Imidazotriadine derivatives as IL-17 modulators

Abstract

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

Description

[Technical Field]

[0001] This invention relates to heterocyclic compounds and their use in therapy. More specifically, this 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 treating and / or preventing pathological conditions, including adverse 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 an early member of the IL-17 family (Rouvier et al., J.Immunol., 1993, 150, 5445-5456). Subsequently, five additional members of the family (IL-17B to IL-17F) were identified, including the most closely related IL-17F (ML-1) (which shares approximately 55% amino acid sequence homology with IL-17A) (Moseley et al., Cytokine Growth Factor Rev., 2003, 14, 155-174). IL-17A and IL-17F are expressed by Th17, a recently defined autoimmune-associated subset of T helper cells that also express IL-21 and IL-22 signature cytokines (Korn et al., Ann. Rev. Immunol., 2009, 27, 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, 181, 2799-2805). IL-17A and F signal via the receptors IL-17R, IL-17RC, or IL-17RA / RC receptor complexes (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F are associated with several autoimmune diseases.

[0003] Therefore, compounds according to the present invention, which are potent modulators of human IL-17 activity, are beneficial for the treatment and / or prevention of various human diseases, including inflammatory disorders and autoimmune disorders.

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

[0005] International Publication Nos. 2013 / 116682 and International Publication Nos. 2014 / 066726 relate to a distinct class of chemical compounds that modulate the activity of IL-17 and are said to be useful in treating medical conditions, including inflammatory diseases.

[0006] International Publication Nos. 2018 / 229079 and International Publication Nos. 2020 / 011731 describe spirocyclic molecules that act as modulators of IL-17 activity and are therefore said to be beneficial in treating pathological conditions, including harmful inflammatory disorders and autoimmune disorders.

[0007] International Publication Nos. 2019 / 138017, 2020 / 260425, 2020 / 260426, and 2020 / 261141 describe various classes of fusion bicyclic imidazole derivatives that act as modulators of IL-17 activity and are therefore said to be beneficial in treating pathological conditions, including adverse inflammatory disorders and autoimmune disorders. The fusion bicyclic imidazole derivatives acting as modulators of IL-17 activity are also included in the concurrently pending international patent applications PCT / EP2021 / 054519 and PCT / EP2021 / 054523 (both published on September 2, 2021, as International Publication No. 2021 / 170627 and International Publication No. 2021 / 170631, respectively), and the concurrently pending international patent applications PCT / EP2021 / 058937 and PCT / EP2021 / 058940 (both published on September 2, 2021, as International Publication No. 2021 / 204800 and National Publication No. It is described in the concurrently pending international patent applications PCT / EP2021 / 080250 and PCT / EP2021 / 080251 (both published on May 12, 2022, as international publications 2022 / 096411 and 2022 / 096412, respectively), and the concurrently pending international patent application PCT / EP2021 / 084448 (published on June 23, 2022, as international publication 2022 / 128584).

[0008] International Publication Nos. 2020 / 120140 and 2020 / 120141 describe separate classes of chemical compounds that act as modulators of IL-17 activity and are therefore said to be beneficial in treating pathological conditions, including adverse inflammatory disorders and autoimmune disorders.

[0009] Heterocyclic compounds that inhibit IL-17A and are useful as immunomodulators are described in International Publication Nos. 2019 / 223718, 2021 / 027721, 2021 / 027722, 2021 / 027724, 2021 / 027729, and 2021 / 098844.

[0010] Heterocyclic compounds that are said to be able to modulate IL-17 activity are also described in International Publication Nos. 2020 / 127685, 2020 / 146194, and 2020 / 182666.

[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. [Overview of the project]

[0012] In addition to being potent modulators of human IL-17 activity, compounds according to the present invention possess other notable advantages. In particular, the compounds of the present invention exhibit valuable metabolic stability when required in either microsomal or hepatocyte incubation. The compounds of the present invention also exhibit valuable permeability when required by standard assays, such as Caco-2 permeability assays.

[0013] The present invention provides a compound of formula (I), its N-oxide, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, E is an expression of (Ea), (Eb), (Ec), (Ed), or (Ee): [ka] represents a group of the formula (wherein the asterisk (*) represents the point of attachment to the remainder of the molecule); A is a group of formula (Aa), (Ab), (Ac), (Ad) or (Ae):

Chemical Formula

Chemical Formula

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

[0015] The present invention also provides compounds of formula (I) defined above, or their N-oxides, or pharmaceutically acceptable salts thereof, for use in therapeutic purposes.

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

[0017] The present invention also provides the use of a compound of formula (I) defined above, 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.

[0018] The present invention also provides a method for treating and / or preventing a disorder for which administration of an IL-17 functional modulator is indicated, the method comprising administering an effective amount of a compound of formula (I) as defined above, or its N-oxide, or a pharmaceutically acceptable salt thereof, to a patient requiring such treatment.

[0019] Where it is stated that any of the groups in the compound of formula (I) above are optionally substituted, this group may be unsubstituted or substituted with one or more substituents. Generally, such groups are either unsubstituted or substituted with one, two, three, or four substituents. Typically, such groups are either unsubstituted or substituted with one, two, or three substituents. Preferably, such groups are either unsubstituted or substituted with one or two substituents.

[0020] When used in medicine, the salt of the compound of formula (I) may be a pharmaceutically acceptable salt. However, other salts may be useful in the preparation of the compound of formula (I) or their 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, for example, acid addition salts that can be formed 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 the compound of formula (I) described above. The technical term "co-crystal" is used to describe the situation where neutral molecular components are present within a crystalline compound in a fixed stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modification of the crystalline form of an active pharmaceutical ingredient, which allows modification of its physicochemical properties without impairing the 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 in the compound used in the present invention include linear and branched C 1-6 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and linear 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 1-6Derived expressions such as "alkylamino" should be interpreted accordingly.

[0023] The term "C" used herein 3-9 The term "cycloalkyl" refers to a monovalent group of 3 to 9 carbon atoms derived from saturated monocyclic hydrocarbons, and may include its benzo-fused analogues. Preferred C 3-9 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononanyl.

[0024] The term "C" used herein 4-12 The term "bicycloalkyl" refers to a monovalent group of 4 to 12 carbon atoms derived from saturated bicyclic hydrocarbons. Typical bicycloalkyl groups include bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, and bicyclo[2.2.2]octanyl.

[0025] As used herein, the term "aryl" refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or multiple fused aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

[0026] Preferred aryl(C) 1-6 Examples of alkyl groups include benzyl, phenylethyl, phenylpropyl, and naphthylmethyl.

[0027] The term "C" used herein 3-7The term "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 may include its benzofused analogs. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, 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.

[0028] As used herein, "C 4-9 The term "heterobicycloalkyl" refers to C in which one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur and nitrogen 4-9This corresponds to bicycloalkyl groups. Typical heterobicycloalkyl groups include 6-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]-heptanyl, 6-azabicyclo[3.2.0]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]-heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, and 2-oxa-5-azabicyclo[2.2.2] Examples include kutanyl, 8-oxabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]-octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, and 3,9-diazabicyclo[4.2.1]nonanyl.

[0029] As used herein, the term “heteroaryl” refers to a monovalent aromatic group containing at least five atoms derived from a monocyclic or multi-cyclic fused ring, where 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]dioxynyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl. Dinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, imidazo[4, 5-b]pyridinyl, imidazo[1,2-b]pyridazinyl, prinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyradinyl, 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]pyradinyl, 5,6,7,8-tetrahydro[1,2, Examples include [4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyradinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridadinyl, sinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl, and clomenyl groups.

[0030] As used herein, the term "halogen" is intended to include fluorine, chlorine, bromine, and iodine atoms, typically fluorine, chlorine, or bromine.

[0031] If a compound of formula (I) has one or more chiral centers, it may exist as an enantiomer accordingly. If a compound according to the present invention has two or more chiral centers, they may also exist as diastereomers. The present invention should be understood to extend to the use of all such enantiomers and diastereomers, as well as mixtures thereof, including racemates in any proportion. Formula (I) and the formulas shown below are intended to represent all individual stereoisomers and all possible mixtures thereof unless otherwise specified or indicated. In addition, compounds of formula (I) may exist as tautomers, e.g., keto (CH2C=O) ↔ enol (CH=CHOH) tautomers or amide (NHC=O) ↔ hydroxyimine (N=COH) tautomers. Formula (I) and the formulas shown below are intended to represent all individual tautomers and all possible mixtures thereof unless otherwise specified or indicated.

[0032] It should be understood that each individual atom present in formula (I) or the formulas shown below may actually exist in any of its naturally occurring isotopes, and the most abundant isotope(s) is preferred. Therefore, as an example, each individual hydrogen atom present in formula (I) or the formulas shown below, 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 It can exist as H. Similarly, as an example, each individual carbon atom in formula (I) or the formula shown below, 12 C, 13 C or 14 C atom, preferably a C atom. 12 It can exist as C.

[0033] In the first embodiment, E represents the base of formula (Ea). In the second embodiment, E represents the base of formula (Eb). In the third embodiment, E represents the base of formula (Ec). In the fourth embodiment, E represents the base of formula (Ed). In the fifth embodiment, E represents the base of formula (Ee).

[0034] Typically, E represents the base of formula (Ea), (Eb), or (Ed).

[0035] Preferably, E represents the base of formula (Ea) or (Ed).

[0036] Generally, the present invention relates to formulas (IA-1), (IA-2), (IA-3), (IA-4), or (IA-5): [ka] (In the formula, A, R 1 and R 6 The present invention provides a compound of (as defined above), its N-oxide, or a pharmaceutically acceptable salt thereof.

[0037] Typically, the present invention provides compounds of formulas (IA-1), (IA-2), or (IA-4) defined above, or their N-oxides, or pharmaceutically acceptable salts thereof.

[0038] Preferably, the present invention provides compounds of formula (IA-1) or (IA-4) as defined above, or their N-oxides, or pharmaceutically acceptable salts thereof.

[0039] In the first embodiment, A represents the base of formula (Aa). In the second embodiment, A represents the base of formula (Ab). In the third embodiment, A represents the base of formula (Ac). In the fourth embodiment, A represents the base of formula (Ad). In the fifth embodiment, A represents the base of formula (Ae).

[0040] Preferably, A represents a base of formula (Ab) or (Ad).

[0041] Generally, the present invention relates to formulas (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5): [ka] (In the formula, E, Y, Z, R 1 , R 2 , R 3 , R 4a , R 4b and R 6 The present invention provides a compound of (as defined above), its N-oxide, or a pharmaceutically acceptable salt thereof.

[0042] Preferably, the present invention provides compounds of formula (IB-2) or (IB-4) as defined above, or their N-oxides, or pharmaceutically acceptable salts thereof.

[0043] In the first embodiment, Y represents -O-. In the second embodiment, Y represents -N(R 7 ) represents -. In the third embodiment, Y is -C(R 5a )(R 5b In the fourth embodiment, Y represents -S-. In the fifth embodiment, Y represents -S(O)-. In the sixth embodiment, Y represents -S(O)2-. In the seventh embodiment, Y represents -S(O)(NR 8 ) represents -.

[0044] Typically, Y is -O-, -N(R 7 )-,-C(R 5a )(R 5b )- or -S(O)2- represents, and in the formula, R 5a , R 5b and R 7 This is as defined above.

[0045] Preferably, Y is -O-, -C(R 5a )(R 5b )- or -S(O)2- represents, and in the formula, R 5a and R 5b This is as defined above.

[0046] Generally, Z includes furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b][1,4]dioxynyl, 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 pyrazolo[3,4-d]pyridinyl. Midinyl, pyrazolo[1,5-a]pyradinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-b]pyrida Dinyl, prinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyradinyl, 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]pyradinyl, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo [1,5-a]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyradinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthilidinyl, pyridadinyl, synnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl, or clomenyl, any of these groups may optionally be substituted by one or more substituents.

[0047] Suitablely, Z represents pyrazolyl, pyrazolo[1,5-a]pyridinyl, isoxazolyl, isothiazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, tetrazolyl, pyridinyl, pyridadinyl, pyrimidinyl, or pyrazinyl, any of these groups may optionally be substituted by one or more substituents.

[0048] Typically, Z represents imidazolyl, triazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, or tetrazolyl, any of these groups may optionally be substituted with one or more substituents.

[0049] Preferably, Z represents a triazolyl group, which may be optionally substituted with one or more substituents.

[0050] Typical examples of optional substituents on Z include halogens, cyanos, nitros, and C. 1-6 Alkyl, difluoromethyl, difluoroethyl, trifluoro(C) 1-6 )Alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxy(C 1-6 ) alkyl, oxo, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkylsulfonyl, amino, C 1-6 Alkylamino, di(C1-6 ) alkylamino, amino(C 1-6 ) alkyl, di(C 1-6 ) Alkylamino(C 1-6 ) Alkyl, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) Alkylaminosulfonyl and di(C 1-6 ) One, two, or (if possible) three substituents independently selected from the alkylsulfoxiimino.

[0051] Suitable examples of optional substituents on Z include halogens, cyanosides, and C12. 1-6 Alkyl, difluoromethyl, difluoroethyl, trifluoro(C) 1-6 ) Alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, cyanobicyclo[1.1.1]pentanyl and C 1-6 Examples include one, two, or (if possible) three substituents independently selected from the alkylamino.

[0052] Typical examples of specific substituents on Z include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, oxo, methoxy, isopropyl Examples of substituents independently selected from poxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, aminomethyl, dimethylaminomethyl, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoxyimino include one, two, or (if possible) three substituents.

[0053] Suitable examples of specific substituents on Z include one, two, or (where possible) three substituents independently selected from fluoro, cyano, methyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, cyanobicyclo[1.1.1]pentanyl, and methylamino.

[0054] Typical values ​​of Z include trifluoroethylpyrazolyl, (methyl)(trifluoroethyl)pyrazolyl, pyrazolo[1,5-a]pyridinyl, methylindazolyl, trifluoroethylisoxazolyl, (methyl)(trifluoroethyl)isoxazolyl, trifluoroethylisothiazolyl, trifluoroethylimidazolyl, cyclopropylmethylimidazolyl, (methyl)(trifluoroethyl)imidazolyl, imidazo[1,2-a]pyridinyl, difluoroethyltriazolyl, trifluoroethyltriazolyl, difluorocyclopropyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[1.1.1]pentanyl Examples include riazolyl, (fluoro)(trifluoroethyl)triazolyl, (methyl)(trifluoroethyl)triazolyl, (difluoromethyl)(trifluoroethyl)triazolyl, (cyclopropylmethyl)(difluoromethyl)triazolyl, (methylamino)(trifluoroethyl)triazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, fluoro[1,2,4]triazolo[4,3-a]pyridinyl, cyano[1,2,4]triazolo[4,3-a]pyridinyl, benzotriazolyl, trifluoroethyltetrazolyl, trifluoroethylpyridinyl, trifluoroethylpyridazinyl, trifluoroethylpyrimidinyl, and trifluoroethylpyradinyl.

[0055] Examples of Z values ​​include cyclopropylmethylimidazolyl, difluoroethyltriazolyl, trifluoroethyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[1.1.1]pentanyltriazolyl, fluoro[1,2,4]triazolo[4,3-a]pyridinyl, cyano[1,2,4]triazolo[4,3-a]pyridinyl, and trifluoroethyltetrazolyl.

[0056] Preferably, Z is a number of the formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh), (Zj), (Zk), (Zl), (Zm), (Zn), (Zp), (Zq), (Zr), (Zs), (Zt), (Zu), (Zv), (Zw), (Zx), (Zy), (Zz), (Zaa), or (Zab): [ka] [ka] (In the formula, An asterisk (*) represents a bond point with the rest of the molecule; R 1z is hydrogen, C 1-6 Alkyl, difluoromethyl, difluoroethyl, trifluoro(C) 1-6 ) Alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy(C 2-6 ) Alkyl, C 1-6 Alkyl sulfonyl, amino(C 2-6 ) alkyl, di(C 1-6 ) Alkylamino(C 1-6 ) Alkyl, C 2-6 Alkylcarbonyl, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl or di(C) 1-6 ) Represents alkylaminosulfonyl; R 2z Hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, difluoromethyl, trifluoro(C) 1-6)Alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxy(C 1-6 ) Alkyl, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkylsulfonyl, amino, C 1-6 Alkylamino, di(C 1-6 ) alkylamino, amino(C 1-6 ) alkyl, di(C 1-6 ) Alkylamino(C 1-6 ) Alkyl, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) Alkylaminosulfonyl or di(C 1-6 (Represents alkylsulfoximino) It represents the basis of.

[0057] Specific values ​​of Z include the bases of the equations (Zk), (Zm), (Zp), (Zq), (Zt), (Zu), (Zv), (Zw), and (Zx) defined above.

[0058] Typically, R 1z is hydrogen, C 1-6 Alkyl, difluoroethyl, trifluoro(C) 1-6) represents alkyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, or cyanobicyclo[1.1.1]pentanyl.

[0059] R 1z Appropriate values ​​for include hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxyethyl, hydroxyisopropyl, methylsulfonyl, aminoethyl, dimethylaminomethyl, acetyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, and dimethylaminosulfonyl.

[0060] R 1z Typical values ​​include hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoroethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, and cyanobicyclo[1.1.1]pentanyl.

[0061] Typically, R 2z These are hydrogen, halogen, cyano, and C 1-6 Alkyl, trifluoro(C) 1-6 ) Alkyl, cyclopropylmethyl, difluorocyclopropylmethyl or C 1-6 Represents alkylamino.

[0062] Preferably, R 2zR represents hydrogen, halogen, or cyano. In the first embodiment, R 2z represents hydrogen. In the second embodiment, R 2z represents halogens, particularly fluorocarbons. In the third embodiment, R 2z This represents cyano.

[0063] R 2z Appropriate values ​​include hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl Examples include propyl, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, ethylamino, dimethylamino, aminomethyl, dimethylaminomethyl, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoxyimino.

[0064] R 2z Typical values ​​include hydrogen, fluoro, cyano, methyl, difluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropylmethyl, difluorocyclopropylmethyl, and methylamino.

[0065] R 2zSuitable values ​​include hydrogen, fluorocarbon, and cyanocarbon.

[0066] In the first embodiment, R 1 represents hydrogen. In the second embodiment, R 1 represents fluoro. In the third embodiment, R 1 represents chloro. In the fourth embodiment, R 1 represents methyl. In the fifth embodiment, R 1 represents difluoromethyl. In the sixth embodiment, R 1 This represents trifluoromethyl.

[0067] Typically, R 1 represents hydrogen, fluoro, chloro, or methyl.

[0068] In general, R 1 This represents hydrogen or fluorocarbon.

[0069] Preferably, R 1 This represents hydrogen.

[0070] Typically, R 2 C 3-9 Cycloalkyl, C 4-12 Bicycloalkyl or C 3-7 This represents a heterocycloalkyl group, and any of these groups may optionally be substituted with one or more substituents.

[0071] Preferably, R 2 C 4-12 Bicycloalkyl or C 3-7 Represents a heterocycloalkyl group, where any of these groups may optionally be substituted by one or more substituents.

[0072] R 2 Typical examples include cyclobutyl, bicyclo[1.1.1]pentanyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, and morpholinyl, any of which may be optionally substituted with one or more substituents.

[0073] R 2 Preferred examples include bicyclo[1.1.1]pentanyl and tetrahydropyranyl, in which either of these groups may be optionally substituted with one or more substituents.

[0074] R 2 Typical examples of the optional substituents mentioned above include one, two, three, or four substituents that can be selected independently of the halogen.

[0075] R 2 Typical examples of the specific substituents mentioned above include one, two, three, or four substituents that are independently selected from fluoro.

[0076] R 2 Typical values ​​include difluorocyclobutyl, fluorobicyclo[1.1.1]pentanyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, difluorotetrahydropyranyl, and tetrafluoromorpholinyl.

[0077] R 2 Suitable values ​​include fluorobicyclo[1.1.1]pentanyl and difluorotetrahydropyranyl.

[0078] In the first embodiment, R 2a is C 1-6 Represents alkyl. In the second embodiment, R 2a C is substituted in some cases. 3-9 This represents a cycloalkyl group.

[0079] Typically, R 2a is C 1-6 Represents alkyl; or R 2a represents cyclobutyl, which may optionally be substituted by one or more substituents.

[0080] R 2aTypical examples of the optional substituents above include halogens, cyanos, nitros, and 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 Alkyl sulfinyl, 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 sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl and di(C 1-6 Examples include one, two, or three substituents independently selected from alkylaminosulfonyl molecules.

[0081] R 2a Suitable examples of the optional substituents mentioned above include one, two, or three substituents that can be selected independently of the halogen.

[0082] R 2aTypical examples of the specific substituents listed above include one, two, or three 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, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, and dimethylaminosulfonyl.

[0083] R 2a Preferred examples of the specific substituents mentioned above include one, two, or three substituents independently selected from fluoro.

[0084] R 2a Exemplary examples of specific values ​​include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, and difluorocyclobutyl.

[0085] In the first embodiment, R 3 -NR 3a R 3b This represents R 3 This represents the base of the formula (Wa) defined above.

[0086] In the first embodiment, R 3a represents hydrogen. In the second embodiment, R 3a C 1-6 Represents alkyl, particularly methyl or ethyl. In the first embodiment of the present invention, R 3a represents methyl. In a second embodiment of the embodiment, R 3a 'Ethyl' represents ethyl.

[0087] Typically, R 3b C 1-6 Alkyl or C 3-7 Cycloalkyl (C 1-6 ) represents an alkyl group, and any of these groups may optionally be substituted by one or more substituents.

[0088] Preferably, R 3b C 1-6 This represents an alkyl group, which may optionally be substituted by one or more substituents.

[0089] In the first embodiment, R 3b C is substituted in some cases. 1-6 Represents alkyl. In the second embodiment, R 3b C is substituted in some cases. 3-7 Represents a cycloalkyl group. In the third embodiment, R 3b C is substituted in some cases. 3-7 Cycloalkyl (C 1-6 ) represents alkyl. In the fourth embodiment, R 3b C is substituted in some cases. 4-12 Represents bicycloalkyl. In the fifth embodiment, R 3b represents an aryl that may be substituted. In the sixth embodiment, R 3b This is the aryl(C) which may be substituted in some cases. 1-6 ) represents alkyl. In the seventh embodiment, R 3b C is substituted in some cases. 3-7 Represents heterocycloalkyl. In the eighth embodiment, R 3b C is substituted in some cases. 3-7 Heterocycloalkyl (C 1-6 ) represents alkyl. In the ninth embodiment, R 3b R represents a heteroaryl that may be substituted. In the tenth embodiment, R 3b This is a heteroaryl (C) that may be substituted in some cases. 1-6 ) Represents alkyl.

[0090] R 3bTypical examples include ethyl, propyl, isopropyl, 2-methylpropyl, and cyclopropylmethyl, any of which may be optionally substituted with one or more substituents.

[0091] R 3b A preferred example is propyl, which may optionally be substituted with one or more substituents.

[0092] R 3b Typical examples of the optional substituents above include halogens, cyanos, nitros, and C. 1-6 Alkyl, trifluoromethyl, hydroxy, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkylsulfonyl, amino, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) Alkylaminosulfonyl and di(C 1-6 Examples include one, two, or three substituents independently selected from the alkylsulfoxiimino.

[0093] R 3b Suitable examples of the optional substituents mentioned above include one, two, or three substituents that can be selected independently of the halogen.

[0094] R3b Typical examples of the specific substituents listed above include one, two, or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoxiimino.

[0095] R 3b Preferred examples of the specific substituents mentioned above include one, two, or three substituents selected independently of fluoro.

[0096] R 3b Typical values ​​include difluoroethyl, trifluoroethyl, difluoropropyl, trifluoroisopropyl, methylaminocarbonyl-2-methylpropyl, (cyclopropyl)(trifluoromethyl)methyl, and difluorocyclopropylmethyl.

[0097] R 3b A suitable value for this is difluoropropyl.

[0098] In the first embodiment, W represents a optionally substituted saturated monocyclic ring residue containing 3 to 6 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing 1 or fewer O or S atoms. In the first aspect of that embodiment, W represents a optionally substituted saturated monocyclic ring residue containing 3 or 4 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing 1 or fewer O or S atoms.

[0099] In the second embodiment, W represents a residue of an optionally substituted saturated bicyclic ring system containing 4 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing 1 or fewer O or S atoms. In the first aspect of that embodiment, W represents a residue of an optionally substituted saturated bicyclic ring system containing 5, 6, or 7 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing 1 or fewer O or S atoms.

[0100] In the third embodiment, W represents a residue of an optionally substituted saturated spirocyclic ring system containing 5 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing 1 or fewer O or S atoms. In the first aspect of that embodiment, W represents a residue of an optionally substituted saturated spirocyclic ring system containing 5, 6, or 7 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing 1 or fewer O or S atoms.

[0101] Preferably, W represents an optionally substituted saturated monocyclic ring residue containing 3 or 4 carbon atoms, 1 nitrogen atom, and 0 or 1 oxygen atom. In the first embodiment, W represents an optionally substituted saturated monocyclic ring residue containing 3 or 4 carbon atoms and 1 nitrogen atom. In the first aspect of that embodiment, W represents an optionally substituted saturated monocyclic ring residue containing 3 carbon atoms and 1 nitrogen atom. In the second aspect of that embodiment, W represents an optionally substituted saturated monocyclic ring residue containing 4 carbon atoms and 1 nitrogen atom. In the second embodiment, W represents an optionally substituted saturated monocyclic ring residue containing 4 carbon atoms, 1 nitrogen atom, and 1 oxygen atom.

[0102] In the first embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and no additional heteroatoms (i.e., an optionally substituted azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, or hexahydroazepine-1-yl ring). In the second embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and one additional heteroatom selected from N, O, and S. In the first aspect of that embodiment, the group of formula (Wa) is an optionally substituted morpholine-4-yl moiety. In the third embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and two additional heteroatoms selected from N, O, and S, one or less of which are O or S. In the fourth embodiment, the group of formula (Wa) represents a saturated monocyclic ring comprising one nitrogen atom and three additional heteroatoms selected from N, O, and S, one or less of which are O or S.

[0103] Typical values ​​for the group in formula (Wa) include azetidine-1-yl, pyrrolidine-1-yl, oxazolidine-3-yl, thiazolidin-3-yl, isothiazolidine-2-yl, imidazolidine-1-yl, piperidine-1-yl, piperazine-1-yl, homopiperazine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, azepan-1-yl, [1,4]oxazepan-4-yl, [1,4]diazepan-1-yl, [1,4]thiadiazepan-4-yl, azocan-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, 2- Oxa-5-azabicyclo[2.2.1]heptane-5-yl, 6-azabicyclo[3.2.0]heptane-6-yl, 3-azabicyclo[3.1.1]heptane-3-yl, 6-oxa-3-azabicyclo[3.1.1]heptane-3-yl, 3-azabicyclo[4.1.0]heptane-3-yl, 2-oxa-5-azabicyclo[2.2.2]octane-5-yl, 3-azabicyclo[3.2.1]octane-3-yl, 8-azabicyclo[3.2.1]octane-8-yl, 3-oxa-8-azabicyclo[3.2.1]octane-8-yl, 3, 8-Diazabicyclo[3.2.1]octan-3-yl, 3,8-Diazabicyclo[3.2.1]octan-8-yl, 3,6-Diazabicyclo[3.2.2]nonane-3-yl, 3,6-Diazabicyclo[3.2.2]nonane-6-yl, 3-Oxa-7-azabicyclo[3.3.1]nonane-7-yl, 3,7-Dioxa-9-azabicyclo[3.3.1]nonane-9-yl, 3,9-Diazabicyclo[4.2.1]nonane-3-yl, 3,9-Diazabicyclo[4.2.1]nonane-9-yl, 5-Azaspiro[2.3]hexane-5-yl, 5- Azaspiro[2.4]heptane-5-yl, 2-azaspiro[3.3]heptane-2-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 3-oxa-6-azaspiro[3.3]heptane-6-yl, 6-thia-2-azaspiro[3.3]heptane-2-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 2-oxa-6-azaspiro[3.5]nonane-6-yl, 7-oxa-2-azaspiro[3.5]nonane-2-yl, 2-oxa-7-azaspiro[3.5]nonane-7-yl, 2,4,8-triazaspiro[4.Examples include 5]decane-2-yl, 2,4,8-triazaspiro[4.5]decane-4-yl, and 2,4,8-triazaspiro[4.5]decane-8-yl, any of these groups may optionally be substituted with one or more substituents.

[0104] Preferred values ​​for the group in formula (Wa) include azetidine-1-yl and pyrrolidine-1-yl, and either of these groups may be optionally substituted with one or more substituents.

[0105] In the first embodiment, the group of formula (Wa) is unsubstituted. In the second embodiment, the group of formula (Wa) is substituted with one or more substituents, typically 1 to 6 substituents, preferably 2 to 4 substituents. In the first aspect of the embodiment, the group of formula (Wa) is substituted with 1 substituent. In the second aspect of the embodiment, the group of formula (Wa) is substituted with 2 substituents. In the third aspect of the embodiment, the group of formula (Wa) is substituted with 3 substituents. In the fourth aspect of the embodiment, the group of formula (Wa) is substituted with 4 substituents. In the fifth aspect of the embodiment, the group of formula (Wa) is substituted with 5 substituents. In the sixth aspect of the embodiment, the group of formula (Wa) is substituted with 6 substituents.

[0106] Typical examples of optional substituents on the base of formula (Wa) include halogens, C 1-6 Alkyl, trifluoromethyl, hydroxy, hydroxy(C) 1-6 ) Alkyl, C 1-6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 Alkoxy(C) 1-6 ) Alkyl, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, cyano, oxo, formyl, C 2-6 Alkylcarbonyl, carboxy, carboxy(C 1-6 ) Alkyl, C 2-6 Alkoxycarbonyl, C 2-6Alkoxycarbonyl (C 1-6 ) alkyl, 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 Alkylsulfonylamino, aminocarbonyl, C 1-6 Alkylaminocarbonyl and di(C 1-6 Examples include alkylaminocarbonyl compounds.

[0107] Examples of optional substituents on the group of formula (Wa) include halogens and trifluoromethyl compounds.

[0108] A suitable example of an optional substituent on the group of formula (Wa) is a halogen.

[0109] Typical examples of specific substituents on the group of formula (Wa) include fluoro, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulfonyl, cyano, oxo, formyl, acetyl, ethylcarbonyl, tert-butylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino, aminomethyl, methylamino, ethylamino, dimethylamino, acetylamino, tert-butoxycarbonylamino, methylsulfonylamino, aminocarbonyl, methylaminocarbonyl, and dimethylaminocarbonyl.

[0110] Selected examples of specific substituents on the group of formula (Wa) include fluoromethyl and trifluoromethyl.

[0111] A preferred example of a specific substituent on the group of formula (Wa) is fluoro.

[0112] Selected values ​​for the base of formula (Wa) include trifluoromethylazetidine-1-yl and tetrafluoropyrrolidine-1-yl.

[0113] In general, R 4a represents hydrogen or fluoro; or R 4a is C 1-6 This represents an alkyl group, which may optionally be substituted by one or more substituents.

[0114] Typically, R 4a represents hydrogen; or R 4a is C 1-6 This represents an alkyl group, which may optionally be substituted by one or more substituents.

[0115] Preferably, R 4a C 1-6 This represents an alkyl group, which may optionally be substituted by one or more substituents.

[0116] In the first embodiment, R 4a represents hydrogen. In the second embodiment, R 4a represents fluoro. In the third embodiment, R 4a represents hydroxyl. In the fourth embodiment, R 4a C 1-6 R represents an alkyl group, particularly a methyl or ethyl group, which may optionally be substituted with one or more substituents. In the first embodiment of the embodiment, 4a R represents a substituted methyl group, if applicable. In a second aspect of the embodiment, R 4a This represents ethyl substituted in some cases.

[0117] R 4a Typical examples of the optional substituents above include halogens, cyano, nitro, hydroxy, and C. 1-6Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkylsulfonyl, amino, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) Alkylaminosulfonyl and di(C 1-6 Examples include one, two, or three substituents independently selected from the alkylsulfoxiimino.

[0118] R 4a Suitable examples of the optional substituents mentioned above include one, two, or three substituents that can be selected independently of the halogen.

[0119] R 4a Typical examples of the specific substituents listed above include one, two, or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoxyimino.

[0120] R 4a Preferred examples of the specific substituents mentioned above include one, two, or three substituents selected independently of fluoro.

[0121] R 4a Exemplary values ​​include hydrogen, fluoro, hydroxy, methyl, difluoroethyl, and trifluoroethyl.

[0122] In the first embodiment, R 4b represents hydrogen. In the second embodiment, R 4b represents fluoro. In the third embodiment, R 4b C 1-6 R represents alkyl, particularly methyl or ethyl. In the first embodiment of the present invention, R 4b represents methyl. In a second embodiment of the embodiment, R 4b 'Ethyl' represents ethyl.

[0123] R 4b Typical values ​​include hydrogen and fluorocarbons.

[0124] Alternatively, R 4a and R 4b These may combine to form a substituted annular portion, depending on the case. Therefore, R 4a and R 4b They both, together with the carbon atoms to which they are bonded, C 3-7 Cycloalkyl or C 3-7 These can represent heterocycloalkyl groups, any of which may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0125] In the first embodiment, R 4a and R 4b They both, together with the carbon atoms to which they are bonded, C 3-7A cycloalkyl group can be preferably represented, and this group may be unsubstituted or substituted with one or more substituents, typically one or two substituents. A general example of such embodiments is R 4a and R 4b Together with the carbon atoms to which they are both bonded, these groups can suitably represent cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, any of which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. A specific example of this embodiment is R 4a and R 4b Together with the carbon atoms to which they are both bonded, they can suitably represent cyclobutyl or cyclohexyl, and either of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In the first embodiment of the embodiment, R 4a and R 4b Together with the carbon atoms to which they are both bonded, they can suitably represent a cyclopropyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a second aspect of the embodiment, R 4a and R 4b Together with the carbon atoms to which they are both bonded, they can suitably represent a cyclobutyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a third aspect of the embodiment, R 4a and R 4b Together with the carbon atoms to which they are both bonded, they can suitably represent a cyclopentyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a fourth aspect of the embodiment, R 4a and R 4bThese, together with the carbon atoms to which they are both bonded, can suitably represent a cyclohexyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0126] In the second embodiment, R 4a and R 4b They both, together with the carbon atoms to which they are bonded, C 3-7 A heterocycloalkyl group can be suitably represented, and this group may be unsubstituted or substituted with one or more substituents, typically one or two substituents. A general example of such embodiments is R 4a and R 4b Together with the carbon atoms to which they are both bonded, these can suitably represent oxetanyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents. A specific example of this embodiment is R 4a and R 4b Together with the carbon atoms to which they are both bonded, these can suitably represent pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents. As a more specific example of its embodiment, R 4a and R 4b Together with the carbon atoms to which they are both bonded, these groups can suitably represent tetrahydropyranyl or piperidinyl, and either of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In the first embodiment of this model, R 4a and R 4bTogether with the carbon atoms to which they are both bonded, they can suitably represent an oxetanyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a second aspect of the embodiment, R 4a and R 4b Together with the carbon atoms to which they are both bonded, they can suitably represent a pyrrolidinyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a third aspect of the embodiment, R 4a and R 4b Together with the carbon atoms to which they are both bonded, they can suitably represent a tetrahydropyranyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a fourth aspect of the embodiment, R 4a and R 4b These, together with the carbon atoms to which they are both bonded, can suitably represent a piperidinyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0127] Typically, R 4a and R 4b Together with the carbon atoms to which they are both bonded, these can represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0128] Appropriately, R 4a and R 4bTogether with the carbon atoms to which they are both bonded, these can represent cyclohexyl, tetrahydropyranyl, or piperidinyl, any of which may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0129] Preferably, R 4a and R 4b Together with the carbon atoms to which they are both bonded, these groups can represent cyclohexyl or tetrahydropyranyl, and either of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0130] R 4a and R 4b A typical example of an optional substituent on the cyclic portion formed by is C 1-6 Alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, 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 Examples include one, two, or three substituents independently selected from the alkylamino. An additional example is oxetanyl.

[0131] R 4a and R 4b Suitable examples of optional substituents on the cyclic portion formed by include one, two, or three substituents independently selected from halogens and oxetanyls.

[0132] R 4a and R 4bPreferred examples of optional substituents on the cyclic portion formed by include one, two, or three substituents independently selected from the halogen.

[0133] R 4a and R 4b Typical examples of specific substituents on the cyclic moiety formed by include one, two, or three substituents independently selected from methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, and dimethylamino. An additional example is oxetanyl.

[0134] R 4a and R 4b Suitable examples of specific substituents on the cyclic portion formed by include one, two, or three substituents independently selected from fluoro and oxetanyl.

[0135] R 4a and R 4b Preferred examples of specific substituents on the cyclic portion formed by include one, two, or three substituents independently selected from fluoro.

[0136] R 4a and R 4b Typical examples of cyclic moieties formed by these compounds include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonylpyrrolidinyl, tetrahydropyranyl, piperidinyl, and methoxycarbonylpiperidinyl. An additional example is oxetanylpiperidinyl.

[0137] R 4a and R 4b Selected examples of cyclic moieties formed by this include difluorocyclohexyl, tetrahydropyranil, and oxetanylpiperidinil.

[0138] R 4a and R 4b Preferred examples of the cyclic portions formed by this include difluorocyclohexyl and tetrahydropyranil.

[0139] In the first embodiment, R 5a represents hydrogen. In the second embodiment, R 5a represents fluoro. In the third embodiment, R 5a represents methyl. In the fourth embodiment, R 5a represents difluoromethyl. In the fifth embodiment, R 5a This represents trifluoromethyl.

[0140] Typically, R 5a represents hydrogen, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0141] Appropriately, R 5a represents hydrogen, methyl, difluoromethyl, or trifluoromethyl.

[0142] Preferably, R 5a This represents difluoromethyl or trifluoromethyl.

[0143] In the first embodiment, R 5b represents hydrogen. In the second embodiment, R 5b represents fluoro. In the third embodiment, R 5b represents methyl. In the fourth embodiment, R 5b represents hydroxyl.

[0144] Typically, R 5b represents hydrogen, fluoro, or hydroxyl.

[0145] Preferably, R 5b This represents fluoro or hydroxy, especially hydroxy.

[0146] Alternatively, R 5a and R 5bThey may come together to form a spiro bond. Therefore, R 5a and R 5b These, together with the carbon atoms to which they are bonded, can represent cyclopropyl.

[0147] Typically, R 6 は-OR 6a Or -NR 6b R 6c Represents; or R 6 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 ) represents alkyl, and any of these groups may optionally be substituted by one or more substituents.

[0148] Appropriately, R 6 は-OR 6a Or -NR 6b R 6c Represents; or R 6 C 3-9 The terms represent a cycloalkyl, aryl, or heteroaryl group, and any of these groups may optionally be substituted with one or more substituents.

[0149] Preferably, R 6 は-OR 6a Represents; or R 6 C 3-9 Represents a cycloalkyl or heteroaryl group, where any of these groups may be optionally substituted by one or more substituents.

[0150] In the first embodiment, R 6 C is substituted in some cases. 1-6 Represents alkyl. In the second embodiment, R 6 C is substituted in some cases. 3-9 Represents a cycloalkyl group. In the third embodiment, R6 C is substituted in some cases. 3-9 Cycloalkyl (C 1-6 ) represents alkyl. In the fourth embodiment, R 6 represents an aryl that may be substituted. In the fifth embodiment, R 6 This is the aryl(C) which may be substituted in some cases. 1-6 ) represents alkyl. In the sixth embodiment, R 6 C is substituted in some cases. 3-7 Represents heterocycloalkyl. In the seventh embodiment, R 6 C is substituted in some cases. 3-7 Heterocycloalkyl (C 1-6 ) represents alkyl. In the eighth embodiment, R 6 R represents a heteroaryl that may be substituted. In the ninth embodiment, R 6 This is a heteroaryl (C) that may be substituted in some cases. 1-6 ) represents alkyl. In the tenth embodiment, R 6 は-OR 6a This represents R. In the 11th embodiment, R 6 -NR 6a R 6b It represents.

[0151] R 6 A typical example of this is -OR 6a or -NR 6a R 6b Examples include methyl, ethyl, propyl, 2-methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, triazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, or pyridinylmethyl, any of these groups may optionally be substituted with one or more substituents.

[0152] R 6 A good example of this is -OR 6a or -NR 6a R 6bExamples include cyclopropyl, phenyl, pyrazolyl, isoxazolyl, oxadiazolyl, or triazolyl, any of which may be optionally substituted with one or more substituents.

[0153] R 6 Selected examples include -OR 6a Examples include cyclopropyl, pyrazolyl, oxadiazolyl, or triazolyl groups, any of which may be optionally substituted with one or more substituents.

[0154] R 6 A good example of this is -OR 6a Examples include cyclopropyl, pyrazolyl, or oxadiazolyl, any of which may be optionally substituted with one or more substituents.

[0155] R 6 Exemplary examples include pyrazolyl, isoxazolyl, oxadiazolyl, and triazolyl, any of which may be optionally substituted with one or more substituents.

[0156] R 6 Common examples include pyrazolyl, oxadiazolyl, and triazolyl, any of which may be optionally substituted with one or more substituents.

[0157] R 6 Typical examples include pyrazolyl and oxadiazolyl, in which either of these groups may be optionally substituted with one or more substituents.

[0158] R 6 A specific example of this is oxadiazolyl, which may optionally be substituted by one or more substituents.

[0159] R 6Typical examples of the optional substituents above include halogens, cyanos, nitros, and C. 1-6 Alkyl, trifluoromethyl, cyclopropyl, phenyl, fluorophenyl, hydroxy, hydroxy(C 1-6 ) alkyl, oxo, C 1-6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, 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 Alkylcarbonylamino(C 1-6 ) Alkyl, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) Alkylaminosulfonyl and di(C 1-6 Examples include one, two, or three substituents independently selected from the alkylsulfoxyiminyl.

[0160] R 6 Suitable examples of the optional substituents above include halogens, C 1-6 Examples include one, two, or three substituents independently selected from alkyl and cyclopropyl groups.

[0161] R 6 Preferred examples of the optional substituents above include halogens and C 1-6 Examples include one, two, or three substituents independently selected from the alkyl group.

[0162] R 6 Typical examples of the specific substituents listed above include one, two, or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoxyiminyl.

[0163] R 6 Suitable examples of the specific substituents mentioned above include one, two, or three substituents independently selected from fluoro, methyl, ethyl, isopropyl, and cyclopropyl.

[0164] R 6 Preferred examples of the above specific substituents include one, two, or three substituents independently selected from fluoro, methyl, and isopropyl.

[0165] R 6Examples of specific values ​​include methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxyethyl, difluoropropyl, 2-methylpropyl, butyl, fluorocyclopropyl, cyanocyclopropyl, methylcyclopropyl, ethylcyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chlorophenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethylsulfoxyiminylphenyl, benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, (chloro)(fluoro)benzyl, dichlorobenzyl, (chloro)(difluoro)benzyl, bromobenzyl, cyanobenzyl, methyl Examples include benzyl, 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.

[0166] R 6Typical values ​​include fluorocyclopropyl, methylpyrazolyl, ethylpyrazolyl, isopropylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl, and isopropyltriazolyl.

[0167] R 6 Selected values ​​include fluorocyclopropyl, methylpyrazolyl, isopropylpyrazolyl, methyloxadiazolyl, and isopropyltriazolyl.

[0168] R 6 Suitable values ​​include fluorocyclopropyl, isopropylpyrazolyl, and methyloxadiazolyl.

[0169] In the first embodiment, R 6a C is substituted in some cases. 1-6 Represents alkyl. In the second embodiment, R 6a C is substituted in some cases. 3-9 Represents a cycloalkyl group. In the third embodiment, R 6a This is the aryl(C) which may be substituted in some cases. 1-6 ) Represents alkyl.

[0170] Typically, R 6a C 1-6 The group represents alkyl, cyclobutyl, or benzyl, and any of these groups may optionally be substituted with one or more substituents.

[0171] R 6a Typical examples of the optional substituents above include halogens, cyanos, nitros, and 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 Alkyl sulfinyl, C 1-6Alkyl 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 sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl and di(C 1-6 Examples include one, two, or three substituents independently selected from alkylaminosulfonyl molecules.

[0172] R 6a Suitable examples of the optional substituents mentioned above include one, two, or three substituents that can be selected independently of the halogen.

[0173] R 6a Typical examples of the specific substituents listed above include one, two, or three 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, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, and dimethylaminosulfonyl.

[0174] R 6aPreferred examples of the specific substituents mentioned above include one, two, or three substituents independently selected from fluoro.

[0175] R 6a Exemplary examples of specific values ​​include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, difluorocyclobutyl, and benzyl.

[0176] Typically, R 6a represents benzyl.

[0177] Typically, R 6b represents hydrogen or methyl.

[0178] In the first embodiment, R 6b represents hydrogen. In the second embodiment, R 6b C 1-6 This represents alkyl, especially methyl.

[0179] Typically, R 6c represents hydrogen or methyl.

[0180] In the first embodiment, R 6c represents hydrogen. In the second embodiment, R 6c C 1-6 This represents alkyl, especially methyl.

[0181] Alternatively, partial-NR 6b R 6c This can preferably represent azetidine-1-yl, pyrrolidine-1-yl, oxazolidine-3-yl, isoxazolidine-2-yl, thiazolidin-3-yl, isothiazolidine-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 optionally be substituted by one or more substituents.

[0182] Complex ring part - NR6b R 6c Selected examples of preferred substituents above include C 1-6 Alkyl, C 1-6 Alkylsulfonyl, hydroxy, hydroxy(C 1-6 ) alkyl, amino(C 1-6 ) Alkyl, cyano, oxo, C 2-6 Alkylcarbonyl, Carboxylate, C 2-6 Alkoxycarbonyl, amino, C 2-6 Alkylcarbonylamino, C 2-6 Alkylcarbonylamino(C 1-6 ) Alkyl, C 2-6 Alkoxycarbonylamino, C 1-6 Examples include alkylsulfonylaminos and aminocarbonyls.

[0183] Complex ring part - NR 6b R 6c Examples of specific substituents selected above include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxycarbonylamino, methylsulfonylamino, and aminocarbonyl.

[0184] Generally, R 7 -COR 7a , -CO2R 7a Or -SO2R 7b Represents; or R 7 represents hydrogen; or R 7 is C 1-6 The group represents an alkyl group, which may optionally be substituted with one or more fluorine atoms, generally one, two, or three fluorine atoms, typically two fluorine atoms.

[0185] Preferably, R 7 -CO2R 7a It represents.

[0186] In the first embodiment, R 7 ha-COR7a This represents R 7 -CO2R 7a This represents R. In the third embodiment, R 7 -CO2R 7a This represents R. In the fourth embodiment, R 7 represents hydrogen. In the fifth embodiment, R 7 C is a carbon atom optionally substituted with one or more fluorine atoms, typically one, two, or three fluorine atoms. 1-6 Represents an alkyl group. In one embodiment of this, R 7 is unsubstituted C 1-6 R represents alkyl, particularly methyl or ethyl. In another embodiment of the present invention, R 7 C is a carbon atom substituted with one, two, or three fluorine atoms, typically two fluorine atoms. 1-6 It represents an alkyl group. An example of this embodiment is difluoroethyl. In the sixth embodiment, R 7 C is a carbon atom optionally substituted with one or more fluorine atoms, typically one, two, or three fluorine atoms. 3-9 Represents a cycloalkyl group. In one embodiment, R 7 is unsubstituted C 3-9 This represents cycloalkyl, particularly cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment of the present invention, R 7 C is a carbon atom substituted with one, two, or three fluorine atoms, typically two fluorine atoms. 3-9 This represents a cycloalkyl group. An example of this form is difluorocyclobutyl.

[0187] Typically, R 7a C is optionally substituted with 1, 2, or 3 fluorine atoms. 1-6 Represents alkyl.

[0188] Preferably, R 7a C 1-6 Alkyl or difluoro(C) 1-6 ) Represents alkyl.

[0189] In the first embodiment, R7a C 1-6 Represents alkyl, particularly methyl or ethyl. In the first embodiment of the present invention, R 7a represents methyl. In a second embodiment of the embodiment, R 7a represents ethyl. In the second embodiment, R 7a is difluoro(C 1-6 ) Represents alkyl, especially difluoroethyl.

[0190] R 7a Specific values ​​include methyl and difluoroethyl.

[0191] Preferably, R 7b R represents methyl or ethyl. In the first embodiment, R 7b represents methyl. In the second embodiment, R 7b 'Ethyl' represents ethyl.

[0192] Preferably, R 8 R represents methyl or ethyl. In the first embodiment, R 8 represents methyl. In the second embodiment, R 8 'Ethyl' represents ethyl.

[0193] Various subclasses of the compounds according to the present invention are of formula (IIA-1), (IIA-2), (IIA-3), (IIB-1), (IIC-1), and (IIC-2): [ka] [ka] (In the formula, X represents CH or N; R 16 is represented by methyl, ethyl, isopropyl, or cyclopropyl; R 26 represents fluoro or trifluoromethyl; A is as defined above.) It is represented by the compound and its N-oxide, as well as its pharmaceutically acceptable salts.

[0194] In the first embodiment, X represents CH. In the second embodiment, X represents N.

[0195] In the first embodiment, R 16 represents methyl. In the second embodiment, R 16 represents ethyl. In the third embodiment, R 16 represents isopropyl. In the fourth embodiment, R 16 This represents cyclopropyl.

[0196] Typically, R 16 This represents methyl, ethyl, or isopropyl.

[0197] Preferably, R 16 This represents methyl or isopropyl.

[0198] In the first embodiment, R 26 represents fluoro. In the second embodiment, R 26 This represents trifluoromethyl.

[0199] Specific novel compounds according to the present invention include each of the compounds described in the appended examples, as well as their pharmaceutically acceptable salts and solvates.

[0200] Compounds according to the present invention are beneficial for the treatment and / or prevention of various human diseases, including inflammatory disorders and autoimmune disorders.

[0201] Compounds according to the present invention are useful for treating and / or prophylaxis of pathological disorders mediated by or associated with elevated levels of pro-inflammatory IL-17 cytokines. Generally, pathological symptoms include infections (viruses, bacteria, fungi, and parasites), infection-related endotoxin shock, 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 disease, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthritis, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, folliculitis, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, The following conditions are selected from the group consisting of type 1 diabetes, Lyme arthritis, meningoencephalitis, immune-mediated inflammatory diseases of the central and peripheral nervous systems, such as multiple sclerosis and Guillain-Barré syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, scleroderma or systemic sclerosis, cancer (both solid tumors such as melanoma, hepatoblastoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, and hematological malignancies, particularly acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), ischemic diseases such as myocardial infarction, as well as heart diseases including atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria, and pain (particularly pain associated with inflammation).

[0202] International Publication No. 2009 / 089036 demonstrates 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). As a result, compounds according to the present invention are useful for the treatment and / or prevention of 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, full-thickness corneal transplantation, corneal transplantation, laminar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, corneal prosthetic surgery, corneal surface inflammatory symptoms, conjunctival scarring disorders, autoimmune symptoms of the eye, bullous pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye diseases, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjögren's syndrome, Sjögren's syndrome-associated keratoconjunctivitis sicca, non-Sjögren's syndrome-associated keratoconjunctivitis sicca, keratitis sicca, dry eye syndrome, xerophthalmos, tear film dysfunction, decreased tear volume, tear deficiency (ATD), meibomian gland dysfunction, and evaporation loss.

[0203] Exemplary examples, the compounds of the present invention may be useful in the treatment and / or prophylaxis of pathological disorders selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway 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 spondyloarthropathy, cancer, and pain (particularly pain associated with inflammation).

[0204] Preferably, the compounds of the present invention are useful for the treatment and / or prophylaxis of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis, or ankylosing spondylitis.

[0205] The present invention also provides a pharmaceutical composition comprising a compound according to the present invention described above or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers.

[0206] The pharmaceutical composition according to the present invention can take a form suitable for oral, buccal, parenteral, nasal, topical, ocular, or rectal administration, or a form suitable for administration by inhalation or blown-in.

[0207] For oral administration, pharmaceutical compositions may take the form of tablets, lozenges, or capsules, prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); 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 of solutions, syrups, or suspensions, or may be presented as dry products to be mixed with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifiers, non-aqueous vehicles, or preservatives. The preparations may also contain buffer salts, flavoring agents, coloring agents, or sweeteners, as needed.

[0208] Preparations for oral administration may be suitably formulated to provide controlled release of the active compound.

[0209] For buccal administration, the composition may take the form of tablets or lozenges, formulated in a conventional manner.

[0210] The compounds according to the present invention may be formulated for parenteral administration by injection, for example, by bolus injection or infusion. The formulation for injection may be presented in unit dosage forms, for example, glass ampoules or multi-dose containers, for example, glass vials. The composition for injection may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspending agents, stabilizers, preservatives, and / or dispersants. Alternatively, the active ingredient may be in powder form for preparation with a suitable vehicle before use, for example, sterile pyrogen-free water.

[0211] In addition to the formulations described above, the compounds according to the present invention may also be formulated as depot preparations. Such long-acting formulations may be administered by transplantation or intramuscular injection.

[0212] For nasal or inhalation administration, the compounds according to the present invention may be conveniently delivered in the form of a pressurized pack or aerosol spray presentation for nebulizers using a suitable propellant, such as dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases or mixtures of gases.

[0213] The composition may be presented in a pack or dispenser device, which may optionally contain one or more unit dosage forms containing the active ingredient. The pack or dispenser device may be accompanied by instructions for administration.

[0214] For topical administration, the compounds according to the present invention may be conveniently formulated into suitable ointments containing the active component 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 may be formulated into suitable lotions containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol, and water.

[0215] For ocular administration, the compound according to the present invention may be conveniently formulated as a microparticle suspension in isotonic, pH-adjusted sterile physiological saline, with or without a bactericide or antifungal agent, such as a preservative including phenylmercury nitrate, benzylalkonium chloride, or chlorhexidine acetate. Alternatively, for ocular administration, the compound according to the present invention may be formulated as an ointment such as petrolatum.

[0216] For rectal administration, the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component 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 component. Examples of such substances include cocoa butter, beeswax, and polyethylene glycol.

[0217] The amount of the compound according to the present invention required for the prophylaxis or treatment of a specific symptom may vary depending on the compound selected and the symptoms of the patient being treated. However, generally, the daily dose may range from about 10 ng / kg body weight to 1000 mg / kg body weight, typically 100 ng / kg body weight to 100 mg / kg body weight, e.g., about 0.01 mg / kg body weight to 40 mg / kg body weight, for oral or buccal administration; from about 10 ng / kg body weight to 50 mg / kg body weight for parenteral administration; and from about 0.05 mg to about 1000 mg, e.g., about 0.5 mg to about 1000 mg for nasal administration or by inhalation or inhalation.

[0218] If desired, the compounds according to the present invention may be administered co-administered with another pharmaceutically active agent, such as an anti-inflammatory molecule.

[0219] The compound of formula (I) above is of formula R 6 -CO2H can be prepared by a process comprising reacting a carboxylic acid of CO2H or a salt thereof (e.g., its lithium salt) with the compound of formula (III): [ka] In the formula, A, E, R 1 and R 6 This is as defined above.

[0220] The reaction is conveniently achieved 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-trioxatriphospholinane-2,4,6-trioxide; and 2-chloro-1-methylpyridinium iodide. Suitable bases include organic amines, such as trialkylamines such as N,N-diisopropylethylamine; or pyridines. The reaction is conveniently carried out at ambient temperature or high temperature in a suitable solvent, such as a cyclic ether such as tetrahydrofuran; or a bipolar aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate.

[0221] Alternatively, the reaction may be conveniently achieved in the presence of a coupling agent such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI). The reaction is preferably carried out in a suitable solvent, such as an organic nitrile solvent such as acetonitrile, at a suitable temperature, for example, in the range of 0°C.

[0222] R 6 C 1-6 When an alkyl group, for example methyl, is represented, the compound of formula (I) above is represented by formula R 6 The compound can be prepared by a process involving the reaction of a -COCl compound, such as acetyl chloride, with the compound of formula (III) defined above. The reaction is conveniently achieved in the presence of a base. Suitable bases include organic amines, such as trialkylamines such as N,N-diisopropylethylamine. The reaction conveniently proceeds at ambient temperature in a suitable solvent, such as a cyclic ether such as tetrahydrofuran.

[0223] R 6 ga-OR 6a When representing, the compound of formula (I) above is (i) formula R 6aThe compound can be prepared by a two-step process comprising: (i) reacting the -OH compound with N,N'-disuccinimidylcarbonate, ideally in the presence of a base, such as an organic amine such as triethylamine; and (ii) reacting the resulting substance with the compound of formula (III) defined above. Steps (i) and (ii) can be conveniently carried out at ambient temperature in a suitable solvent, such as a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile.

[0224] The intermediate of equation (III) above is equation (IV): [ka] (In the formula, A, E and R 1 As defined above, R p (represents an N-protecting group) from the compound R p It can be prepared by removing [something].

[0225] N-protecting group R p Preferably, this is tert-butoxycarbonyl (BOC), in which case its removal may be conveniently induced by treatment with an acid, such as a mineral acid like hydrochloric acid, or an organic acid like trifluoroacetic acid.

[0226] Alternatively, the N-protecting group R p This may be benzyloxycarbonyl, in which case its removal may be conveniently induced by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of a hydrogenation catalyst, such as palladium carbon or palladium carbon hydroxide. N-protecting group R p In the modification procedure where benzyloxycarbonyl is present, its removal may be caused by treatment with hydrogen bromide and acetic acid.

[0227] In the alternative procedure, the compound of formula (I) above, in which A represents the group of formula (Ad), (i) Formula (V): [ka] (In the formula, E, R 1 , R 4a , R 4b and R 6 As defined above, Alk 1 C 1-4 Saponification of alkyl compounds (representing, for example, methyl, ethyl, or tert-butyl); and (ii) Compound (III) and formula R 6 Regarding the reaction between CO2H and carboxylic acids, under conditions similar to those described above, the resulting carboxylic acid derivative and formula R 3 - Reaction with H compounds It can be prepared by a two-step process that includes [the following].

[0228] Similarly, the intermediate of the above equation (IV) in which A represents the base of equation (Ad) is (i) Equation (VI): [ka] (In the formula, E, R 1 , R 4a , R 4b , R p and Alk 1 This is the saponification of compounds (as defined above); and (ii) Compound (III) and formula R 6 Regarding the reaction between CO2H and carboxylic acids, under conditions similar to those described above, the resulting carboxylic acid derivative and formula R 3 - Reaction with H compounds It can be prepared by a two-step process that includes [the following].

[0229] Alk 1If represents methyl or ethyl, the saponification reaction in step (i) is generally caused by treatment with a base. Suitable bases include inorganic hydroxides, such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. The reaction is carried out with water and a suitable organic solvent, such as a cyclic ether such as tetrahydrofuran, or C such as methanol or ethanol. 1-4 This process can be conveniently carried out at ambient temperature or high temperature in a chlorinated solvent such as an alkanol or dichloromethane.

[0230] Alternatively, Alk 1 If represents tert-butyl, the saponification reaction in step (i) may generally be induced by treatment with an acid, such as an organic acid such as trifluoroacetic acid. The reaction conveniently takes place at ambient temperature in a suitable organic solvent, such as a chlorinating solvent such as dichloromethane.

[0231] The intermediates of formula (V) above are compound (III) and formula R 6 For the reaction between CO2H and carboxylic acids, under conditions similar to those described above, formula R 6 -CO2H can be prepared by reacting the carboxylic acid with the compound of formula (VII): [ka] In the formula, E, R 1 , R 4a , R 4b , R 6 and Alk 1 This is as defined above.

[0232] The intermediate of formula (VII) above is formed from the N-protecting group R from the compound of formula (IV). p Regarding the removal of the N-protecting group R under conditions similar to those described above, remove the N-protecting group R from the compound of formula (VI) defined above. P It can be prepared by removing [something].

[0233] The intermediate of formula (VI) above can be prepared by reacting the compound of formula (VIII) with the compound of formula (IX): [ka] In the formula, E, R 1 , R 4a , R 4b Alk 1 and R p As defined above, L 1 This represents a suitable leaving group.

[0234] Leaving group L 1 These are typically halogen atoms, such as bromo.

[0235] The reaction is typically carried out in the presence of a base. Preferably, the base may be an inorganic base, such as a bicarbonate such as sodium bicarbonate; or an organic base such as pyridine. The reaction is carried out in a suitable solvent, such as ethanol or isopropanol. 1-4 This is conveniently induced at high temperatures in alkanols or cyclic ethers such as 1,4-dioxane.

[0236] In the alternative procedure, the compound of formula (I) above, in which A represents a group of formula (Aa), (Ab), or (Ac), becomes compound (III) and formula R 6 For the reaction between CO2H and carboxylic acids, under conditions similar to those described above, formula R 2 The carboxylic acid of -CO2H is given by formula (X): [ka] (In the formula, A 1 This is the formula (Aa-1), (Ab-1), or (Ac-1): [ka] (In the formula, an asterisk (*) represents a bond point with the rest of the molecule) E, Y, R 1 , R 2 and R 6 (As defined above) It can be prepared by a process that includes reacting it with a compound.

[0237] The intermediate of the above equation (X) is equation (XI): [ka] (In the formula, A 2 This is the formula (Aa-2), (Ab-2), or (Ac-2): [ka] (In the formula, an asterisk (*) represents a bond point with the rest of the molecule) R z represents an N-protecting group; E, Y, R 1 and R 6 (As defined above) N-protecting group R from the compound z It can be prepared by removing [something].

[0238] N-protecting group R z Preferably, this is tert-butoxycarbonyl (BOC), in which case its removal may be conveniently induced by treatment with an acid, such as a mineral acid like hydrochloric acid, or an organic acid like trifluoroacetic acid.

[0239] The intermediate of the above equation (XI) is obtained in the following steps: (i) Equation (XII) under conditions similar to those above: [ka] (In the formula, E, A 2 , R 1 and R p The N-protecting group R from the compound (as defined above)p Removal of; and (ii) Compound (III) and formula R 6 Regarding the reaction between CO2H and carboxylic acids, under conditions similar to those described above, the substance obtained and formula R 6 Reaction of -CO2H with carboxylic acid It can be prepared by a two-step procedure, including [the following].

[0240] Alternatively, the intermediate of formula (IV) above, where A is a base of formula (Aa), (Ab), or (Ac), is obtained in the following steps: (i) Under conditions similar to those described above, the N-protecting group R from the compound of formula (XII) defined above. z Removal of; and (ii) Compound (III) and formula R 6 Regarding the reaction between CO2H and carboxylic acids, under conditions similar to those described above, the substance obtained and formula R 2 Reaction of -CO2H with carboxylic acid It can be prepared by a two-step procedure, including [the following].

[0241] The intermediate of the above formula (XII) is obtained in the presence of a transition metal catalyst, as shown in formula A 2 -CO2H compounds can be prepared by reacting them with the compound of formula (XIII): [ka] In the formula, E, A 2 , R 1 and R p This is as defined above.

[0242] Suitable transition metal catalysts used in 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; and tris[2-phenylpyridinate-C] 2[,N]iridium(III) is one example. The reaction is generally carried out by exposing the reactants to a bright light source. A suitable bright light source is typically the "integrated photoreactor" described in ACS Cent.Sci., 2017, 3, 647-653; or the Penn photoreactor M2 system. The reaction is conveniently carried out at ambient temperature in a suitable solvent, such as a bipolar aprotic solvent such as N,N-dimethylformamide, or an organic disulfide such as dimethyl sulfoxide.

[0243] Alternatively, the intermediate of equation (XI) above is obtained in the following steps: (i) Under conditions similar to those described above, the N-protecting group R from the compound of formula (XIII) defined above. p Removal of; (ii) Compound (III) and formula R 6 Regarding the reaction between the carboxylic acid of -CO2H or its salt (e.g., its lithium salt) under conditions similar to those described above, the substance obtained and formula R 6 - Reaction of CO2H with carboxylic acids or their salts (e.g., lithium salts thereof); and (iii) Compound (XIII) and Formula A 2 Regarding the reaction between CO2H and carboxylic acids, under conditions similar to those described above, the substance obtained thereby and formula A 2 - Reaction with CO2H compounds It can be prepared by a three-step procedure, including [the following].

[0244] Alternatively, the compound of formula (I) above, where A is the group of formula (Ad), is as follows: (i) Under conditions similar to those described above, the N-protecting group R from the compound of formula (XIII) defined above. p Removal of; (ii) Compound (III) and formula R 6 Regarding the reaction between the carboxylic acid of -CO2H or its salt (e.g., its lithium salt) under conditions similar to those described above, the substance obtained and formula R 6- Reaction of CO2H with carboxylic acids or their salts (e.g., lithium salts thereof); and (iii) Compound (XIII) and Formula A 2 Reaction between carboxylic acids of -CO2H and the resulting substance with the compound of formula A-CO2H under similar conditions as described above. It can be prepared by a three-step process that includes [the following].

[0245] The intermediate of formula (XIII) above is obtained by the reaction between compounds (VIII) and (IX) under similar conditions as above, using the compound of formula (IX) defined above as formula (XIV): [ka] (In the formula, R 1 It can be prepared by reacting it with a compound (as defined above).

[0246] In the alternative procedure, as defined above, A represents the base of equation (Ae), and Z represents equation (Zt) (where R 2z Compounds of formula (I) representing the group (where represents hydrogen) are of formula R 1z -NH2 compounds and trialkyl orthoformate HCl (O-Alk 1 )3 can be prepared by a process that includes reacting it with a compound of formula (XV): [ka] In the formula, E, R 1 , R 4a , R 4b , R 6 , R 1z and Alk 1 This is as defined above.

[0247] The reaction conveniently proceeds at high temperatures in the presence of acetic acid. Typically, the reaction can be carried out in a suitable solvent, such as a cyclic ether like 1,4-dioxane.

[0248] The intermediate of formula (XV) above can be prepared by reacting the compound of formula (V) defined above with hydrazine hydrate.

[0249] The reaction is carried out in a suitable solvent, such as ethanol. 1-4 This process conveniently occurs at high temperatures within alkanol.

[0250] As defined above, the intermediate of the above formula (IV), where A represents the base of formula (Ae) and Z represents the base of formula (Zu), is formed in the following steps: (i) Saponification of the compound of formula (VI) defined above by treatment with a base; (ii) Compound (III) and formula R 6 Regarding the reaction between CO2H and carboxylic acids, under conditions similar to those described above, the resulting carboxylic acid derivative and formula (XVI): [ka] (In the formula, R 2z The reaction of compounds (as defined above); and (iii) Cyclization of the obtained substance by treatment with triphenylphosphine in the presence of a base. It can be prepared by a three-step procedure, including [the following].

[0251] The saponification reaction in step (i) is generally caused by treatment with a base. Suitable bases include inorganic hydroxides, such as alkali metal hydroxides like lithium hydroxide.

[0252] Suitable bases for use in step (iii) include organic amines, such as trialkylamines such as triethylamine. The reaction conveniently proceeds at ambient temperature in the presence of hexachloroethane and a suitable solvent, such as a cyclic ether such as tetrahydrofuran.

[0253] In another procedure, as defined above, A represents the base of equation (Ae), and Z represents equation (Zw) or (Zx) (where R 1z Compounds of formula (I) representing a group other than hydrogen are formed in the following steps: (i) Alkali metal azides are given by formula (XVII): [ka] (In the formula, E, R 1 , R 4a , R 4b and R 6 (as defined above) react with the compound; and (ii) The obtained substance is given by formula R 1z -L 3 (In the formula, R 1z L is as defined above (and is not hydrogen), 3 (represents a suitable leaving group) It can be prepared by a two-step procedure, including [the following].

[0254] In step (i), the alkali metal azide is preferably sodium azide. The reaction is conveniently carried out at high temperature in the presence of ammonium chloride and a suitable solvent, such as a dipolar aprotic solvent such as N,N-dimethylformamide.

[0255] Leaving group L 3 Preferably, the derivative may be a sulfonyloxy derivative, such as trifluoromethanesulfonyloxy.

[0256] Step (ii) is generally achieved in the presence of a base. Suitable bases include alkali metal carbonates, such as potassium carbonate. The reaction is conveniently carried out at high temperatures in a suitable solvent, such as a carbonyl-containing solvent like acetone.

[0257] The intermediate of the above equation (XVII) is obtained in the following steps: (i) reacting a compound of formula (XIII) defined above with ammonia; and (ii) React the substance obtained therefrom with trifluoroacetic anhydride in the presence of pyridine. It can be prepared by a two-step procedure, including [the following].

[0258] Step (i) is to use a suitable solvent, such as methanol. 1-4 This process conveniently occurs at high temperatures within alkanol.

[0259] Step (ii) is conveniently carried out at ambient temperature in a suitable solvent, for example, a cyclic ether such as 1,4-dioxane.

[0260] As defined above, A represents the base of equation (Ae), and Z represents equation (Zq) (where R 2z The intermediate of the above formula (IV), which represents the group (where is hydrogen), is given by formula R in the presence of a transition metal catalyst. 1z -N3 azide derivatives are given by formula (XVIII): [ka] (In the formula, E, R 1 , R 4a , R 4b , R 1z and R p It can be prepared by reacting it with a compound (as defined above).

[0261] A suitable transition metal catalyst for use in the above reaction is chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II).

[0262] The reaction is conveniently carried out at high temperatures in a suitable solvent or mixture of solvents. Typical solvents include alkyl ethers, e.g., tert-butyl methyl ether; or 1,2-dimethoxyethane; and cyclic ethers, e.g., tetrahydrofuran.

[0263] The intermediate of the above equation (XVIII) is equation (XIX): [ka] (In the formula, E, R 1 , R 4a , R 4b and R p It can be prepared by reacting the compound (as defined above) with dimethyl(1-diazo-2-oxopropyl)phosphonate.

[0264] The reaction generally takes place in the presence of a base. Preferably, the base may be an alkali metal carbonate, such as potassium carbonate. The reaction conveniently proceeds at ambient temperature in a suitable solvent or mixture of solvents. Typical solvents include C 1-4 Examples include alkanols, such as methanol; and chlorinated solvents, such as dichloromethane.

[0265] The intermediates of the above equation (XIX) are as follows: (i) Formula (XX): [ka] (In the formula, E, R 1 , R 4a , R 4b and R p As defined above, R s (represents an O-protecting group) from the compound R s Removal of; and (ii) Treatment of the compound obtained thereby with an oxidizing agent It can be prepared by a two-step procedure, including [the following].

[0266] O-protecting group R s Preferably, it is acetyl.

[0267] R sIf represents acetyl, its removal in step (i) above may be conveniently induced by treatment with a base. Preferably, the base may be an alkali metal carbonate, such as potassium carbonate. The reaction is carried out in a suitable solvent, such as methanol. 1-4 In alkanols, this is conveniently triggered by ambient temperature.

[0268] A suitable oxidizing agent for use in step (ii) above is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (Dess Martinperiodinane). The reaction is conveniently carried out at ambient temperature in a suitable solvent, such as a chlorinating solvent like dichloromethane.

[0269] Alternatively, the oxidizing agent used in step (ii) above may include a sulfur trioxide pyridine complex, in which case the reaction may be conveniently achieved in the presence of a base. Preferably, the base may be an organic amine, such as N,N-diisopropylethylamine.

[0270] The intermediate of formula (XX) above is obtained by the reaction between compounds (VIII) and (IX) under similar conditions to those described above, using the compound of formula (IX) defined above as formula (XXI): [ka] (In the formula, R 1 , R 4a , R 4b and R s It can be prepared by reacting it with a compound (as defined above).

[0271] If they are not commercially available, the starting materials of formulas (VIII), (IX), (XIV), (XVI), and (XXI) may be prepared by methods similar to those described in the accompanying examples, or by standard methods well known in the art.

[0272] It will be understood that any compound of formula (I) initially obtained from any of the above processes can, where appropriate, subsequently be synthesized into further compounds of formula (I) by techniques known in the art. For example, a compound containing an N-BOC moiety (BOC being an abbreviation for tert-butoxycarbonyl) may be converted to a corresponding compound containing an NH moiety by treatment with an acid, such as a mineral acid like hydrochloric acid, or an organic acid like trifluoroacetic acid.

[0273] Compounds containing an NH functional group may typically be alkylated, for example, methylated, by treatment with a suitable alkyl halide, such as iodomethane, in the presence of a base, such as an inorganic carbonate such as sodium carbonate.

[0274] Compounds containing an NH functional group may typically be acylated, for example, acetylated, by treatment with a suitable acyl halogenate, such as acetyl chloride, in the presence of a base, such as an organic base such as N,N-diisopropylethylamine or triethylamine. Similarly, compounds containing an NH functional group may typically be acylated, for example, acetylated, by treatment with a suitable acyl anhydride, such as acetic anhydride, in the presence of a base, such as an organic base such as triethylamine.

[0275] Similarly, compounds containing an NH functional group typically exhibit appropriate C in the presence of a base, such as an organic base like triethylamine. 1-4 Treatment with an alkyl sulfonyl chloride reagent, such as methyl sulfonyl chloride, results in NS(O)2Alk 1 Functional group (in the formula, Alk 1 This may be converted into the corresponding compound containing (as defined above).

[0276] Similarly, compounds containing an NH functional group may be converted to the corresponding compound containing a carbamate or urea moiety, respectively, by treatment with a suitable chloroformic acid or carbamoyl chloride reagent in the presence of a base, such as an organic base such as triethylamine or N,N-diisopropylethylamine. Alternatively, compounds containing an NH functional group may be converted to the corresponding compound containing a urea moiety by treatment with a suitable amine-substituted (3-methylimidazole-3-ium-1-yl)methanone iodide derivative in the presence of a base, such as an organic base such as triethylamine. Alternatively, compounds containing an NH functional group may be converted to the corresponding compound containing a urea moiety by treatment with a suitable isocyanate derivative Alk, in the presence of a base, such as an organic base such as triethylamine. 1 -Processing with N=C=O produces the urea portion NC(O)N(H)Alk 1 (In the formula, Alk 1 This may be converted into the corresponding compound containing (as defined above).

[0277] Compounds containing an NH functional group may be converted to the corresponding compound containing an NC(H) functional group by treatment with a suitable aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.

[0278] C 1-4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1 Compounds containing the (as defined above) moiety may be converted to the corresponding compound containing the carboxylic acid (-CO2H) moiety by treatment with a base, such as an alkali metal hydroxide salt such as lithium hydroxide. Alternatively, compounds containing the tert-butoxycarbonyl moiety may be converted to the corresponding compound containing the carboxylic acid (-CO2H) moiety by treatment with trifluoroacetic acid.

[0279] Compounds containing the carboxylic acid (-CO2H) moiety are compound (III) and formula R 6The reaction between -CO2H and carboxylic acids may be converted to the corresponding compound containing the amide moiety by treatment with a suitable amine under conditions similar to those described above.

[0280] C 1-4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1 Compounds containing (as defined above) may be converted to the corresponding compound containing the hydroxymethyl (-CH2OH) moiety by treatment with a reducing agent such as lithium aluminum hydride.

[0281] C 1-4 Alkylcarbonyloxy portion - OC(O)Alk 1 (In the formula, Alk 1 Compounds containing (as defined above), such as acetoxy, may be converted to the corresponding compound containing the hydroxy(-OH) moiety by treatment with a base, such as an alkali metal hydroxide salt such as sodium hydroxide.

[0282] Compounds containing a halogen atom, such as bromo, may be converted to corresponding compounds optionally containing a substituted aryl, heterocycloalkenyl, or heteroaryl moiety by treatment with their cyclic esters formed using appropriately substituted aryl, heterocycloalkenyl, or heteroaryl boronic acids, or organic diols, such as pinacol, 1,3-propanediol, or neopentyl glycol. The 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(O), which may be advantageously used in combination with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). Preferably, the base may be an inorganic base such as sodium carbonate or potassium carbonate.

[0283] Compounds containing a halogen atom, such as bromo, may be converted to a corresponding compound optionally containing a substituted aryl or heteroaryl moiety by a two-step procedure comprising (i) reaction with bis(pinacolato)diborone, and (ii) reaction of the compound obtained thereby with a suitably substituted bromoaryl or bromoheteroaryl derivative. Step (i) is conveniently induced in the presence of a transition metal catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium acetate. Step (ii) is conveniently induced in the presence of a transition metal catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and an inorganic base such as sodium carbonate or potassium carbonate.

[0284] Compounds containing the cyano(-CN) moiety may be converted to the corresponding compound containing the 1-aminoethyl moiety by a two-step process comprising (i) reaction with methylmagnesium chloride, ideally in the presence of titanium(IV) isopropoxide, and (ii) treatment of the resulting substance with a reducing agent such as sodium borohydride. If excess methylmagnesium chloride is used in step (i), the corresponding compound containing the 1-amino-1-methylethyl moiety may be obtained.

[0285] Compounds containing a partial -S- may be converted to corresponding compounds containing a partial -S(O)(NH)- by treatment with (diacetoxyiodo)benzene and ammonium carbamate.

[0286] Compounds containing a C=C double bond may be converted to corresponding compounds containing a CH-CH single bond by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst, such as palladium-carbon.

[0287] Compounds containing aromatic nitrogen atoms may be converted to corresponding compounds containing an N-oxide moiety by treatment with a suitable oxidizing agent, such as 3-chloroperbenzoic acid.

[0288] If a mixture of products is obtained from any of the above processes for preparing the compounds according to the present invention, the desired product may be separated therefrom at appropriate stages by preparative HPLC; or by conventional methods such as column chromatography utilizing silica and / or alumina in combination with a suitable solvent system.

[0289] If the above process for preparing the compound according to the present invention results in a mixture of stereoisomers, these isomers may be separated by conventional techniques. In particular, if it is desired to obtain a specific enantiomer of the compound of formula (I), it may be produced from the corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. For example, a diastereomer derivative, e.g., a salt, may be produced by the reaction of a mixture of enantiomers of formula (I), e.g., a racemate, with a suitable chiral compound, e.g., a chiral base. The diastereomers may then be separated by any convenient means, e.g., crystallization, and the desired enantiomer may be recovered, e.g., by treatment with acid if the diastereomer is a salt. In another resolving process, the racemate of formula (I) may be separated using chiral HPLC. Furthermore, if desired, a specific enantiomer may be obtained by using a suitable chiral intermediate in one of the above processes. Alternatively, specific enantiomers may be obtained by enantiomer-specific enzymatic biotransformation, for example, by ester hydrolysis using an esterase, followed by purification of only the enantiomerically pure hydrolyzed acid from the unreacted ester counterpart. Chromatography, recrystallization, and other conventional separation procedures may be used with intermediates or final products if it is desirable to obtain specific geometric isomers of the present invention.

[0290] During any of the above synthetic sequences, it may be necessary and / or desirable to protect any sensitive or reactive groups of the molecules involved. This can be achieved by conventional protecting groups, such as those described in Greene's Protective Groups in Organic Synthesis, edited by PGMWuts, John Wiley & Sons, 5th edition, 2014. Protecting groups can be removed at any convenient subsequent step using methods known in the art.

[0291] The compounds according to the present invention potently inhibit the release of IL-17-inducible IL-6 from human dermal fibroblasts. Therefore, when tested in the HDF cell line assay described below, the compounds of the present invention exhibit pIC values ​​of 5.0 or higher, generally 6.0 or higher, usually 7.0 or higher, typically 7.2 or higher, preferably 7.5 or higher, ideally 7.8 or higher, and preferably 8.0 or higher. 50 It exhibits a value (pIC 50 -log 10 [I C 50 ] is equal to IC 50 Since it is expressed as molar concentration, a person skilled in the art can determine a higher pIC 50 (You will understand that the higher the value, the more active the compound.)

[0292] Inhibition of IL-17A-induced IL-6 release from dermal fibroblast cell lines The purpose of this assay is to test the neutralizing ability of the IL-17 protein in primary human cell lines. While IL-17 alone stimulates normal human dermal fibroblasts (HDFs) with only a very weak signal, when combined with certain other cytokines such as TNFα, a synergistic effect can be observed in the production of inflammatory cytokines, namely IL-6.

[0293] HDF was stimulated with IL-17A (50 pM) combined with TNF-α (25 pM). The resulting IL-6 response was then measured using a Cisbio homogeneous time-resolved FRET kit. The kit utilizes two monoclonal antibodies: one labeled with Eu-Cryptate (donor) and the other 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 × 10⁴).

[0294] This assay measures the ability of compounds to inhibit the release of IL-17-induced IL-6 from human dermal fibroblasts.

[0295] HDF cells (Sigma#106-05n) were cultured in complete medium (DMEM + 10% FCS + 2 mM L-glutamine) and maintained in tissue culture flasks using standard techniques. Cells were harvested from the tissue culture flasks on the morning of the assay using TrypLE (Invitrogen#12605036). TrypLE was neutralized with complete medium (45 mL), and the cells were centrifuged at 300 × g for 3 minutes. The cells were resuspended in complete medium (5 mL), counted, and the result was 3.125 × 10⁶. 4 After adjusting the concentration to cells / mL, 40 μL / well was added to a 384-well assay plate (Corning #3701). The cells were left at 37°C / 5% CO2 for a minimum of 3 hours to allow them to adhere to the plate.

[0296] After serially diluting the compound with DMSO, the aqueous dilution was placed in a 384-well dilution plate (Greiner #781281), 5 μL from the titration plate was transferred to 45 μL of complete medium, and the mixture was obtained to obtain a solution containing 10% DMSO.

[0297] A mixture of TNFα and IL-17 cytokines was prepared in complete medium at a final concentration of TNFα 25 pM / IL-17A 50 pM, and then 30 μL of the solution was added to a 384-well reagent plate (Greiner #781281).

[0298] 10 μL from an aqueous dilution plate was transferred to a reagent plate containing 30 μL of diluted cytokine to obtain a 2.5% DMSO solution. The compound was incubated with the cytokine mixture at 37°C for 5 hours. After incubation, 10 μL was transferred to an assay plate to obtain a 0.5% DMSO solution, which was then incubated at 37°C / 5% CO2 for 18–20 hours.

[0299] Europium cryptotate and Alexa 665 from the Cisbio IL-6 FRET kit (Cisbio#62IL6PEB) were diluted in reconstituted buffer and mixed 1:1 according to the kit insert. FRET reagent (10 μL) was added to a white low-volume 384-well plate (Greiner#784075), and the supernatant (10 μL) was then transferred from the assay plate to the Greiner reagent plate. The mixture was incubated at room temperature for 3 hours with gentle shaking (<400 rpm), and then read using a Synergy Neo2 plate reader (excitation: 330 nm; emission: 615 / 645 nm).

[0300] When tested with the HDF cell line assay described above, the example compound in the attached example yielded the following pIC values: 50 It was found that it exhibits a value. [Table 1]

[0301] The following examples illustrate the preparation of compounds according to the present invention.

[0302] example Abbreviation DCM: Dichloromethane THF: Tetrahydrofuran MeOH: methanol EtOH: ethanol DMSO: Dimethyl sulfoxide DIPEA: N,N-Diisopropylethylamine DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide æ: ethyl acetate TFA: trifluoroacetic acid IPA: Isopropyl alcohol DMAP: 4-(dimethylamino)pyridine TBME: tert-butylmethyl ether LDA: lithium diisopropylamide AcOH: Acetic acid TBAF: Tetra-n-butylammonium fluoride DMPU:1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone EDCI.HCl:N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride TMEDA: N,N,N',N'-Tetramethylethylenediamine T3P (registered trademark): Anhydrous propylphosphonic acid solution 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; molar concentration RT: Retention time HPLC: High-Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry SFC: Supercritical Fluid Chromatography FCC: Flash Column Chromatography

[0303] Analysis and separation methods Method 1 Short pH10 Stationary phase: Phenomenex Gemini NX-C18 2×20mm, 3μm Mobile phase A: 10 mM ammonium formate in water + 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

[0304] Method 2 Stationary phase: Phenomenex Kinetex-XB C18, 2.1mm x 100mm, 1.7μm Column temperature: 40℃ Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Flow rate: 0.6mL / min Gradient program: Time A% B% 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5

[0305] Method 3 Stationary phase: Chiralpak AD-3, 100×6.4mm, 3μm Column temperature: 35℃ Mobile phase A: CO2 Mobile phase B: IPA (0.05%IP Am) Flow rate: 3.4mL / min Gradient program: Time A% B% 0.00 95 5 2.00 60 40 3.00 60 40 3.60 95 5 4.00 95 5

[0306] Method 4 Stationary phase: Phenomenex Gemini NX-C18 2×50mm, 3μm Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water 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 1.80 5.00 95.00 2.10 5.00 95.00 2.30 95.00 5.00

[0307] Method 5 Stationary phase: Kinetex Core-Shell C18, 2.1×50mm, 5μm Column temperature: 40℃ Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% Formic Acid Flow rate: 1.2mL / min Gradient program: Time A% B% 0.00 95 5 1.20 0 100 1.30 0 100 1.31 95 5

[0308] Method 6 Stationary phase: Phenomenex Gemini NX-C18 2×20mm, 3μm Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water 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

[0309] Method 7 MSDXT, pH10 Stationary phase: Waters Acquity UPLC BEH C18 2.1×50mm, 1.7μm Mobile phase A: 10 mM ammonium formate in water + 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

[0310] Method 8 Long pH10 Stationary phase: Phenomenex Gemini NX-C18 2×20mm, 3μm Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate in water + 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

[0311] Method 9 Purification was performed using SFC with a Lux Cellulose-1 250×21.2mm, 5μm column, 100mL / min flow rate, column temperature 40°C, and an isocratic 7% MeOH (+0.1% NH4OH) elution method (ABPR 60 bar) on a Waters Prep 100fractionlynx system in conjunction with a Waters SQD2 mass spectrometer, using a 14-minute run time.

[0312] Method 10 The analysis is performed in conjunction with the Waters QDa mass spectrometer and the Waters UPC. 2The elution was performed using a Lux Cellulose-C1 150×4.6mm, 3μm column, flow rate of 3mL / min, column temperature of 35°C, with a run time of 6.5 minutes using the Acquity system and an elution gradient of 3–40% MeOH (+0.1% NH4OH) (ABPR 120 bar).

[0313] Method 11 Purification was performed using a Waters Prep150fractionlynx system in conjunction with a Waters QDa mass spectrometer, with a 10-minute run time. The elution method was 10–25% MeOH (+0.1% NH4OH) (ABPR 60 bar) using a Lux Cellulose-4 250×21.2mm, 5μm column, flow rate 100mL / min, column temperature 40°C, and SFC.

[0314] Method 12 The analysis is performed in conjunction with the Waters QDa mass spectrometer and the Waters UPC. 2 The elution was performed using a Lux Cellulose-C4 150×4.6mm, 3μm column, flow rate of 3mL / min, column temperature of 35°C, with a run time of 6.5 minutes using the Acquity system and an elution gradient of 3–40% MeOH (+0.1% NH4OH) (ABPR 120 bar).

[0315] Method 13 Purification was performed using a Waters Prep150fractionlynx system in conjunction with a Waters QDa mass spectrometer, with a run time of 7.5 minutes. The elution method was 3–40% MeOH (+0.1% NH4OH) (ABPR 60 bar) using a Lux Cellulose-2 250×21.2mm, 5μm column, flow rate of 100mL / min, column temperature of 40°C, and SFC.

[0316] Method 14 The analysis is performed in conjunction with the Waters QDa mass spectrometer and the Waters UPC. 2The elution was performed using a Lux Cellulose-C2 150×4.6mm, 3μm column, flow rate of 3mL / min, and column temperature of 35°C, with a run time of 6.5 minutes using the Acquity system and an elution gradient of 3–40% MeOH (+0.1% NH4OH) (ABPR 120 bar).

[0317] Method 15 SFC purification was performed using a Waters Prep150fractionlynx system in conjunction with a Waters QDa mass spectrometer, with a run time of 7.5 minutes, using a Chiralpak IB250×20mm, 5μm column, flow rate of 100mL / min, and column temperature of 40°C, eluting by the 3–40% MeOH (+0.1% NH4OH) method (ABPR 60 bar).

[0318] Method 16 The analysis is performed in conjunction with the Waters QDa mass spectrometer and the Waters UPC. 2 The elution was performed using a Chiralpak IB cell, eluted by the 3-40% MeOH (+0.1% NH4OH) method (ABPR 120 bar), with a 150 × 4.6 mm, 3 μm column, a flow rate of 3 mL / min, and a column temperature of 35°C, using an Acquity system with a run time of 6.5 minutes.

[0319] Method 17 Purification was performed using a Waters Prep100fractionlynx system in conjunction with a Waters SQD2 mass spectrometer, with a 5-minute run time, eluting by isocratic 5% MeOH (ABPR 60 bar) using a Torus DEA 150×19mm, 5μm column, flow rate of 100mL / min, and column temperature of 40°C.

[0320] Method 18 The analysis was performed using a UV-oriented Agilent 1290 Infinity system with an 8-minute run time, eluting by isocratic method with 50% EtOH:50% n-heptane (+0.1% diethylamine) using a (R,R)Whelk-O1 150×4.6 mm, 3.5 μm column, flow rate 1.5 mL / min, and column temperature 30°C.

[0321] Method 19 SFC purification was performed using a Chiralpak, 250×20mm, 5μm column at a column temperature of 40°C, with a flow rate of 100 mL / min, using the 3–40% MeOH (+0.1% NH4OH) method (ABPR 60 bar) on a Waters Prep100fractionlynx system in conjunction with an SQD2 mass spectrometer, with a run time of 6.5 minutes.

[0322] method 20 Chiral analysis is performed in conjunction with the Waters QDa mass spectrometer and Waters UPC. 2 Elution was performed using a Chiralpal IC150×4.6mm, 3μm column, flow rate of 3mL / min, and column temperature of 35°C, with a run time of 6.5 minutes using the Acquity system and eluting by the 3-40% MeOH (+0.1% NH4OH) method (ABPR 120 bar).

[0323] Method 21 SFC purification was performed using a Chiralpak, 250×20mm, 5μm column at a column temperature of 40°C, with a flow rate of 100 mL / min, using the 3–40% MeOH (+0.1% NH4OH) method (ABPR 60 bar) on a Waters Prep150fractionlynx system in conjunction with a QDa mass spectrometer, with a run time of 7.5 minutes.

[0324] Method 22 SFC purification was performed using a Lux Cellulose-4, 250 × 21.2 mm, 5 μm column, flow rate 100 mL / min, column temperature 40°C, eluted by the 3–40% MeOH (+0.1% NH4OH) method (ABPR 60 bar), with a Waters Prep100 fractionlynx system in conjunction with an SQD2 mass spectrometer, using a run time of 7.5 minutes.

[0325] Method 23 SFC purification was performed using a Regis(R,R)-Whelk-O1, 250×21.1mm, 5μm column at a column temperature of 40°C, with a flow rate of 100 mL / min, using the 3–40% MeOH (+0.1% NH4OH) method (ABPR 60 bar) on a Waters Prep100fractionlynx system in conjunction with an SQD2 mass spectrometer, with a run time of 7.5 minutes.

[0326] Method 24 Chiral analysis is performed in conjunction with the Waters QDa mass spectrometer and Waters UPC. 2 The elution was performed using a Regis(R,R)-Whelk-O1 column, 150×4.6mm, 5μm column, flow rate of 3mL / min, and column temperature of 35°C, with a run time of 6.5 minutes using the Acquity system and the elution method (ABPR 120 bar) with 3-40% MeOH (+0.1% NH4OH).

[0327] Method 25 Chiral analysis was performed using a Cellulose-4, 4.6 × 250 mm, 5 μm column with a flow rate of 4 mL / min, eluting in an isocratic gradient of 15% methanol:85% CO2.

[0328] Method 26 SFC purification was performed using a Regis(R,R)-Whelk-O1, 250×21.1mm, 5μm column at a column temperature of 40°C, with a flow rate of 100 mL / min, using a Waters Prep100fractionlynx system with a run time of 7.5 minutes in conjunction with an SQD2 mass spectrometer, and eluting with 3-40% MeOH (no additives) (ABPR 60 bar).

[0329] Method 27 The analysis is performed in conjunction with the Waters QDa mass spectrometer and the Waters UPC. 2 The elution was performed using a Regis(R,R)-Whelk-O1 column, 150×4.6mm, 5μm column, flow rate of 3mL / min, and column temperature of 35°C, with a run time of 6.5 minutes using the Acquity system and eluting by the 3-40% MeOH (no additives) method (ABPR 120 bar).

[0330] Method 28 SFC purification was performed in conjunction with an SQD2 mass spectrometer using a Waters FractionLynx SFC Prep100 for 12 minutes, eluting with a 10–25% methanol (no additives) gradient (60 bar) using a ChiralpakIC, 250 × 20.0 mm, 5 μm column, flow rate of 100 mL / min, and column temperature of 40°C.

[0331] Method 29 The analysis is performed in conjunction with the Waters QDa mass spectrometer and the Waters UPC. 2 The analysis was performed using the Acquity system with a run time of 6.5 minutes, eluting Chiralpak IC using the 3-40% MeOH (no additives) method (ABPR 120 bar), with a 150 × 4.6 mm, 3 μm column, a flow rate of 3 mL / min, and a column temperature of 35°C.

[0332] method 30 Stationary phase: Phenomenex Gemini-NX C18 2.0×50mm, 3μm column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water 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 5.00 5.00 95.00 5.40 5.00 95.00 5.42 95.00 5.00

[0333] Method 31 Stationary phase: Waters UPLC(registered trademark) BEH(trademark) C18, part number 186005297, 2.1 × 50 mm, 1.7 μm column Column temperature: 40℃ Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% Formic Acid Flow rate: 0.9mL / min Gradient program: Time A% B% 0.00 95.00 5.00 1.10 0.00 100 1.358 0.00 100 1.40 95.00 5.00

[0334] Method 32 Preparative HPLC was performed using a Waters Sunfire C18 column (30 × 100 mm, 10 μm) at room temperature with a flow rate of 40 mL / min, using a Gilson system with UV detection at 215 nm and a gradient of 30–95% acetonitrile + 0.1% formic acid in water + 0.1% formic acid.

[0335] Method 33 Preparative chiral LC was performed on a Gilson system equipped with a 321 / 322 pump, GX-241 autosampler, 171 / 172 detector, and preparative FC fraction collector. Column: Chiralcel OD-H, 20 × 250 mm, 5 μm Column temperature: Room temperature Flow rate: 18mL / min Gradient: 85% Heptane: 15% EtOH

[0336] Method 34 Chiral analysis was performed on a Waters2795 with a Waters2998 PDA detector. Purity and / or enantiomer purity were determined by UV (210–400 nm), and identity was confirmed by MS. Column: Chiralcel OD-H, 4.6 × 250 mm, 5 μm Column temperature: Room temperature Flow rate: 1mL / min Gradient: 70% Heptane: 30% EtOH

[0337] Intermediate 1 tert-butyl 4-(trifluoromethyl)-4-(trimethylsilyloxy)piperidine-1-carboxylate To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.06 g, 10.3 mmol) at room temperature in THF (20.7 mL) and DMPU (6.4 mL), CsF (471 mg, 3.10 mmol) was added in one step. The mixture was stirred for 5 minutes, and then (trifluoromethyl)trimethylsilane (3.06 mL, 20.7 mmol) was added dropwise via syringe over 10 minutes. The reaction mixture was stirred at room temperature for 15 minutes, and then diluted with siRNA (40 mL) and water (20 mL). The layers were separated, and the aqueous layer was re-extracted with siRNA (2 × 50 mL). The combined organic layers were washed with brine (2 × 40 mL), dried, and concentrated under vacuum in (Na₂SO₄). The title compound (3.12 g, 80%) was obtained as a pale yellow oil by purification by flash chromatography eluting with siRNA / isohexane (0–10% gradient). δ H (400 MHz, CDCl3) 4.11-3.96 (m, 2H), 3.07-2.90 (m, 2H), 1.79-1.63 (m, 4H), 1.49 (s, 9H), 0.20 (s, 9H).R f 0.59 (isohexane:siRNA, 90:10), non-UV, KMnO4.

[0338] Intermediate 2 1-tert-butoxycarbonyl-4-(trifluoromethyl)-4-(trimethylsilyloxy)piperidine-2-carboxylic acid To a solution of intermediate 1 (4.40 g, 13.0 mmol) and TMEDA (3.50 mL, 23.0 mmol) in diethyl ether (128 mL) at -78°C, sec-butyllithium (1.3 M, 17.0 mL, 24.0 mmol) was added dropwise over 10 minutes. The mixture was stirred at -78°C for 10 minutes, during which time a dull yellow color developed. After this time, the reaction mixture was heated to -40°C (replacing the dry ice / acetone bath with a dry ice / acetonitrile bath) and stirred at -40°C for 20 minutes. The reaction mixture was cooled back down to -78°C, and CO2 was bubbling into the mixture for 30 minutes. After this time, the reaction mixture was heated to room temperature and stirred for 1 hour, then quenched by adding saturated aqueous NH4Cl (100 mL) and H2O (50 mL) (to solubilize the resulting precipitate). The layers were separated, and the aqueous layer was washed with diethyl ether (2 × 100 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under vacuum. Purification by flash chromatography eluting with siRNA / isohexane (0–100% gradient) followed by DCM / MeOH (90:10) revealed the title compound (assumed to be a mixture of two diastereomers). 1 (Indistinguishable by 1H NMR) (2.58g, 52%) was obtained as a dark yellow oily substance. δ H (400 MHz, DMSO-d6) 13.05-12.40 (br s, 1H), 4.25 (dd, J 8.3, 6.4 Hz, 1H), 3.74-3.58 (m, 1H), 3.39-3.19 (obscured m, 1H), 2.16 (dd, J 14.2, 8.4 Hz, 1H), 2.08 (dd, J14.2, 6.5 Hz, 1H), 2.01-1.91 (m, 1H), 1.87-1.75 (m, 1H), 1.38 (s, 9H), 0.15 (s, 9H).

[0339] Intermediate 3 1-tert-butoxycarbonyl-4-hydroxy-4-(trifluoromethyl)piperidine-2-carboxylic acid To a solution of Intermediate 2 (1.73 g, 4.49 mmol) at room temperature in THF (45 mL), TBAF (1 M in THF, 6.73 mL, 6.73 mmol) was added dropwise over 2 minutes. The mixture was stirred at room temperature for 30 minutes, and TLC analysis after that time showed the appearance of different acids (100% siRNA, baseline streaking, but more polar than the starting material). The mixture was concentrated under vacuum and then redissolved in diethyl ether (20 mL), and H2O (20 mL) was added. The layers were separated, and the aqueous layer was re-extracted with diethyl ether (2 × 20 mL). The combined organic extract was dried (Na2SO4) and concentrated under vacuum. siRNA (approximately 1 mL, the minimum amount to solubilize) and then isohexane (approximately 5 mL) were added to the crude substance. The resulting suspension was stirred overnight at room temperature and then filtered under suction using a Buchner funnel. The precipitate was washed with isohexane and then dried under vacuum to obtain the title compound (assumed to be a mixture of two diastereomers). 1 (Indistinguishable by 1H NMR) (1.13g, 80%) was obtained as a beige solid. δ H (400 MHz, DMSO-d6) 13.07-12.34 (br s, 1H), 6.16 (s, 1H), 4.17 (dd, J 9.0, 6.1 Hz, 1H), 3.61-3.44 (m, 1H), 3.42-3.23 (obscured m, 1H), 2.09-1.93 (m, 2H), 1.88-1.76 (m, 1H), 1.75-1.63 (m, 1H), 1.38 (s, 9H).

[0340] Intermediate 4 O 1 -tert-butylO 2 -(1,3-dioxoisoindolin-2-yl)4-hydroxy-4-(trifluoromethyl)piperidine-1,2-dicarboxylate To a solution of intermediate 3 (990 mg, 3.16 mmol) and N-hydroxyphthalimide (567 mg, 3.48 mmol) in DCM (15 mL) at room temperature, EDCI.HCl (666 mg, 3.47 mmol) was added in one step. The yellow mixture was stirred for 18 hours and then concentrated under vacuum. Purification by flash chromatography eluting with siRNA / isohexane (0-60% gradient) revealed the title compound (assumed to be a mixture of two diastereomers). 1 (861 mg, 59%) was obtained as a white solid (indistinguishable by 1H NMR). H (400 MHz, 373K, DMSO-d6) 8.00-7.92 (m, 4H), 6.13 (s, 1H), 4.80 (dd, J 10.0, 5.9 Hz, 1H), 3.73 (dt, J 12.9, 6.2 Hz, 1H), 3.43 (ddd, J 13.4, 7.8, 5.3 Hz, 1H), 2.35 (ddd, J14.0, 5.7, 1.2 Hz, 1H), 2.21 (dd, J 14.0, 10.1 Hz, 1H), 2.02-1.93 (m, 1H), 1.90-1.80 (m, 1H), 1.48 (s, 9H).LCMS (Method 1): [M+H-H2O] + m / z476.2, RT1.40 minutes.

[0341] Intermediate 5 5-(dicyclopropylmethyl)imidazolidined-2,4-dione A mixture of diammonium carbonate (47.10 g, 0.501 mol), 2,2-dicyclopropylacetaldehyde (95%, 26.10 g, 0.200 mol), and potassium cyanide (13.09 g, 0.201 mol) in a mixture of ethanol (140 mL) and water (140 mL) was heated at 60°C for 18 hours. To the cooled reaction mixture, 2N HCl (200 mL), followed by 6N HCl (100 mL), was added little by little. An additional 2N HCl (60 mL) was added, and the mixture was stirred at room temperature for 1 hour. An additional 2N HCl (50 mL) was added to the mixture, the solid was filtered off, washed with water (2 × 200 mL), and dried to obtain the title compound (95% purity) (32.81 g, 80%) as a white solid. δ H (500 MHz, DMSO-d6) 10.58 (s, 1H), 8.04 (s, 1H), 4.05 (d, J 1.5 Hz, 1H), 0.91-0.81 (m, 1H), 0.82-0.73 (m, 1H), 0.52-0.36 (m, 3H), 0.36-0.23 (m, 3H), 0.23-0.17 (m, 1H), 0.13-0.07 (m, 1H), 0.06-0.00 (m, 1H).LCMS (Method 2): [M+H] + m / z195, RT1.72 minutes.

[0342] Intermediate 6 2-(Benzyloxycarbonylamino)-3,3-dicyclopropylpropanoic acid Intermediate 5 (95%, 1.00 g, 4.89 mmol) was stirred in 1,4-dioxane (6 mL), to which 5 M sodium hydroxide aqueous solution (6.0 mL, 30.0 mmol) was added. The mixture was heated at 100 °C for 18 hours, then 1,4-dioxane (6 mL) and water (6 mL) were added, and the mixture was heated at 120 °C for 2 days. TBME (10 mL) and water (10 mL) were added to the cooled reaction mixture. The two-phase mixture was filtered. 6N HCl (6 mL) and TBME (10 mL) were added to the filtrate. Undissolved solids were filtered off. TBME (10 mL) was added to the filtrate. The layers were separated, and the aqueous layer was washed with TBME (3 × 10 mL). 5N NaOH aqueous solution (0.5 mL) was added to the aqueous layer, and the pH of the solution was adjusted to pH 7 using 6N HCl / 5M NaOH aqueous solution. To an aqueous solution (approximately 40 mL), THF (20 mL), then NaHCO3 (1.01 g), then disodium carbonate (1.01 g, 9.53 mmol), and then 1-(benzyloxycarbonyloxy)pyrrolidine-2,5-dione (0.90 g, 3.61 mmol) were added at room temperature. The mixture was stirred at room temperature for 2.5 days, then TBME (20 mL), followed by water (30 mL). The organic layer was separated. Water (10 mL) was added to the aqueous layer. The aqueous layer was washed with TBME (10 mL), then filtered, and washed again with TBME (10 mL). The pH of the aqueous layer was adjusted to pH 3 using 6N HCl (approximately 4 mL). Crystals from the previous batch were seeded, and then the flask was cooled externally and left for 2 hours. The contents were filtered, then washed with water (2 × 10 mL), and dried to obtain the title compound (719 mg, 49%) as a white solid. δ H (500 MHz, DMSO-d6) 12.53 (s, 1H), 7.47 (d, J 8.9 Hz, 1H), 7.41-7.28 (m, 5H), 5.11-5.01 (m, 2H), 4.19 (dd, J 8.9, 4.4 Hz, 1H), 1.03-0.92 (m, 1H), 0.85-0.74 (m, 1H), 0.57-0.49 (m, 1H), 0.49-0.43 (m, 1H), 0.41-0.20 (m, 4H), 0.19-0.01 (m, 3H).LCMS(Method 2):[M+H]+ m / z304, RT3.13 minutes.

[0343] Intermediates 7 and 8 (2S)-2-(benzyloxycarbonylamino)-3,3-dicyclopropylpropanoic acid (intermediate 7) (2R)-2-(benzyloxycarbonylamino)-3,3-dicyclopropylpropanoic acid (intermediate 8) Intermediate 6 (100% purity) (850 g, 2.80 mol) was subjected to preparative SFC (column: Daicel Chiralpak AD, 250 mm × 50 mm, 10 μm; mobile phase: [Neu-IPA]; B%: 45%-45%, 6 min), and the fraction was concentrated at 45°C under vacuum to obtain the title compound (peak 1, 324 g, 1.07 mol, 100% purity; and peak 2, 351 g, 1.16 mol, 100% purity) as a white solid. 1 1H NMR and LC-MS were consistent with those of intermediate 6. Chiral analysis (Method 3): Peak 1, RT 1.97 min; Peak 2, RT 2.29 min.

[0344] Intermediate 9 Benzyl N-{(1S)-1-(dicyclopropylmethyl)-3-[dimethyl(oxo)-λ 6 [-Sulfanylidene]-2-Oxopropyl Carbamate Potassium tert-butoxide (2.19 g, 19.1 mmol) was added in a suspension of room temperature trimethylsulfoxonium iodide (4.57 g, 20.4 mmol) in THF (42 mL) over 2 minutes. A reflux condenser was attached, and the mixture was heated at 70 °C for 2 hours, then cooled to -5 °C (ice / water / salt bath) to obtain the ylide. Meanwhile, in a separate flask, intermediate 7 (2.00 g, 6.59 mmol), THF (22.8 mL), DIPEA (1.53 mL, 8.77 mmol), and HATU (3.20 g, 8.25 mmol) were added sequentially and stirred at room temperature for 150 minutes. The resulting activated acid mixture was added dropwise to the ylide via a cannula over 30 minutes, maintaining the internal temperature of the newly turbid mixture below 0 °C. After addition, the mixture was stirred for 5 minutes, then quenched with H2O (15 mL) and saturated NaHCO3 aqueous solution (15 mL), and stirred for 1 hour. The reaction mixture was extracted with toluene (2 × 100 mL), the combined organic extract was washed with brine (150 mL), then dried, (Na2SO4), and concentrated under vacuum. The title compound (2.13 g, 86%) was obtained as a white solid by purification by flash chromatography using toluene / isohexane (0-100% gradient) followed by elution with DCM / MeOH (90:10). δ H (400 MHz, DMSO-d6) 7.42-7.27 (m, 5H), 6.98 (d, J 9.5 Hz, 1H), 5.11-4.99 (m, 2H), 4.88 (s, 1H), 4.05-3.97 (m, 1H), 2.70 (s, 6H), 0.85-0.73 (m, 1H), 0.73-0.63 (m, 1H), 0.59-0.49 (m, 1H), 0.45-0.37 (m, 1H), 0.37-0.00 (m, 7H).LCMS (Method 1): [M+H] + m / z378.2, RT1.18 minutes.

[0345] Intermediate 10 Benzyl N-[3-bromo-1-(dicyclopropylmethyl)-2-oxopropyl]carbamate To a solution of intermediate 9 (2.13 g, 5.64 mmol) in THF (26.1 mL) at 0°C, LiBr (495 mg, 5.64 mmol) was added all at once. After about 2 minutes, the LiBr was completely dissolved, and methanesulfonic acid (0.37 mL, 5.70 mmol) was added dropwise over about 30 seconds. The mixture was stirred for 5 minutes until it turned bright yellow and became turbid, then heated to room temperature (removal of ice / water bath) and stirred for 30 minutes. The resulting mixture was heated at 65°C for 2 hours and then cooled to room temperature. Saturated aqueous NaHCO3 (20 mL) was added, and the reaction mixture was further diluted with H2O (10 mL), and then extracted with siRNA (2 × 100 mL). The combined organic extract was dried (Na2SO4) and concentrated under vacuum. Purification by flash chromatography using ethyl acetate / isohexane (0-20% gradient) yielded the title compound (617 mg, 29%) as a white solid. δ H (400 MHz, DMSO-d6) 7.82 (d, J 8.4 Hz, 1H), 7.45-7.27 (m, 5H), 5.09 (d, J 12.6 Hz, 1H), 5.06 (d, J12.6 Hz, 1H), 4.51 (s, 2H), 4.50 (dd, J 8.7, 4.9 Hz, 1H), 0.98-0.87 (m, 1H), 0.87-0.77 (m, 1H), 0.66 (td, J 9.6, 4.9 Hz, 1H), 0.53-0.44 (m, 1H), 0.42-0.14 (m, 5H), 0.11-0.02 (m, 1H), 0.02 to -0.06 (m 1H).LCMS (Method 1): [M+H] + m / z380.2, 382.2, RT1.18 min.

[0346] Intermediate 11 Benzyl N-[(1S)-2,2-dicyclopropyl-1-(imidazo[1,2-b][1,2,4]triazine-6-yl)ethyl]carbamate To a solution of intermediate 10 (>99%ee) (984 mg, 2.59 mmol) and 1,2,4-triazine-3-amine (248 mg, 2.58 mmol) in IPA (18 mL) at room temperature, NaHCO3 (260 mg, 3.10 mmol) was added in one step. The mixture was stirred at 80°C for 24 hours, then cooled to room temperature and concentrated under vacuum. Purification by flash chromatography eluting with Âxy / isohexane (0-100% gradient) yielded the title compound (99%ee) (354 mg, 36%) as a brown solid. δ H (400 MHz, DMSO-d6) 8.63 (d, J 2.0 Hz, 1H), 8.53 (d, J 2.0 Hz, 1H), 8.21 (s, 1H), 7.76 (d, J 9.6 Hz, 1H), 7.43-7.20 (m, 5H), 5.13-5.04 (m, 3H), 0.85-0.66 (m, 3H), 0.43-0.29 (m, 2H), 0.29-0.17 (m, 2H), 0.16-0.06 (m, 2H), 0.03 to -0.05 (m, 1H), -0.19 to -0.28 (m, 1H).LCMS(Method 1):[M+H] + m / z378.2, RT1.32 minutes.

[0347] Intermediates 12 and 13 tert-butyl2-{6-[(1S)-1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (syn isomer) (intermediate 12) tert-butyl2-{6-[(1S)-1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (anti-isomer) (intermediate 13) Intermediate 11 (356 mg, 0.94 mmol), intermediate 4 (649 mg, 1.42 mmol), DMF (18 mL), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (22.0 mg, 0.020 mmol), and TFA (0.11 mL, 1.50 mmol) were sequentially introduced into screw-cap vials. The vials were capped, the mixture was purged with N2 for 5 minutes, then the caps were sealed with Parafilm, and the mixture was irradiated for 20 hours (450 nm) using an "integrated photoreactor" (ACS Cent.Sci., 2017, 3, 647~653) (settings: fan=1612 rpm; stirring=392 rpm; LED=100%). The mixture was diluted with SiO2 (20 mL) and washed with H2O (2 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography eluting with siRNA / isohexane (0-60% gradient) to obtain intermediate 13 (sub-constituent, anti-constituent, two stereoisomers) (56.0 mg, 9%) as a yellow foam, along with several additional impurities. Further purification of the additional substances by flash chromatography eluting with diethyl ether / isohexane (0-80% gradient) yielded intermediate 12 (syn-constituent, two stereoisomers) (231 mg, 38%) as a white foam. LCMS (Method 1): [M+H] + m / z 645.2, RT 1.59 min (main syn isomer), RT 1.55 min (minor anti isomer).

[0348] Intermediate 14 Benzyl N-[(1S)-2,2-dicyclopropyl-1-{3-[4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}ethyl]carbamate trifluoroacetate Intermediate 12 (syn-constituent, two stereoisomers) (231 mg, 0.36 mmol) was dissolved in DCM (2.6 mL), and TFA (0.41 mL, 5.40 mmol) was added. The solution was stirred at room temperature for 3 hours, and then neutralized with saturated NaHCO3 aqueous solution (5 mL). SiO (10 mL) was added to the mixture, and the layers were separated. The aqueous layer was re-extracted with SiO (2 × 10 mL), and the combined organic layers were dried (Na2SO4) and concentrated under vacuum to obtain the title compound (mixture of two syn-constituent stereoisomers) (236 mg, quantitative) as an orange oily substance, which was used without further purification. LC-MS (Method 1): [M+H] + m / z545.2, RT1.36 minutes.

[0349] Intermediate 15 Benzyl N-[(1S)-2,2-dicyclopropyl-1-{3-[1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}ethyl]carbamate Intermediate 14 (a mixture of two syn-constituent stereoisomers) (236 mg) at room temperature, 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (51.0 mg, 0.39 mmol), and DIPEA (0.25 mL, 1.40 mmol) were dissolved in DMF (5 mL), to which HATU (169 mg, 0.43 mmol) was added in one step. The mixture was stirred for 10 minutes, and then H2O (10 mL) was added. The mixture was extracted with ELISA (2 × 20 mL), the combined organic extract was washed with brine (20 mL), dried, and concentrated in vacuum with (Na2SO4). Purification by flash chromatography eluting with ELISA / isohexane (0-80% gradient) yielded the title compound (a mixture of two stereoisomers) (104 mg, 44%) as a yellow foam. LCMS (Method 1): [M+H] + m / z657.2, RT1.49 minutes.

[0350] Intermediate 16 [(2S,4R)-2-{6-[(1S)-1-amino-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-yl](3-fluorobicyclo[1.1.1]pentan-1-yl)methanone To a solution of intermediate 15 (a mixture of two stereoisomers) (50.0 mg, 0.076 mmol) at room temperature in EtOH (2.2 mL), 4N HCl (0.02 mL, 0.08 mmol) and 10% Pd / C (10 mg) in 1,4-dioxane were sequentially added. The vessel was evacuated, purged three times with H2, and then stirred at room temperature for 210 minutes. The mixture was evacuated and placed under an Ar atmosphere, and Na2CO3 (16.1 mg, 0.152 mmol) was added. The mixture was stirred for 5 minutes and then filtered under suction through a Celite® (10 g) pad using EtOH (20 mL). The filtrate was concentrated under vacuum to obtain the title compound (a mixture of two stereoisomers) (40.0 mg, quantitative) as a dark yellow solid, which was used without further purification. LCMS (Method 1): [M+H] + m / z523.2, RT1.24 minutes.

[0351] Intermediate 17 O 4 -tert-butylO 3 -(1,3-dioxoisoindoline-2-yl)morpholine-3,4-diccarboxylate A solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (500 mg, 2.16 mmol), N-hydroxyphthalimide (440 mg, 2.70 mmol), and EDCI.HCl (520 mg, 2.70 mmol) in DCM (15 mL) was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by flash column chromatography with elution under a gradient of 0–40% siRNA in hexane to obtain the title compound (812 mg, 99%) as an off-white solid. δ H(400 MHz, DMSO-d6) 8.02-7.92 (m, 4H), 4.99 (d, J 4.0 Hz, 1H), 4.31 (dt, J 12.2, 1.1 Hz, 1H), 3.92 (dd, J 11.6, 3.9 Hz, 1H), 3.83 (dd, J 12.3, 4.1 Hz, 1H), 3.75-3.66 (m, 1H), 3.51 (td, J 11.8, 3.1 Hz, 1H), 3.20 (td, J12.7, 3.9 Hz, 1H), 1.47 (s, 9H).

[0352] Intermediate 18 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]carbamate A mixture of benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (300 mg, 0.74 mmol), 1,2,4-triazine-3-amine (70.0 mg, 0.74 mmol), and NaHCO3 (75.0 mg, 0.89 mmol) in IPA (5 mL) was stirred overnight at 80°C. The reaction mixture was concentrated, and the residue was purified twice by flash column chromatography with elution under a gradient of 0-60% siRNA in hexane to obtain the title compound (111 mg, 36%) as a brown solid. LC-MS (Method 1): [M+H] + m / z402.2, RT1.27 minutes.

[0353] Intermediate 19 tert-butyl3-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}morpholine-4-carboxylate Solutions of intermediate 17 (190 mg, 0.50 mmol), intermediate 18 (135 mg, 0.34 mmol), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (8.0 mg, 7.1 μmol), and TFA (40.0 μL, 0.53 mmol) in DMF (7 mL) were purged with nitrogen gas for 5 minutes. The reaction mixture was left under 450 nm irradiation for 3 hours, then diluted with SiO (20 mL) and washed with water (20 mL). The aqueous layer was extracted with SiO (20 mL). The combined organic layers were dried over Na2SO4, then filtered and concentrated. The residue was purified by flash column chromatography with elution at a gradient of 0–40% SiO in hexane to obtain the title compound (156 mg, 79%) as an off-white solid. LCMS (Method 1): [M+H] + m / z 587.2, RT 1.47 minutes.

[0354] Intermediate 20 (S)-(4,4-difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazine-6-yl)methaneamine To a solution of intermediate 18 (900 mg, 2.02 mmol) in AcOH (6 mL), hydrogen bromide (35%, 3.3 mL, 20.2 mmol) in AcOH was added. The solution was stirred at room temperature for 2 hours. Diethyl ether (50 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting precipitate was collected by vacuum filtration. The viscous residue was washed with diethyl ether (2 × 50 mL) and transferred from the filter paper to a separatory funnel by rinsing with water. The aqueous layer was washed with DCM (50 mL) and then basicized with saturated NaHCO3 aqueous solution. The obtained substance was extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the title compound (435 mg, 78%). δ H(500 MHz, CDCl3) 8.42 (d, J 2.0 Hz, 1H), 8.33 (d, J 2.0 Hz, 1H), 7.90 (s, 1H), 4.07 (d, J 6.3 Hz, 1H), 2.38-1.87 (m, 6H), 1.82-1.58 (m, 3H), 1.56-1.36 (m, 2H).LCMS (Method 4): [M+H] + 268.2, RT 1.26 min.

[0355] Intermediate 21 N-[(S)-(4,4-difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 20 (435 mg, 1.58 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (222 mg, 1.74 mmol), and DIPEA (0.55 mL, 3.16 mmol) were dissolved in anhydrous DMF (10 mL) to which HATU (720 mg, 1.89 mmol) was added. The mixture was stirred at room temperature for 30 minutes, then diluted with RINKAN (25 mL), washed with water (2 × 25 mL), and then brine (10 mL). The organic layer was dried over MgSO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of RINKAN in heptane to obtain the title compound (460 mg, 77%). δ H (500 MHz, CDCl3) 8.49 (d, J 1.9 Hz, 1H), 8.39 (d, J 1.9 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J 9.0 Hz, 1H), 5.35-5.28 (m, 1H), 2.60 (s, 3H), 2.31-2.21 (m, 1H), 2.21-2.11 (m, 1H), 2.11-1.98 (m, 2H), 1.85-1.61 (m, 3H), 1.58-1.46 (m, 1H), 1.44-1.32 (m, 1H).LCMS(Method 4):[M+H] + 378.2, RT 2.09 min.

[0356] Intermediate 22 tert-butyl3-(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)morpholine-4-carboxylate Solutions of intermediate 17 (1.34 g, 3.55 mmol), intermediate 21 (940 mg, 2.37 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (53 mg, 0.047 mmol) in anhydrous DMF (45 mL) were equally divided between two 40 mL vials. TFA (136 μL, 1.79 mmol) was added to each vial. The solutions were purged for 10 minutes by bubbling nitrogen while stirring, then sealed under nitrogen using Parafilm, and irradiated with a blue LED lamp (40 W, Kessil A160WE LED Aquarium Light; Tuna Blue; light set to maximum intensity and greater blue setting) while stirring at approximately 21°C (temperature maintained with fan). The vials were positioned approximately 5 cm from the nearest light source. After 24 hours, the solutions were combined, diluted with siRNA (100 mL), and then washed with water (2 × 100 mL), followed by brine (50 mL). The organic fraction was dried over MgSO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography using a gradient of siRNA in heptane to obtain the title compound (950 mg, 66%). δ H (400 MHz, CDCl3) 8.34-8.27 (m, 1H), 7.90-7.84 (m, 1H), 7.80-7.71 (m, 1H), 5.35-5.12 (m, 2H), 4.80-4.63 (m, 1H), 4.04-3.80 (m, 3H), 3.67-3.54 (m, 1H), 3.54-3.08 (m, 1H), 2.63-2.56 (m, 3H), 2.32-1.99 (m, 4H), 1.86-1.59 (m, 3H), 1.59-1.30 (m, 11H).LCMS(Method 4):[M+H] + 563.2, RT 2.36 min.

[0357] Intermediate 23 Benzyl N-{(S)-(4,4-difluorocyclohexyl)[3-(morpholine-3-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]methyl}carbamate trifluoroacetate Intermediate 19 (488 mg, 0.83 mmol) was dissolved in DCM (5.9 mL), and TFA (0.94 mL, 12.0 mmol) was added. The solution was stirred at room temperature for 160 minutes, and then neutralized with saturated NaHCO3 aqueous solution (10 mL). SiO2 (10 mL) was added to the mixture, and the layers were separated. The aqueous layer was re-extracted with SiO2 (2 × 20 mL), and the combined organic layers were dried (Na2SO4) and concentrated under vacuum to obtain the title compound (500 mg, quantitative) as an orange oily substance, which was used without further purification. LC-MS (Method 1): [M+H] + m / z 487.2, RT 1.22 minutes.

[0358] Intermediate 24 N-{(S)-(4,4-difluorocyclohexyl)[3-(morpholine-3-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride To intermediate 22 (1.00 g, 1.65 mmol), 4N HCl in 1,4-dioxane (15 mL) was added, and the solution was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to obtain the title compound (1.04 g, 99%). δ H(400 MHz, CDCl3) 10.57-10.41 (m, 1H), 9.97-9.82 (m, 1H), 9.57 (d, J 8.9 Hz, 1H), 9.01-8.91 (m, 1H), 8.45 (s, 1H), 5.29-5.19 (m, 1H), 4.92-4.83 (m, 1H), 4.43-4.28 (m, 1H, obs. by water), 4.07-3.98 (m, 1H), 3.88-3.72 (m, 2H), 3.43-3.34 (m, 1H), 3.32-3.19 (m, 1H), 2.48-2.45 (m, 3H), 2.28-2.15 (m, 1H), 2.13-1.95 (m, 2H), 1.95-1.60 (m, 4H), 1.50-1.37 (m, 1H), 1.37-1.24 (m, 1H).LCMS (Method 4): [M+H] + 463.2, RT 1.79 min.

[0359] Intermediate 25 Benzyl N-[(S)-(4,4-difluorocyclohexyl){3-[4-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]carbamate To a solution of Intermediate 23 (500 mg, 0.83 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (124 mg, 0.95 mmol), and DIPEA (0.60 mL, 3.50 mmol) in DMF (20 mL) at room temperature, HATU (408 mg, 1.04 mmol) was added in one step. The mixture was stirred for 45 minutes, and then H2O (30 mL) was added. The mixture was extracted with RINKAN (2 × 50 mL), the combined organic extract was washed with brine (100 mL), dried, and concentrated in (Na2SO4) under vacuum. Purification by flash chromatography eluting with RINKAN / isohexane (0-100% gradient) yielded the title compound (444 mg, 89% over two steps) as an orange foam. LCMS (Method 1): [M+H] + m / z 599.2, RT 1.36 min.

[0360] Intermediate 26 (3-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}morpholine-4-yl)(3-fluorobicyclo[1.1.1]pentan-1-yl)methanone To a solution of intermediate 25 (444 mg, 0.74 mmol) at room temperature in EtOH (22 mL), 4N HCl (0.23 mL, 0.92 mmol) and 10% Pd / C (85 mg) in 1,4-dioxane were sequentially added. The vessel was evacuated, purged three times with H2, and then stirred at room temperature for approximately 5 hours. The mixture was filtered under suction using EtOH (60 mL) through a Celite® (10 g) pad. The filtrate was concentrated under vacuum to obtain the title compound (71% purity by LC-MS) (405 mg, quantitative), which was used without further purification. LC-MS (Method 1): [M+H] + m / z 465.2, RT 1.10 min.

[0361] Intermediate 27 tert-butyl3-{6-[(1S)-1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazine-3-yl}morpholine-4-carboxylate Intermediate 11 (355 mg, 0.94 mmol), intermediate 17 (531 mg, 1.41 mmol), DMF (18 mL), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (21.0 mg, 0.019 mmol), and TFA (0.11 mL, 1.50 mmol) were sequentially introduced into screw-cap vials. The vials were capped, the mixture was purged with N2 for 5 minutes, then the caps were sealed with Parafilm, and the mixture was irradiated for 16 hours (450 nm) using an "integrated photoreactor" (ACS Cent.Sci., 2017, 3, 647~653) (settings: fan = 1612 rpm; stirring = 392 rpm; LED = 100%). The mixture was diluted with SiO2 (40 mL) and washed with H2O (2 × 20 mL). The combined organic fraction was dried (Na2SO4) and concentrated in vacuum. Purification by flash chromatography with elution using siRNA / isohexane (0-100% gradient) yielded the title compound (a mixture of two stereoisomers, in a 1:1 ratio) (278 mg, 52%) as an orange foam. LC-MS (Method 1): [M+H] + m / z563.2, RT1.45 minutes.

[0362] Intermediate 28 tert-butyl3-{6-[(1S)-1-amino-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazine-3-yl}morpholine-4-carboxylate To a solution of intermediate 27 (278 mg, 0.49 mmol) at room temperature in EtOH (22 mL), 4N HCl (0.15 mL, 0.60 mmol) in 1,4-dioxane and 10% Pd / C (28 mg) were sequentially added. The vessel was evacuated, purged three times with H2, and then stirred at room temperature for approximately 3 hours (95% conversion of the starting material by LC-MS). The mixture was filtered under suction through a Celite® (10 g) pad using EtOH (60 mL). The filtrate was concentrated under vacuum to obtain the title compound (a mixture of two stereoisomers, in a 1:1 ratio) (purity 85% by LC-MS) (249 mg, quantitative), which was used without further purification. LC-MS (Method 1): [M+H] +m / z429.2, RT1.23 minutes.

[0363] Intermediate 29 tert-butyl3-(6-{(1S)-2,2-dicyclopropyl-1-[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]ethyl}imidazo[1,2-b][1,2,4]triazine-3-yl)morpholine-4-carboxylate To a solution of intermediate 28 (249 mg, 0.58 mmol) at room temperature, 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (75.0 mg, 0.59 mmol), and DIPEA (0.40 mL, 2.30 mmol) in DMF (10 mL), HATU (274 mg, 0.70 mmol) was added in one step. The mixture was stirred for 30 minutes, and then H2O (25 mL) was added. The mixture was extracted with RINKAN (3 × 20 mL), the combined organic extract was washed with brine (40 mL), dried, and concentrated in (Na2SO4) under vacuum. Purification by flash chromatography eluting with RINKAN / isohexane (0-75% gradient) yielded the title compound (a mixture of two stereoisomers, in a 1:1 ratio) (175 mg, 56% over two steps) as an orange solid. LCMS (Method 1): [M+H] + m / z539.2, RT1.43 minutes.

[0364] Intermediate 30 N-{(1S)-2,2-dicyclopropyl-1-[3-(morpholine-3-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]ethyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide trifluoroacetate Intermediate 29 (175 mg, 0.32 mmol) was dissolved in DCM (1.9 mL), and TFA (0.37 mL, 4.90 mmol) was added. The solution was stirred at room temperature for 130 minutes, and then neutralized with saturated NaHCO3 aqueous solution (10 mL). SiO2 (10 mL) was added to the mixture, and the layers were separated. The aqueous layer was re-extracted with SiO2 (2 × 20 mL). The combined organic layers were dried (Na2SO4), and then concentrated under vacuum to obtain the title compound (a mixture of two stereoisomers, in a 1:1 ratio) (206 mg, quantitatively) as an orange oil, which was used without further purification. LC-MS (Method 1): [M+H] + m / z439.2, RT1.21 min.

[0365] Intermediates 31 and 32 tert-butyl2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (syn isomer) (intermediate 31) tert-butyl2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (anti isomer) (intermediate 32) TFA (143 μL, 1.87 mmol) was added to solutions of intermediate 4 (856 mg, 1.87 mmol), intermediate 18 (500 mg, 1.25 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (28 mg, 0.025 mmol) in anhydrous DMF (20 mL). The solution was purged by bubbling nitrogen for 10 minutes with stirring, then sealed under nitrogen using Parafilm, and irradiated at 450 nm for 50 hours in a Penn M2 photoreactor (LED 100%, stirring 50%, fan 50%). The solution was diluted with SiO2 (50 mL) and washed with water (2 × 50 mL), followed by brine (25 mL). The organic portion was dried over MgSO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography using a gradient of ethyl heptane to obtain the title compound (syn isomer, 390 mg, 44%; and anti isomer, 140 mg, 15%). LC-MS (Method 5): [M+H] + 669.2, RT 2.51 min (syn isomer). LCMS (Method 4): [M+H] + 669.2, RT 2.45 min (anti isomer).

[0366] Intermediate 33 Benzyl N-[(S)-(4,4-difluorocyclohexyl){3-[4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]carbamate hydrochloride To intermediate 31 (syn isomer) (390 mg, 0.55 mmol), 4N HCl in 1,4-dioxane (5 mL) was added, and the solution was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to obtain the title compound (mixture of syn stereoisomers) (415 mg, 89%). δ H(400 MHz, DMSO-d6) 10.58-9.89 (m, 1H), 9.71-9.48 (m, 1H), 8.97-8.90 (m, 1H), 8.30-8.15 (m, 1H), 7.97-7.86 (m, 1H), 7.42-7.16 (m, 5H), 5.19-5.11 (m, 1H), 5.11-4.97 (m, 2H), 4.85-4.70 (m, 1H), 3.43-3.27 (m, 1H), 2.64-2.56 (m, 1H), 2.47-2.38 (m, 1H), 2.28-2.15 (m, 1H), 2.15-1.86 (m, 5H), 1.86-1.55 (m, 4H), 1.48-1.32 (m, 1H), 1.32-1.20 (m, 1H). No interchangeable proton signals were observed. LCMS (Method 4): [M+H] + 569.2, RT 1.95 min.

[0367] Intermediate 34 Benzyl N-[(S)-(4,4-difluorocyclohexyl){3-[1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]carbamate 3-Fluorobicyclo[1.1.1]pentane-1-carboxylic acid (70 mg, 0.57 mmol), DIPEA (255 μL, 1.46 mmol), and intermediate 33 (415 mg, 0.49 mmol) were dissolved in DCM (5 mL) and HATU (222 mg, 0.58 mmol) was added. The solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified twice by column chromatography eluting with a gradient of ethyl in heptane to obtain the title compound (a mixture of syn stereoisomers) (240 mg, 67%). δ H(400 MHz, DMSO-d6) 8.79-8.69 (m, 1H), 8.17-8.05 (m, 1H), 7.90-7.78 (m, 1H), 7.43-7.16 (m, 5H), 5.99-5.56 (m, 2H), 5.11-4.97 (m, 2H), 4.82-4.68 (m, 1H), 4.53-4.04 (m, 1H), 3.80-3.65 (m, 1H), 2.65-2.54 (m, 1H), 2.49-2.41 (m, 3H), 2.32-2.09 (m, 3H), 2.09-1.90 (m, 3H), 1.88-1.51 (m, 7H), 1.44-1.20 (m, 2H).LCMS (Method 4): [M+H] + 681.2, RT 2.39 minutes.

[0368] Intermediate 35 [2-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-yl](3-fluorobicyclo[1.1.1]pentan-1-yl)methanone To a solution of intermediate 34 (240 mg, 0.33 mmol) in EtOH (10 mL), 10% Pd / C (55-65% wet) (5.0%, 70 mg, 0.033 mmol) was added. The mixture was stirred at room temperature for 4 hours under a hydrogen balloon. The flask was flushed three times with nitrogen, and then the mixture was filtered through Celite® while washing with EtOH. The residue was concentrated under reduced pressure to obtain the title compound (mixture of syn stereoisomers) (180 mg, 90%). δ H (400 MHz, DMSO-d6) 8.76-8.65 (m, 1H), 8.18-8.08 (m, 1H), 5.98-5.54 (m, 2H), 4.56-3.65 (m, 4H), 2.49-2.06 (m, 6H), 2.06-1.47 (m, 12H), 1.47-1.26 (m, 2H).LCMS (Method 4): [M+H] + 547.2, RT 1.85 min.

[0369] Intermediate 36 O 4 -tert-butylO 3 -(1,3-dioxoisoindolin-2-yl)1,1-dioxo-1,4-thiadinane-3,4-dicarboxylate To a suspension of 4-tert-butoxycarbonyl-1,1-dioxo-1,4-thiadinane-3-carboxylic acid (1.25 g, 4.48 mmol) at room temperature in DCM (30 mL), N-hydroxyphthalimide (1.03 g, 6.13 mmol), DMAP (56 mg, 0.45 mmol), and EDCI.HCl (1.32 g, 6.75 mmol) were added in fractions. The resulting white suspension was stirred, and a yellow solution slowly formed. This was stirred for 18 hours and then concentrated under vacuum. The resulting yellow syrup was partitioned between siRNA (200 mL) and brine (300 mL). The aqueous phase was extracted with further siRNA (2 × 200 mL). The combined organic extracts were washed with brine, then dried over anhydrous Na₂SO₄ and filtered. Volatile substances were removed under vacuum. The resulting foamy, pale solid was purified by column chromatography of silica eluted under a gradient of 0-80% siRNA in hexane to obtain the title compound (1.62 g, 85%) as a white solid. δ H (400 MHz, DMSO-d6) 8.23-7.88 (m, 4H), 6.13-5.80 (m, 1H), 4.65-4.30 (m, 1H), 3.94-3.73 (m, 1H), 3.70-3.36 (m, 3H), 3.29-3.07 (m, 1H), 1.46 (s, 9H).

[0370] Intermediate 37 (NE)2-methyl-N-{[trans-4-(trifluoromethyl)cyclohexyl]methylene}propane-2-sulfinamide To a solution of trans-4-(trifluoromethyl)cyclohexanecarboxaldehyde (16.1 g, 74.2 mmol) in DCM (500 mL) was added (S)-(-)-2-methyl-2-propanesulfinamide (8.70 g, 70.0 mmol), followed by titanium(IV) ethoxide (52 mL, 223.2 mmol). The mixture was heated under reflux for 2 hours, then cooled to room temperature and treated with water (50 mL). After vigorous stirring, the fine suspension was filtered through Celite®. The filtrate was passed through a hydrophobic frit and concentrated in vacuo to give the title compound (18.8 g, 89%) as an off-white solid. [α] 25 D +145° (c 1.00, DCM). δ H (300 MHz, CDCl3) 8.00 (d, J 4.3 Hz, 1H), 2.57-2.40 (m, 1H), 2.17-1.96 (m, 5H), 1.54-1.28 (m, 4H), 1.21 (s, 9H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -73.84 (s, 3F).

[0371] Intermediate 38 N-{(S)-cyano[trans-4-(trifluoromethyl)cyclohexyl]methyl}-2-methylpropane-2-sulfinamide To a solution of Intermediate 37 (18.8 g, 66.3 mmol) in DCM (180 mL) at 25°C was added cesium fluoride (1.00 g, 6.58 mmol), followed by trimethylsilyl cyanide (18.0 mL, 134 mmol). The mixture was stirred at 25°C for 17 hours. Saturated aqueous sodium bicarbonate (150 mL) was added and the mixture was stirred for 1 hour. The biphasic mixture was separated, and the organic layer was concentrated in vacuo. The obtained pale yellow oil was purified by flash column chromatography (0~100% EtOAc / isohexane), then recrystallized from EtOAc:isohexane (1:2; 90 mL) to give the title compound (single diastereomer) (7.20 g, 35%) as a white solid. δ H(400 MHz, CDCl3) 4.05 (dd, J 8.0, 6.4 Hz, 1H), 3.66 (d, J 8.0 Hz, 1H), 2.15-1.99 (m, 5H), 1.91-1.74 (m, 1H), 1.45-1.32 (m, 2H), 1.28 (s, 9H), 1.26-1.11 (m, 2H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -73.80 (s, 3F).

[0372] Intermediate 39 (2S)-2-amino-2-[trans-4-(trifluoromethyl)cyclohexyl]acetonitrile hydrochloride To a solution of Intermediate 38 (7.00 g, 22.6 mmol) in MeOH (17 mL) was added HCl (4N, 12 mL) in 1,4-dioxane, whereupon a white precipitate formed. After 4 hours, the mixture was concentrated under reduced pressure. Isohexane (100 mL) was added to the resulting oily slurry. After vigorous stirring, the obtained white solid was filtered off to give the title compound (5.20 g, 95%). δ H (300 MHz, DMSO-d6) 9.15 (s, 3H), 4.57 (d, J 5.5 Hz, 1H), 2.39-2.20 (m, 1H), 2.11-1.79 (m, 5H), 1.40-1.01 (m, 4H).

[0373] Intermediate 40 (2S)-2-amino-2-[trans-4-(trifluoromethyl)cyclohexyl]acetic acid hydrochloride Acetic acid (35 mL) and HCl (33%, 50 mL) in H2O were added to Intermediate 39 (5.20 g, 21.0 mmol). The mixture was heated under reflux for 4 hours, then cooled to 20°C with stirring. After 18 hours, the white precipitate was filtered off and dried under a stream of air to give the title compound (4.40 g, 74%) as a white solid. [α] 25 D +22.1° (c 1.0, MeOH). δ H(300 MHz, DMSO-d6) 13.81 (s, 1H), 8.46 (s, 3H), 3.75 (d, J 4.3 Hz, 1H), 2.34-2.05 (m, 1H), 2.03-1.66 (m, 5H), 1.47-1.04 (m, 4H). 19 F { 1 H} NMR (282-MHz, DMSO-d6) δ -72.33 (s, 3F).

[0374] Intermediate 41 (2S)-2-(benzyloxycarbonylamino)-2-[4-(trifluoromethyl)cyclohexyl]acetic acid N-(benzyloxycarbonyloxy)succinimide (4.47 g, 17.6 mmol) was added in three fractions to a suspension of intermediate 40 (5.00 g, 19.1 mmol) and triethylamine (10 mL, 71.7 mmol) in DCM (100 mL) at 0°C. The reaction mixture was warmed at room temperature overnight. The reaction mixture was diluted with DCM (10 mL), washed with 5% hydrochloric acid (2 × 15 mL) and water (15 mL), then dried (Na₂SO₄), concentrated under vacuum to obtain the title compound (6.34 g, 92%) as a white solid. δ H (300 MHz, DMSO-d6) 12.65 (s, 1H), 7.54 (d, J 8.4 Hz, 1H), 7.40-7.28 (m, 5H), 5.04 (s, 2H), 3.89 (dd, J8.4, 5.9 Hz, 1H), 2.26-2.05 (m, 1H), 1.96-1.80 (m, 2H), 1.80-1.59 (m, 3H), 1.32-1.07 (m, 4H).

[0375] Intermediate 42 Benzyl N-{(1S)-3-[dimethyl(oxo)-λ 6 [-Sulfanylidene]-2-oxo-1-[4-(trifluoromethyl)cyclohexyl]propyl}carbamate Trimethylsulfoxonium iodide (70.00 g, 0.318 mol) was dissolved in THF (350 mL), and 1 M potassium tert-butoxide (300 mL, 0.300 mol) in THF was added. The resulting mixture was stirred under nitrogen at 70°C (external temperature) for 2 hours, and then cooled to -5°C under nitrogen in an ice / salt bath to obtain the ylide. Meanwhile, in a separate flask, intermediate 41 (37.00 g, 0.103 mol) was dissolved in THF (350 mL), and HATU (49.00 g, 0.129 mol), followed by DIPEA (24 mL, 0.137 mol), was added. The reaction mixture was stirred under nitrogen for 150 minutes, and then added dropwise to the cooled ylide solution over approximately 50 minutes, maintaining the internal temperature below 1°C. The reaction mixture was stirred under nitrogen at -4°C for 5 minutes, then quenched at -4°C by adding water (700 mL) and saturated NaHCO3 aqueous solution (700 mL). The resulting suspension was extracted with TBME (3 L). The organic layer was washed with brine (500 mL) and concentrated to dryness under vacuum. The residue was suspended in TBME (500 mL) and water (50 mL), then heated to 50°C, cooled to room temperature, then filtered, and then washed with TBME (100 mL) and heptane (100 mL). Each time, more solid precipitated from the solution in the filtrate, so three additional crops were obtained. The four crops of solid were combined, and then water (400 mL) was added. The mixture was sonicated to break up large lumps, then cooled to 0°C, filtered, and washed with water (150 mL). The residue was dried overnight in a vacuum oven to obtain the title compound (36.15 g, 81%) as a colorless solid. δ H (400 MHz, DMSO-d6) 7.42-7.27 (m, 5H), 7.06 (d, J 9.2 Hz, 1H), 5.01 (s, 2H), 4.87 (s, 1H), 3.67 (dd, J 9.1, 6.6 Hz, 1H), 3.43 (s, 6H), 2.20-2.03 (m, 1H), 1.92-1.78 (m, 2H), 1.76-1.54 (m, 3H), 1.26-0.99 (m, 4H).LCMS (Method 6): [M+H] + 434.2, RT 2.70 minutes.

[0376] Intermediate 43 Benzyl N-{(1S)-3-bromo-2-oxo-1-[4-(trifluoromethyl)cyclohexyl]propyl}carbamate Intermediate 42 (28.08 g, 64.8 mmol) was dissolved in THF (300 mL) and cooled to 0°C (external temperature) under nitrogen. LiBr (5.69 g, 64.8 mmol) was added and the mixture was stirred until completely dissolved (approximately 2 minutes). Methanesulfonic acid (4.2 mL, 64.7 mmol) was added and the mixture was stirred under nitrogen at 0°C for 5 minutes, then heated to room temperature and stirred under nitrogen for 30 minutes. The resulting suspension was heated to 58°C (internal temperature; 65°C heating block) over approximately 30 minutes and stirred under nitrogen at this temperature for 1 hour. The reaction mixture was cooled to room temperature and quenched by adding saturated NaHCO3 aqueous solution (450 mL). The resulting mixture was diluted with water (200 mL) and extracted with toluene (600 mL). The organic layer was washed with saturated NaBr aqueous solution (400 mL), then dried (Na2SO4), and concentrated to dryness under vacuum. The residue was purified by FCC (750g Biotage KP-Sil cartridge, wet-loaded into 150mL DCM, eluted with 10-20% siRNA in heptane), and the product fraction was concentrated to dryness under vacuum to obtain the title compound (19.80g, 68%) as a colorless solid. The mixed fraction was isolated, concentrated to dryness under vacuum, and then re-purified by FCC (100g Biotage Sfar Duo cartridge, wet-loaded into 20mL DCM, eluted with 10-20% siRNA in heptane), and the product fraction was concentrated to dryness under vacuum to obtain a second crop of the title compound (4.90g, 17%) as a colorless solid. δ H(500 MHz, CDCl3) 7.44-7.29 (m, 5H), 5.31 (d, J 8.7 Hz, 1H), 5.11 (s, 2H), 4.66 (dd, J8.7, 4.6 Hz, 1H), 4.03 (q, J 13.3 Hz, 2H), 2.03-1.92 (m, 3H), 1.92-1.83 (m, 2H), 1.63 (d, J 13.0 Hz, 1H), 1.42-1.18 (m, 3H), 1.06 (qd, J 13.0, 3.2 Hz, 1H).LCMS (Method 4): [M+H] + 436.0 / 438.0, RT 3.27 min.

[0377] Intermediate 44 Benzyl N-{(S)-(imidazo[1,2-b][1,2,4]triazine-6-yl)[4-(trifluoromethyl)cyclohexyl]methyl}carbamate To a suspension of intermediate 43 (5.09 g, 11.67 mmol) at ambient temperature in EtOH (75 mL), 3-amino-1,2,4-triazine (recrystallized from acetonitrile) (2.3 g, 23.22 mmol) was added. When the resulting suspension was heated to 80°C, it became a red solution. After 1 hour, the reaction mixture was cooled and poured into a mixture of saturated NaHCO3 aqueous solution (300 mL) and siRNA (200 mL). The organic phase was separated. The aqueous phase was diluted with brine (200 mL) and further extracted with siRNA (2 × 200 mL). The combined organic extract was washed twice with brine, then dried over anhydrous Na2SO4 and filtered. Volatile substances were removed under vacuum. The resulting brown solid was purified by column chromatography of silica eluted with a gradient of siRNA (0–80% in hexane) to obtain the title compound (1.8 g, 36%) as a reddish-brown crystalline solid. δ H(400 MHz, DMSO-d6) 8.64 (d, J 2.0 Hz, 1H), 8.55 (d, J 2.1 Hz, 1H), 8.20 (s, 1H), 7.82 (d, J 9.2 Hz, 1H), 7.55-7.04 (m, 5H), 5.03 (d, J 2.3 Hz, 2H), 4.69 (dd, J 9.2, 7.2 Hz, 1H), 2.19 (s, 1H), 1.85 (dd, J16.6, 7.2 Hz, 4H), 1.59 (d, J 12.6 Hz, 1H), 1.30-0.95 (m, 4H).

[0378] Intermediate 45 tert-butyl3-(6-{(S)-benzyloxycarbonylamino[4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)-1,1-dioxo-1,4-thiadinane-4-carboxylate TFA (140 μL, 1.85 mmol) was added dropwise to solutions of intermediate 44 (517 mg, 1.19 mmol), intermediate 36 (777 mg, 1.83 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (35 mg, 0.031 mmol) in anhydrous DMF (12 mL) under nitrogen. The mixture was purged with nitrogen for 5 minutes, then placed in a photoreactor and irradiated at 450 nm for 20 hours at ambient temperature. The reaction mixture was poured into a mixture of SiO (50 mL) and saturated NaHCO3 aqueous solution (150 mL). The organic phase was separated, and the aqueous phase was extracted with SiO (2 × 100 mL). The combined organic extract was washed with brine (2 × 100 mL), then dried over anhydrous Na2SO4, and filtered. The solvent was removed under vacuum. The resulting brown residue was purified by silica column chromatography (gradient elution in hexane with 0-80% siRNA) to obtain the title compound (402 mg, 51%) as a pale orange solid. δ H(400 MHz, DMSO-d6) 8.81 (d, J 4.0 Hz, 1H), 8.15 (s, 1H), 7.65 (br s, 1H), 7.33 (m, 5H), 6.10-5.93 (m, 1H), 5.17-4.92 (m, 2H), 4.68 (t, J 8.1 Hz, 1H), 4.53-4.33 (m, 1H), 4.20-3.96 (m, 1H), 3.92-3.63 (m, 2H), 3.36 (td, J 12.9, 11.6, 4.2 Hz, 1H), 3.17-3.01 (m, 1H), 2.27-2.07 (m, 1H), 1.85 (m, 4H), 1.64 (d, J12.4 Hz, 1H), 1.44 (m, 10H), 1.30-0.93 (m, 3H).LCMS (Method 1): [M+H] + 667, RT 1.50 min.

[0379] Intermediate 46 Benzyl N-{(S)-[3-(1,1-dioxo-1,4-thiadinan-3-yl)imidazo[1,2-b][1,2,4]triazine-6-yl][4-(trifluoromethyl)cyclohexyl]methyl}carbamate To a solution of intermediate 45 (483 mg, 0.72 mmol) in DCM (6 mL), cooled on an ice / water bath, TFA (2 mL) was slowly added. The yellow-orange solution was stirred at ambient temperature for 18 hours. Volatile substances were removed under vacuum, and the residue was azeotropically reacted with toluene (2 × 30 mL). The residue was dissolved in DCM (30 mL) and washed with saturated NaHCO3 aqueous solution. The aqueous phase was extracted with DCM (20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and then the solvent was removed under vacuum to obtain the title compound (450 mg, quantitatively) as a yellow-orange glassy solid. LCMS (Method 1): [M+H] + 567, RT 1.33 min.

[0380] Intermediate 47 [3-(6-{(S)-amino[4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)-1,1-dioxo-1,4-thiadinan-4-yl](3-fluorobicyclo[1.1.1]pentan-1-yl)methanone To Example 12 (120 mg, 0.177 mmol), HBr (33% solution in AcOH) (5 mL, 30.38 mmol) was added. The resulting yellow suspension was briefly sonicated to secure the solution, and the reaction mixture was stirred at ambient temperature. After 10 minutes, diethyl ether (20 mL) was added. The mixture was stirred at ambient temperature for 5 minutes, then the solid was collected on a frit, washed with additional diethyl ether, and dried under suction. The solid was dissolved in MeOH (10 mL) and loaded onto a 2 g SCX column to be eluted with MeOH (30 mL), followed by 7N ammonia in MeOH (30 mL). The yellow methanolic ammonia portion was concentrated under vacuum to obtain the title compound (59 mg, 52%) as a yellow film. LC-MS (Method 1): [M+H] + 545, RT 1.18 min.

[0381] Intermediate 48 Ethyl 1-acetyl-4,4-difluorocyclohexanecarboxylate To a solution of ethyl 4,4-difluorocyclohexane carboxylate (11 g, 57.2 mmol) in THF (57 mL) at -78°C, LDA (2.0 mol / L, 31 mL, 63 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred for a further 30 minutes, and then acetic anhydride (8.1 mL, 85.8 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. Water (200 mL) and hexane (200 mL) were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with hexane (2 × 100 mL). The combined organic extracts were dried over Na₂SO₄, passed through a phase separator, and concentrated under vacuum. The crude substance was purified by column chromatography (Biotage SFAR HC DUO, 350 g, Isolera, 0-20% RINKAN in isohexane) to obtain the title compound (6.37 g, 48%) as a yellow oil. δ H(300 MHz, CDCl3) 4.36-4.17 (m, 2H), 2.45-2.21 (m, 2H), 2.20 (s, 3H), 2.15-1.74 (m, 6H), 1.30 (td, J 7.1, 4.7 Hz, 3H).

[0382] Intermediate 49 Ethyl 1-(2,2-dibromoacetyl)-4,4-difluorocyclohexanecarboxylate Bromine (2.4 mL, 46.96 mmol) was added dropwise to a solution of intermediate 48 (5.5 g, 23.48 mmol) in DCM (23 mL). The reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (200 mL) and washed with saturated Na2CO3 aqueous solution (200 mL), saturated sodium thiosulfate aqueous solution (20 mL), and brine (200 mL). The organic layer was dried over Na2SO4, then passed through a phase separator and concentrated under vacuum. The crude substance was purified by column chromatography (Biotage SFAR HC DUO, 250 g, Isolera, 0-20% siRNA in isohexane) to obtain the title compound (7.85 g, 85%) as a colorless oil. δ H (300 MHz, CDCl3) 6.26 (s, 1H), 4.28 (q, J 7.1 Hz, 2H), 2.45-2.30 (m, 2H), 2.27-1.79 (m, 6H), 1.33 (t, J 7.2 Hz, 3H).

[0383] Intermediate 50 Ethyl 1-(3-amino-1,2,4-triazin-5-yl)-4,4-difluorocyclohexanecarboxylate Morpholine (6.2 mL, 71.42 mmol) was added dropwise to a vial containing a solution of intermediate 49 (7 g, 17.86 mmol) in THF (18 mL). The reaction mixture was stirred overnight at 65°C. The resulting suspension was filtered through a Celite® pad while washing with THF (100 mL). The filtrate was concentrated under vacuum to obtain an orange oily substance. AcOH (4.1 mL, 71.423 mmol) was added to a separate vial containing aminoguanidine bicarbonate (2.48 g, 17.86 mmol) in MeOH (18 mL). The suspension was stirred at room temperature for 18 hours and then added to the aforementioned solution of the orange oily substance in MeOH (18 mL). The reaction mixture was stirred at reflux temperature for 4 hours and then concentrated under vacuum. The crude residue was dissolved in SiO2 (200 mL) and washed with water (200 mL). The aqueous layer was further extracted with ELISA (2 × 200 mL). The combined organic extracts were dried and concentrated in vacuum. The crude material was polished with diethyl ether (3 × 50 mL), the solid was filtered, and dried in vacuum to obtain the title compound (1.52 g, 30%) as a colorless amorphous solid. δ H (300 MHz, DMSO-d6) 8.71 (s, 1H), 7.30 (s, 2H), 4.15 (q, J 7.1 Hz, 2H), 2.42-2.08 (m, 5H), 2.08-1.72 (m, 5H), 1.14 (t, J 7.1 Hz, 3H).LCMS(Method 8):[M+H] + 287.2, RT 1.37 min.

[0384] Intermediate 51 Ethyl 1-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4,4-difluorocyclohexanecarboxylate IPA (10 mL) was added to a vial containing intermediate 50 (490 mg, 1.71 mmol), benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (1.04 g, 2.57 mmol), and NaHCO3 (288 mg, 3.43 mmol). The reaction mixture was stirred at 80°C for 18 hours. Additional NaHCO3 (70 mg, 0.86 mmol) was added, and heating at 80°C was continued for 5 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with HCl (20 mL), washed with water (20 mL), and the aqueous layer was further extracted with HCl (2 × 20 mL). The combined organic extracts were concentrated under vacuum. The crude substance was purified by column chromatography (Biotage SFAR HC DUO, 25 g, Isolera, 0-40% siRNA / hexane) to obtain the title compound (590 mg, 58%). δ H (300 MHz, CDCl3) 8.62 (d, J 12.7 Hz, 1H), 7.87 (s, 1H), 7.51-7.04 (m, 5H), 6.42-6.22 (m, 1H), 5.22-5.00 (m, 4H), 4.25 (qd, J 7.1, 3.5 Hz, 2H), 2.63 (d, J14.1 Hz, 2H), 2.57-2.27 (m, 3H), 2.29-1.90 (m, 6H), 1.96-1.35 (m, 4H), 1.35-0.98 (m, 3H).LCMS (Method 1): [M+H] + 592.2, RT 1.53 min.

[0385] Intermediate 52 1-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4,4-difluorocyclohexanecarboxylate sodium salt Intermediate 51 (200 mg, 0.34 mmol) at room temperature was stirred in THF (4 mL), EtOH (4 mL), and water (2 mL), to which an aqueous solution of NaOH (2 mol / L, 0.5 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum (water bath, 30°C) to obtain the title compound (200 mg, quantitatively) as a yellow oily substance, which was rapidly used without further purification. LC-MS (Method 1): [M+H] + 564.2, RT 1.10 min.

[0386] Intermediate 53 Benzyl N-[(S)-(4,4-difluorocyclohexyl){3-[1-(2,2-difluoropropylcarbamoyl)-4,4-difluorocyclohexyl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]carbamate To a solution containing crude intermediate 52 (200 mg, 0.34 mmol) suspended in DMF (2 mL), DIPEA (0.15 mL, 0.86 mmol) and 2,2-difluoropropylamine hydrochloride (50 mg, 0.36 mmol) were added, followed by the addition of HATU (155.6 mg, 0.4092 mmol) in fractional amounts. The reaction mixture was stirred at room temperature for 18 hours, and then diluted with RINKAN (20 mL) and water (5 mL). The aqueous layer was extracted with RINKAN (3 × 25 mL). The combined organic extract was concentrated under vacuum. The resulting yellow oily substance was purified by column chromatography (Biotage SFAR HC DUO, 25 g, Isolera, 0-100% RINKAN / hexane) to obtain the title compound (impure mixture) (200 mg, 91%) as a clear oily substance, which was used without further purification. LCMS (Method 3): [M+H] + 641.2, RT 1.46 min.

[0387] Intermediate 54 1-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-N-(2,2-difluoropropyl)-4,4-difluorocyclohexanecarboxamide Pd / C (10% by mass) (20 mg, 0.019 mmol) was added to a solution containing crude intermediate 53 (200 mg, 0.31 mmol) in EtOH (3 mL) under evacuated and N2 conditions. The reaction flask was placed under an H2 atmosphere and stirred at room temperature for 1 hour. The reaction mixture was filtered through a Celite® pad and concentrated under vacuum to obtain the title compound (160 mg, quantitative) as a crude brown oily substance, which was used without further purification. LCMS (Method 1): [M+H] + 507.2, RT 1.24 min.

[0388] Intermediate 55 Methyl 4-acetyltetrahydropyran-4-carboxylate To a vigorously stirred solution of methyltetrahydro-2H-pyran-4-carboxylate (0.91 mL, 6.94 mmol) in THF (15 mL) at -75°C (internal temperature), 2M LDA (3.9 mL, 7.86 mmol) in THF was added over 10 minutes. After 50 minutes, acetic anhydride (0.98 mL, 10.4 mmol) was added to the reaction mixture over 5 minutes. The reaction mixture was stirred at room temperature for 75 minutes and then cooled to 0°C. Heptane (10 mL) and water (5 mL) were added. The two-phase mixture was transferred to a separatory funnel and further diluted with heptane (30 mL) and water (30 mL). The phases were separated, and the aqueous phase was re-extracted with heptane (2 × 30 mL). The combined organic extracts were dried (phase separator) and concentrated under vacuum. The resulting crude yellow oily substance was purified by automated FCC (Isolera 4, Sfar Duo 100g, 0-100% toluene in heptane) to obtain the title compound (0.85g, 59%) as a yellow oily substance. δ H (500 MHz, CDCl3) 3.81-3.72 (m, 5H), 3.63-3.53 (m, 2H), 2.19-2.10 (m, 5H), 2.02-1.94 (m, 2H).

[0389] Intermediate 56 Methyl 4-(2,2-dibromoacetyl)tetrahydropyran-4-carboxylate Bromine (0.52 mL, 10.1 mmol) was added to a stirred solution of intermediate 55 (0.84 g, 4.06 mmol) at room temperature in DCM (6 mL). After 6 hours, the mixture was diluted with DCM (30 mL) and washed with saturated NaHCO3 aqueous solution (30 mL). The aqueous phase was re-extracted with DCM (30 mL), and the combined organic extract was washed with saturated Na2S2O3 aqueous solution (30 mL). The organic phase was dried (phase separator) and then concentrated under vacuum to obtain the title compound (1.46 g, 94%) as a yellow-orange oil. δ H (500 MHz, CDCl3) 6.24 (s, 1H), 3.85-3.74 (m, 5H), 3.70-3.57 (m, 2H), 2.29-2.18 (m, 2H), 2.17-2.06 (m, 2H).

[0390] Intermediate 57 Methyl 4-[2,2-di(morpholine-4-yl)acetyl]tetrahydropyran-4-carboxylate Morpholine (1.8 mL, 15.2 mmol) was added to a stirred solution of intermediate 56 (1.44 g, 3.77 mmol) at room temperature in THF (15 mL). The resulting solution was heated to 55°C over 45 minutes and then heated at 55°C for a further 18 hours. Additional morpholine (0.9 mL, 7.6 mmol) was added, and heating was continued at 55°C for 3 hours. The reaction mixture was cooled to room temperature, stirred overnight, then the suspension was filtered, washed with THF (20 mL), and concentrated under vacuum. The oily orange residue was azeotropically mixed with heptane (3 × 30 mL), and then dried under vacuum at room temperature for 3 hours to obtain the title compound ( 1 ¹H NMR yielded an orange oily substance with a purity of approximately 65% ​​(1.59 g, 77%), which was used without further purification. δ H (500 MHz, CDCl3) 3.89-3.84 (m, 2H), 3.80 (s, 1H), 3.78 (s, 3H), 3.78-3.53 (m, 8H), 3.50-3.43 (m, 2H), 2.74-2.67 (m, 4H), 2.59-2.51 (m, 4H), 2.24-2.17 (m, 2H), 2.01-1.92 (m, 2H).

[0391] Intermediate 58 Methyl 4-(3-amino-1,2,4-triazine-5-yl)tetrahydropyran-4-carboxylate Intermediate 57 (65%, 1.55 g, 2.83 mmol), MeOH (10 mL), aminoguanidine hydrochloride (0.32 g, 2.93 mmol), and AcOH (0.33 mL, 5.77 mmol) were added to a round-bottom flask. The mixture was stirred at room temperature for 30 minutes, then heated at 65°C for 24 hours, then cooled to room temperature and left overnight at room temperature. The reaction mixture was concentrated under vacuum. The crude residue was diluted with HCl (50 mL), H2O (50 mL), and saturated Na2CO3 aqueous solution (10 mL), and the phases were separated. The aqueous phase was re-extracted with HCl (2 × 50 mL). The combined organic extracts were dried (phase separator) and concentrated under vacuum. The residue was purified using automated chromatography (Isolera 4, Sfar Duo 50 g, 0-10% MeOH in DCM as eluate) to obtain the title compound ( 1 ¹H NMR was used to obtain a yellow-orange solid with a purity of approximately 65% ​​(650 mg, 63%), which was used without further purification. H (400 MHz, DMSO-d6) 8.69 (s, 1H), 7.37-7.18 (m, 2H), 3.72-3.62 (m, 5H), 3.57-3.44 (m, 2H), 2.27-2.16 (m, 2H), 2.14-2.04 (m, 2H).

[0392] Intermediate 59 Methyl 4-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}tetrahydropyran-4-carboxylate Intermediate 58 (65%, 0.65 g, 1.76 mmol), benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (1.08 g, 2.62 mmol), and NaHCO3 (0.29 g, 3.48 mmol) were suspended in IPA (8.38 mL) and heated at 65°C for 18 hours under nitrogen. After cooling, the mixture was diluted with water (50 mL) and saturated NaHCO3 aqueous solution (50 mL) and extracted with ELISA (3 × 50 mL). The combined organic extract was washed with brine (50 mL). The phases were separated, and the organic phase was then dried (hydrophobic frit) and concentrated under vacuum. The crude residue was purified by automated FCC (Isolera 4, Sfar Duo 100g, 0-100% siRNA in heptane) to obtain the title compound (0.64g, 57%) as a reddish-brown oily substance, which was used without further purification. δ H (400 MHz, DMSO-d6) 8.83 (s, 1H), 8.17 (s, 1H), 7.86 (d, J 9.3 Hz, 1H), 7.42-7.25 (m, 5H), 5.05 (d, J 12.6 Hz, 1H), 5.01 (d, J 12.5 Hz, 1H), 4.80-4.72 (m, 1H), 3.78-3.64 (m, 5H), 3.63-3.47 (m, 2H), 2.41-1.49 (m, 11H), 1.46-1.20 (m, 2H).

[0393] Intermediate 60 Benzyl N-[(S)-(4,4-difluorocyclohexyl){3-[4-(2,2-difluoropropylcarbamoyl)tetrahydropyran-4-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]carbamate To a solution of intermediate 59 (200 mg, 0.353 mmol) at 20°C in DCM (3 mL), a 3 M solution of NaOH in MeOH (118 μL, 0.353 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then an additional 3 M solution of NaOH in MeOH (118 μL, 0.353 mmol) was added. The reaction mixture was stirred at room temperature for a further 25 minutes. This procedure was repeated three more times, and then the reaction mixture was concentrated to dryness under a stream of nitrogen. The resulting sodium carboxylate (195 mg) was taken into DCM (3.8 mL), and then 2,2-difluoropropane-1-amine hydrochloride (1:1) (52 mg, 0.392 mmol), DIPEA (137 μL, 0.785 mmol), and HATU (119 mg, 0.314 mmol) were added in portions. The reaction mixture was stirred at room temperature for 64 hours, and then DMF (3.8 mL) and additional 2,2-difluoropropane-1-amine hydrochloride (1:1) (52 mg, 0.392 mmol), DIPEA (137 μL, 0.785 mmol), and HATU (119 mg, 0.314 mmol) were rapidly added in succession. The reaction mixture was stirred at room temperature for 10 minutes, and then diluted with ELISA (10 mL), saturated NaHCO3 aqueous solution (5 mL), and water (5 mL). The two-phase mixture was stirred at room temperature for 20 minutes. The layers were separated, and then the organic phase was dried (hydrophobic frit) and concentrated under vacuum. The crude residue was purified by automated FCC (Isolera 4, Sfar Duo 50g, 0-100% ethyl phosphate in heptane) to obtain a mixture of the title compound (47%) and inseparable impurities identified as benzyl N-{(S)-(4,4-difluorocyclohexyl)[3-(tetrahydropyran-4-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]methyl}carbamate (53%) (117 mg, 34%) as a yellow oily substance, which was used without further purification. LCMS (Method 8): [M+H] + m / z607, RT3.90 minutes.

[0394] Intermediate 61 4-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-N-(2,2-difluoropropyl)tetrahydropyran-4-carboxamide To a stirred solution of intermediate 60 (46%, 107 mg, 0.0811 mmol) in EtOH (5 mL) under nitrogen (3 cycles of vacuum / nitrogen gas), 10% Pd / C (50% wet) (5.0%, 35 mg, 0.016 mmol) was added in one step. The reaction mixture was stirred under hydrogen (3 cycles of vacuum / nitrogen gas, followed by 3 cycles of vacuum / hydrogen gas) for 3 hours. The reaction mixture was filtered through Celite®, washing with additional MeOH. The combined filtrate was concentrated under vacuum and then purified using automated chromatography (Isolera 4, Sfar KP Amino D, 11 g, 0-10% MeOH in DCM) to obtain the title compound (purity 89.0%) (33 mg, 77%) as a yellow oil, which was used without further purification. LCMS (Method 8): [M+H] + m / z473, RT2.93 minutes.

[0395] Intermediate 62 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(3-{1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]carbamate Intermediate 33 (a 1:1 mixture of two syn stereoisomers) (310 mg, 0.51 mmol), intermediate 79 (94.0 mg, 0.57 mmol), and DIPEA (0.36 mL, 2.10 mmol) were dissolved in DMF (15 mL) at room temperature, to which HATU (242 mg, 0.62 mmol) was added all at once. The mixture was stirred for 10 minutes, and then H2O (20 mL) was added. The mixture was extracted with ELISA (3 x 20 mL). The combined organic extract was washed with brine (40 mL), then dried, (Na2SO4), and concentrated under vacuum. Purification by flash chromatography eluting with ELISA / isohexane (0-100% gradient) yielded the title compound (a 1:1 mixture of two syn stereoisomers, indistinguishable by LC-MS) (246 mg, 67%) as a yellow foam. LCMS (Method 1): [M+H] + m / z717.2, RT1.46 minutes.

[0396] Intermediate 63 [2-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-yl][(2S)-5,5-difluorotetrahydropyran-2-yl]methanone To a solution of intermediate 62 (a 1:1 mixture of two syn stereoisomers) (246 mg, 0.34 mmol) in EtOH (10 mL) at room temperature, 10% Pd / C (25 mg) was added. The vessel was evacuated, purged three times with H2, and then stirred at room temperature for approximately 255 minutes. The mixture was filtered through a Celite® (10 g) pad under suction, while washing with EtOH (60 mL). The filtrate was concentrated under vacuum. Purification by flash chromatography (KP-NH column) eluting with  / isohexane (0-100% gradient) and then DCM:MeOH (90:10) yielded the title compound (a 1:1 mixture of two stereoisomers, indistinguishable by LC-MS) (purity 85%) (162 mg, 69%) as a yellow foam. LC-MS (Method 1): [M+H] + m / z583.2, RT1.21 minutes.

[0397] Intermediate 64 tert-butyl 4-(difluoromethyl)-4-(trimethylsilyloxy)piperidine-1-carboxylate To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.06 g, 10.3 mmol) at room temperature in THF (20.7 mL) and DMPU (6.4 mL), CsF (471 mg, 3.10 mmol) was added in one step. The mixture was stirred for 5 minutes, and then (difluoromethyl)trimethylsilane (2.82 mL, 20.7 mmol) was added dropwise via syringe over 2 minutes. The reaction mixture was stirred overnight at 70°C, and then diluted with siRNA (20 mL) and H₂O (20 mL). The layers were separated, and the aqueous layer was re-extracted with siRNA (2 × 20 mL). The combined organic layers were washed with brine (2 × 40 mL), dried, and concentrated under vacuum in (Na₂SO₄). The title compound (2.32 g, 69%) was obtained as a white solid by purification by flash chromatography eluting with siRNA / isohexane (0–10% gradient). R f 0.50 (isohexane:siRNA, 90:10), non-UV, KMnO4. δ H (400 MHz, CDCl3) 5.49 (t, J 56.0 Hz, 1H), 4.09-3.90 (m, 2H), 3.11-2.94 (m, 2H), 1.67-1.53 ​​(m, 4H), 1.49 (s, 9H), 0.18 (s, 9H).

[0398] Intermediate 65 1-(tert-butoxycarbonyl)-4-(difluoromethyl)-4-(trimethylsilyloxy)piperidine-2-carboxylic acid To a solution of intermediate 64 (2.95 g, 9.12 mmol) and TMEDA (2.47 mL, 16.4 mmol) in diethyl ether (91 mL) at -78°C, sec-butyllithium (1.3 M in cyclohexane, 12.0 mL, 17.0 mmol) was added dropwise over 10 minutes. The mixture was stirred at -78°C for 10 minutes, during which time a bright orange color developed. After this time, the reaction mixture was heated to -40°C (replacing the dry ice / acetone bath with a dry ice / acetonitrile bath) and stirred at -40°C for 20 minutes. The reaction mixture was cooled back down to -78°C, and CO2 was bubbling into the mixture for 30 minutes. After this time, the reaction mixture was heated to room temperature and stirred for 1 hour, then quenched by adding saturated aqueous NH4Cl (30 mL) and H2O (5 mL) (to solubilize the resulting precipitate). The layers were separated, and the aqueous layer was washed with diethyl ether (2 × 20 mL) and siRNA (2 × 20 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under vacuum. The title compound (a mixture of two diastereomers) was purified by flash chromatography using siRNA / isohexane (0-100% gradient) followed by elution with DCM:MeOH (90:10). 1 (Indistinguishable by 1H NMR) (1.97g, 59%) was obtained as a dark yellow oily substance. δ H (400 MHz, CDCl3) 5.58 (t, J 55.8 Hz, 1H), 4.43 (dd, J 9.0, 5.9 Hz, 1H), 3.76-3.64 (m, 1H), 3.44 (ddd, J 13.6, 8.6, 4.8 Hz, 1H), 2.16 (dd, J 14.1, 9.0 Hz, 1H), 2.10-2.01 (obscured dd, 1H), 1.98-1.88 (m, 1H), 1.82-1.72 (m, 1H), 1.49 (s, 9H), 0.18 (s, 9H). No proton signal of carboxylic acid was observed.

[0399] Intermediate 66 1-(tert-butoxycarbonyl)-4-(difluoromethyl)-4-hydroxypiperidine-2-carboxylic acid To a solution of intermediate 65 (1.97 g, 5.36 mmol) at room temperature in THF (50 mL), TBAF (1 M in THF, 8.04 mL, 8.04 mmol) was added dropwise over 2 minutes. The mixture was stirred at room temperature for 30 minutes, then concentrated to dryness and loaded onto SiO2. Purification by flash chromatography eluting with siRNA / isohexane (0-100% gradient) followed by DCM:MeOH (90:10) revealed the title compound (a mixture of two diastereomers). 1 (Indistinguishable by 1H NMR) (1.54 g, 97%) was obtained as a beige-colored foamy substance. δ H (400 MHz, 373K, DMSO-d6) 12.69-11.65 (br s, 1H), 5.72 (t, J56.0 Hz, 1H), 5.34-5.97 (br s, 1H), 4.27 (dd, J 8.6, 6.3 Hz, 1H), 3.66-3.56 (m, 1H), 3.35-3.25 (m, 1H), 2.01-1.88 (m, 2H), 1.85-1.76 (m, 1H), 1.64-1.54 (m, 1H), 1.41 (s, 9H).

[0400] Intermediate 67 O 1 -tert-butylO 2 -(1,3-dioxoisoindolin-2-yl)4-(difluoromethyl)-4-hydroxypiperidine-1,2-dicarboxylate To a solution of intermediate 66 (800 mg, 2.71 mmol) and N-hydroxyphthalimide (486 mg, 2.98 mmol) in DCM (15 mL) at room temperature, EDCI.HCl (571 mg, 2.98 mmol) was added in one step. The yellow mixture was stirred for 18 hours and then concentrated under vacuum. Purification by flash chromatography eluting with siRNA / isohexane (0-60% gradient) revealed the title compound (a mixture of the two diastereomers, LCMS or 1 (Indistinguishable by 1H NMR) (566 mg, 47%) was obtained as a white foamy substance. δ H(400 MHz, DMSO-d6) 8.00-7.93 (m, 4H), 5.83 (t, J 55.9 Hz, 1H), 5.48-5.33 (br s, 1H), 4.78 (dd, J 9.9, 6.0 Hz, 1H), 3.73 (dt, J 13.6, 6.0 Hz, 1H), 3.34 (ddd, J 13.6, 8.3, 5.1 Hz, 1H), 2.21 (dd, J 14.2, 5.9 Hz, 1H), 2.12 (dd, J 14.0, 9.9 Hz, 1H), 1.88 (dt, J 14.2, 5.7Hz, 1H), 1.75-1.65 (m, 1H), 1.48 (s, 9H).LCMS (Method 1): [M+H-BOC] + m / z341.0, RT1.30 minutes.

[0401] Intermediates 68 and 69 tert-butyl2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (syn isomer) (intermediate 68) tert-butyl2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (anti-isomer) (intermediate 69) Intermediate 18 (345 mg, 0.86 mmol), intermediate 67 (568 mg, 1.29 mmol), DMF (17 mL), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (20.0 mg, 0.018 mmol), and TFA (0.10 mL, 1.30 mmol) were sequentially introduced into screw-cap vials. The vials were capped, the mixtures were purged with N2 for 5 minutes, then the caps were sealed with Parafilm, and the mixtures were irradiated for 20 hours (450 nm) using an "integrated photoreactor" (ACS Cent.Sci., 2017, 3, 647~653) (settings: fan=1612 rpm; stirring=392 rpm; LED=100%). The mixtures were diluted with SiO2 (20 mL) and washed with H2O (2 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography eluting with SiO2 / isohexane (0-70% gradient) to obtain intermediate 68 (syn-component, main) (two stereoisomers in a 1:1 ratio, LC-MS or 1 (Indistinguishable by 1H NMR) (192 mg, 34%) and intermediate 69 (anti-constituent, secondary) (two stereoisomers in a 1:1 ratio, LC-MS or 1 (Indistinguishable by 1H NMR) (56.0 mg, 10%) was obtained as a yellow foamy substance. LC-MS (Method 1): [M+H] + m / z 651.2, RT 1.46 min (sub-anti-diastereomer), RT 1.50 min (main syn-diastereomer).

[0402] Intermediate 70 Benzyl N-[(S)-(4,4-difluorocyclohexyl){3-[4-(difluoromethyl)-4-hydroxypiperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]carbamate hydrochloride (syn isomer) To intermediate 68 (a 1:1 mixture of two syn stereoisomers) (192 mg, 0.30 mmol), 4N HCl in 1,4-dioxane (2.70 mL, 11.0 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes, and then carefully neutralized with saturated NaHCO3 aqueous solution. SiO2 (20 mL) was added, and the layers were separated. The aqueous layer was extracted with SiO2 (2 × 20 mL). The combined organic extracts were dried (Na2SO4) and then concentrated under vacuum to obtain the title compound (a 1:1 mixture of two syn stereoisomers, LCMS or 1 (Indistinguishable by 1H NMR) (169 mg, 98%) was obtained as a yellow foamy substance and used without further purification. LC-MS (Method 1): [M+H] + m / z551.2, RT1.23 minutes.

[0403] Intermediate 71 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(3-{4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]carbamate (syn isomer) Intermediate 70 (a 1:1 mixture of two syn stereoisomers) (169 mg, 0.29 mmol), intermediate 79 (53.0 mg, 0.32 mmol), and DIPEA (0.20 mL, 1.20 mmol) were dissolved in DMF (10 mL) at room temperature, to which HATU (136 mg, 0.35 mmol) was added all at once. The mixture was stirred for 45 minutes, and then H2O (20 mL) was added. The mixture was extracted with SiO (3 x 20 mL). The combined organic extract was washed with brine (40 mL), then dried, (Na2SO4), and concentrated under vacuum. Purification by flash chromatography eluting with SiO / isohexane (0-100% gradient) yielded the title compound (a 1:1 mixture of two syn stereoisomers, indistinguishable by LC-MS) (177 mg, 88%) as a yellow foam. LCMS (Method 1): [M+H] + m / z 699.2, RT 1.42 min.

[0404] Intermediate 72 [2-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazine-3-yl}-4-(difluoromethyl)-4-hydroxypiperidine-1-yl][(2S)-5,5-difluorotetrahydropyran-2-yl]methanone (syn isomer) To a solution of intermediate 71 (a 1:1 mixture of two syn stereoisomers) (177 mg, 0.25 mmol) at room temperature in EtOH (10 mL), 10% Pd / C (17 mg) was added. The vessel was evacuated, purged three times with H2, and then stirred at room temperature for approximately 90 minutes. The mixture was filtered through a Celite® (10 g) pad under suction, while washing with EtOH (60 mL). The filtrate was concentrated under vacuum. Purification by flash chromatography (KP-NH column) eluting with siRNA / isohexane (0-100% gradient) and then DCM:MeOH (90:10) yielded the title compound (a 1:1 mixture of two stereoisomers, indistinguishable by LC-MS) (124 mg, 88%) as a yellow foam. LC-MS (Method 1): [M+H] + m / z565.2, RT1.14 minutes.

[0405] Intermediate 73 tert-butyl3-(6-{(S)-benzyloxycarbonylamino[4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)morpholine-4-carboxylate Intermediate 44 (99%ee) (400 mg, 0.92 mmol), intermediate 17 (521 mg, 1.38 mmol), DMF (18 mL), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (21.0 mg, 0.019 mmol), and TFA (0.11 mL, 1.50 mmol) were sequentially introduced into screw-cap vials. The vials were capped, the mixture was purged with N2 for 5 minutes, then the caps were sealed with Parafilm, and the mixture was irradiated for 48 hours (450 nm) using a Hepatochem "PhotoRedOx Box" photoreactor (U.S. Patent No. 10,906,022). Next, the mixture was transferred to an "integrated photoreactor" (ACS Cent.Sci., 2017, 3, 647-653) (settings: fan = 1612 rpm; stirring = 392 rpm; LED = 100%) and irradiated for a further 5 hours. The mixture was diluted with HCl (40 mL) and washed with H2O (2 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash chromatography eluting with HCl / isohexane (0-100% gradient) to obtain the title compound (a 1:1 mixture of two stereoisomers, LCMS or 1 (Indistinguishable by 1H NMR) (400 mg, 70%) was obtained as an orange foamy substance. LC-MS (Method 1): [M+H] + m / z619.2, RT1.48 minutes.

[0406] Intermediate 74 tert-butyl3-(6-{(S)-amino[4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)morpholine-4-carboxylate To a solution of intermediate 73 (two stereoisomers in a 1:1 ratio) (400 mg, 0.65 mmol) at room temperature in EtOH (22 mL), 4N HCl (0.20 mL, 0.80 mmol) in 1,4-dioxane and 10% Pd / C (40 mg) were sequentially added. The vessel was evacuated, purged three times with H2, and then stirred at room temperature for approximately 330 minutes. The mixture was filtered through a Celite® (10 g) pad under suction while washing with EtOH (60 mL). The filtrate was concentrated under vacuum. The title compound (a mixture of two stereoisomers in a 1:1 ratio, LCMS or 1 (Indistinguishable by 1H NMR) (purity 85%) (240 mg, 65%) was obtained as an orange foamy substance. LC-MS (Method 1): [M+H] + m / z 485.2, RT 1.31 minutes.

[0407] Intermediate 75 tert-butyl3-(6-{(S)-[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino][4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)morpholine-4-carboxylate Intermediate 74 (two stereoisomers in a 1:1 ratio) (85% purity) (240 mg, 0.50 mmol) at room temperature, 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (64.0 mg, 0.50 mmol), and DIPEA (0.34 mL, 2.00 mmol) were dissolved in DMF (10 mL), to which HATU (233 mg, 0.59 mmol) was added all at once. The mixture was stirred for 50 minutes, and then H2O (25 mL) was added. The mixture was extracted with RINKAN (3 x 20 mL). The combined organic extract was washed with brine (40 mL), then dried, (Na2SO4), and concentrated under vacuum. Purification by flash chromatography eluting with RINKAN / isohexane (0-75% gradient) revealed the title compound (a mixture of two stereoisomers in a 1:1 ratio, LCMS or 1cannot be distinguished by ¹H NMR) (159 mg, 54%) was obtained as an orange solid. LCMS (Method 1): [M+H] + m / z 595.2, RT 1.50 min.

[0408] Intermediate 76 4-methyl-N-{(S)-[3-(morpholin-3-yl)imidazo[1,2-b][1,2,4]triazin-6-yl][4-(trifluoromethyl)cyclohexyl]methyl}-1,2,5-oxadiazole-3-carboxamide trifluoroacetate Intermediate 75 (two stereoisomers in a 1:1 ratio) (159 mg, 0.27 mmol) was dissolved in DCM (1.9 mL), and TFA (0.30 mL, 4.00 mmol) was added. The solution was stirred at room temperature for 165 minutes, then neutralized with saturated aqueous NaHCO₃ (10 mL). EtOAc (10 mL) was added to the mixture, and the layers were separated. The aqueous layer was re-extracted with EtOAc (2×20 mL). The combined organic layers were dried (Na₂SO₄), then concentrated in vacuo to give the title compound (a 1:1 mixture of two stereoisomers, which cannot be distinguished by LCMS or 1 ¹H NMR) (187 mg, quantitative) was obtained as an orange foam, which was used without further purification. LCMS (Method 1): [M+H] + m / z 495.2, RT 1.25 min.

[0409] Intermediates 77 and 78 (3R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl (2R)-5,5-difluorotetrahydropyran-2-carboxylate (Intermediate 77) (3R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl (2S)-5,5-difluorotetrahydropyran-2-carboxylate (Intermediate 78) 5,5-Difluorooxane-2-carboxylic acid (5.00 g, 28.6 mmol), (R)-(-)-pantractone (4.00 g, 30.4 mmol), and DMAP (176 mg, 1.43 mmol) were dissolved in DCM (145 mL), and EDCI.HCl (6.35 g, 31.5 mmol) was added. The reaction mixture was stirred overnight at room temperature, then diluted with DCM and water, and passed through a phase separator. The organic phase was dried over Na2SO4 and concentrated under vacuum. The title compound (peak 1, 3.34 g, 42%; peak 2, 2.91 g, 36%) was obtained by purification by flash column chromatography of silica eluted at 0-5% siRNA / DCM. Peak 1: δ H (400 MHz, DMSO-d6) 5.65 (s, 1H), 4.55-4.47 (m, 1H), 4.16 (d, J 8.6 Hz, 1H), 4.08 (d, J8.6 Hz, 1H), 4.02-3.90 (m, 1H), 3.83-3.68 (m, 1H), 2.29-2.06 (m, 3H), 1.93-1.78 (m, 1H), 1.13 (s, 3H), 1.00 (s, 3H). Peak 2: δ H (400 MHz, DMSO-d6) 5.67 (s, 1H), 4.51 (dd, J 9.9, 2.9 Hz, 1H), 4.16 (d, J 8.6 Hz, 1H), 4.08 (d, J 8.6 Hz, 1H), 4.02-3.90 (m, 1H), 3.84-3.69 (m, 1H), 2.29-2.07 (m, 3H), 1.95-1.81 (m, 1H), 1.12 (s, 3H), 1.00 (s, 3H).

[0410] Intermediate 79 (2S)-5,5-difluorotetrahydropyran-2-carboxylic acid Intermediate 78 (2.91 g, 10.4 mmol) was dissolved in a mixture of THF (20 mL), water (2 mL), and MeOH (2 mL), and treated with lithium hydroxide monohydrate (4.38 g, 104 mmol). The reaction mixture was heated at 50°C for 1 hour and then cooled to room temperature. The mixture was adjusted to pH 2 with concentrated HCl and then extracted three times with SiO2. The combined organic phase was washed twice with saturated NaHCO3 aqueous solution, and the resulting aqueous layer was adjusted to pH 2 with concentrated HCl. The title compound (1.10 g, 63%) was obtained by three extractions with SiO2 and concentration of the organic phase under vacuum. δ H (400 MHz, DMSO-d6) 12.92 (s, 1H), 4.20-4.13 (m, 1H), 3.97-3.85 (m, 1H), 3.75-3.60 (m, 1H), 2.22-1.96 (m, 3H), 1.86-1.70 (m, 1H).

[0411] Intermediates 80 and 81 tert-butyl2-(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-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (syn isomer) (intermediate 80) tert-butyl2-(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-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (anti-isomer) (intermediate 81) Intermediate 21 (500 mg, 1.33 mmol), intermediate 67 (875 mg, 1.99 mmol), DMF (10.5 mL), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (30 mg, 0.026 mmol), and TFA (0.12 mL, 1.9 mmol) were sequentially introduced into screw-cap vials. The vials were capped, the mixtures were purged with N2 for 5 minutes, then the caps were sealed with Parafilm, and the mixtures were irradiated (450 nm) for 20 hours using an "integrated photoreactor" (ACS Cent.Sci., 2017, 3, 647~653) (settings: fan=1612 rpm; stirring=392 rpm; LED=100%). The mixtures were diluted with DCM (20 mL) and water (20 mL), and then washed with brine (2 × 10 mL). The combined organic layers were separated by phase separation using hydrophobic frit and concentrated under vacuum. Purification by flash chromatography with elution using Â1 / Isohexane (0-100% gradient) yielded intermediate 80 (main syn isomer, 370 mg, 45%) and intermediate 81 (secondary anti isomer, 102 mg, 12%) as a yellow foamy substance. Intermediate 80: LCMS (Method 1): [M+H] + m / z527.2, RT1.47 minutes. Intermediate 81: LCMS (Method 1): [M+H] + m / z527.2, RT1.43 minutes.

[0412] Intermediate 82 N-[(S)-(4,4-difluorocyclohexyl){3-[4-(difluoromethyl)-4-hydroxypiperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (syn isomer) To intermediate 80 (a 1:1 mixture of two syn stereoisomers) (337 mg, 0.54 mmol), 4N HCl in 1,4-dioxane (4.90 mL, 20.0 mmol) was added dropwise. The mixture was stirred at room temperature for 25 minutes, and then carefully neutralized with saturated NaHCO3 aqueous solution. SiO2 (30 mL) was added, and the layers were separated. The aqueous layer was extracted with SiO2 (2 × 30 mL). The combined organic layers were dried (Na2SO4) and then concentrated under vacuum to obtain the title compound (a 1:1 mixture of two syn stereoisomers, LCMS or 1 (Indistinguishable by 1H NMR) (303 mg, quantitative) was obtained as a yellow foamy substance. LC-MS (Method 1): [M+H] + m / z527.2, RT1.17 minutes.

[0413] Intermediate 83 N-[(S)-(4,4-difluorocyclohexyl){3-[4-(difluoromethyl)-4-hydroxypiperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (anti-isomer) To intermediate 81 (a 1:1 mixture of two anti-stereoisomers) (104 mg, 0.17 mmol), 4N HCl in 1,4-dioxane (1.51 mL, 6.04 mmol) was added dropwise. The mixture was stirred at room temperature for 70 minutes, and then carefully neutralized with saturated NaHCO3 aqueous solution. SiO2 (10 mL) was added, and the layers were separated. The aqueous layer was extracted with SiO2 (2 × 10 mL). The combined organic layers were dried (Na2SO4), and then concentrated under vacuum to obtain the title compound (a 1:1 mixture of two anti-stereoisomers, LCMS or 1 (93.4 mg, quantitative) was obtained as a yellow foamy substance (indistinguishable by 1H NMR). LC-MS (Method 1): [M+H] + m / z527.2, RT1.19 minutes.

[0414] Intermediates 84 and 85 tert-butyl2-(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-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (syn isomer) (intermediate 84) tert-butyl2-(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-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (anti-isomer) (intermediate 85) Intermediate 21 (210 mg, 0.56 mmol), intermediate 4 (383 mg, 0.84 mmol), DMF (10.5 mL), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (13.0 mg, 0.012 mmol), and TFA (0.06 mL, 0.80 mmol) were sequentially introduced into screw-cap vials. The vials were capped, the mixture was purged with N2 for 5 minutes, then the caps were sealed with Parafilm, and the mixture was irradiated for 40 hours (450 nm) using an "integrated photoreactor" (ACS Cent.Sci., 2017, 3, 647~653) (settings: fan=1612 rpm; stirring=392 rpm; LED=100%). The mixture was diluted with ELISA (20 mL) and washed with H2O (2 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuum. Purification by flash chromatography using toluene / isohexane (0-80% gradient) yielded intermediate 84 (main syn isomer, 250 mg, 70%) and intermediate 85 (secondary anti isomer, 43.0 mg, 12%) as a yellow foamy substance. Intermediate 84: LCMS (Method 1): [M+H] + m / z645.2, RT1.52 minutes. Intermediate 85: LCMS (Method 1): [M+H] + m / z645.2, RT1.49 minutes.

[0415] Intermediate 86 N-[(S)-(4,4-difluorocyclohexyl){3-[4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (anti-isomer) To intermediate 85 (a 1:1 mixture of two anti-stereoisomers) (43.0 mg, 0.07 mmol), 4N HCl in 1,4-dioxane (0.61 mL, 2.40 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, and then carefully neutralized with saturated NaHCO3 aqueous solution. SiO2 (10 mL) was added, and the layers were separated. The aqueous layer was extracted with SiO2 (2 × 10 mL). The combined organic layers were dried (Na2SO4), and then concentrated under vacuum to obtain the title compound (a 1:1 mixture of two anti-stereoisomers, LCMS or 1 (Indistinguishable by 1H NMR) (38.8 mg, quantitative) was obtained as a yellow foamy substance. LC-MS (Method 1): [M+H] + m / z545.2, RT1.25 minutes.

[0416] Intermediate 87 1-(tert-butoxycarbonyl)-4-hydroxy-4-methylpiperidine-2-carboxylic acid To a solution of 1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (5.24 g, 20.9 mmol) in THF (40 mL) at -40°C, 21 mL, 63 mmol, 3 M methylmagnesium chloride solution in THF was added dropwise. The mixture was stirred overnight at room temperature, and then water was carefully added until no more gas was produced. An equal volume of RINKAN was added with vigorous stirring. The layers were separated, and the aqueous layer was washed with RINKAN. The mixture was adjusted to pH 3 with concentrated HCl, and then extracted twice with RINKAN. The combined organic phases were washed with brine, then dried over Na₂SO₄, and concentrated under vacuum to obtain the title compound (3.68 g, 68%). δ H(400 MHz, 373K, DMSO-d6) 11.78 (s, 1H), 4.48-4.42 (m, 1H), 3.72-3.64 (m, 1H), 3.37-3.26 (m, 1H), 2.14 (dt, J 13.8, 2.3 Hz, 1H), 1.62 (dd, J 13.8, 7.1 Hz, 1H), 1.53-1.47 (m, 1H), 1.43-1.38 (m, 10H), 1.14 (s, 3H). No proton signal was observed for OH.

[0417] Intermediates 88 and 89 tert-butyl2-(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-hydroxy-4-methylpiperidine-1-carboxylate (syn isomer) (intermediate 88) tert-butyl2-(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-hydroxy-4-methylpiperidine-1-carboxylate (anti-isomer) (intermediate 89) Intermediate 21 (480 mg, 1.27 mmol), intermediate 86 (694 mg, 2.54 mmol), cesium carbonate (1.25 g, 3.82 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (15 mg, 0.013 mmol) were dissolved in DMF (25 mL). The solutions were purged with nitrogen for 10 minutes and then irradiated with a Penn photoreactor M2 system for 3 hours (450 nm wavelength; fan = 3000 rpm; stirring = 500 rpm; LED = 100%). The same procedure was performed three times in batches, and the resulting reaction mixtures were combined. The combined mixture was partitioned between SiO2 and brine, and the layers were separated. The aqueous phase was extracted with SiO2, and then the combined organic phase was washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by flash column chromatography of silica eluted at 20-60% Â / DCM yielded intermediate 88 (syn isomer) (550 mg, 25%) and intermediate 89 (anti isomer) (255 mg, 11%). Intermediate 88 (syn isomer): δ H (400 MHz, DMSO-d6) 9.49 (d, J 9.0 Hz, 1H), 8.65-8.60 (m, 1H), 8.24-8.19 (m, 1H), 5.49-5.25 (m, 3H), 5.23-5.14 (m, 1H), 4.07 (s, 1H), 3.87 (br d, J 12.8 Hz, 1H), 2.49-2.44 (m, 3H), 2.43-2.35 (m, 1H), 2.25-2.16 (m, 1H), 2.11-1.70 (m, 4H), 1.70-1.60 (m, 1H), 1.53-1.20 (m, 14H), 1.13 (s, 3H).LCMS(Method 1):[M+H] + m / z591.2, RT1.40 minutes. Intermediate 89 (anti isomer): δ H(400 MHz, DMSO-d6) 9.49 (dd, J 8.9, 1.9 Hz, 1H), 8.66 (s, 1H), 8.26 (s, 1H), 5.39 (br s, 1H), 5.20 (t, J 8.5 Hz, 1H), 5.00 (dd, J 7.9, 5.7 Hz, 1H), 4.65 (s, 1H), 3.70-3.59 (m, 1H), 3.57-3.46 (m, 1H), 2.47 (s, 3H), 2.24-2.17 (m, 1H), 2.09-1.69 (m, 3H), 1.66-1.55 (m, 3H), 1.47-1.24 (m, 5H), 1.20 (s, 9H), 1.03 (s, 3H).LCMS (Method 1): [M+H] + m / z591.2, RT1.33 minutes.

[0418] Intermediate 90 N-{(S)-(4,4-difluorocyclohexyl)[3-(4-hydroxy-4-methylpiperidine-2-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (syn isomer) Intermediate 88 (665 mg, 1.126 mmol) was dissolved in 10 mL of 4N HCl in 1,4-dioxane. The mixture was stirred at room temperature for 1 hour, then neutralized with saturated aqueous NaHCO3 solution and diluted with SiO2. The layers were separated, and the aqueous layer was re-extracted with SiO2. The combined organic phases were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (a pair of syn stereoisomers, assumed to be in a 1:1 ratio) (504 mg, 91%). LC-MS (Method 1): [M+H] + m / z 491.2, RT 1.09 minutes.

[0419] Intermediate 91 N-{(S)-(4,4-difluorocyclohexyl)[3-(4-hydroxy-4-methylpiperidine-2-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (anti-isomer) Intermediate 89 (270 mg, 0.457 mmol) was dissolved in 4N HCl (4.5 mL) in 1,4-dioxane. The mixture was stirred at room temperature for 1 hour, then neutralized with saturated NaHCO3 aqueous solution and diluted with SiO2. The layers were separated, and the aqueous layer was re-extracted with SiO2. The combined organic phases were dried over Na2SO4 and concentrated under vacuum to obtain the title compound (anti-stereoisomer pair, assumed to be in a 1:1 ratio) (224 mg, 99%). LC-MS (Method 1): [M+H] + m / z491.2, RT1.10 minutes.

[0420] Intermediate 92 tert-butyl 4-[tert-butyl(dimethyl)silyl]oxypiperidine-1-carboxylate To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.99 g, 24.8 mmol) and DIPEA (6.70 mL, 38.3 mmol) in DCM (70 mL), cooled in an ice bath, tert-butyl(dimethyl)silyltrifluoromethanesulfonate (5.20 mL, 22.6 mmol) was added. The solution was stirred for 1 hour while cooling, and then the bath was removed. The solution was allowed to reach room temperature, and then stirred for a total of 6 hours. DCM (100 mL) and semi-saturated Na2CO3 aqueous solution (100 mL) were added. The layers were separated, the organic layer was washed with an additional semi-saturated Na2CO3 aqueous solution (50 mL), then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with an siRNA gradient in heptane to obtain the title compound (5.41 g, 76%). δ H (400 MHz, CDCl3) 3.86 (tt, J 7.0, 3.4 Hz, 1H), 3.61 (ddd, J 11.9, 7.5, 3.6 Hz, 2H), 3.24 (ddd, J 13.1, 7.6, 3.7 Hz, 2H), 1.74-1.63 (m, 2H), 1.53-1.45 (m, 2H), 1.45 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H).

[0421] Intermediate 93 1-(tert-butoxycarbonyl)-4-[tert-butyl(dimethyl)silyl]oxypiperidine-2-carboxylic acid (racemic) To a solution of intermediate 92 (5.41 g, 17.1 mmol) in diethyl ether (120 mL) under nitrogen at -78°C, TMEDA (4.6 mL, 30.9 mmol) was added, followed by the dropwise addition of 1.3 M sec-butyllithium in hexane (24 mL, 30.9 mmol) over 10 minutes. The mixture was stirred at -78°C for 2.5 hours, followed by the addition of solid CO2 (5 medium-sized pellets, approximately 10 g). The mixture was stirred at -78°C for 10 minutes, followed by heating to room temperature. HCl aqueous solution (1 M, 100 mL) was carefully added. The organic layer was diluted with siRNA (100 mL), and the layers were separated. The organic layer was washed with 1 M HCl aqueous solution (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained substance was purified by column chromatography using a gradient of ethyl acetate in heptane to obtain the title compound (3.96 g, 57%). δ H (500 MHz, DMSO-d6) 12.14 (s, 1H), 4.40 (dd, J 45.1, 6.2 Hz, 1H), 4.04 (s, 1H), 3.71-3.60 (m, 1H), 3.30-3.14 (m, 1H), 2.20-2.10 (m, 1H), 1.86-1.76 (m, 1H), 1.67-1.44 (m, 2H), 1.43-1.31 (m, 9H), 0.83 (s, 9H), 0.00 (s, 6H).

[0422] Intermediate 94 O 1 -tert-butylO 2 -(1,3-dioxoisoindolin-2-yl)4-[tert-butyl(dimethyl)silyl]oxypiperidine-1,2-dicarboxylate(racemic) To a solution of intermediate 93 (89%, 1.65 g, 4.08 mmol) and N-hydroxyphthalimide (1.00 g, 6.13 mmol) in DCM (35 mL), EDCI.HCl (1:1) (1.17 g, 6.13 mmol) was added. The turbid mixture became a clear yellow solution and was stirred at room temperature for 2 hours. Additional N-hydroxyphthalimide (0.67 g, 4.08 mmol) and EDCI.HCl (1:1) (0.78 g, 4.08 mmol) were added, and stirring was continued at room temperature for 2 hours. The solution was washed with water (50 mL) and passed through hydrophobic frit while washing through DCM. The obtained substance was concentrated under reduced pressure and purified by column chromatography eluting with a gradient of siRNA in heptane to obtain the title compound (1.65 g, 67%). δ H (500 MHz, CDCl3) 7.91-7.84 (m, 2H), 7.82-7.73 (m, 2H), 5.26-4.97 (m, 1H), 4.21-4.10 (m, 1H), 4.04-3.75 (m, 1H), 3.71-3.41 (m, 1H), 2.48-2.39 (m, 1H), 2.08-1.99 (m, 1H), 1.78-1.61 (m, 2H), 1.52 (s, 9H), 0.83 (s, 9H), 0.12-0.06 (m, 6H).LCMS(Method 19):[M-BOC+H] + m / z405.2, RT2.82 minutes.

[0423] Intermediate 95 tert-butyl4-[tert-butyl(dimethyl)silyl]oxy-2-(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)piperidine-1-carboxylate Intermediate 94 (84%, 1.53g, 2.54 mmol), Intermediate 21 (800 mg, 2.12 mmol), and Tris[2-phenylpyridinato-C] 2To a solution of iridium(III) (28 mg, 42.4 μmol) in anhydrous DMSO (24 mL), TFA (243 μL, 3.18 mmol) was added. The solution was purged by bubbling nitrogen over it for 10 minutes with stirring, and then sealed under nitrogen using Parafilm. The reaction mixture was irradiated with a Penn M2 photoreactor (450 nm; LED 100%; stirring 50%; fan 100%) at room temperature for 4 hours. The mixture was diluted with RINKAN (50 mL) and then washed with water (2 × 50 mL) and brine (20 mL). The resulting substance was dried over MgSO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of RINKAN in heptane to obtain the title compound (unresolved mixture of diastereomers) (970 mg, 37%). LCMS (Method 4): [M+H] + m / z691.4, RT2.76 min (minor isomer); [M+H] + m / z 691.4, RT 2.85 min (main isomer).

[0424] Intermediate 96 tert-butyl2-(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-hydroxypiperidine-1-carboxylate To a solution of intermediate 95 (56%, 970 mg, 0.79 mmol) in THF (5 mL), 1 M TBAF (1.0 mL, 1.00 mmol) in THF was added. The solution was stirred at room temperature for 21 hours. An additional 1 M TBAF (1 mL) in THF was added, and stirring continued for 26 hours. An additional 1 M TBAF (0.5 mL) in THF was added, and stirring continued for 19 hours. The reaction mixture was diluted with Depositphotos (20 mL) and washed with semi-saturated NaHCO3 aqueous solution (2 × 20 mL), followed by brine (20 mL). The organic layer was dried over MgSO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of Depositphotos in heptane to obtain the title compound (undissolved mixture of isomers) (350 mg, 73%). δ H(400 MHz, CDCl3) 8.47-8.33 (m, 1H), 7.92-7.82 (m, 1H), 7.81-7.73 (m, 1H), 5.88-5.50 (m, 1H), 5.33-5.21 (m, 1H), 4.32-3.91 (m, 2H), 3.30-2.67 (m, 2H), 2.65-2.55 (m, 3H), 2.48-2.11 (m, 3H), 2.12-1.86 (m, 3H), 1.86-1.31 (m, 16H).LCMS (Method 4): [M+H] + m / z577.2, RT2.27 minutes.

[0425] Intermediate 97 N-{(S)-(4,4-difluorocyclohexyl)[3-(4-hydroxypiperidine-2-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride Intermediate 96 (94%, 350 mg, 0.57 mmol) was mixed with 10 mL of 4 M HCl in 1,4-dioxane. The solution was stirred at room temperature for 4 hours, then the solvent was removed under reduced pressure, and the crude product was allowed to stand for 16 hours. The residue was dissolved in 10 mL of 4 M HCl in 1,4-dioxane and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the title compound (360 mg, 100%). LC-MS (Method 4): [M+H] + m / z 477.2, RT 1.76 minutes.

[0426] Intermediate 98 N-[(S)-(4,4-difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide Intermediate 20 (9.40 g, 33.4 mmol), lithium 2-isopropyl-1,2,4-triazole-3-carboxylate (5.90 g, 36.6 mmol), and DIPEA (12 mL, 68.7 mmol) were stirred in anhydrous DMF (130 mL), to which HATU (15.00 g, 39.4 mmol) was added in fractional amounts. The reaction mixture was stirred at room temperature for 16 hours, then diluted with siRNA (400 mL), washed with brine (4 × 200 mL), dried over anhydrous Na₂SO₄, and filtered. The solvent was removed under vacuum. The residue was purified using automated chromatography (Isolera 4, 350 g SFAR HC Duo column) with elution at a gradient of siRNA (5-65%) in heptane to obtain the title compound (13.90 g, 93%) as an orange solid. δ H (500 MHz, DMSO-d6) 8.99 (d, J 9.2 Hz, 1H), 8.65 (d, J 2.0 Hz, 1H), 8.57 (d, J 2.0 Hz, 1H), 8.38 (s, 1H), 8.10 (d, J 0.6 Hz, 1H), 5.53 (hept, J 6.6 Hz, 1H), 5.20 (t, J8.7 Hz, 1H), 2.25-2.15 (m, 1H), 2.09-1.94 (m, 2H), 1.93-1.87 (m, 1H), 1.86-1.68 (m, 2H), 1.61 (d, J 13.6 Hz, 1H), 1.42 (d, J 6.6 Hz, 3H), 1.37 (d, J 6.6 Hz, 3H), 1.35-1.25 (m, 2H).LCMS (Method 2): [M+H] + m / z405, RT2.90 minutes.

[0427] Intermediates 99 and 100 tert-butyl(2S,4S)-2-(6-{(S)-(4,4-difluorocyclohexyl)[(2-isopropyl-1,2,4-triazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)-4-hydroxypiperidine-1-carboxylate tert-butyl(2R,4S)-2-(6-{(S)-(4,4-difluorocyclohexyl)[(2-isopropyl-1,2,4-triazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)-4-hydroxypiperidine-1-carboxylate Intermediate 98 (450 mg, 1.11 mmol), (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxylic acid (410 mg, 1.67 mmol), DMSO (11.1 mL), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (25.0 mg, 0.022 mmol), and Cs2CO3 (544 mg, 1.67 mmol) were sequentially introduced into a screw-cap vial. The vial was capped, the mixture was purged with N2 for 10 minutes, then the cap was sealed with Parafilm, and the mixture was irradiated (450 nm) using an "integrated photoreactor" (ACS Cent.Sci., 2017, 3, 647~653) (settings: fan=1612 rpm; stirring=392 rpm; LED=100%) and vigorously stirred for 20 hours. The mixture was diluted with toluene (20 mL) and washed with H₂O (2 × 10 mL). The combined organic layers were dried and concentrated under vacuum. The title compound (a mixture of two stereoisomers in an approximately 3:1 anti:syn ratio) (237 mg, 35%) was obtained as an orange oily / foamy substance by flash chromatography using toluene / isohexane (0–100% gradient) followed by elution with 5% MeOH / DCM. LC-MS (Method 1): [M+H] + m / z604.4, 604.2, RT1.36 min.

[0428] Intermediates 101 and 102 N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4S)-4-hydroxypiperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide hydrochloride N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-4-hydroxypiperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide hydrochloride To intermediates 99 and 100 (a mixture of anti:syn stereoisomers in an approximately 3:1 ratio) (237 mg, 0.39 mmol), 4N HCl in 1,4-dioxane (3.60 mL, 14.0 mmol) was added dropwise. The mixture was stirred at room temperature. After 10 minutes, diethyl ether (25 mL) was added to induce precipitation. The mixture was stirred for 10 minutes and then filtered under suction. The viscous solid filtration cake was washed with a large amount of diethyl ether. The filtrate was discarded. The solid was redissolved in MeOH and concentrated under vacuum to obtain the title compound (a mixture of anti:syn stereoisomers in an approximately 3:1 ratio) (235 mg, quantitatively) as an orange oily substance, which was used without further purification. LC-MS (Method 1): [M+H] + m / z504.2, RT1.09 minutes.

[0429] Intermediate 103 tert-butyl2-(6-{(S)-(4,4-difluorocyclohexyl)[(2-isopropyl-1,2,4-triazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazine-3-yl)-4-hydroxy-4-methylpiperidine-1-carboxylate A mixture of intermediate 87 (458 mg, 1.77 mmol), intermediate 98 (353 mg, 0.804 mmol), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (18 mg, 16.1 μmol), and Cs2CO3 (786 mg, 2.41 mmol) was mixed with anhydrous DMF (16 mL). The mixture was degassed by bubbling nitrogen over it for 10 minutes with stirring, and then irradiated at room temperature for 2 × 3 hours in a Penn M2 photoreactor (450 nm, LED 100%, stirring 100%, fan 100%). The reaction mixture was diluted with SiO2 (25 mL), washed with water (2 × 25 mL) and brine (25 mL), then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was taken into DCM (10 mL) and manganese dioxide (1.40 g, 16.1 mmol) was added. The reaction mixture was stirred for 1 hour. The suspension was filtered through Celite® and then concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with a gradient of  in heptane, followed by reversed-phase C18 column chromatography eluting with a gradient of acetonitrile in water containing 0.1% formic acid to obtain the title compound (mixture of syn isomers) (87 mg, 16%). δ H (500 MHz, CDCl3) 8.36 (s, 1H), 8.29-8.11 (m, 1H), 8.10-7.67 (m, 3H), 5.79-5.70 (m, 1H), 5.69-5.35 (m, 1H), 5.24-5.13 (m, 1H), 4.10-3.89 (m, 1H), 3.28-3.05 (m, 1H), 2.85-2.70 (m, 1H), 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.99 (dd, J 14.2, 6.5 Hz, 2H), 1.80-1.57 (m, 4H), 1.55-1.33 (m, 19H), 1.31 (s, 3H).LCMS (Method 4): [M+H] + m / z618.02, RT2.41 min.

[0430] Intermediate 104 N-{(S)-(4,4-difluorocyclohexyl)[3-(4-hydroxy-4-methylpiperidine-2-yl)imidazo[1,2-b][1,2,4]triazine-6-yl]methyl}-2-isopropyl-1,2,4-triazole-3-carboxamide hydrochloride Intermediate 103 (87 mg, 0.130 mmol) was dissolved in 1,4-dioxane in 4 M HCl (0.9 mL) and stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (71 mg, 99%). LC-MS (Method 4): [M+H] + m / z518.2, RT1.79 minutes.

[0431] Intermediate 105 O 1 -tert-butylO 4 -Methyl 4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)piperidine-1,4-dicarboxylate DIPEA (2.0 mL, 11.7 mmol) was added to a stirred suspension in DCM (20 mL) of 1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidine-4-carboxylic acid (1.05 g, 3.65 mmol), 3,3,4,4-tetrafluoropyrrolidine hydrochloride (1:1) (0.72 g, 4.01 mmol), and HATU (1.81 g, 4.76 mmol) at room temperature. The reaction mixture was stirred for 64 hours, then diluted in DCM (50 mL) and quenched with saturated NaHCO3 aqueous solution (50 mL). The phases were separated, and the aqueous phase was further extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (fritted), filtered, and concentrated under vacuum. The obtained crude substance was purified by flash column chromatography using ethyl acetate / heptane (0-100% gradient) to obtain the title compound (90% purity) (0.70 g, 42%) as a yellow solid. δ H (500 MHz, DMSO-d6) 4.19-4.00 (m, 4H), 3.72 (s, 3H), 3.49-3.24 (obs. m, 4H), 2.01-1.83 (m, 4H), 1.39 (s, 9H).LCMS (Method 30): [M-BOC+H] +m / z313, RT4.00 min.

[0432] Intermediate 106 1-(tert-butoxycarbonyl)-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)piperidine-4-carboxylic acid To a stirred solution of intermediate 105 (0.70 g, 1.52 mmol) at room temperature in THF (15 mL), 1 M lithium hydroxide (4.6 mL, 4.55 mmol) was added all at once. The reaction mixture was stirred for 18 hours. An additional 1 M lithium hydroxide (4.6 mL, 4.55 mmol) was added all at once, and the reaction mixture was stirred for 3.5 hours. An additional 1 M lithium hydroxide (4.6 mL, 4.55 mmol) was added all at once, and the reaction mixture was stirred for 1 hour. Then, the pH was acidified to 2 with 1 N HCl, and the mixture was extracted with RINKAN (3 x 30 mL). The combined organic phase was washed with water (30 mL) and brine (30 mL), then dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound (0.60 g, 99%) as a white solid. δ H (500 MHz, DMSO-d6) 14.66-12.36 (m, 1H), 4.19-4.00 (m, 4H), 3.52-3.09 (obs. m, 4H), 1.99-1.83 (m, 4H), 1.39 (s, 9H).LCMS(Method 30):[M-BOC+H] + m / z299, RT3.33 minutes.

[0433] Intermediate 107 O 1 -tert-butylO 4 -(1,3-dioxoisoindolin-2-yl)4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)piperidine-1,4-dicarboxylate To a stirred suspension of intermediate 106 (0.78 g, 1.95 mmol) and 2-hydroxy-1H-isoindole-1,3(2H)-dione (0.35 g, 2.13 mmol) in DCM (25 mL), EDCI.HCl (0.41 g, 2.14 mmol) was added. The resulting clear yellow solution was stirred under N2 for 2 hours, and then the solvent was concentrated under vacuum. The residue was purified by flash column chromatography eluting with siRNA / heptane (0-100% gradient) to obtain the title compound (90% purity) (0.80 g, 68%) as a white solid. δ H (500 MHz, DMSO-d6) 8.06-8.00 (m, 2H), 8.00-7.94 (m, 2H), 4.61-4.09 (m, 4H), 3.68-3.53 (m, 2H), 3.46-3.23 (m, 2H), 2.26-2.08 (m, 4H), 1.41 (s, 9H).LCMS (Method 30): [M-BOC+H] + m / z444, RT3.98 minutes.

[0434] Intermediate 108 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-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)piperidine-1-carboxylate TFA (84 mL, 1.20 mmol) was added to a stirred solution of intermediate 21 (275 mg, 0.73 mmol), intermediate 107 (792 mg, 1.46 mmol), and {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (16.5 mg, 14.7 μmol) in anhydrous DMSO (24.5 mL) at room temperature. The mixture was purged by bubbling N2 for 10 minutes while stirring, then sealed under N2 with Parafilm and irradiated for 18 hours in a Penn M2 photoreactor (450 nm, LED 100%, stirring 50%, fan 100%). The reaction mixture was diluted with water (40 mL), quenched with saturated NaHCO3 aqueous solution (40 mL), and extracted with SiO2 (5 × 40 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), then dried over MgSO4, filtered, and concentrated under vacuum. The resulting crude material was purified by flash column chromatography using ethyl acetate / heptane (0-100% gradient) to obtain the title compound (77% purity) (374 mg, 50%) as a yellow-orange solid. δ H (500 MHz, DMSO-d6) 9.54 (d, J 9.0 Hz, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 5.23 (t, J 8.6 Hz, 1H), 4.43-3.84 (m, 5H), 3.80-3.65 (m, 2H), 3.25-2.95 (m, 2H), 2.46 (s, 3H), 2.32-1.55 (m, 10H), 1.40 (s, 9H), 1.36-1.21 (m, 2H).LCMS (Method 31): [M+H] + m / z730, RT1.03 minutes.

[0435] Intermediate 109 N-[(S)-(4,4-difluorocyclohexyl){3-[4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)piperidine-4-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a stirred solution of intermediate 108 (370 mg, 0.390 mmol) at room temperature in DCM (15 mL), TFA (3.3 mL) was added. The solution was stirred for 2 hours, then passed through a 20 g SCX-2 cartridge, washed with MeOH, and eluted with 7N NH3 in MeOH. The latter phase was concentrated under vacuum to obtain the title compound (90% purity) (285 mg, quantitative) as a yellow-orange oily substance, which solidified upon standing. δ H (500 MHz, DMSO-d6) 9.53 (d, J 9.1 Hz, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 5.23 (t, J 8.6 Hz, 1H), 4.23-3.80 (m, 4H), 2.94-2.85 (m, 2H), 2.84-2.73 (m, 2H), 2.47 (s, 3H), 2.27-2.17 (m, 3H), 2.07 (s, 4H), 1.96-1.87 (m, 1H), 1.87-1.71 (m, 2H), 1.70-1.60 (m, 2H), 1.51-1.25 (m, 2H).LCMS(Method 30):[M+H] + m / z630, RT3.20 minutes.

[0436] Intermediate 110 O 1 -tert-butylO 4 -Methyl 4-[3-(trifluoromethyl)azetidine-1-carbonyl]piperidine-1,4-dicarboxylate DIPEA (0.1 mL, 0.6 mmol), followed by HATU (95 mg, 0.25 mmol), was added to a solution of 3-(trifluoromethyl)azetidine hydrochloride (1.2 g, 7.1 mmol) and 1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidine-4-carboxylic acid (1.9 g, 6.4 mmol) in DCM (25 mL). The reaction mixture was left at room temperature overnight, then diluted in DCM (25 mL) and washed with NH4Cl aqueous solution (25 mL). The resulting substance was passed through hydrophobic frit and concentrated under vacuum. The residue was purified by flash chromatography (hexane / Depositphotos, 1-50% gradient, 25 g silica cartridge) to obtain the title compound (1.7 g, 67%) as a pale yellow solid. LCMS (Method 1): [MO t [AD+H] + m / z339.0, RT1.06 minutes.

[0437] Intermediate 111 Lithium 1-(tert-butoxycarbonyl)-4-[3-(trifluoromethyl)azetidine-1-carbonyl]piperidine-4-carboxylate Lithium hydroxide monohydrate (138 mg, 3.33 mmol) was dissolved in water (1 mL) and added to a solution of intermediate 110 (1 g, 2.54 mmol) in THF (5 mL). The mixture was stirred overnight. An additional lithium hydroxide monohydrate (30 mg) in water (approximately 0.5 mL) was added, along with MeOH (1 mL) to aid dissolution. The reaction mixture was stirred for a further 5 hours, then evaporated under vacuum and azeotropically mixed with MeOH and diethyl ether to obtain the title compound (985 mg, quantitative) as a white solid. LC-MS (Method 1): [MO t [AD+H] + m / z325.0, RT0.61 min.

[0438] Intermediate 112 O 1 -tert-butylO 4 -(1,3-dioxoisoindolin-2-yl)4-[3-(trifluoromethyl)azetidine-1-carbonyl]piperidine-1,4-dicarboxylate Intermediate 111 (1 g, 2.447 mmol) was added to a solution of N-hydroxyphthalimide (620 mg, 3.69 mmol) in DMF (10 mL), followed by the addition of EDCI.HCl (720 mg, 3.68 mmol). After 18 hours, additional N-hydroxyphthalimide (300 mg) and EDCI.HCl (300 mg) were added. The reaction mixture was allowed to stand for a further 2 hours, then diluted with DCM (25 mL) and washed with aqueous NH4Cl (25 mL) and brine (2 × 20 mL). The resulting substance was passed through hydrophobic frit and evaporated under vacuum. The residue was purified by flash chromatography using a 25 g silica column with elution using hexane and siRNA (1–33% gradient) to obtain the title compound (780 mg, 55%) as an off-white solid. LCMS (Method 1): [M-BOC+H] + m / z426.2, RT1.25 minutes.

[0439] Intermediate 113 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-[3-(trifluoromethyl)azetidine-1-carbonyl]piperidine-1-carboxylate Intermediate 21 (125 mg, 0.331 mmol) was dissolved in DMSO (5 mL) and treated with intermediate 112 (365 mg, 0.660 mmol) and TFA (0.030 mL, 0.36 mmol), then with {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (6 mg, 0.0053 mmol). N2 was bubbling, and the mixture was then placed in a Merck Penn photoreactor and stirred at 450 nm for 7 hours. The reaction mixture was separated between siRNA (20 mL) and brine (20 mL). The organic layer was washed with brine (2 × 10 mL), then passed through hydrophobic frit and concentrated under vacuum. The resulting yellow solid was purified by flash chromatography (hexane / siRNA, 1–100% gradient, 25 g silica column) to obtain the title compound (60 mg, 23%). LCMS (Method 8): [M+H] +m / z712.2, RT2.71 minutes.

[0440] Intermediate 114 N-[(S)-(4,4-difluorocyclohexyl)(3-{4-[3-(trifluoromethyl)azetidine-1-carbonyl]piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 113 (70 mg, 0.049 mmol) was dissolved in DCM (4 mL) and treated with TFA (2 mL). The mixture was stirred for 3 hours, then diluted with DCM (20 mL) and washed with water (10 mL) and 0.5 M HCl (5 mL). The combined aqueous layer was basicized with saturated NaHCO3 aqueous solution and extracted with DCM (3 × 10 mL). The organic layer was passed through hydrophobic frit and evaporated under vacuum to obtain the title compound (47 mg, 92%). LC-MS (Method 7): [M + H] + m / z612.4, RT1.68 minutes.

[0441] Intermediate 115 O 1 -tert-butylO 4 -Methyl 4-(2,2-difluoropropylcarbamoyl)piperidine-1,4-dicarboxylate 1-(tert-butoxycarbonyl)-4-methoxycarbonylpiperidine-4-carboxylic acid (1.00 g, 3.48 mmol), 2,2-difluoropropylamine hydrochloride (572 mg, 4.18 mmol), and DIPEA (1.82 mL, 10.4 mmol) were dissolved in DMF (17 mL), to which HATU (1.62 g, 4.18 mmol) was added. The mixture was stirred at room temperature for 10 minutes, then diluted with water (100 mL) and extracted with RINKAN (3 × 50 mL). The combined organic extract was passed through a phase separator and concentrated under vacuum. The crude substance was purified by column chromatography with elution in isohexane under a gradient of 0-50% RINKAN to obtain the title compound (1.26 g, 99%) as a colorless oil. LCMS (Method 1): [M-BOC+H] + m / z265.2, RT0.98 min.

[0442] Intermediate 116 1-(tert-butoxycarbonyl)-4-(2,2-difluoropropylcarbamoyl)piperidine-4-carboxylic acid To a solution of intermediate 115 (1.26 g, 3.45 mmol) in THF (14 mL), a solution of lithium hydroxide monohydrate (294 mg, 6.89 mmol) in water (3.5 mL) was added. The reaction mixture was stirred at room temperature for 72 hours. The second part of lithium hydroxide monohydrate (294 mg, 6.89 mmol) was added, and the reaction mixture was stirred for 2 hours. Then, the pH was acidified to 4 with 2.0 M aqueous HCl (7 mL) and diluted with water (50 mL). The aqueous layer was extracted with RINKAN (3 × 50 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to obtain the title compound (1.12 g, 93%) as a colorless amorphous solid. LC-MS (Method 1): [M-BOC+H] + m / z251.2, RT0.57 min.

[0443] Intermediate 117 O 1 -tert-butylO 4 -(1,3-dioxoisoindolin-2-yl)4-(2,2-difluoropropylcarbamoyl)piperidine-1,4-dicarboxylate To a solution of intermediate 116 (1.12 g, 3.20 mmol) and N-hydroxyphthalimide (591 mg, 3.52 mmol) in DMF (16 mL), EDCI.HCl (681 mg, 3.52 mmol) was added. The mixture was stirred at room temperature for 1.5 hours, then diluted with water (50 mL) and extracted with RINKAN (3 × 50 mL). The combined organic extract was passed through a phase separator and concentrated under vacuum. The crude substance was purified by column chromatography eluting with a gradient of 0 to 100% RINKAN in isohexane to obtain the title compound (1.22 g, 77%) as a colorless amorphous solid. LCMS (Method 1): [M-BOC+H] + m / z396.2, RT1.19 minutes.

[0444] Intermediate 118 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-(2,2-difluoropropylcarbamoyl)piperidine-1-carboxylate N2 gas was bubbling for 5 minutes through solutions of intermediate 21 (400 mg, 1.06 mmol), intermediate 117 (1050 mg, 2.12 mmol), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (24 mg, 0.02 mmol), and TFA (121 μL, 1.59 mmol) in DMSO (21 mL). The reaction mixture was left at room temperature under 450 nm irradiation for 45 hours, then quenched with saturated NaHCO3 aqueous solution (100 mL), and extracted with SiO2 (3 × 50 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum. The crude material was purified by column chromatography eluting with a gradient of 0–50% SiO2 in isohexane to obtain the title compound (500 mg, 69%) as an orange amorphous solid. LCMS (Method 1): [M+H] + m / z682.4, RT1.25 minutes.

[0445] Intermediate 119 N-[(S)-(4,4-difluorocyclohexyl){3-[4-(2,2-difluoropropylcarbamoyl)piperidine-4-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 118 (500 mg, 0.73 mmol) in DCM (3.0 mL), TFA (1.0 mL) was added. The mixture was stirred at room temperature for 3.5 hours, and then quenched with aqueous NaHCO3 solution (50 mL). The aqueous layer was extracted with DCM (3 × 25 mL). The combined organic extracts were passed through a phase separator and concentrated under vacuum to obtain the title compound (316 mg, 74%) as a colorless amorphous solid. LC-MS (Method 1): [M + H] + m / z582.4, RT0.92min.

[0446] Examples 1 and 2 [ka] N-[(1S)-2,2-dicyclopropyl-1-{3-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(1S)-2,2-dicyclopropyl-1-{3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 16 (a mixture of two stereoisomers) (40.0 mg, 0.076 mmol) at room temperature, 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (10.0 mg, 0.078 mmol), and DIPEA (0.06 mL, 0.30 mmol) were dissolved in DMF (4 mL), to which HATU (36.0 mg, 0.092 mmol) was added all at once. The mixture was stirred for 15 minutes, and then H2O (10 mL) was added. The mixture was extracted with siRNA (3 × 20 mL), the combined organic extract was washed with brine (20 mL), then dried, (Na2SO4) was added, and concentrated under vacuum. The residue was purified by flash chromatography eluting with siRNA / isohexane (0-75% gradient). The obtained substance (35.0 mg) was subjected to chiral purification (Method 9), and after lyophilization, the title compound (Peak 1, 9.0 mg, yield 18.7%, >99% de; and Peak 2, 9.0 mg, yield 18.7%, 82.9% de) was obtained. Peak 1: δ H(400 MHz, DMSO-d6) 9.26-9.16 (m, 1H, main and sub-rotational isomers), 8.77 (d, J 11.1 Hz, 1H), 8.30 (d, J 11.2 Hz, 1H), 6.63-5.84 (br s, 1H, and app.d, J 6.9 Hz, 1H, main rotational isomer), 5.61 (app.d, J 6.3 Hz, 1H, sub-rotational isomer), 5.57-5.47 (m, 1H), 4.53-4.43 (m, 1H, sub-rotational isomer), 4.14-4.02 (m, 1H, main rotational isomer), 3.82-3.69 (m, 1H, main rotational isomer), 3.24-3.11 (m, 1H, sub-rotational isomer), 2.66-2.40 (2 x unclear m, 4H, and unclear s,3H),2.32-2.10(m,4H),1.81-1.67(m,2H),1.03-0.90(m,1H),0.86-0.66(m, 2H),0.47-0.34(m,2H),0.33-0.16(m,4H),0.13-0.06(m,2H).LCMS(Method 7):[M+H] + m / z 633.4, RT 2.15 min. Chiral analysis (Method 10): RT 8.07 min. Peak 2: δ H( 400 MHz, DMSO-d6) 9.26-9.16 (m, 1H, main and sub-rotational isomers), 8.76 (d, J 12.6 Hz, 1H), 8.29 (d, J 9.5 Hz, 1H), 6.10-5.86 (br.s, 1H, and app.d, J 6.8 Hz, 1H, main rotational isomer), 5.61 (app.d, J 6.3 Hz,1H, subrotational isomer), 5.56-5.46 (m,1H), 4.53-4.43 (m,1H, subrotational isomer), 4.14-4.02 (m,1H, main rotational isomer), 3.81-3.68 (m,1H, main rotational isomer), 3.27-3.14 (m,1H, subrotational isomer), 2.66-2.40 (2 x unclear m,4H, and unclear s,3H), 2.31-2.10 (m,4H), 1.82-1.67 (m,2H), 1.04-0.90 (m,1H), 0.85-0.68 (m,2H), 0.48-0.34 (m,2H), 0.33-0.15 (m,4H), 0.12 to-0.07(m,2H).LCMS(Method 7):[M+H] +m / z 633.4, RT 2.15 min. Chiral analysis (Method 10): RT 9.31 min.

[0447] Examples 3 and 4 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(3R)-4-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)morpholin-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)-4-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of Intermediate 26 (405 mg, 0.74 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (95.0 mg, 0.74 mmol), and DIPEA (0.52 mL, 3.00 mmol) in DMF (15 mL) at room temperature, HATU (349 mg, 0.89 mmol) was added in one step. The mixture was stirred for 10 minutes, and then H2O (25 mL) was added. The mixture was extracted with siRNA (3 × 40 mL), the combined organic extract was washed with brine (80 mL), dried, and concentrated in vacuum with (Na2SO4). The residue was purified by flash chromatography eluting with siRNA / isohexane (0-75% gradient). The obtained substance (244 mg) was subjected to chiral purification (Method 11), and after lyophilization, the title compound (peak 1, 13.0 mg, yield 3%, >97.8% de; and peak 2, 13.0 mg, yield 3%, 89.3% de) was obtained. Peak 1: δ H(400 MHz, 373K, DMSO-d6) 9.06 (d, J 8.4 Hz, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 5.56-5.32 (br s, 1H), 5.27 (t, J 8.2 Hz, 1H), 4.53 (app. d, J 12.3 Hz, 1H), 4.11-3.93 (br s, 1H), 3.92-3.81 (m, 2H), 3.57 (app. t, J 11.1 Hz, 1H), 2.65-2.46 (obscured s, 3H), 2.46-2.37 (m, 7H), 2.31-2.18 (m, 1H), 2.16–1.91 (m, 3H), 1.91–1.68 (m, 3H), 1.56–1.42 (m, 1H), 1.42–1.30 (m, 1H). LCMS (Method 7): [M+H] + m / z575.2, RT1.83 points.キラル analysis (method 12): RT2.51 points. ピーク2:δ H (400 MHz, 373K, DMSO-d6) 9.07 (d, J 8.4 Hz, 1H), 8.67 (s, 1H), 8.27 (s, 1H), 5.54-5.41 (br s, 1H), 5.27 (t, J 8.2 Hz, 1H), 4.53 (app. d, J 12.3 Hz, 1H), 4.11-3.92 (br s, 1H), 3.92-3.82 (m, 2H), 3.57 (app. t, J 11.0 Hz, 1H), 2.58-2.47 (obscured s, 3H), 2.47-2.37 (m, 7H), 2.32-2.18 (m, 1H), 2.15-1.91 (m, 3H), 1.91-1.68 (m, 3H), 1.56-1.42 (m, 1H), 1.42-1.31 (m, 1H). LCMS (Method 7): [M+H] + m / z575.2, RT1.88 points.キラル analysis (method 12): RT2.61 points.

[0448] Example 5および6

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[0449] Example 7および8

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[0450] Examples 9 and 10 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4R)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-[(2R,4S)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 35 (60 mg, 0.099 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (15 mg, 0.12 mmol), and pyridine (0.032 mL, 0.40 mmol) in DCM (1.5 mL), T3P® (50 wt%) in toluene (176 μL, 0.30 mmol) was added. The solution was stirred at room temperature for 16 hours, then diluted with DCM (20 mL) and washed with saturated NaHCO3 aqueous solution:water (1:1, 20 mL). The mixture was passed through hydrophobic frit, washed through DCM, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of toluene in heptane. The obtained substance was further purified by chiral HPLC (90:10 heptane:EtOH, Cellulose-4, 21.2 × 250 mm, 5 μm @ 9 mL / min) to obtain the title compound (peak 1, 3.7 mg, 6%; and peak 2, 5.7 mg, 8%). Peak 1: δ H (400 MHz, DMSO-d6) 9.55-9.46 (m, 1H), 8.80-8.74 (m, 1H), 8.32-8.23 (m, 1H), 5.97-5.56 (m, 2H), 5.26-5.12 (m, 1H), 4.53-4.01 (m, 1H), 3.80-3.13 (m, 1H), 2.65-2.51 (m, 5H, obs. by DMSO), 2.48-2.44 (m, 3H), 2.32-1.52 (m, 12H), 1.47-1.19 (m, 2H).LCMS (Method 2): [M+H] + 657.3°C, RT 3.57 min. Chiral analysis (Method: 90:10 heptane:EtOH, Cellulose-4, 4.6 × 250 mm, 5 μm @ 0.5 mL / min): RT 20.92 min. Peak 2: δ H(400 MHz, DMSO-d6) 9.56-9.44 (m, 1H), 8.81-8.73 (m, 1H), 8.33-8.23 (m, 1H), 5.96-5.57 (m, 2H), 5.24-5.12 (m, 1H), 4.53-4.02 (m, 1H), 3.81-3.11 (m, 1H), 2.64-2.51 (m, 5H, obs. by DMSO), 2.47-2.44 (m, 3H), 2.31-1.55 (m, 12H), 1.47-1.20 (m, 2H).LCMS (Method 2): [M+H] + 657.3°C, RT 3.57 min. Chiral analysis (Method: 90:10 heptane:EtOH, Cellulose-4, 4.6 × 250 mm, 5 μm @ 0.5 mL / min): RT 27.55 min.

[0451] Examples 11 and 12 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4R)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-1-fluorocyclopropanecarboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-1-fluorocyclopropanecarboxamide To a solution of intermediate 35 (60 mg, 0.099 mmol), 1-fluorocyclopropane-1-carboxylic acid (12 mg, 0.119 mmol), and pyridine (0.032 mL, 0.40 mmol) in DCM (1.5 mL), T3P® (50 wt% in ethyl phosphate) (176 μL, 0.30 mmol) was added. The solution was stirred at room temperature for 16 hours, then diluted with DCM (20 mL) and washed with saturated Na2CO3 aqueous solution:water (1:1, 20 mL). The mixture was passed through hydrophobic frit, washed through DCM, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of ethyl phosphate in heptane. The obtained substance was further purified by chiral LC (Method: 90:10 heptane:EtOH, Cellulose-4, 21.2 × 250 mm, 5 μm @ 18 mL / min) to obtain the title compound (peak 1, 6.3 mg, 10%; and peak 2, 12 mg, 19%) as a white solid. Peak 1: δ H (500 MHz, DMSO-d6) 8.79-8.72 (m, 1H), 8.59-8.50 (m, 1H), 8.27-8.19 (m, 1H), 5.96-5.58 (m, 2H), 5.10-5.00 (m, 1H), 4.54-4.03 (m, 1H), 3.79-3.17 (m, 1H), 2.62-2.51 (m, 5H, obs. by DMSO), 2.33-1.85 (m, 7H), 1.85-1.65 (m, 4H), 1.53 (d, J 14.8 Hz, 1H), 1.39-1.09 (m, 6H).LCMS(Method 2):[M+H] + 633.3°C, RT 3.36 min. Chiral analysis (Method: 90:10 heptane:EtOH, Cellulose-4, 4.6 × 250 mm, 5 μm @ 0.5 mL / min): RT 20.78 min. Peak 2: δ H(500 MHz, DMSO-d6) 8.79-8.72 (m, 1H), 8.62-8.50 (m, 1H), 8.28-8.19 (m, 1H), 5.99-5.59 (m, 2H), 5.12-4.98 (m, 1H), 4.53-4.02 (m, 1H), 3.81-3.17 (m, 1H), 2.63-2.51 (m, 5H, obs. by DMSO), 2.33-1.85 (m, 7H), 1.85-1.64 (m, 4H), 1.63-1.47 (m, 1H), 1.42-1.08 (m, 6H).LCMS(Method 2):[M+H] + 633.3°C, RT 3.36 min. Chiral analysis (Method: 90:10 heptane:EtOH, Cellulose-4, 4.6 × 250 mm, 5 μm @ 0.5 mL / min): RT 28.62 min.

[0452] Example 13 [ka] Benzyl N-[(S)-{3-[4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-1,1-dioxo-1,4-thiadinan-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]carbamate To a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (117 mg, 0.855 mmol) in anhydrous DMA (2 mL), DIPEA (113 μL, 0.765 mmol), followed by 2-chloro-1-methylpyridinium iodide (228 mg, 0.866 mmol), was added. The resulting yellow suspension was stirred at ambient temperature for 10 minutes, and then a solution of intermediate 46 (170 mg, 0.300 mmol) in DMA (3 mL) was added. The reaction mixture was stirred at ambient temperature for 72 hours, and then partitioned between siRNA (20 mL) and water (50 mL). The organic phase was separated, and the aqueous phase was extracted with siRNA (2 × 30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by column chromatography of silica eluted with siRNA (0-100% in hexane) to obtain the title compound (120 mg, 59%) as a pale yellow solid. δ H (400 MHz, DMSO-d6) 8.91 (dd, J 43.4, 2.6 Hz, 1H), 8.31-8.02 (m, 1H), 7.79 (d, J 9.0 Hz, 1H), 7.56-6.97 (m, 5H), 6.42 (s, 1H), 5.24-4.80 (m, 2H), 4.65 (q, J8.3 Hz, 1H), 4.52-4.13 (m, 2H), 4.03-3.69 (m, 2H), 3.41 (1H, m, obs by DMSO), 3.10 (d, J 13.2 Hz, 1H), 2.43-2.07 (m, 6H), 1.89 (m, 4H), 1.61 (d, J14.1 Hz, 1H), 1.20 (m, 5H).LCMS (Method 7): [M+H] + 679, RT 2.23 minutes.

[0453] Examples 14 and 15 [ka] 1-Fluoro-N-[(S)-{3-[(3R)-4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-1,1-dioxo-1,4-thiadinan-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]cyclopropanecarboxamide 1-Fluoro-N-[(S)-{3-[(3S)-4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-1,1-dioxo-1,4-thiadinan-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]cyclopropanecarboxamide To a solution of intermediate 47 (59 mg, 0.108 mmol) in anhydrous DMF (2 mL), 1-fluorocyclopropanecarboxylic acid (35 mg, 0.333 mmol), DIPEA (75 μL, 0.431 mmol), and HATU (83 mg, 0.212 mmol) were sequentially added. The resulting yellow solution was stirred at ambient temperature for 18 hours and then diluted with siRNA (20 mL) and water (20 mL). The organic phase was separated, and the aqueous phase was extracted with additional siRNA (2 × 50 mL). The combined organic phase was washed with brine (2 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude residue was purified by silica column chromatography (gradient elution, 0-80% siRNA in hexane) and freeze-dried from acetonitrile / water. The resulting pale yellow solid was subjected to chiral separation (Method 15) to obtain the title compound (peak 1, 17 mg, yield 25%, 82% de; and peak 2, 15 mg, yield 22%, 85% de). Peak 1: δ H(400 MHz, DMSO-d6) 9.14-8.80 (m, 1H), 8.66-8.43 (m, 1H), 8.39-8.11 (m, 1H), 6.69-5.80 (m, 1H), 4.97 (m, 1.5H), 4.59-4.11 (m, 1.5H), 4.08-3.69 (m, 2H), 3.50-3.30 (1H, m, obs by DMSO), 3.10 (d, J 12.9 Hz, 1H), 2.45-2.13 (m, 5H), 2.11-1.71 (m, 4H), 1.69-1.47 (m, 1H), 1.43-0.93 (m, 10H). A mixture of rotational isomers in a ratio of approximately 3:2 1 Observed by 1H NMR spectrum. LC-MS (Method 7): [M+H] + 631, RT 1.95 min. Chiral analysis (Method 16): RT 3.97 min. Peak 2: δ H (400 MHz, DMSO-d6) 9.14-8.80 (m, 1H), 8.66-8.43 (m, 1H), 8.39-8.11 (m, 1H), 6.69-5.80 (m, 1H), 4.97 (m, 1.5H), 4.59-4.11 (m, 2H), 4.08-3.69 (m, 2H), 3.50-3.30 (1H, m, obs by DMSO), 3.10 (d, J 12.9 Hz, 1H), 2.45-2.13 (m, 5H), 2.11-1.71 (m, 4H), 1.69-1.47 (m, 1H), 1.43-0.93 (m, 10H). A mixture of rotational isomers in a ratio of approximately 3:2 1 Observed by 1H NMR spectrum. LC-MS (Method 7): [M+H] + 631, RT 1.95 min. Chiral analysis (Method 16): RT 4.44 min.

[0454] Example 16 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[1-(2,2-difluoropropylcarbamoyl)-4,4-difluorocyclohexyl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-2-isopropylpyrazole-3-carboxamide HATU (140 mg, 0.36 mmol) was added to a solution in DMF (2 mL) containing intermediate 54 (150 mg, 0.30 mmol), 1-isopropyl-1H-pyrazole-5-carboxylic acid (58 mg, 0.36 mmol), and DIPEA (0.16 mL, 0.92 mmol). The reaction mixture was stirred at room temperature for 1 hour and then diluted with RINKAN (15 mL) and water (5 mL). The aqueous layer was extracted with RINKAN (3 × 15 mL), and the combined organic extract was concentrated under vacuum. The crude substance was purified by SFC preparative chromatography (Method 17) to obtain the title compound (41 mg, 21.5%) as a white solid. δ H (400 MHz, DMSO-d6) 8.82 (dd, J 9.0, 2.0 Hz, 1H), 8.69 (d, J 2.0 Hz, 1H), 8.30 (d, J2.0 Hz, 1H), 8.17 (t, J 6.1 Hz, 1H), 7.50 (d, J 2.2 Hz, 1H), 6.96 (t, J 2.1 Hz, 1H), 5.39 (pd, J 6.6, 2.0 Hz, 1H), 5.21 (td, J8.7, 2.0 Hz, 1H), 3.50 (dt, J 12.6, 9.5 Hz, 2H), 2.55 (s, 1H), 2.43-2.33 (m, 4H), 2.22 (d, J 10.3 Hz, 1H), 2.11-1.98 (m, 6H), 1.92 (d, J13.1 Hz, 1H), 1.85-1.72 (m, 1H), 1.66 (d, J 13.2 Hz, 1H), 1.57-1.48 (m, 2H), 1.48-1.23 (m, 7H).LCMS (Method 7): [M+H] + 643.4, RT 2.05 min.

[0455] Example 17 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[4-(2,2-difluoropropylcarbamoyl)tetrahydropyran-4-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide DIPEA (33 μL, 0.186 mmol) was added at room temperature to a stirred solution of intermediate 61 (89%, 33 mg, 0.06 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (10 mg, 0.075 mmol), and HATU (35 mg, 0.0932 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 45 minutes, then diluted with siRNA (7 mL), and quenched with saturated aqueous NaHCO3 (7 mL). The two-phase mixture was stirred at room temperature for 20 minutes. The layers were separated, and the aqueous phase was extracted with siRNA (2 × 7 mL). The combined organic extracts were dried over MgSO4, then filtered, and concentrated under vacuum. The residue was purified by acidic open-access preparative HPLC (Gilson 4, standard method; column: Sunfire® Prep.C18 10 μm OBD™, 30 × 100 mm; mobile phase: 30-95% acetonitrile (0.1% formic acid) in water (0.1% formic acid) for 10 minutes; flow rate: 40 mL / min; UV: 215 and 254 nm), and after freeze-drying, the title compound (19 mg, 52%) was obtained as a white solid. δ H(400 MHz, DMSO-d6) 9.52 (d, J 9.0 Hz, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.18 (t, J 6.2 Hz, 1H), 5.21 (t, J 8.5 Hz, 1H), 3.75-3.65 (m, 2H), 3.65-3.56 (m, 2H), 3.56-3.45 (m, 2H), 2.47 (s, 3H), 2.45-2.35 (m, 2H), 2.28-2.14 (m, 3H), 2.13-1.97 (m, 2H), 1.97-1.88 (m, 1H), 1.88-1.68 (m, 2H), 1.68-1.59 (m, 1H), 1.49 (t, J 19.0 Hz, 3H), 1.43-1.18 (m, 2H).LCMS (Method 2): [M+H] + 583, RT 3.23 minutes.

[0456] Examples 18 and 19 [ka] N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 63 (two stereoisomers in a 1:1 ratio) (85% purity) (82.0 mg, 0.14 mmol) at room temperature, 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (18.0 mg, 0.14 mmol), and DIPEA (0.10 mL, 0.58 mmol) were dissolved in DMF (5 mL), to which HATU (67.0 mg, 0.17 mmol) was added all at once. The mixture was stirred for 20 minutes, and then H2O (20 mL) was added. The mixture was extracted with siRNA (3 x 20 mL). The combined organic extract was washed with brine (40 mL), then dried, (Na2SO4), and concentrated under vacuum. The residue was purified by flash chromatography eluting with siRNA / isohexane (0-100% gradient). Further chiral purification of the obtained white foamy substance (77.0 mg) was performed by SFC (in conjunction with a Waters QDa mass spectrometer, using a Waters Prep150 fractionlynx system with a 10-minute run time, eluting by 3-40% MeOH (+0.1% NH4OH) method (ABPR 60 bar) with a Lux Cellulose-1 250 × 21.2 mm, 5 μm column, flow rate 100 mL / min, column temperature 40°C). After lyophilization, the separated title compound (peak 1, 15.0 mg, yield 15.4%, 96.7% de; and peak 2, 14.0 mg, yield 14.4%, 95.7% de) was obtained. Peak 1 ( 1 A mixture of rotational isomers in a 2.2:1 ratio, as determined by 1H NMR): δ H(400 MHz, DMSO-d6) 9.51 (d, J 9.3 Hz, 1H, sub-rotational isomer), 9.48 (d, J 9.0 Hz, 1H, main rotational isomer), 8.81 (s, 1H, main rotational isomer), 8.71 (s, 1H, sub-rotational isomer), 8.28 (s, 1H), 5.94-5.89 (m, 1H, main rotational isomer), 6.11-5.81 (v br s, 1H), 5.65-5.60 (m, 1H, sub-rotational isomer), 5.20 (unclear t, J 8.8 Hz, 1H, sub-rotational isomer), 5.18 (t, J 8.7 Hz, 1H, main rotational isomer), 4.75-4.68 (m, 1H, main rotational isomer), 4.61-4.52 (m, 2H, 2 x sub-rotational isomer), 4.15-4.05 (m, 1H, main rotational isomer), 4.02-3.82 (m, 1H and 1H, main rotational isomer), 3.74-3.63 (m, 1H, main rotational isomer), 3.58-3.43 (m, 2H, 2 x sub-rotational isomer), 2.70-2.57 (unclear m, 1H), 2.47 (s, 3H), 2.32-1.57 (m, 14H), 1.48-1.21 (m, 2H). LCMS (Method 7): [M+H] + m / z 693.2, RT 2.01 min. Chiral analysis (Method 10): RT 3.15 min. Peak 2 ( 1 A mixture of rotational isomers in a 1.4:1 ratio was determined by 1H NMR): δ H(400 MHz, DMSO-d6) 9.51 (d, J 8.9 Hz, 1H, sub-rotational isomer), 9.50 (d, J 8.9 Hz, 1H, main rotational isomer), 8.87 (s, 1H, sub-rotational isomer), 8.71 (s, 1H, main rotational isomer), 8.28 (s, 1H, sub-rotational isomer), 8.26 (s, 1H, main rotational isomer), 6.11-5.84 (v br s, 1H), 5.94 (d, J 6.9 Hz, 1H, main rotational isomer), 5.73 (d, J 6.2 Hz, 1H, sub-rotational isomer), 5.19 (t, J 8.5 Hz, 2H, main and sub-rotational isomers), 4.72-4.66 (m, 1H, main rotational isomer), 4.51-4.42 (m, 1H, sub-rotational isomer), 4.33-4.25 (m, 1H, sub-rotational isomer), 4.16-3.99 (m, 2H, 2 x main rotational isomer), 3.98-3.69 (m, 1H and 2H, main and sub-rotational isomers), 3.25-3.12 (m, 1H, sub-rotational isomer), 2.79 (app d, J 14.4 Hz, 1H, sub-rotational isomer), 2.62 (app d, J 14.2 Hz, 1H, main rotamer), 2.47(s, 3H), 2.31-1.57(m, 14H), 1.47-1.22(m, 2H).LCMS (Method 7): [M+H] + m / z 693.2, RT 2.02 min. Chiral analysis (Method 10): RT 3.74.

[0457] Examples 20 and 21 [ka] N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-1-fluorocyclopropanecarboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-1-fluorocyclopropanecarboxamide HATU (65.0 mg, 0.17 mmol) was added in a single solution of room temperature intermediate 63 (two stereoisomers in a 1:1 ratio) (85% purity) (80.0 mg, 0.14 mmol), 1-fluorocyclopropanecarboxylic acid (15.0 mg, 0.14 mmol), and DIPEA (0.10 mL, 0.58 mmol) in DMF (5 mL). The mixture was stirred for 20 minutes, and then H2O (20 mL) was added. The mixture was extracted with ELISA (3 x 20 mL). The combined organic extract was washed with brine (40 mL), then dried, (Na2SO4), and concentrated under vacuum. The residue was purified by flash chromatography eluting with ELISA / isohexane (0-100% gradient). Further chiral purification of the obtained white foamy substance (77 mg) was performed by SFC (Lux Cellulose-1 250 × 21.2 mm, 5 μm column, flow rate 100 mL / min, column temperature 40°C, eluted by 3-40% MeOH (+0.1% NH4OH) method (ABPR 60 bar) using a Waters Prep150 fractionlynx system in conjunction with a Waters QDa mass spectrometer, with a run time of 10 minutes). After lyophilization, the separated title compound (peak 1, 20.0 mg, yield 21.8%, 98.6% de; and peak 2, 17.0 mg, yield 18.5%, 98.5% de) was obtained. Peak 1 ( 1 A mixture of rotational isomers in a 2.6:1 ratio was determined by 1H NMR):δ H(400 MHz, DMSO-d6) 8.81 (s, 1H, major rotational isomer), 8.70 (s, 1H, minor rotational isomer), 8.56 (d, J 9.0 Hz, minor rotational isomer), 8.53 (d, J 9.5 Hz, major rotational isomer), 8.24 (s, 1H), 5.92 (app d, J 6.8 Hz, 1H, major rotational isomer), 5.94-5.81 (v br s, 1H), 5.63 (app d, J 6.3 Hz, 1H, minor rotational isomer), 5.07 (unclear t, J 9.0 Hz, 1H, minor rotational isomer), 5.05 (t, J 8.9 Hz, 1H, major rotational isomer), 4.72 (t, J 6.4 Hz, 1H, main rotational isomer), 4.62-4.52 (m, 2H, 2 x sub-rotational isomer), 4.15-4.05 (m, 1H, main rotational isomer), 4.02-3.82 (m, 1H and 1H, main rotational isomer), 3.76-3.65 (m, 1H, main rotational isomer), 3.60-3.42 (m, 2H, 2 x sub-rotational isomer), 2.70-2.56 (unclear m, 1H), 2.32-1.63 (m, 13H), 1.62-1.49 (m, 1H), 1.40-1.11 (m, 6H). LCMS (Method 7): [M+H] + m / z 669.2, RT 1.92 min. Chiral analysis (Method 10): RT 3.00 min. Peak 2 ( 1 A mixture of rotational isomers in a 1.3:1 ratio was determined by 1H NMR): δ H(400 MHz, DMSO-d6) 8.86 (s, 1H, sub-rotational isomer), 8.70 (s, 1H, main rotational isomer), 8.54 (app t, J 8.7 Hz, 2H, main and sub-rotational isomers), 8.24 (s, 1H, sub-rotational isomer), 8.23 ​​(s, 1H, main rotational isomer), 5.97-5.91 (m, 1H, main rotational isomer), 5.92-5.85 (v br s, 1H), 5.76-5.70 (m, 1H, sub-rotational isomer), 5.06 (t, J 8.5 Hz, 1H, main rotational isomer), 5.05 (t, J 8.9 Hz, 1H, subrotational isomer), 4.73-4.66 (m, 1H, main rotational isomer), 4.52-4.42 (m, 1H, subrotational isomer), 4.34-4.26 (m, 1H, subrotational isomer), 4.17-4.00 (m, 2H, 2 x main rotational isomer), 3.97-3.68 (m, 1H and 2H, main and subrotational isomers), 3.27-3.16 (m, 1H, subrotational isomer), 2.78 (app d, J 14.4 Hz, 1H, subrotational isomer), 2.62 (app d, J 14.2 Hz, 1H, main rotamer), 2.32-1.63(m, 13H), 1.62-1.50(m, 1H), 1.42-1.09(m, 6H).LCMS (Method 7): [M+H] + m / z 669.2, RT 1.91 min. Chiral analysis (Method 10): RT 3.54 min.

[0458] Examples 22 and 23 [ka] N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2R,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of Intermediate 72 (two stereoisomers in a 1:1 ratio) (124 mg, 0.22 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (28.0 mg, 0.22 mmol), and DIPEA (0.16 mL, 0.92 mmol) in DMF (5 mL) at room temperature, HATU (104 mg, 0.27 mmol) was added in one step. The mixture was stirred for 45 minutes, and then H2O (20 mL) was added. The mixture was extracted with siRNA (3 x 20 mL). The combined organic extract was washed with brine (40 mL), then dried, (Na2SO4), and concentrated under vacuum. The residue was purified by flash chromatography eluting with siRNA / isohexane (0-100% gradient). Further chiral purification of the obtained white foamy substance (140 mg) was performed by SFC (in conjunction with a Waters QDa mass spectrometer, using a Waters Prep150 fractionlynx system with a 10-minute run time, eluting by 3-40% MeOH (+0.1% NH4OH) method (ABPR 60 bar) with a Lux Cellulose-1 250 × 21.2 mm, 5 μm column, flow rate 100 mL / min, column temperature 40°C). After lyophilization, the separated title compound (peak 1, 37.0 mg, yield 25%, 98.9% de; and peak 2, 27.0 mg, yield 18.2%, 94.2% de) was obtained. Peak 1 ( 1 A mixture of rotational isomers in a 2.8:1 ratio, as determined by 1H NMR):δ H(400 MHz, DMSO-d6) 9.50 (d, J 9.4 Hz, 1H, sub-rotational isomer), 9.47 (d, J 8.9 Hz, 1H, main rotational isomer), 8.76 (s, 1H, main rotational isomer), 8.65 (s, 1H, sub-rotational isomer), 8.26 (s, 1H), 5.90-5.84 (m, 1H, main rotational isomer), 5.78 (t, J 56.0 Hz, 1H, main rotational isomer), 5.75 (t, J 56.1 Hz, 1H, sub-rotational isomer), 5.60-5.55 (m, 1H, sub-rotational isomer), 5.26-5.07 (unclear v br s, 1H), 5.18 (app t, J 8.8 Hz, 2H, main and subrotational isomers), 4.70 (app t, J 6.3 Hz, 1H, main rotational isomer), 4.61-4.44 (m, 2H, 2 x subrotational isomer), 4.11-3.80 (m, 1H and 2H, 2 x main rotational isomers), 3.73-3.60 (m, 1H, main rotational isomer), 3.59-3.40 (m, 2H, 2 x subrotational isomer), 2.64-2.41 (unclear m, 1H), 2.47 (s, 3H), 2.31-1.51 (m, 14H), 1.47-1.21 (m, 2H).LCMS (Method 7): [M+H] + m / z 675.2, RT 1.88 min. Chiral analysis (Method 10): RT 3.52 min. Peak 2 ( 1 A mixture of rotational isomers in a 1.3:1 ratio was determined by 1H NMR): δ H(400 MHz, DMSO-d6) 9.51 (d, J 8.9 Hz, 1H, sub-rotational isomer), 9.50 (d, J 9.0 Hz, 1H, main rotational isomer), 8.80 (s, 1H, sub-rotational isomer), 8.65 (s, 1H, main rotational isomer), 8.27 (s, 1H, sub-rotational isomer), 8.25 (s, 1H, main rotational isomer), 5.91-5.86 (m, 1H, main rotational isomer), 5.78 (t, J 55.7 Hz, 1H, sub-rotational isomer), 5.77 (t, J 56.0 Hz, 1H, main rotational isomer), 5.69-5.65 (m, 1H, sub-rotational isomer), 5.28-5.10 (unclear v br s, 1H), 5.19 (t, J 8.6 Hz, 1H, main rotational isomer), 5.19 (t, J 8.8 Hz, 1H, sub-rotational isomer), 4.72-4.65 (m, 1H, main rotational isomer), 4.46-4.36 (m, 1H, sub-rotational isomer), 4.31-4.23 (m, 1H, sub-rotational isomer), 4.11-3.98 (m, 2H, 2 x main rotational isomer), 3.94-3.67 (m, 1H and 2H, main and sub-rotational isomers), 3.22-3.10 (m, 1H, sub-rotational isomer), 2.67-2.42 (unclear m, 1H), 2.47 (s, 3H), 2.32-1.52 (m, 14H), 1.47-1.22 (m, 2H).LCMS (Method 7): [M+H] + m / z 675.2, RT 1.89 min. Chiral analysis (Method 10): RT 4.04 min.

[0459] Examples 24 and 25 [ka] N-{(S)-(3-{(3R)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)[4-(trifluoromethyl)cyclohexyl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide N-{(S)-(3-{(3S)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)[4-(trifluoromethyl)cyclohexyl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 76 (two stereoisomers in a 1:1 ratio) (91.0 mg, 0.15 mmol), intermediate 79 (25.0 mg, 0.15 mmol), and DIPEA (0.10 mL, 0.58 mmol) were dissolved in DMF (5 mL) at room temperature, to which HATU (71.0 mg, 0.18 mmol) was added all at once. The mixture was stirred for 16 hours, and then H2O (20 mL) was added. The mixture was extracted with SiO (3 x 20 mL). The combined organic extract was washed with brine (40 mL), then dried, (Na2SO4), and concentrated under vacuum. The residue was purified by flash chromatography eluting with SiO / isohexane (0-100% gradient). Further chiral purification of the obtained white foamy substance (57.0 mg) was performed (eluting by 40% EtOH:60% n-heptane (+0.1% diethylamine) isocratic method using a UV-oriented Agilent 1100 / 1200 hybrid system with a run time of 19 minutes on a (R,R)Whelk-O1 250×10 mm, 5 μm column, flow rate 4.7 mL / min, column temperature ambient) and lyophilized to obtain the separated title compound (peak 1, 7.3 mg, yield 7.6%, >99% de; and peak 2, 12.0 mg, yield 12.5%, 99% de). Peak 1: δ H(400 MHz, 373K, DMSO-d6) 8.96 (d, J 8.8 Hz, 1H), 8.65 (s, 1H), 8.24 (s, 1H), 5.64-5.39 (v br s, 1H), 5.18 (t, J 8.2 Hz, 1H), 4.61 (dd, J 8.2, 4.0 Hz, 1H), 4.56 (app d, J 12.2 Hz, 1H), 4.12-3.44 (m, 6H), 3.07-2.93 (obscured m, 1H), 2.49 (s, 3H), 2.31-1.85 (m, 9H), 1.81-1.71 (m, 1H), 1.37-1.16 (m, 4H).LCMS(Method 7):[M+H] + m / z643.2, RT2.07 points.キラル analysis (method 18): RT3.75 points. ピーク2:δ H (400 MHz, 373K, DMSO-d6) 8.98 (d, J 8.8 Hz, 1H), 8.74-8.53 (v br s, 1H), 8.25 (s, 1H), 5.61-5.50 (br s, 1H), 5.18 (t, J 8.2 Hz, 1H), 4.71-4.42 (m, 2H), 4.15-3.73 (m, 5H), 3.67-3.51 (m, 1H), 3.07-2.93 (obscured m, 1H), 2.49 (s, 3H), 2.31-1.85 (m, 9H), 1.81-1.70 (m, 1H), 1.38-1.13 (m, 4H).LCMS (Method 7): [M+H] + m / z643.2, RT2.09 points.キラル analysis (method 18): RT4.80 points.

[0460] Example 26および27

change

[0461] Examples 28 and 29 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4S)-4-(difluoromethyl)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxypiperidine-2-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-[(2R,4R)-4-(difluoromethyl)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxypiperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 83 (a 1:1 mixture of two anti-stereoisomers) (93.4 mg, 0.17 mmol) at room temperature, 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (25.0 mg, 0.18 mmol), and DIPEA (0.12 mL, 0.69 mmol) were dissolved in DMF (5 mL), to which HATU (78.0 mg, 0.20 mmol) was added all at once. The mixture was stirred for 80 minutes, and then H2O (10 mL) was added. The mixture was extracted with RINKAN (3 × 10 mL), the combined organic layer was washed with brine (20 mL), then dried, and concentrated under vacuum in (Na2SO4). The residue was purified by flash chromatography eluting with RINKAN / isohexane (0 to 100% gradient). The resulting white foamy substance (42.0 mg) was subjected to chiral purification (Method 19), and after lyophilization, the title compound (Peak 1, 10.0 mg, yield 9.4%, >99% de; and Peak 2, 9.0 mg, yield 8.5%, 98.0% de) was obtained. Peak 1: δ H (400 MHz, DMSO-d6) 9.48 (d, J 8.9 Hz, 1H), 8.60 (s, 1H), 8.25 (s, 1H), 5.83 (t, J56.1 Hz, 1H), 5.64-5.55 (br s, 1H), 5.18 (app. t, J 8.5 Hz, 1H), 5.15-5.05 (m, 1H), 3.92-3.79 (m, 1H), 3.75-3.61 (m, 1H), 2.64-2.48 (obscured m, 1H), 2.47 (s, 3H), 2.45-2.35 (br s, 6H), 2.29-2.16 (m, 1H), 2.16-1.58 (m, 9H), 1.48-1.21 (m, 2H).LCMS (Method 7): [M+H] +m / z 639.2, RT 1.89 min. Chiral analysis (Method 20): RT 3.16 min. Peak 2: δ H (400 MHz, DMSO-d6) 9.48 (d, J 8.9 Hz, 1H), 8.60 (s, 1H), 8.25 (s, 1H), 5.83 (t, J56.2 Hz, 1H), 5.66-5.55 (br s, 1H), 5.18 (app. t, J 8.5 Hz, 1H), 5.15-5.05 (m, 1H), 3.93-3.79 (m, 1H), 3.75-3.62 (m, 1H), 2.62-2.48 (obscured m, 1H), 2.47 (s, 3H), 2.45-2.35 (br s, 6H), 2.26-2.16 (m, 1H), 2.16-1.58 (m, 9H), 1.48-1.21 (m, 2H).LCMS (Method 7): [M+H] + m / z 639.2, RT 1.89 min. Chiral analysis (Method 20): RT 3.59 min.

[0462] Examples 30 and 31 [ka] N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2R,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 83 (a 1:1 mixture of two anti-stereoisomers) (73.7 mg, 0.13 mmol) at room temperature, intermediate 79, and DIPEA (0.09 mL, 0.50 mmol) were dissolved in DMF (5 mL), to which HATU (62.0 mg, 0.16 mmol) was added all at once. The mixture was stirred for 35 minutes, and then H2O (20 mL) was added. The mixture was extracted with siRNA (3 × 20 mL), the combined organic layer was washed with brine (40 mL), then dried, and concentrated under vacuum in (Na2SO4). The residue was purified by flash chromatography eluting with siRNA / isohexane (0-100% gradient) to obtain roughly divided anti-diastereomers. Diastereomer 1 was subjected to chiral purification (Method 21) to obtain peak 1 (8 mg, 9%). Diastereomer 2 was subjected to chiral purification (Method 22) to obtain peak 2 (8 mg, 9%). Peak 1: δ H (400 MHz, DMSO-d6) 9.48 (d, J 8.9 Hz, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 5.83 (t, J56.1 Hz, 1H), 5.64-5.54 (br s, 1H), 5.18 (t, J 8.6 Hz, 1H), 5.13 (dd, J9.1, 7.6 Hz, 1H), 4.56 (t, J 6.2 Hz, 1H), 3.97-3.75 (m, 3H), 3.69-3.57 (m, 1H), 2.47 (s, 3H), 2.29-1.58 (m, 15H), 1.47-1.20 (m, 2H).LCMS(Method 7):[M+H] + m / z675.2, RT1.90 minutes. Peak 2: δ H(400 MHz, DMSO-d6) 9.48 (d, J 8.7 Hz, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 6.03-5.54 (m, 2H), 5.19 (t, J 8.3 Hz, 1H), 5.15-5.07 (m, 1H), 4.54-4.45 (m, 1H), 4.00-3.63 (m, 4H), 2.47 (s, 3H), 2.29-1.54 (m, 15H), 1.48-1.22 (m, 2H).LCMS (Method 7): [M+H] + m / z675.2, RT1.91 minutes.

[0463] Examples 32 and 33 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4S)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-[(2R,4R)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 86 (a 1:1 mixture of two anti-stereoisomers) (38.8 mg, 0.067 mmol) at room temperature, 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (10.0 mg, 0.073 mmol), and DIPEA (0.05 mL, 0.30 mmol) were dissolved in DMF (5 mL), to which HATU (32.0 mg, 0.08 mmol) was added all at once. The mixture was stirred for 30 minutes, and then H2O (10 mL) was added. The mixture was extracted with RINKAN (3 × 10 mL), the combined organic layer was washed with brine (20 mL), then dried, and concentrated under vacuum in (Na2SO4). The residue was purified by flash chromatography eluting with RINKAN / isohexane (0 to 100% gradient). The obtained white foamy substance (35.0 mg) was subjected to chiral purification (Method 23), and after lyophilization, the title compound (Peak 1, 11.0 mg, yield 25.1%, >99% de; and Peak 2, 9.0 mg, yield 20.6%, 92.6% de) was obtained. Peak 1: δ H (400 MHz, DMSO-d6) 9.49 (d, J 8.9 Hz, 1H), 8.67-8.58 (br s, 1H), 8.30-8.21 (br s, 1H), 5.37-5.27 (br s, 1H), 5.18 (app. t, J 8.6 Hz, 1H), 5.17-5.08 (m, 1H), 3.95-3.81 (m, 1H), 3.81-3.68 (m, 1H), 2.47 (s, 3H), 2.45-2.36 (m, 6H), 2.35-2.14 (m, 3H), 2.12-1.68 (m, 7H), 1.68-1.59 (m, 1H), 1.48-1.22 (m, 2H).LCMS (Method 7): [M+H] + m / z 657.2, RT 2.01 min. Chiral analysis (Method 24): RT 4.04 min. Peak 2: δ H(400 MHz, DMSO-d6) 9.48 (d, J 8.9 Hz, 1H), 8.67-8.57 (br s, 1H), 8.32-8.22 (br s, 1H), 6.37-6.26 (br s, 1H), 5.18 (t, J 8.5 Hz, 1H), 5.17-5.08 (m, 1H), 3.96-3.81 (m, 1H), 3.81-3.67 (m, 1H), 2.47 (s, 3H), 2.45-2.36 (m, 6H), 2.35-2.14 (m, 3H), 2.13-1.68 (m, 7H), 1.67-1.57 (m, 1H), 1.47-1.21 (m, 2H).LCMS (Method 7): [M+H] + m / z 657.2, RT 2.00 min. Chiral analysis (Method 24): RT 4.54 min.

[0464] Examples 34 and 35 [ka] N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-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-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide HATU (240 mg, 0.612 mmol) was added to a solution of intermediate 90 (277 mg, 0.473 mmol), intermediate 79 (100 mg, 0.602 mmol), and DIPEA (220 μL, 1.3 mmol) in DMF (5 mL). The solution was stirred overnight at room temperature and then partitioned between siRNA and brine. The aqueous phase was extracted twice with siRNA, the combined organic phase was washed with brine, dried over Na₂SO₄, and concentrated under vacuum. After lyophilization, the title compound (peak 1, 45 mg, yield 15%, 100.0% de; and peak 2, 37 mg, yield 12%, 96.1% de) was obtained by flash column chromatography of silica eluted with 30–100% siRNA / isohexane, followed by chiral purification (Method 19). Peak 1: δ H (400 MHz, 373K, DMSO-d6) 9.03-8.96 (m, 1H), 8.62-8.58 (m, 1H), 8.16 (s, 1H), 5.74 (br s, 1H), 5.23 (t, J8.3 Hz, 1H), 4.74-4.54 (m, 1H), 4.07-3.65 (m, 4H), 2.56-2.52 (m, 2H), 2.49 (s, 3H), 2.30-2.19 (m, 2H), 2.08-1.93 (m, 6H), 1.90-1.69 (m, 4H), 1.62-1.33 (m, 4H), 1.19 (s, 3H).LCMS(Method 7):[M+H] + m / z 639.4, RT 1.85 min. Chiral analysis (Method 20): RT 3.35 min. Peak 2: δ H(400 MHz, 373K, DMSO-d6) 9.02 (d, J 8.8 Hz, 1H), 8.69-8.45 (m, 1H), 8.16 (s, 1H), 5.69 (br s, 1H), 5.24 (t, J 8.3 Hz, 1H), 4.77-4.16 (m, 1H), 4.10-3.65 (m, 4H), 2.59-2.52 (m, 2H), 2.49 (s, 3H), 2.30-2.19 (m, 2H), 2.09-1.92 (m, 6H), 1.90-1.70 (m, 4H), 1.61-1.30 (m, 4H), 1.20 (s, 3H).LCMS(Method 7):[M+H] + m / z 639.4, RT 1.86 min. Chiral analysis (Method 20): RT 3.74 min.

[0465] Examples 36 and 37 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4R)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-methylpiperidine-2-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-[(2R,4S)-1-(3-fluorobicyclo[1,1,1]pentan-1-carbonyl)-4-hydroxy-4-methylpiperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide HATU (177 mg, 0.452 mmol) was added to a solution of intermediate 90 (220 mg, 0.376 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxy...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, E is given by the formulas (Ea), (Eb), or (Ed): 【Chemistry 2】 【change】 【change】 (In the formula, an asterisk (*) represents a bond point with the rest of the molecule) represents the base; A is given by equation (Ab) or (Ad): 【Transformation 3】 【change】 (In the formula, an asterisk (*) represents a bond point with the rest of the molecule) represents the base; Y is -O-, -C(R ５ａ ) (Caution ５ｂ ) -, or -S(O) ２ - represents; R1 represents hydrogen; R ２ C ４－１２ Bicycloalkyl, or C ３－７ Representing a heterocycloalkyl group, any of these groups may be optionally substituted with one, two, three, or four substituents independently selected from halogens; R ３ represents -NR ３ａ R ３ｂ ; or R ３ is of formula (Wa): 【Chemistry 4】 (In the formula, an asterisk (*) represents a bond point with the rest of the molecule) represents the base; The group of formula (Wa) represents azetidine-1-yl or pyrrolidine-1-yl, and either of the said groups may be optionally substituted with 1 to 6 substituents independently selected from halogens and trifluoromethyl; R ３ａ This represents hydrogen; R ３ｂ C １－６ Represents an alkyl group, which may be optionally substituted with one, two, or three substituents independently selected from the halogen; R ４ａ and R ４ｂ They both, together with the carbon atom to which they are bonded, C ３－９ Cycloalkyl or C ３－７ Representing heterocycloalkyl groups, any of these groups may be optionally substituted with one, two, or three substituents independently selected from C1-6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, and oxetanyl; R ５ａ represents hydrogen, methyl, difluoromethyl, or trifluoromethyl; R ５ｂ This represents hydrogen; R ６ is either -OR 6a or R ６ C ３－９ Representing a cycloalkyl or heteroaryl group, any of these groups may be optionally substituted with one, two, or three substituents independently selected from halogens, C1-6 alkyl groups, and cyclopropyl groups; R ６ａ C １－６ Alkyl, C ３－９ Cycloalkyl or aryl (C １－６ ) Represents alkyl, and any of these groups may be optionally substituted with one, two, or three substituents independently selected from halogens. A compound of formula (I), or a pharmaceutically acceptable salt thereof.

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

3. R ６ The compound according to claim 1 or claim 2, wherein the group represents a heteroaryl group, and this group may be optionally substituted with one, two, or three substituents independently selected from halogens and C1-6 alkyl groups.

4. Formula (IIA-1): 【Transformation 5】 (In the formula, X represents CH or N, R １６ This represents methyl, ethyl, isopropyl, or cyclopropyl. A is as defined in claim 1.) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

5. Formula (IIA-2): 【Transformation 6】 (In the formula, A is as defined in claim 1, X and R １６ (This is as defined in claim 4.) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

6. Formula (IIA-3): 【Transformation 7】 (In the formula, A is as defined in claim 1, X and R １６ (This is as defined in claim 4.) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

7. Equation (IIB-1): 【Transformation 8】 (In the formula, A is as defined in claim 1, X and R １６ (This is as defined in claim 4.) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

8. Formula (IIC-1): 【Chemistry 9】 (In the formula, A is as defined in claim 1, R ２６ (This represents fluoro) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

9. Formula (IIC-2): 【Chemistry 10】 (In the formula, A is as defined in claim 1, R ２６ (This is as defined in claim 8.) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

10. A compound according to any one of claims 1 to 9, wherein A represents a group of formula (Ab) as defined in claim 1.

11. N-[(1S)-2,2-dicyclopropyl-1-{3-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(1S)-2,2-dicyclopropyl-1-{3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(3R)-4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)morpholin-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)-4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(1S)-2,2-dicyclopropyl-1-(3-{(3R)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(1S)-2,2-dicyclopropyl-1-(3-{(3S)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(3R)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-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)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-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-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-1-fluorocyclopropanecarboxamide, Benzyl N-[(S)-{3-[4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-1,1-dioxo-1,4-thiadinan-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]carbamate, 1-Fluoro-N-[(S)-{3-[(3R)-4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-1,1-dioxo-1,4-thiadinan-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]cyclopropanecarboxamide, 1-Fluoro-N-[(S)-{3-[(3S)-4-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-1,1-dioxo-1,4-thiadinan-3-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]cyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[1-(2,2-difluoropropylcarbamoyl)-4,4-difluorocyclohexyl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-2-isopropylpyrazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[4-(2,2-difluoropropylcarbamoyl)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-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2R,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-{(S)-(3-{(3R)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)[4-(trifluoromethyl)cyclohexyl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-{(S)-(3-{(3S)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholine-3-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)[4-(trifluoromethyl)cyclohexyl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4R)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxypiperidine-2-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-[(2R,4S)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxypiperidine-2-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-[(2S,4S)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxypiperidine-2-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-[(2R,4R)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxypiperidine-2-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-{(2S,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2R,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-[(2S,4S)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-[(2R,4R)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidine-2-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-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-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-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-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-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-methylpiperidine-2-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-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-methylpiperidine-2-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-{(2S,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-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-{(2R,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-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-[(2S,4S)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-methylpiperidine-2-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-[(2R,4R)-1-(3-fluorobicyclo[1.1.1]pentan-1-carbonyl)-4-hydroxy-4-methylpiperidine-2-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-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2S,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2R,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-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-{(2S,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-methylpyrazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-[(2R,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)-methyl]-2-methylpyrazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidine-2-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[1-(oxetan-3-yl)-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)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-(oxetan-3-yl)-4-[3-(trifluoromethyl)azetidine-1-carbonyl]piperidine-4-yl}imidazo[1,2-b][1,2,4]triazine-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, and N-[(S)-(4,4-difluorocyclohexyl){3-[4-(2,2-difluoropropylcarbamoyl)-1-(oxetan-3-yl)piperidine-4-yl]imidazo[1,2-b][1,2,4]triazine-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide A compound according to claim 1, selected from the following.

12. A pharmaceutical composition comprising a compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

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

14. The pharmaceutical composition according to claim 12, for use in the treatment and / or prevention of inflammatory disorders or autoimmune disorders.

15. A pharmaceutical composition comprising a compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

16. Use of a compound of formula (I) according to claim 1, 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.

17. Use of a compound of formula (I) according to claim 1, 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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