inhibit IL-17-induced IL-6 release from human dermal fibroblasts.

[0167] HDF cells (Sigma product no. 106-05n) were cultured in complete medium (DMEM + 10% FCS + 2 mM L-glutamine) and maintained in tissue culture flasks using standard techniques. On the morning of the assay, cells were harvested from the tissue culture flasks using TrypLE (Invitrogen catalog no. 12605036). The TrypLE was neutralized with 45 mL of complete medium, and the cells were centrifuged at 300 x g for 3 minutes. Cells were resuspended in 5 mL of complete medium at a concentration of 3.125 x 10 per mL. 4 After adjusting the cell concentration, 40 μL was added per well to a 384-well assay plate (Corning product no. 3701). Cells were allowed to adhere to the plate for a minimum of 3 hours at 37°C / 5% CO2.

[0168] Compounds were serially diluted in DMSO and then the aqueous dilutions were dispensed into a 384-well dilution plate (Greiner product no. 781281), and 5 μL from the titration plate was transferred to 45 μL of complete medium and mixed to give a solution containing 10% DMSO.

[0169] A mixture of TNFα and IL-17 cytokines was prepared in complete medium to a final concentration of 25 pM TNFα / 50 pM IL-17A, and 30 μL of the solution was added to a 384-well reagent plate (Greiner product no. 781281).

[0170] Ten microliters of the diluted solution was transferred to a reagent plate containing 30 μL of diluted cytokines, resulting in a 2.5% DMSO solution. The compounds were incubated with the cytokine mixture at 37°C for 5 h. After incubation, 10 μL was transferred to an assay plate to yield a 0.5% DMSO solution, which was then incubated at 37°C / 5% CO2 for 18–20 h.

[0171] Europium cryptate and Alexa 665 from the Cisbio IL-6 FRET kit (Cisbio Product No. 62IL6PEB) were diluted in reconstitution buffer and mixed 1:1 according to the kit package insert. The FRET reagent (10 μL) was added to a low-volume white 384-well plate (Greiner Product No. 784075), and then the supernatant (10 μL) was transferred from the assay plate to the Greiner reagent plate. The mixture was incubated at room temperature with gentle shaking (<400 rpm) for 3 h before being read on a Synergy Neo 2 plate reader (excitation: 330 nm, emission: 615 / 645 nm).

[0172] When tested in the HDF cell line assay described above, the compounds of the accompanying examples exhibited the following pIC 50 It was found to exhibit value. [Table A]

[0173] The following examples illustrate the preparation of compounds according to the invention. [Example]

[0174] Abbreviation DCM: dichloromethane THF: tetrahydrofuran MeOH: Methanol IPA: Isopropanol DMSO: Dimethyl sulfoxide DIPEA: N,N-Diisopropylethylamine DMF: N,N-dimethylformamide EtOAc: ethyl acetate TFA: Trifluoroacetic acid DPPA: Diphenylphosphoryl azide DMAP: 4-(dimethylamino)pyridine EDC.HCl: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate {Ir[dF(CF3)ppy]2(dtbpy)}PF6: [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis-{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C}iridium(III) hexafluorophosphate h: time rt: room temperature M: mass; moles RT: retention time HPLC: High-performance liquid chromatography LCMS: Liquid Chromatography Mass Spectrometry SFC: Supercritical Fluid Chromatography ABPR: Automatic Back Pressure Regulator

[0175] Analytical and Separation Methods Method 1: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0176] Method 2: X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0177] Method 3: Phenomenex Kinetex XB-C18 2.1 x 100 mm, 1.7 μm column Column temperature: 40℃ Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid solution in acetonitrile Injection volume: 1 μL Flow rate: 0.6mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 5.30 0 100 5.80 0 100 5.82 95.00 5.00 7.00 95.00 5.00

[0178] Method 4: Waters UPLC® BEH™ C18, part number 186002352, 2.1 x 100 mm, 1.7 μm column Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate solution, buffered to pH 10 Mobile phase B: acetonitrile Flow rate: 0.6mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 5.30 0 100 5.80 0 100 5.82 95.00 5.00 7.00 95.00 5.00

[0179] Method 5: Phenomenex Gemini NX-C18 2 x 20 mm, 3 μm column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

[0180] Method 6: Waters Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 μm Column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1.5mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00

[0181] Method 7 Stationary phase: Phenomenex Gemini NX-C18 2 x 20 mm, 3 μm column Mobile phase A: 10 mM ammonium formate aqueous solution + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0182] Method 8: Waters SFC Prep 150 FractionLynx System in Tandem with a Waters QDa Mass Spectrometer Stationary phase: Chiralpak IC, 250 x 20.0 mm, 5 μm column Column temperature: 40℃ Mobile phase A: CO2 Mobile phase B: MeOH (+0.1%NH4OH) Flow rate: 100mL / min ABPR pressure: 60 bar Run Time: 7.5 minutes Gradient Program: Time A% B% 0.0 97.0 3.0 0.5 97.0 3.0 6.0 60.0 40.0 6.5 97.0 3.0

[0183] Method 9: Waters QDa Mass Spectrometer and Tandem Waters UPC 2 ACQUITY System Stationary phase: Chiralpak IC, 150 x 4.6mm, 3μm column Column temperature: 35℃ Mobile phase A: CO2 Mobile phase B: MeOH (+0.1%NH4OH) Flow rate: 3mL / min ABPR pressure: 120 bar Run Time: 6.5 minutes Gradient Program: Time A% B% 0.0 97.0 3.0 5.0 60.0 40.0 5.1 97.0 3.0

[0184] Method 10: Waters SFC Prep 150 FractionLynx System in Tandem with a Waters QDa Mass Spectrometer Stationary phase: Lux Cellulose-1, 250 x 21.2 mm, 5 μm column Column temperature: 40℃ Mobile phase A: CO2 Mobile phase B: MeOH (+0.1%NH4OH) Flow rate: 100mL / min ABPR pressure: 120 bar Run Time: 15 minutes Gradient Program: Time A% B% 0.0 90.0 10.0 15.0 90.0 10.0

[0185] Method 11: Waters QDa Mass Spectrometer and Tandem Waters UPC 2 ACQUITY System Stationary phase: Lux Cellulose-1, 150 x 4.6 mm, 3 μm column Column temperature: 35℃ Mobile phase A: CO2 Mobile phase B: MeOH (+0.1%NH4OH) Flow rate: 3mL / min ABPR pressure: 120 bar Run Time: 6.5 minutes Gradient Program: Time A% B% 0.0 97.0 3.0 5.0 60.0 40.0 5.1 97.0 3.0

[0186] Intermediate 1 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-carbamate 1,2,4-Triazin-3-amine (0.50 g, 5.20 mmol), benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (2.31 g, 5.72 mmol), and sodium bicarbonate (1.31 g, 15.6 mmol) were heated with stirring at 80 °C in IPA (20 mL) for 18 h. The reaction mixture was filtered through Celite® and then concentrated to near dryness in vacuo. The material was dissolved in ethyl acetate (50 mL) and water (25 mL) and separated. The aqueous layer was extracted with additional ethyl acetate (25 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica column chromatography using 0-10% MeOH in DCM as the eluent, followed by reverse-phase C18 chromatography using 5-100% aqueous acetonitrile containing 0.1% formic acid as the eluent. The combined clean column fractions were saturated with NaHCO3 (10 mL) and extracted with DCM (3 x 50 mL) to produce the first sample of material. Meanwhile, the impure fractions were further purified by silica column chromatography using 0-100% ethyl acetate in heptane as the eluent to produce the second sample of material. The first and second samples of material were combined, and the solvent was removed to produce the title compound (570 mg, 27%) as a brown solid. LCMS (Method 1): [M+H] + m / z 402.2, RT 1.84 min.

[0187] Intermediate 2 (1,3-Dioxoisoindolin-2-yl)1-(tert-butoxycarbonylamino)-3,3-difluorocyclobutanecarboxylate To a solution of 1-(tert-butoxycarbonylamino)-3,3-difluorocyclobutanecarboxylic acid (0.50 g, 1.99 mmol) in THF (10 mL) was added 2-hydroxy-1H-isoindole-1,3(2H)-dione (357 mg, 2.19 mmol), DMAP (24 mg, 0.199 mmol), and N,N'-dicyclohexyl-carbodiimide (493 mg, 2.39 mmol). The solution was stirred at rt for 18 h. The solid was filtered off, and the filtrate was concentrated. The crude product was purified by silica column chromatography using 0-100% EtOAc in heptane as the eluent to give the title compound (609 mg, 77%) as a white solid. LCMS (Method 1): [2M+Na] + m / z815, RT1.94 minutes.

[0188] Intermediate 3 tert-Butyl N-(1-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-imidazo[1,2-b][1,2,4]triazin-3-yl}-3,3-difluorocyclobutyl)carbamate A solution of Intermediate 1 (200 mg, 0.498 mmol), Intermediate 2 (296 mg, 0.747 mmol), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (11 mg, 9.96 μmol), and TFA (57 μL, 0.747 mmol) in anhydrous DMF (10 mL) was purged with nitrogen gas for 5 minutes. The reaction mixture was irradiated at 450 nm for 3 hours, then diluted with EtOAc (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography using 0-50% EtOAc in heptane as the eluent to yield the title compound (207 mg, 68%) as a pale yellow solid. LCMS (Method 1): [M+H] + m / z607.2, RT2.05 minutes.

[0189] Intermediate 4 Benzyl N-{(S)-[3-(1-amino-3,3-difluorocyclobutyl)imidazo[1,2-b][1,2,4]triazin-6-yl](4,4-difluorocyclohexyl)methyl}carbamate To a stirred solution of intermediate 3 (207 mg, 0.341 mmol) in DCM (3 mL) was added TFA (0.42 mL, 5.46 mmol). The solution was stirred at rt for 3 h and then diluted with DCM and saturated aqueous NaHCO3 (20 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2 x 20 mL). The organic fractions were combined, then dried over sodium sulfate and concentrated in vacuo to yield the title compound (170 mg, 98%) as a yellow solid. LCMS (Method 1): [M+H] + m / z507.2, RT1.74 minutes.

[0190] Intermediate 5 2-{[(1-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-3,3-difluorocyclobutyl)amino]methyl}-3,3,3-trifluoropropanoic acid To Intermediate 4 (18 mg, 0.0355 mmol) in anhydrous MeOH (1 mL) in a sealed vial, 2-(trifluoromethyl)prop-2-enoic acid (15 mg, 0.107 mmol) was added dropwise. The reaction mixture was stirred at rt for 16 h, then at 40° C. for 16 h. 2-(trifluoromethyl)prop-2-enoic acid and NaHCO (3 equiv.) were added, and the reaction mixture was stirred at rt for 48 h. Again, additional 2-(trifluoromethyl)prop-2-enoic acid and NaHCO (3 equiv.) were added. The reaction mixture was stirred at 50° C. for 16 h, then diluted with DCM (10 mL) and water (10 mL). The aqueous layer was acidified to pH 6 with 1 M HCl, and the organic layer was separated. The aqueous phase was extracted with DCM (2×10 mL). The organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica column chromatography using 0-10% MeOH in DCM as eluent to give the title compound (12 mg, 52%) as a pale yellow solid. LCMS (Method 1): [M+H]+ m / z 647.2, RT 2.36 min.

[0191] Intermediate 6 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(3-{3,3-difluoro-1-[2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]cyclobutyl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]carbamate To a solution of intermediate 5 (115 mg, 0.178 mmol) and sodium 2-methylpropan-2-olate (51 mg, 0.534 mmol) in anhydrous 1,4-dioxane (3 mL) in a sealed vial under nitrogen was added DPPA (0.15 mL, 0.711 mmol). The reaction mixture was stirred at 80 °C for 5 h and then diluted with DCM (15 mL) and saturated aqueous NaHCO (15 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2 × 20 mL). The organic fractions were combined, dried over sodium sulfate, and then concentrated in vacuo. The residue was purified by silica column chromatography using 0-100% EtOAc in heptane as the eluent to yield the title compound (57 mg, 50%) as a yellow solid. LCMS (Method 1): [M+H] + m / z644.2, RT2.35 minutes.

[0192] Intermediate 7 1-(1-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-3,3-difluorocyclobutyl)-4-(trifluoromethyl)imidazolidin-2-one Hydrogen bromide (30% in acetic acid) (5.1 M, 0.45 mL, 2.30 mmol) was added to a solution of intermediate 6 (57 mg, 0.0886 mmol) in acetic acid (1.2 mL). The reaction mixture was stirred at rt for 3 h and then concentrated in vacuo. The crude material was dissolved in water (30 mL) and washed with EtOAc (3 x 10 mL). The aqueous layer was made basic with solid NaHCO3 and extracted with EtOAc (3 x 30 mL). The organic phase was dried over sodium sulfate, then filtered and concentrated in vacuo to yield the title compound (44 mg, 85%) as a yellow gum. LCMS (Method 1): [M+H] + m / z510, RT1.82 minutes.

[0193] Intermediate 8 (S)-(4,4-Difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazin-6-yl)methanamine Intermediate 1 (3.00 g, 7.47 mmol) was dissolved in hydrogen bromide (25 mL, 0.154 mol) in acetic acid (35%). The reaction mixture was stirred at rt for 30 min, then hydrogen bromide (25 mL, 0.154 mol) in acetic acid (35%) and acetic acid (30 mL) were further added. The reaction mixture was stirred at rt for 1.5 h, then diethyl ether (100 mL) was added. The mixture was stirred for 30 min. The resulting precipitate was collected by vacuum filtration, washed with diethyl ether, dissolved in water, and washed with DCM. The aqueous portion was made basic with saturated aqueous NaHCO3 and extracted with DCM (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound (1.33 g, 60%) as a dark brown gum. LCMS (Method 1): [M+H] + m / z268.2, RT1.27 minutes.

[0194] Intermediate 9 N-[(S)-(4,4-Difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide A solution of intermediate 8 (90%, 1.33 g, 4.48 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (631 mg, 4.93 mmol), and DIPEA (1.6 mL, 8.96 mmol) in anhydrous DMF (27 mL) was treated with HATU (2.04 g, 5.37 mmol) and stirred at rt for 1 h. The mixture was diluted with ethyl acetate (50 mL) and washed with water (2 × 50 mL) and brine (10 mL), then dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography using 50–80% EtOAc in heptane as the eluent to yield the title compound (1.39 g, 78%) as a pale orange solid. LCMS (Method 1): [M+H] + m / z378.2, RT2.10 minutes.

[0195] Intermediate 10 (1,3-Dioxoisoindolin-2-yl)1-(tert-butoxycarbonylamino)cyclopropanecarboxylate EDC.HCl (1.00 g, 5.22 mmol) was added in portions to a solution of 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (1.00 g, 4.97 mmol) and 2-hydroxy-1H-isoindole-1,3(2H)-dione (0.89 g, 5.47 mmol) in DCM (20 mL) at 0 °C. After 5 min, the cooling was removed and the reaction mixture was allowed to warm to rt overnight before being washed with water (50 mL). The aqueous phase was back-extracted with DCM (2 × 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to dryness. Purification by silica column chromatography using 10–100% EtOAc in heptane as the eluent afforded the title compound (0.54 g, 29%) as a white powder. LCMS (Method 1): [M+NH4] + m / z364, RT2.24 minutes.

[0196] Intermediate 11 tert-Butyl N-[1-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)cyclopropyl]carbamate A solution of intermediate 9 (100 mg, 0.265 mmol), intermediate 10 (87 mg, 0.252 mmol), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (5.7 mg, 5.05 μmol), and TFA (23 μL, 0.303 mmol) in anhydrous DMF (4.3 mL) was degassed with nitrogen. The reaction mixture was stirred at rt and irradiated at 450 nm for 6 h, then diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 and water (3 × 20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by silica column chromatography using 10–100% EtOAc in heptane as the eluent to yield the title compound (72 mg, 48%) as a yellow solid. LCMS (Method 2): [M+H] +m / z533, RT4.08 minutes.

[0197] Intermediate 12 N-{(S)-[3-(1-aminocyclopropyl)imidazo[1,2-b][1,2,4]triazin-6-yl](4,4-difluoro-cyclohexyl)methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide TFA (0.50 mL, 6.53 mmol) was added to a stirred solution of Intermediate 11 (72 mg, 0.135 mmol) in DCM (2 mL). The solution was stirred at rt for 2 h and then concentrated in vacuo. The residue was purified by Isolute SCX-22 column using methanol as eluent and then 3.5 M NH3 in methanol as eluent to yield the title compound (64 mg, 101%) as a yellow gum. LCMS (Method 1): [M+H] + m / z433, RT1.80 minutes.

[0198] Intermediate 13 2-({[1-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)cyclopropyl]amino}methyl)-3,3,3-trifluoro-propanoic acid 2-(Trifluoromethyl)prop-2-enoic acid (28 mg, 0.203 mmol) was added to a mixture of sodium bicarbonate (34 mg, 0.406 mmol) and Intermediate 12 (58 mg, 0.135 mmol) in anhydrous 1,4-dioxane (1.35 mL) at rt. The reaction mixture was stirred at rt for 16 h. The obtained material was used without further purification. LCMS (Method 1): [M+H] + m / z 573, RT 2.19 min.

[0199] Intermediate 14 (1,3-Dioxoisoindolin-2-yl)4-(tert-butoxycarbonylamino)tetrahydropyran-4-carboxylate To a stirred suspension of 4-(tert-butoxycarbonylamino)tetrahydropyran-4-carboxylic acid (0.80 g, 3.26 mmol) and 2-hydroxy-1H-isoindole-1,3(2H)-dione (586 mg, 3.59 mmol) in anhydrous DCM (13 mL) was added EDC.HCl (690 mg, 3.60 mmol) under nitrogen at 0 °C. The mixture was stirred at 0 °C for 30 min and then at 20 °C for 1.5 h before being concentrated in vacuo. The residue was purified by flash column chromatography using 0-70% ethyl acetate in heptane as the eluent to yield the title compound (1.18 g, 90%) as a white powder. LCMS (Method 1): [M+NH4] + m / z408.2, RT2.20 minutes.

[0200] Intermediate 15 tert-Butyl N-[4-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)tetrahydropyran-4-yl]carbamate Intermediate 9 (160 mg, 0.40 mmol), Intermediate 14 (243 mg, 0.604 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (9.1 mg, 8.1 μmol) were dissolved in anhydrous DMF (8 mL), and TFA (46.2 μL, 0.38 mmol) was added. The solution was degassed with nitrogen, sealed under nitrogen, and irradiated with LED light at 450 nm for 12 h. The reaction mixture was diluted with water (30 mL), quenched with saturated aqueous sodium bicarbonate (20 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica column chromatography using 0-100% ethyl acetate in heptane as the eluent to give the title compound (51% purity) (119 mg) as an orange powder (containing 38% of the impurity of Intermediate 9). LCMS (Method 2): [M+H] + m / z577.2, RT3.92 minutes.

[0201] Intermediate 16 N-{(S)-[3-(4-aminotetrahydropyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl](4,4-difluoro-cyclohexyl)methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide TFA (0.40 mL, 5.22 mmol) was added to a stirred solution of intermediate 15 (64%, 118 mg, 0.131 mmol) in DCM (1.5 mL). The solution was stirred at rt for 2 h and then concentrated in vacuo. The residue was purified by Isolute SCX-2 column using methanol as eluent followed by 3.5 M NH in methanol as eluent, followed by silica column chromatography using 70-100% ethyl acetate in heptane as eluent followed by 10% methanol in ethyl acetate as eluent to yield the title compound (NMR purity 92%) (45 mg, 66%) as an orange solid. LCMS (Method 1): [M+H] + m / z477, RT1.78 minutes.

[0202] Intermediate 17 2-({[4-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)tetrahydropyran-4-yl]amino}methyl)-3,3,3-trifluoropropanoic acid Intermediate 16 (45 mg, 0.0944 mmol), sodium bicarbonate (20 mg, 0.236 mmol), and 2-(trifluoromethyl)prop-2-enoic acid (19 mg, 0.132 mmol) were stirred overnight at rt in 1,4-dioxane (1.5 mL). The reaction mixture was re-treated with 2-(trifluoromethyl)prop-2-enoic acid (3.0 mg, 0.0214 mmol) and sodium bicarbonate (3.0 mg, 0.0357 mmol) and stirred for an additional 2.5 h. The crude mixture (92% pure) was used without further purification. LCMS (Method 1): [M+H] + m / z617.2, RT2.15 minutes.

[0203] Intermediate 18 O 1 -tert-Butyl O 4 -Methyl 4-[2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]piperidine-1,4-dicarboxylate Sodium bicarbonate (924 mg, 11.0 mmol) was added to a solution of 2-(trifluoromethyl)acrylic acid (943 mg, 6.60 mmol) and 1-tert-butyl 4-methyl-4-aminopiperidine-1,4-dicarboxylate (1.50 g, 5.50 mmol) in 1,4-dioxane (55 mL). The reaction mixture was stirred at RT for 19 h, after which 1,4-dioxane (55 mL) was added, followed by DPPA (2.93 mL, 13.2 mmol) and sodium tert-butoxide (793 mg, 8.25 mmol). Stirring was continued at 80 °C for an additional 4.5 h, after which additional DPPA (2.93 mL, 13.2 mmol) and sodium tert-butoxide (793 mg, 8.25 mmol) were added. The reaction mixture was stirred at 80° C. for an additional 5.5 h, then concentrated in vacuo, diluted with DCM (100 mL), and washed with water (2×100 mL). The combined aqueous phases were extracted with DCM (2×50 mL). The organic layers were combined and washed with brine (50 mL), then passed through a phase separator and concentrated in vacuo. The crude residue was purified by flash column chromatography using a gradient elution with 0-100% EtOAc in hexanes to give the title compound (1.62 g, 74%) as a pale yellow foam. δ H (400 MHz, CDCl3) 5.14 (s, 1H), 4.17-4.08 (m, 1H), 3.88-3.77 (m, 3H), 3.75 (s, 3H), 3.60 (dd, J 9.3, 3.7 Hz, 1H), 3.20-3.08 (m, 2H), 2.60-2.48 (m, 1H), 2.14-2.01 (m, 3H), 1.46 (s, 9H).LCMS (Method 5): [M-100+H] + m / z296.2, RT1.20 minutes.

[0204] Intermediate 19 O 1-tert-Butyl O 4 -(1,3-Dioxoindolin-2-yl)4-[2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]piperidine-1,4-dicarboxylate To a solution of Intermediate 18 (1.61 g, 4.08 mmol) in THF (16.3 mL) and water (4.1 mL) was added lithium hydroxide monohydrate (348 mg, 8.16 mmol). The reaction mixture was stirred at rt for 22 h and then concentrated in vacuo to remove the organic solvent. The remaining aqueous solution was diluted with water (50 mL) and washed with EtOAc (50 mL). The organic layer was discarded, and the aqueous layer was adjusted to pH 3.5-4 by adding 2 M aqueous HCl (3.5 mL). The acidified aqueous layer was extracted with EtOAc (3 × 50 mL). The organic layers were combined, passed through a phase separator, and concentrated in vacuo. The resulting crude white foam (1.60 g) was dissolved in DCM (19.3 mL) and N-hydroxyphthalimide (714 mg, 4.25 mmol) was added, followed by EDC.HCl (823 mg, 4.25 mmol). The reaction mixture was stirred at rt for 4 h before additional N-hydroxyphthalimide (130 mg, 0.772 mmol) and EDC.HCl (150 mg, 0.773 mmol) were added. The reaction mixture was stirred at rt for an additional 1.5 h before being concentrated in vacuo. The crude residue was purified by flash column chromatography using a gradient elution with 0-70% EtOAc in hexanes to afford the title compound (1.85 g, 86%) as a white foam. H (400 MHz, CDCl3) 7.90-7.85 (m, 2H), 7.82-7.77 (m, 2H), 5.31 (s, 1H), 4.26-4.16 (m, 1H), 3.92 (t, J 9.5 Hz, 1H), 3.84-3.72 (m, 2H), 3.69 (dd, J 9.4, 3.5 Hz, 1H), 3.48-3.34 (m, 2H), 2.79-2.65 (m, 1H), 2.43-2.27 (m, 2H), 2.25-2.15 (m, 1H), 1.47 (s, 9H).LCMS(Method 5):[M-100+H] + m / z427.2, RT1.38 minutes.

[0205] Intermediate 20 (1,3-Dioxoisoindolin-2-yl)3-(tert-butoxycarbonylamino)oxetane-3-carboxylate To a solution of 3-(tert-butoxycarbonylamino)oxetane-3-carboxylic acid (400 mg, 1.84 mmol) and 2-hydroxy-1H-isoindole-1,3(2H)-dione (332 mg, 2.04 mmol) in DCM (8 mL) at 0° C. was added EDC.HCl (400 mg, 2.09 mmol). The reaction mixture was stirred at 0° C. for 5 min and then at rt for 1 h. The mixture was re-treated with EDC.HCl (45 mg, 0.235 mmol), stirred overnight at rt, and then washed with water (15 mL). The aqueous layer was extracted with DCM (20 mL). The organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with diethyl ether to yield the title compound (93% pure) (580 mg, 81%) as a white powder. LCMS (Method 1): [M+NH4] + m / z380.2, RT2.15 minutes.

[0206] Intermediate 21 tert-Butyl N-[3-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)oxetan-3-yl]carbamate Intermediate 9 (280 mg, 0.742 mmol), Intermediate 20 (93% pure) (578 mg, 1.48 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (17 mg, 14.8 μmol) were dissolved in DMSO (14 mL), and trifluoroacetic acid (85 mL, 1.11 mmol) was added. The reaction mixture was degassed with nitrogen, sealed, and irradiated with LED light at 450 nm for 20 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with half-saturated aqueous sodium bicarbonate (2 × 10 mL). The aqueous layer was extracted with ethyl acetate (10 mL). The organic fractions were combined and washed with saturated brine (2 × 10 mL), then dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography using 35-55% ethyl acetate in heptane as the eluent to give the title compound (64% purity) (564 mg) as an orange foam. LCMS (Method 1): [M+H] + m / z549.2, RT2.26 minutes.

[0207] Intermediate 22 N-{(S)-[3-(3-aminooxetan-3-yl)imidazo[1,2-b][1,2,4]triazin-6-yl](4,4-difluoro-cyclohexyl)methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 21 (64% pure) (464 mg, 0.541 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.80 mL, 10.4 mmol). The reaction mixture was stirred at rt for 3 h and then washed with half-saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with DCM (10 mL), and then the organic fractions were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by reverse-phase C18 chromatography using 25-40% aqueous acetonitrile containing 0.1% ammonia as the eluent to yield the title compound (96% pure) (229 mg, 91%) as a yellow solid. LCMS (Method 1): [M+H] + m / z449.2, RT1.77 minutes.

[0208] Intermediate 23 2-({[3-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)oxetan-3-yl]amino}methyl)-3,3,3-trifluoro-propanoic acid Intermediate 22 (96% pure) (120 mg, 0.257 mmol), sodium bicarbonate (43 mg, 0.514 mmol), and 2-(trifluoromethyl)prop-2-enoic acid (47 mg, 0.334 mmol) were stirred in 1,4-dioxane (2.5 mL) at rt for 2 h. The mixture was re-treated with 2-(trifluoromethyl)prop-2-enoic acid (47 mg, 0.334 mmol) and sodium bicarbonate (43 mg, 0.514 mmol) and then stirred overnight. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 × 10 mL). The organic fractions were combined and washed with saturated brine (10 mL), then dried over sodium sulfate and concentrated in vacuo. The resulting yellow title compound was used without further purification. LCMS (Method 1): [M+H] + m / z589.2, RT2.14 minutes.

[0209] Intermediate 24 tert-Butyl N-[3-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)tetrahydrofuran-3-yl]carbamate A solution of intermediate 9 (200 mg, 0.53 mmol), (1,3-dioxoisoindolin-2-yl)3-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylate (299 mg, 0.80 mmol), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (12 mg, 0.01 mmol), and TFA (60 μL, 0.80 mmol) in DMF (5.3 mL) was purged with nitrogen gas for 5 min. The reaction mixture was irradiated at 450 nm for 20 h, then diluted with EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (2 × 25 mL) and water (25 mL). The organic layer was passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography using a gradient elution with 0–100% EtOAc in isohexane to give the title compound (121 mg, 40%) as a brown oil. LCMS (Method 7): [M+H]+ m / z 563.2, RT 2.11 min.

[0210] Intermediate 25 N-{(S)-[3-(3-aminotetrahydrofuran-3-yl)imidazo[1,2-b][1,2,4]triazin-6-yl](4,4-difluoro-cyclohexyl)methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 24 (144 mg, 0.26 mmol) in DCM (1.0 mL) at rt was added TFA (0.26 mL). The reaction mixture was stirred for 2 h and then concentrated in vacuo. The crude residue was dissolved in DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography using a gradient elution with 0-100% EtOAc in isohexane followed by a gradient elution with 0-20% MeOH in EtOAc to give the title compound (61 mg, 52%) as a brown amorphous solid. LCMS (Method 7): [M+H] + m / z463.2, RT1.50 minutes.

[0211] (Examples 1 and 2) [ka] N-[(S)-(4,4-Difluorocyclohexyl)(3-{3,3-difluoro-1-[(4S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]cyclobutyl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl)(3-{3,3-difluoro-1-[(4R)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]cyclobutyl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a mixture of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (19 mg, 0.148 mmol) and DIPEA (44 μL, 0.252 mmol) in anhydrous DMF (1 mL) was added HATU (56 mg, 0.148 mmol) at rt. The reaction mixture was stirred at rt for 5 min, then a solution of Intermediate 7 (44 mg, 0.0872 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at rt for 16 h, then diluted with EtOAc (50 mL) and washed with water (10 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by low pH preparative HPLC to yield the title compound mixture as an off-white solid. δ H(400 MHz, CD3OD) 8.70 (s, 1H), 8.19 (s, 1H), 5.28 (d, J 8.6 Hz, 1H), 4.44-4.33 (m, 1H), 3.97 (td, J 9.9, 1.5 Hz, 1H), 3.81 (dd, J 9.9, 3.6 Hz, 1H), 3.62-3.35 (m, 4H), 2.51 (s, 3H), 2.28 (d, J 8.9 Hz, 1H), 2.19-2.04 (m, 2H), 2.03-1.98 (m, 1H), 1.92-1.71 (m, 2H), 1.67 (d, J 14.7 Hz, 1H), 1.56-1.34 (m, 2H). Two NH signals were not observed. LCMS (Method 3): [M+H] + m / z 620, RT 3.44 min.

[0212] The above material was subjected to SFC chromatography (Chiracel OD-H, 10 × 250 mm, 5 μm, MeOH / CO 15:85, 15 mL / min) to separate the mixture and yield the individual title compounds (peak 1, 6.0 mg, 38%; and peak 2, 5.4 mg, 33%) (the absolute stereochemistry of the carbon atom adjacent to the CF group is unknown and arbitrarily determined).

[0213] Peak 1 (Example 1): δ H (500 MHz, CD3OD) 8.70 (s, 1H), 8.20 (s, 1H), 5.29 (d, J 8.6 Hz, 1H), 4.45-4.32 (m, 1H), 3.97 (t, J 9.9 Hz, 1H), 3.81 (dd, J 10.0, 4.0 Hz, 1H), 3.63-3.38 (m, 3H), 2.52 (s, 3H), 2.28 (d, J 9.7 Hz, 1H), 2.15-1.95 (m, 2H), 1.95-1.60 (m, 3H), 1.60-1.24 (m, 3H).LCMS(Method 4):[M+H] +m / z 620, RT 3.46 min. Chiral purity: 100% (SFC, Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 15% methanol: 85% CO , 4 mL / min), RT 2.50 min.

[0214] Peak 2 (Example 2): δ H (500 MHz, CD3OD) 8.70 (s, 1H), 8.20 (s, 1H), 5.28 (d, J 8.6 Hz, 1H), 4.45-4.32 (m, 1H), 3.97 (t, J 9.9 Hz, 1H), 3.82 (dd, J 10.0, 4.0 Hz, 1H), 3.62-3.39 (m, 3H), 2.52 (s, 3H), 2.28 (d, J 9.2 Hz, 1H), 2.20-1.94 (m, 3H), 1.93-1.62 (m, 3H), 1.59-1.33 (m, 2H).LCMS(Method 4):[M+H] + m / z 620, RT 3.47 min. Chiral purity: 100% (SFC, Chiralcel OD-H, 4.6 x 250 mm, 5 μm, 15% methanol:85% CO2, 4 mL / min), RT 4.89 min.

[0215] (Example 3) [ka] N-[(S)-(4,4-Difluorocyclohexyl)(3-{1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-cyclopropyl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide DPPA (87 μL, 0.406 mmol) was added to a solution of intermediate 13 (77 mg, 0.135 mmol) and sodium 2-methylpropan-2-olate (39 mg, 0.41 mmol) in anhydrous 1,4-dioxane (1.35 mL). The reaction mixture was stirred at 80° C. for 3 h, and then additional DPPA (87 μL, 0.406 mmol) was added. The reaction mixture was stirred at 80° C. for an additional 3.5 h, then diluted with DCM (30 mL) and washed with half-saturated aqueous NaHCO3 (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2 × 20 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness. The residue was purified by flash silica chromatography eluting with 20-100% EtOAc in heptane followed by 0-20% MeOH in EtOAc, followed by optically inactive preparative HPLC to give the title compound and its (4R) isomer mixture (19 mg, 25%) as a pale yellow solid. H (400 MHz, CD3OD) 8.35 (s, 1H), 8.08 (s, 1H), 5.25 (d, J 8.5 Hz, 1H), 4.49-4.39 (m, 1H), 4.04 (t, J 10.1 Hz, 1H), 3.70 (dd, J 9.9, 3.9 Hz, 1H), 2.51 (s, 3H), 2.31-2.19 (m, 1H), 2.14-2.05 (m, 1H), 2.03-1.94 (m, 2H), 1.92-1.71 (m, 4H), 1.69-1.58 (m, 3H), 1.55-1.34 (m, 2H). Two NH signals were not observed. LCMS (Method 3): [M+H] + m / z570, RT3.15 minutes.

[0216] The above material was subjected to SFC chromatography (Chiralpak IC, 10 × 250 mm, 5 μm, MeOH / CO 2 5:75, 15 mL / min) to separate the mixture and produce the title compound (peak 1, 6.1 mg, 38%) (the absolute stereochemistry of the carbon atom adjacent to the CF group is unknown and arbitrarily determined) and its isomer (peak 2).

[0217] Peak 1 (Example 3): δ H (400 MHz, CD3OD) 8.35 (s, 1H), 8.08 (s, 1H), 5.25 (d, J 8.5 Hz, 1H), 4.44 (ddd, J 10.3, 7.0, 4.1 Hz, 1H), 4.04 (t, J 10.1 Hz, 1H), 3.70 (dd, J 10.1, 4.1 Hz, 1H), 2.51 (s, 3H), 2.32-1.93 (m, 4H), 1.93-1.55 (m, 7H), 1.55-1.28 (m, 2H).LCMS (Method 4): [M+H] + m / z 570, RT 3.21 min. Chiral purity: 100% (SFC, Chiralpak IC, 4.6 × 250 mm, 5 μm, 25% methanol: 75% CO, 4 mL / min), RT 2.75 min.

[0218] Peak 2: (SFC, Chiralpak IC, 4.6 × 250 mm, 5 μm 25% methanol: 75% CO , 4 mL / min) RT 6.77 min.

[0219] (Examples 4 and 5) [ka] N-[(S)-(4,4-Difluorocyclohexyl)(3-{4-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-tetrahydropyran-4-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl)(3-{4-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-tetrahydropyran-4-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide DPPA (37 μL, 0.173 mmol) was added to a solution of intermediate 17 (92% pure) (58 mg, 0.0865 mmol) and sodium 2-methylpropan-2-olate (17 mg, 0.173 mmol) in 1,4-dioxane (2.5 mL) under nitrogen. The reaction mixture was stirred at 80° C. for 3 h and then re-treated with DPPA (37 μL, 0.173 mmol) and sodium 2-methylpropan-2-olate (17 mg, 0.173 mmol). The reaction mixture was stirred at 80° C. for an additional 2 h before additional sodium 2-methylpropan-2-olate (3.3 mg, 0.0346 mmol) and DPPA (7.4 μL, 0.0346 mmol) were added. The mixture was stirred at 80° C. for 1 h, then cooled to rt, diluted with ethyl acetate (10 mL), and washed with water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL). The organic fractions were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica column chromatography using 35-50% aqueous acetonitrile (+0.1% formic acid) as the eluent to afford a mixture of two isomeric title compounds (13 mg, 25%) as a white powder. H (400 MHz, CD3OD) 8.73 (s, 1H), 8.15 (s, 1H), 5.27 (d, J 8.5 Hz, 1H), 4.40-4.29 (m, 1H), 4.07 (t, J 9.9 Hz, 1H), 3.97-3.90 (m, 1H), 3.86-3.77 (m, 4H), 2.83-2.74 (m, 1H), 2.52 (s, 3H), 2.46-2.34 (m, 3H), 2.34-2.19 (m, 1H), 2.17-1.93 (m, 4H), 1.92-1.61 (m, 4H), 1.57-1.34 (m, 2H).LCMS(Method 3):[M+H] + m / z614.3, RT3.12 minutes.

[0220] The above material was subjected to SFC chromatography (Chiracel OD-H, 10 × 250 mm, 5 μm, MeOH / CO 20:80, 15 mL / min) to separate the mixture and yield the individual title compounds (peak 1, 4.8 mg; and peak 2, 4.2 mg) (the absolute stereochemistry of the carbon atom adjacent to the CF group is unknown and arbitrarily determined).

[0221] Peak 1 (Example 4): δ H (400 MHz, CD3OD) 8.73 (s, 1H), 8.15 (s, 1H), 5.27 (d, J 8.6 Hz, 1H), 4.40-4.29 (m, 1H), 4.07 (t, J 9.9 Hz, 1H), 3.97-3.88 (m, 1H), 3.88-3.76 (m, 4H), 2.81-2.72 (m, 1H), 2.52 (s, 3H), 2.45-2.34 (m, 3H), 2.33-2.19 (m, 1H), 2.17-1.98 (m, 3H), 1.93-1.71 (m, 2H), 1.71-1.63 (m, 1H), 1.56-1.34 (m, 2H).LCMS (Method 3): [M+H] + m / z 614.3, RT 3.12 min. Chiral purity: 100% (SFC, Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 25% methanol: 75% CO, 4 mL / min), RT 1.89 min.

[0222] Peak 2 (Example 5): δ H(400 MHz, CD3OD) 8.73 (s, 1H), 8.15 (s, 1H), 5.27 (d, J 8.6 Hz, 1H), 4.39-4.27 (m, 1H), 4.07 (t, J 9.9 Hz, 1H), 3.98-3.88 (m, 1H), 3.87-3.76 (m, 4H), 2.82-2.74 (m, 1H), 2.52 (s, 3H), 2.46-2.35 (m, 3H), 2.30-2.21 (m, 1H), 2.15-1.97 (m, 3H), 1.91-1.71 (m, 2H), 1.71-1.62 (m, 1H), 1.57-1.36 (m, 2H).LCMS (Method 3): [M+H] + m / z 614.3, RT 3.12 min. Chiral purity: 100% (SFC, Chiralcel OD-H, 4.6 × 250 mm, 5 μm, 25% methanol: 75% CO, 4 mL / min), RT 2.77 min.

[0223] (Example 6) [ka] tert-Butyl 4-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-[2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]piperidine-1-carboxylate TFA (0.21 mL, 2.8 mmol) was added to a 40 mL screw-capped vial containing a solution of Intermediate 19 (1.09 g, 2.07 mmol), Intermediate 9 (520 mg, 1.38 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (23.2 mg, 0.0207 mmol) in DMF (10.3 mL). The vial was sealed, and nitrogen was bubbled through the solution for 10 min before the reaction mixture was irradiated at 450 nm using a Merck Penn PhD Photoreactor for 24 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 × 50 mL). The combined aqueous layers were extracted with EtOAc (2 × 25 mL). The organic layers were combined and washed with brine (50 mL), then passed through a phase separator and concentrated in vacuo. The crude residue was purified by flash column chromatography using a gradient elution with 0-100% EtOAc in hexanes to give an orange oil (206 mg). A sample of this material (20.6 mg) was further purified by basic reverse-phase preparative HPLC to yield, after lyophilization, the title compound (7.6 mg, 37%) as a very pale yellow solid. H (400 MHz, DMSO-d6) 9.52 (dd, J 9.0, 3.0 Hz, 1H), 8.78 (d, J 1.5 Hz, 1H), 8.30 (d, J 1.0 Hz, 1H), 7.70 (s, 1H), 5.20 (t, J 8.6 Hz, 1H), 4.47-4.36 (m, 1H), 3.92 (td, J 9.9, 2.6 Hz, 1H), 3.74-3.57 (m, 3H), 3.29-3.17 (obs. m, 2H), 2.70-2.61 (m, 1H), 2.47 (s, 3H), 2.36-2.27 (m, 1H), 2.28-2.12 (m, 3H), 2.12-1.89 (m, 3H), 1.89-1.69 (m, 2H), 1.69-1.59 (m, 1H), 1.48-1.23 (m, 11H).LCMS (Method 6): [M+H] + m / z 713.2, RT 2.17 min.

[0224] (Example 7) [ka] N-[(S)-(4,4-Difluorocyclohexyl)(3-{4-[2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-piperidin-4-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Example 6 (16.6 mg, 0.0233 mmol) was dissolved in HCl in 1,4-dioxane (4 mol / L, 0.23 mL, 0.92 mmol). The reaction mixture was stirred at rt for 5 h and then concentrated in vacuo. The residue was purified by basic reverse-phase preparative HPLC to yield the title compound (3.3 mg, 23%) as a very pale yellow solid after lyophilization. δ H (400 MHz, DMSO-d6) 9.51 (dd, J 9.1, 2.0 Hz, 1H), 8.74 (s, 1H), 8.29 (s, 1H), 7.61 (d, J 2.3 Hz, 1H), 5.20 (t, J 8.6 Hz, 1H), 4.48-4.36 (m, 1H), 3.98-3.90 (m, 1H), 3.67-3.61 (m, 1H), 2.91-2.70 (m, 4H), 2.62-2.53 (obs. m, 1H), 2.47 (s, 3H), 2.28-1.70 (m, 9H), 1.69-1.59 (m, 1H), 1.47-1.23 (m, 2H). No signal of amine NH proton was observed. LCMS (Method 6): [M+H] + m / z613.2, RT1.53 minutes.

[0225] (Examples 8 and 9) [ka] N-[(S)-(4,4-Difluorocyclohexyl)(3-{3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-oxetan-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl)(3-{3-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-oxetan-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide DPPA (99 mL, 0.46 mmol) and 1,4-dioxane (2.5 mL) were added to Intermediate 23 (89% pure, 152 mg, 0.23 mmol). Sodium tert-butoxide (27 mg, 0.28 mmol) was added, and the reaction mixture was stirred at 80 °C for 1 h. The mixture was retreated with DPPA (50 mL, 0.233 mmol) and sodium tert-butoxide (10 mg, 0.104 mmol) and then stirred at 80 °C for an additional 1 h. The mixture was further retreated with DPPA (50 mL, 0.233 mmol) and sodium tert-butoxide (10 mg, 0.104 mmol) and then stirred at 80 °C for an additional 1 h. The mixture was diluted with half-saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic fractions were combined and washed with saturated brine (10 mL), then dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using 50–70% ethyl acetate in heptane as the eluent. The resulting yellow gum was further purified by reverse-phase C18 chromatography using 35–50% aqueous acetonitrile containing 0.1% ammonia as the eluent. The resulting yellow solid (29 mg) was subjected to SFC chromatography (Chiralpak AD-H, 10 × 250 mm, 5 μm column, IPA:CO2 35:65, 15 mL / min) to yield the title compound as an off-white solid (the absolute stereochemistry of the carbon atom adjacent to the CF3 group is unknown and determined arbitrarily).

[0226] Example 8 (first eluting peak): δ H(500 MHz, DMSO-d6) 9.54 (d, J 8.9 Hz, 1H), 8.82 (s, 1H), 8.37 (s, 1H), 7.91 (d, J 2.4 Hz, 1H), 5.21 (t, J 8.6 Hz, 1H), 5.07-5.01 (m, 2H), 5.01-4.94 (m, 2H), 4.58-4.49 (m, 1H), 3.88 (t, J 9.8 Hz, 1H), 3.72 (dd, J 9.7, 4.0 Hz, 1H), 2.46 (s, 3H), 2.27-2.17 (m, 1H), 2.10-1.89 (m, 3H), 1.87-1.71 (m, 2H), 1.66-1.58 (m, 1H), 1.45-1.35 (m, 1H), 1.35-1.25 (m, 1H). LCMS (method 4): [M+H] + m / z 586.1, RT 3.04 min. Chiral purity: 100% (RT 1.96 min, SFC, IPA 35%, CO 65%, 4 mL / min, Chiralpak AD-H, 4.6 × 250 mm, 5 μm cartridge).

[0227] Example 9 (Second dissolution procedure): δ H (500 MHz, DMSO-d6) 9.53 (d, J 8.9 Hz, 1H), 8.82 (s, 1H), 8.36 (s, 1H), 7.91 (d, J 2.3 Hz, 1H), 5.21 (t, J 8.5 Hz, 1H), 5.07-4.97 (m, 3H), 4.97-4.93 (m, 1H), 4.58-4.50 (m, 1H), 3.89 (t, J 9.8 Hz, 1H), 3.72 (dd, J 9.7, 4.0 Hz, 1H), 2.46 (s, 3H), 2.28-2.18 (m, 1H), 2.10-1.89 (m, 3H), 1.87-1.70 (m, 2H), 1.66-1.58 (m, 1H), 1.45-1.35 (m, 1H), 1.35-1.25 (m, 1H). LCMS (method 4): [M+H] +m / z 586.1, RT 3.04 min. Chiral purity: 99% (RT 5.25 min, SFC, IPA 35%, CO 2 65%, 4 mL / min, Chiralpak AD-H, 4.6 × 250 mm, 5 μm column).

[0228] (Examples 10 to 13) [ka] N-[(S)-(4,4-Difluorocyclohexyl)(3-{(3R)-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl)(3-{(3S)-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl)(3-{(3R)-3-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl)(3-{(3S)-3-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 25 (61 mg, 0.13 mmol) and 2-(trifluoromethyl)-acrylic acid (23 mg, 0.16 mmol) in 1,4-dioxane (1.3 mL) was added NaHCO (22 mg, 0.26 mmol). The reaction mixture was stirred at rt for 24 h, then DPPA (70 μL, 0.32 mmol) and sodium tert-butoxide (19 mg, 0.20 mmol) were added. The reaction mixture was heated at 80 °C for 2 h and then cooled to rt. An additional portion of DPPA (70 μL, 0.32 mmol) and sodium tert-butoxide (19 mg, 0.20 mmol) was added, and the reaction mixture was stirred at 80 °C for an additional 2 h. The reaction mixture was cooled to rt, then diluted with water (20 mL), and extracted with DCM (3 × 20 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography using a gradient of 0–80% EtOAc in isohexane as the eluent. The resulting off-white amorphous solid (52 mg) was subjected to chiral SFC (Lux Cellulose-4 250 × 21.5 mm, 5 μm column, 100 mL / min, 3–40% MeOH (+0.1% NH4OH) as the eluent, 10 min run time) to give the title compounds (peak 1, 5.5 mg, 7%, RT 5.21 min; peak 2, 6.1 mg, 8%, RT 5.45 min; peak 3, 7.2 mg, 9%, RT 6.33 min; and peak 4, 7.3 mg, 9%, RT 8.36 min) as colorless amorphous solids (the absolute stereochemistry of the carbon atom adjacent to the CF3 group and the quaternary carbon atom of the tetrahydrofuranyl moiety is unknown and arbitrarily determined).

[0229] Example 10 (Peak 1): δ H(400 MHz, DMSO-d6) 9.51 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 5.23-5.15 (m, 1H), 4.54-4.44 (m, 1H), 4.26-4.18 (m, 2H), 4.00-3.93 (m, 3H), 3.80 (dd, J 10.0, 3.5 Hz, 1H), 2.81-2.74 (m, 1H), 2.55-2.50 (m, 1H), 2.47 (s, 3H), 2.27-2.17 (m, 1H), 2.11-1.90 (m, 3H), 1.88-1.70 (m, 2H), 1.66-1.59 (m, 1H), 1.46-1.23 (m, 2H).LCMS (Method 6): [M+H] + m / z 600.2, RT 1.74 min. Chiral SFC (Lux Cellulose-4 150 x 4.6 mm, 3 μm column, flow rate 3 mL / min, pressure 120 bar, column temperature 35 °C, 3-40% MeOH (+0.1% NH4OH) as eluent, run time 6.5 min on a Waters UPC2 Acquity system): RT 3.23 min (98%).

[0230] Example 11 (Peak 2): δ H (400 MHz, DMSO-d6) 9.52 (d, J 8.0 Hz, 1H), 8.70 (s, 1H), 8.31 (s, 1H), 7.77 (s, 1H), 5.22-5.18 (m, 1H), 4.54-4.47 (m, 1H), 4.22 (d, J 10 Hz, 1H), 4.10-4.05 (m, 2H), 4.01-3.90 (m, 2H), 3.74 (dd, J 10.0, 4.5 Hz, 1H), 2.84-2.76 (m, 1H), 2.65-2.58 (m, 1H), 2.47 (s, 3H), 2.26-2.17 (m, 1H), 2.11-1.89 (m, 3H), 1.89-1.70 (m, 2H), 1.68-1.59 (m, 1H), 1.45-1.24 (m, 2H).LCMS (Method 6): [M+H] +m / z 600.2, RT 1.74 min. Chiral SFC (Lux Cellulose-4 150 x 4.6 mm, 3 μm column, flow rate 3 mL / min, pressure 120 bar, column temperature 35 °C, 3-40% MeOH (+0.1% NH4OH) as eluent, run time 6.5 min on a Waters UPC2 Acquity system): RT 3.42 min (98%).

[0231] Example 12 (Peak 3): δ H (400 MHz, DMSO-d6) 9.50 (d, J 9.0 Hz, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 5.22-5.18 (m, 1H), 4.54-4.45 (m, 1H), 4.25 (d, J 9.0 Hz, 1H), 4.19 (d, J 9.0 Hz, 1H), 4.00-3.94 (m, 3H), 3.81 (dd, J 10.0, 3.5 Hz, 1H), 2.81-2.74 (m, 1H), 2.56-2.49 (m, 1H), 2.47 (s, 3H), 2.27-2.17 (m, 1H), 2.11-1.90 (m, 3H), 1.88-1.70 (m, 2H), 1.67-1.59 (m, 1H), 1.46-1.22 (m, 2H).LCMS (Method 6): [M+H] + m / z 600.2, RT 1.74 min. Chiral SFC (Lux Cellulose-4 150 x 4.6 mm, 3 μm column, flow rate 3 mL / min, pressure 120 bar, column temperature 35 °C, eluting with 3-40% MeOH (+0.1% NH4OH) on a Waters UPC2 Acquity system with a run time of 6.5 min): RT 4.03 min (>99%).

[0232] Example 13 (Peak 4): δ H(400 MHz, DMSO-d6) 9.50 (d, J 9.0 Hz, 1H), 8.70 (s, 1H), 8.31 (s, 1H), 7.77 (s, 1H), 5.22-5.17 (m, 1H), 4.56-4.47 (m, 1H), 4.21 (d, J 10.5 Hz, 1H), 4.12-4.05 (m, 2H), 4.01-3.91 (m, 2H), 3.74 (dd, J 9.5, 4.5 Hz, 1H), 2.83-2.76 (m, 1H), 2.65-2.59 (m, 1H), 2.47 (s, 3H), 2.28-2.17 (m, 1H), 2.11-1.89 (m, 3H), 1.88-1.70 (m, 2H), 1.68-1.59 (m, 1H), 1.46-1.23 (m, 2H).LCMS (Method 6): [M+H] + m / z 600.2, RT 1.73 min. Chiral SFC (Lux Cellulose-4 150 x 4.6 mm, 3 μm column, flow rate 3 mL / min, pressure 120 bar, column temperature 35 °C, eluting with 3-40% MeOH (+0.1% NH4OH) on a Waters UPC2 Acquity system with a run time of 6.5 min): RT 5.44 min (>99%).

[0233] (Examples 14 and 15) [ka] N-[(S)-(4,4-Difluorocyclohexyl)(3-{1-(2,2-difluoropropyl)-4-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]piperidin-4-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl)(3-{1-(2,2-difluoropropyl)-4-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-piperidin-4-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide 2,2-Difluoropropyl trifluoromethanesulfonate (18.7 mg, 0.082 mmol) was added to a solution of Example 7 (45.7 mg, 0.0746 mmol) and potassium carbonate (20.6 mg, 0.149 mmol) in acetonitrile (0.75 mL) under nitrogen. The reaction mixture was stirred at rt for 18.5 h. Additional potassium carbonate (10.3 mg, 0.0745 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (8.5 mg, 0.037 mmol) were added, and the reaction mixture was stirred for an additional 5.5 h. The reaction mixture was concentrated in vacuo, then redissolved in DCM (30 mL) and washed with saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with DCM (2 × 5 mL), and the combined organic phases were passed through a phase separator and concentrated in vacuo. The crude residue was first purified by flash column chromatography using a gradient elution with 0–100% EtOAc in hexanes, and then by chiral SFC (Method 8) to yield the title compounds (Peak 1, RT 4.44 min, 9.8 mg, 19%; and Peak 2, RT 5.57 min, 10.4 mg, 20%) as pale yellow solids (the absolute stereochemistry of the carbon atom adjacent to the CF group is unknown and determined arbitrarily).

[0234] Example 14 (Peak 1): δ H(400 MHz, DMSO-d6) 9.53 (d, J 8.5 Hz, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.65 (s, 1H), 5.20 (t, J 8.2 Hz, 1H), 4.46-4.35 (m, 1H), 3.92 (t, J 9.9 Hz, 1H), 3.63 (dd, J 10.1, 3.5 Hz, 1H), 2.85-2.66 (m, 5H), 2.62-2.49 (obs. m, 2H), 2.47 (s, 3H), 2.37-2.17 (m, 4H), 2.13-1.58 (m, 9H), 1.47-1.22 (m, 2H).LCMS (method 6): [M+H] + m / z691.2, RT2.08 points.キラルSFC (Method 9): RT3.60 points (100%).

[0235] Example 15(ピーク2):δ H (400 MHz, DMSO-d6) 9.52 (d, J 7.4 Hz, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.65 (s, 1H), 5.21 (t, J 7.5 Hz, 1H), 4.47-4.35 (m, 1H), 3.93 (t, J 9.9 Hz, 1H), 3.64 (dd, J 10.0, 3.5 Hz, 1H), 2.85-2.66 (m, 5H), 2.63-2.49 (obs. m, 2H), 2.47 (s, 3H), 2.36-2.17 (m, 4H), 2.12-1.58 (m, 9H), 1.47-1.22 (m, 2H).LCMS (method 6): [M+H] + m / z691.2, RT2.08 points.キラルSFC (Method 9): RT 4.75 points (100%).

[0236] (Examples 16 and 17)

change

[0237] Example 16 (Peak 1): δ H(400 MHz, DMSO-d6) 9.53 (d, J 8.2 Hz, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 5.20 (t, J 7.9 Hz, 1H), 4.46-4.35 (m, 1H), 3.94 (t, J 9.9 Hz, 1H), 3.64 (dd, J 10.1, 3.4 Hz, 1H), 2.83-2.65 (m, 3H), 2.53-2.39 (obs. m, 7H), 2.35-2.16 (m, 4H), 2.13-1.70 (m, 5H), 1.68-1.59 (m, 1H), 1.48-1.22 (m, 8H). LCMS (method 6): [M+H] + m / z687.2, RT2.16 points.キラルSFC (Method 9): RT3.86 points (100%).

[0238] Example 17(ピーク2):δ H (400 MHz, DMSO-d6) 9.52 (d, J 8.7 Hz, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.63 (s, 1H), 5.21 (t, J 8.3 Hz, 1H), 4.46-4.35 (m, 1H), 3.94 (t, J 9.9 Hz, 1H), 3.65 (dd, J 10.1, 3.4 Hz, 1H), 2.82-2.65 (m, 3H), 2.53-2.39 (obs. m, 7H), 2.36-2.16 (m, 4H), 2.12-1.70 (m, 5H), 1.69-1.60 (m, 1H), 1.48-1.22 (m, 8H). LCMS (method 6): [M+H] + m / z687.2, RT2.16 points.キラルSFC (Method 9): RT 5.20 points (100%).

[0239] (Examples 18 and 19)

change

[0240] Example 18 (Peak 1): δ H(400 MHz, DMSO-d6) 9.53 (d, J 8.8 Hz, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 5.20 (t, J 8.5 Hz, 1H), 4.45-4.35 (m, 1H), 3.91 (t, J 9.9 Hz, 1H), 3.62 (dd, J 10.1, 3.4 Hz, 1H), 2.85-2.74 (m, 1H), 2.66-2.50 (obs. m, 2H), 2.47 (s, 3H), 2.36-2.15 (m, 9H), 2.12-1.90 (m, 3H), 1.89-1.70 (m, 2H), 1.68-1.59 (m, 1H), 1.47-1.20 (m, 2H). LCMS (method 6): [M+H] + m / z627.2, RT1.70 points.キラルSFC (Method 11): RT3.20 points (100%).

[0241] Example 19(ピーク2):δ H (400 MHz, DMSO-d6) 9.53 (d, J 8.1 Hz, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 5.20 (t, J 8.0 Hz, 1H), 4.46-4.35 (m, 1H), 3.92 (t, J 9.9 Hz, 1H), 3.63 (dd, J 10.0, 3.3 Hz, 1H), 2.85-2.74 (m, 1H), 2.66-2.50 (obs. m, 2H), 2.47 (s, 3H), 2.35-2.14 (m, 9H), 2.11-1.89 (m, 3H), 1.89-1.70 (m, 2H), 1.69-1.59 (m, 1H), 1.47-1.19 (m, 2H). LCMS (method 6): [M+H] + m / z627.2, RT1.70 points.キラルSFC (Method 11): RT 3.45 points (98%).

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, E represents the base of formula (Ea), (Eb), (Ec), (Ed), or (Ee): 【Chemistry 2】 asterisk( ＊ ) represents the bond point with the rest of the molecule; Ring A is C ３～７ Cycloalkyl or C ３～７ Represents a heterocycloalkyl group, where either group may be optionally substituted with one or more substituents; R １ represents hydrogen, fluoro, chloro, methyl, difluoromethyl, or trifluoromethyl; R ６ represents -OR ６ａ or -NR ６ｂ R ６ｃ ; or R ６ represents C １～６ alkyl, C ３～９ cycloalkyl, C ３～９ cycloalkyl(C １～６ )alkyl, aryl, aryl(C １～６ )alkyl, C ３～７ heterocycloalkyl, C ３～７ heterocycloalkyl-(C １～６ )alkyl, heteroaryl or heteroaryl(C １～６ )alkyl, and any of these groups may optionally be substituted by one or more substituents; R ６ａ C １～６ Represents alkyl; or R ６ａ C ３～９ Cycloalkyl or C ３～７ Represents a heterocycloalkyl group, where either group may be optionally substituted with one or more substituents; R ６ｂ is hydrogen or C １～６ Represents alkyl; R ６ｃ is hydrogen or C １～６ Represents alkyl; or R ６ｂ and R ６ｃ When these two groups are combined with the nitrogen atom to which they are bonded, they represent azetidine-1-yl, pyrrolidine-1-yl, oxazolidine-3-yl, isoxazolidine-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, piperazine-1-yl, homopiperidine-1-yl, homomorpholine-4-yl, or homopiperazine-1-yl, and any of these groups may be optionally substituted with one or more substituents. The compound or its N-oxide or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein E represents a group of formula (Ea) or (Ed) as described in claim 1.

3. Formula (IA-1): 【Transformation 3】 [In the formula, A, R １ and R ６ This is as described in claim 1. The compound described in claim 1 as expressed by, or its N-oxide, or a pharmaceutically acceptable salt thereof.

4. R １ The compound according to claim 1, wherein hydrogen is represented.

5. R ６ The compound according to claim 1, wherein represents a heteroaryl group, and this group may optionally be substituted with one or more substituents.

6. Formula (IIA): 【Chemistry 4】 [In the formula, X represents CH or N; R １６ is represented by methyl, ethyl, isopropyl, difluoromethyl, or cyclopropyl; A is as described in claim 1. The compound described in claim 1 as expressed by, or its N-oxide, or a pharmaceutically acceptable salt thereof.

7. R １６ The compound according to claim 6, wherein is methyl.

8. Ring A represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, and any of these groups may be unsubstituted, or a halogen, cyano, or C １～６ Alkyl, fluoro(C) １～６ ) alkyl, difluoro(C １～６ ) alkyl, trifluoro(C １～６ ) Alkyl, hydroxy, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Alkyl sulfinyl, C １～６ Alkyl sulfonyl, C ２～６ Alkylcarbonyl, C ２～６ Alkoxycarbonyl, amino, C １～６ Alkylamino and di(C) １～６ The compound according to claim 1, which may be substituted with one, two, or three substituents independently selected from alkylaminos.

9. Ring A represents cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or piperidinyl, and any of these groups may be unsubstituted, or a halogen, C １～６ Alkyl, fluoro(C) １～６ ) alkyl, difluoro(C １～６ ) Alkyl and C ２～６ The compound according to claim 8, which may be substituted with one or two substituents independently selected from alkoxy-carbonyl groups.

10. N-[(S)-(4,4-difluorocyclohexyl)(3-{3,3-difluoro-1-[(4S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]cyclobutyl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{3,3-difluoro-1-[(4R)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]cyclobutyl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]-cyclopropyl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{4-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]-tetrahydropyran-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{4-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]-tetrahydropyran-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, tert-butyl4-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)-4-[2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]piperidine-1-carboxylate, N-[(S)-(4,4-difluorocyclohexyl)(3-{4-[2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]-piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-oxetan-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{3-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-oxetan-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(3R)-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(3S)-3-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(3R)-3-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(3S)-3-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidined-1-yl]tetrahydrofuran-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-(2,2-difluoropropyl)-4-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-(2,2-difluoropropyl)-4-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]-piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-(2-fluoro-2-methylpropyl)-4-[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-(2-fluoro-2-methylpropyl)-4-[(4R)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl]piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-methyl-4-[(4S)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-methyl-4-[(4R)-2-oxo-4-(trifluoromethyl)-imidazolidin-1-yl]piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, or their pharmaceutically acceptable salts A compound according to claim 1, selected from the group consisting of the following.

11. A pharmaceutical composition comprising a compound of formula (I) described in claim 1, its N-oxide, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, for use in the treatment and / or prevention of disorders for which administration of an IL-17 function modulator is indicated.

13. The pharmaceutical composition according to claim 11 for use in the treatment and / or prevention of inflammatory disorders or autoimmune disorders.

14. Use of a compound of formula (I) as described in claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of a disorder for which administration of an IL-17 functional modulator is indicated.

15. Use of a compound of formula (I) as described in claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of inflammatory disorders or autoimmune disorders.

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