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

[0002] IL-17A (originally named CTLA-8 and also known as IL-17) is a proinflammatory cytokine and an early member of the IL-17 family (Rouvier et al., J. Immunol., 1993, 150, 5445-5456). Five additional members of the family (IL-17B through IL-17F) have subsequently been 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 expresses 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 through the receptors IL-17R, IL-17RC or the IL-17RA / RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been linked to several autoimmune diseases.

[0003] Thus, compounds according to the invention, being potent modulators of human IL-17 activity, are beneficial in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

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

[0005] WO 2013 / 116682 and WO 2014 / 066726 relate to distinct classes of chemical compounds which are stated to modulate the activity of IL-17 and are useful in the treatment of medical conditions, including inflammatory diseases.

[0006] WO 2018 / 229079 and WO 2020 / 011731 describe spirocyclic molecules that are said to act as modulators of IL-17 activity and thus be beneficial in the treatment of pathological conditions including deleterious inflammatory and autoimmune disorders.

[0007] WO 2019 / 138017, WO 2020 / 260425, WO 2020 / 260426 and WO 2020 / 261141 describe various classes of fused bicyclic imidazole derivatives which are stated to act as modulators of IL-17 activity and thus be beneficial in the treatment of pathological conditions including deleterious inflammatory and autoimmune disorders. Fused bicyclic imidazole derivatives that act as modulators of IL-17 activity are also disclosed in co-pending international patent applications PCT / EP2021 / 054519 and PCT / EP2021 / 054523 (both published on September 2, 2021 as WO 2021 / 170627 and WO 2021 / 170631, respectively), co-pending international patent applications PCT / EP2021 / 058937 and PCT / EP2021 / 058940 (both published on September 2, 2021 as WO 2021 / 204800 and WO 2021 / 204831, respectively), These and other related compounds are described in co-pending international patent applications PCT / EP2021 / 080250 and PCT / EP2021 / 080251 (both published on May 12, 2022 as WO 2022 / 096411 and WO 2022 / 096412, respectively), and co-pending international patent application PCT / EP2021 / 084448 (published on June 23, 2022 as WO 2022 / 128584).

[0008] WO 2020 / 120140 and WO 2020 / 120141 describe separate classes of chemical compounds that are said to act as modulators of IL-17 activity and thus be beneficial in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders.

[0009] Heterocyclic compounds that inhibit IL-17A and are stated to be useful as immunomodulatory agents are described in WO 2019 / 223718, WO 2021 / 027721, WO 2021 / 027722, WO 2021 / 027724, WO 2021 / 027729 and WO 2021 / 098844.

[0010] Heterocyclic compounds said to be capable of modulating IL-17 activity are also described in WO 2020 / 127685, WO 2020 / 146194 and WO 2020 / 182666.

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

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

[0013] The present invention provides a compound of formula (I) or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, E is of the formula (Ea), (Eb), (Ec), (Ed) or (Ee): [ka] where the asterisk (*) represents the point of attachment to the remainder of the molecule; A is of the formula (Aa), (Ab), (Ac), (Ad) or (Ae): [ka] where the asterisk (*) represents the point of attachment to the remainder of the molecule; Y is -O-, -N(R 7 )-, -C(R 5a )(R 5b )-, -S-, -S(O)-, -S(O) 2 - or -S(O)(NR 8 )-represents; Z represents heteroaryl, which may be optionally substituted by one or more substituents; R 1 represents hydrogen, fluoro, chloro, methyl, difluoromethyl or trifluoromethyl; R 2 -OR 2a or R 2 is C 3-9 Cycloalkyl, C 4-12 Bicycloalkyl, C 3-7 Heterocycloalkyl or C 4-9 any of which may be optionally substituted by one or more substituents; R 2a is C 1-6 represents alkyl; or R 2a is C 3-9 represents cycloalkyl, which may be optionally substituted by one or more substituents; R 3 -NR 3a R 3b or R 3 is expressed as follows: [ka] where the asterisk (*) represents the point of attachment to the remainder of the molecule; W represents the residue of an optionally substituted saturated monocyclic ring 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 not more than 1 O or S atom; or W represents the 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 not more than 1 O or S atom; or W represents the 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 not more than 1 O or S atom; R 3a is hydrogen or C 1-6 represents alkyl; R 3b is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl(C 1-6 ) Alkyl, C 4-12 Bicycloalkyl, aryl, aryl(C 1-6 ) Alkyl, C 3-7 Heterocycloalkyl, C 3-7 Heterocycloalkyl(C 1-6 ) alkyl, heteroaryl or heteroaryl (C 1-6 ) alkyl, any of which may be optionally substituted by one or more substituents; R 4a represents hydrogen, fluoro or hydroxy; or R 4a is C 1-6 represents an alkyl group, which may be optionally substituted by one or more substituents; R 4b is hydrogen, fluoro or C 1-6 represents alkyl; or R4a and R 4b together with the carbon atom to which they are both attached, C 3-9 Cycloalkyl or C 3-7 heterocycloalkyl, any of which may be optionally substituted by one or more substituents; R 5a represents hydrogen, fluoro, methyl, difluoromethyl or trifluoromethyl; R 5b represents hydrogen, fluoro, methyl or hydroxy; or R 5a and R 5b taken together with the carbon atom to which they are both attached represent cyclopropyl; R 6 -OR 6a Or -NR 6b R 6c or R 6 is C 1-6 Alkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl(C 1-6 ) Alkyl, aryl, aryl (C 1-6 ) Alkyl, C 3-7 Heterocycloalkyl, C 3-7 Heterocycloalkyl(C 1-6 ) alkyl, heteroaryl or heteroaryl (C 1-6 ) alkyl, any of which may be optionally substituted by one or more substituents; R 6a is C 1-6 Alkyl, C 3-9 Cycloalkyl or aryl (C 1-6 ) alkyl, any of which may be optionally substituted by one or more substituents; R 6b is hydrogen or C 1-6 represents alkyl; R 6c is hydrogen or C 1-6 represents alkyl; or R 6b and R 6c together with the nitrogen atom to which they are both attached represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R 7 -COR 7a , -CO 2 R 7a Or -SO 2 R 7b or R 7 represents hydrogen; or R 7 is C 1-6 Alkyl or C 3-9 cycloalkyl, any of which may be optionally substituted with one or more fluorine atoms; R 7a is C optionally substituted by one or more fluorine atoms 1-6 represents alkyl; R 7b is C 1-6 represents alkyl; R 8 is C 1-6 Represents alkyl.

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

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

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

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

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

[0019] When any of the groups in the compound of formula (I) above is described as being optionally substituted, this group may be unsubstituted or substituted by one or more substituents.Generally, such groups are unsubstituted or substituted with 1, 2, 3 or 4 substituents.Typically, such groups are unsubstituted or substituted with 1, 2 or 3 substituents.Preferably, such groups are unsubstituted or substituted with 1 or 2 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. The 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, the 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 compounds of formula (I) above. The technical term "co-crystal" is used to describe the situation in which neutral molecular components are present in a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals allows modifications to be made to the crystalline form of an active pharmaceutical ingredient, thereby altering its physicochemical properties without impairing its intended biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters & L. Quere, RSC Publishing, 2012).

[0022] Suitable alkyl groups which may be present in the compounds used in the present invention include straight chain and branched C 1-6 Alkyl groups, e.g., C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, as well as straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3-methylbutyl. 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl" and "C 1-6Derived expressions such as "alkylamino" should be construed accordingly.

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

[0024] As used herein, "C 4-12 The term "bicycloalkyl" refers to a monovalent group of 4 to 12 carbon atoms derived from a saturated bicyclic hydrocarbon. 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] The term "aryl" as used herein refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or from multiple fused aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

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

[0027] As used herein, "C 3-7The term "heterocycloalkyl" refers to a saturated monocyclic ring containing from 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur and nitrogen, and may include benzo-fused analogs thereof. 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 a C alkyl group in which one or more of the carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. 4-9Exemplary 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, 2-oxa-5-az ... and 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] The term "heteroaryl" as used herein refers to a monovalent aromatic group containing at least five atoms from a single ring or multiple fused rings, in which one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b]-[1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo ... pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyrazinyl, 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, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]-triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro[1,2, 4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups.

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

[0031] When the compounds of formula (I) have one or more asymmetric centers, they may exist accordingly as enantiomers. When the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers. It should be understood that the invention extends to the use of all such enantiomers and diastereomers, and mixtures thereof, including racemates, in any proportion. Formula (I) and the formulae depicted below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise stated or indicated. In addition, the compounds of formula (I) may also exist in tautomeric forms, such as keto (CH 2 C=O) <-> enol (CH=CHOH) tautomers or amide (NHC=O) <-> hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or shown.

[0032] It is to be understood that each individual atom present in formula (I) or in the formulae set forth below may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I) or in the formulae set forth below may be: 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H. Similarly, by way of example, each individual carbon atom present in formula (I) or in the formulae shown below may be present as: 12 C. 13 C or 14 C atom, preferably 12 It can exist as C.

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

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

[0035] Suitably, E represents a group of formula (Ea) or (Ed).

[0036] In general, the present invention relates to a compound of formula (IA-1), (IA-2), (IA-3), (IA-4) or (IA-5): [ka] (In the formula, A, R 1 and R 6 is as defined above), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof.

[0037] Typically, the present invention provides a compound of formula (IA-1), (IA-2) or (IA-4) as defined above or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof.

[0038] Suitably, the present invention provides a compound of formula (IA-1) or (IA-4) as defined above or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof.

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

[0040] Suitably, A represents a group of formula (Ab) or (Ad).

[0041] In general, the present invention relates to a compound of formula (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 is as defined above), or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof.

[0042] Suitably, the present invention provides a compound of formula (IB-2) or (IB-4) as defined above or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof.

[0043] In a first embodiment, Y represents -O-. In a second embodiment, Y represents -N(R 7 In a third embodiment, Y represents -C(R 5a )(R 5b In a fourth embodiment, Y represents -S-. In a fifth embodiment, Y represents -S(O)-. In a sixth embodiment, Y represents -S(O) 2 In a 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 -, where R 5a , R 5b and R 7 is as defined above.

[0045] Preferably, Y is -O-, -C(R 5a )(R 5b )-or-S(O) 2 -, where R 5a and R 5bis as defined above.

[0046] In general, Z is furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyridinyl, imidazolyl, pyrazolo[1,5-a]pyrazinyl, 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]pyridinyl Diphenyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo [1,5-a]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl or chromenyl, any of which groups may be optionally substituted by one or more substituents.

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

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

[0049] Suitably, Z represents triazolyl, which may be optionally substituted by one or more substituents.

[0050] Typical examples of optional substituents on Z include halogen, cyano, nitro, 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 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, 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, Carboxy, 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 ) alkylsulfoximino; and 1, 2 or (where possible) 3 substituents independently selected from alkylsulfoximino.

[0051] Suitable examples of optional substituents on Z include halogen, cyano, C 1-6 Alkyl, difluoromethyl, difluoroethyl, trifluoro(C 1-6 ) alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, cyanobicyclo[1.1.1]pentanyl and C 1-6 Included are one, two or (when possible) three substituents independently selected from alkylamino.

[0052] Representative 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. and 1, 2 or (where possible) 3 substituents independently selected from methoxy, 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 dimethylsulfoximino.

[0053] Suitable examples of particular 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 ​​for 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]pentanyltrizolyl, cyclopropylmethyltriazolyl, and cyanobicyclo[1.1.1]pentanyltrizolyl. 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 trifluoroethylpyrazinyl.

[0055] Exemplary values ​​of Z 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] Suitably, Z is represented by 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, The asterisk (*) represents the point of attachment to 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 Alkyl carbonyl, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl or di(C 1-6 ) alkylaminosulfonyl; R 2z is 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 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, 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, Carboxy, 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 ) alkylsulfoximino represents a group.

[0057] Particular values ​​of Z include groups of the formulae (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) alkyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl or cyanobicyclo[1.1.1]pentanyl.

[0059] R 1z Suitable values ​​of 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 ​​of 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 is hydrogen, halogen, cyano, C 1-6 Alkyl, trifluoro(C 1-6 ) alkyl, cyclopropylmethyl, difluorocyclopropylmethyl or C 1-6 It represents alkylamino.

[0062] Preferably, R 2zrepresents hydrogen, halogen or cyano. In a first embodiment, R 2z represents hydrogen. In a second embodiment, R 2z represents halogen, in particular fluoro. In a third embodiment, R 2z represents cyano.

[0063] R 2z Suitable values ​​for are 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, and tert-butyl. Examples of suitable fluoroalkyl groups 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 dimethylsulfoximino.

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

[0065] R 2zSuitable values ​​of include hydrogen, fluoro and cyano.

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

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

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

[0069] Preferably, R 1 represents hydrogen.

[0070] Typically, R 2 is C 3-9 Cycloalkyl, C 4-12 Bicycloalkyl or C 3-7 any of which may be optionally substituted by one or more substituents.

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

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

[0073] R 2 Suitable examples of include bicyclo[1.1.1]pentanyl and tetrahydropyranyl, either of which may be optionally substituted by one or more substituents.

[0074] R 2 Typical examples of the above optional substituents include 1, 2, 3 or 4 substituents independently selected from halogen.

[0075] R 2 Typical examples of the above specific substituents include 1, 2, 3 or 4 substituents independently selected from fluoro.

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

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

[0078] In the first embodiment, R 2a is C 1-6 In a second embodiment, R 2a is an optionally substituted C 3-9 It represents cycloalkyl.

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

[0080] R 2aTypical examples of the above optional substituents include halogen, cyano, nitro, C 1-6 Alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 ) Alkyl, oxo, C 1-6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, amino(C 1-6 ) Alkyl, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl and di(C 1-6 ) alkylaminosulfonyl.

[0081] R 2a Suitable examples of the above optional substituents include 1, 2 or 3 substituents independently selected from halogen.

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

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

[0085] In the first embodiment, R 3 Ha-NR 3a R 3b In a second embodiment, R 3 represents a group of formula (Wa) as defined above.

[0086] In the first embodiment, R 3a represents hydrogen. In a second embodiment, R 3a is C 1-6 In a first aspect of this embodiment, R 3a represents methyl. In a second aspect of that embodiment, R 3a represents ethyl.

[0087] Typically, R 3b is C 1-6 Alkyl or C 3-7 Cycloalkyl(C 1-6 ) alkyl, any of which may be optionally substituted by one or more substituents.

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

[0089] In the first embodiment, R 3b is an optionally substituted C 1-6 In a second embodiment, R 3b is an optionally substituted C 3-7 In a third embodiment, R 3b is an optionally substituted C 3-7 Cycloalkyl(C 1-6 ) alkyl. In a fourth embodiment, R 3b is an optionally substituted C 4-12 In a fifth embodiment, R 3b represents an optionally substituted aryl. In a sixth embodiment, R 3b is an optionally substituted aryl (C 1-6 ) alkyl. In a seventh embodiment, R 3b is an optionally substituted C 3-7 In an eighth embodiment, R 3b is an optionally substituted C 3-7 Heterocycloalkyl(C 1-6 ) alkyl. In a ninth embodiment, R 3b represents an optionally substituted heteroaryl. In a tenth embodiment, R 3b is an optionally substituted heteroaryl (C 1-6 ) alkyl.

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

[0091] R 3b A suitable example of includes propyl, which may be optionally substituted by one or more substituents.

[0092] R 3b Typical examples of the above optional substituents include halogen, cyano, nitro, C 1-6 Alkyl, trifluoromethyl, hydroxy, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, 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, Carboxy, 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 ) alkylsulfoximino.

[0093] R 3b Suitable examples of the above optional substituents include 1, 2 or 3 substituents independently selected from halogen.

[0094] R3b Representative examples of the above specific substituents 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 dimethylsulfoximino.

[0095] R 3b Suitable examples of the above specific substituents include 1, 2 or 3 substituents independently selected from fluoro.

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

[0097] R 3b Suitable values ​​for include difluoropropyl.

[0098] In a first embodiment, W represents the residue of an optionally substituted saturated monocyclic ring 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 not more than 1 O or S atom. In a first aspect of that embodiment, W represents the residue of an optionally substituted saturated monocyclic ring 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 not more than 1 O or S atom.

[0099] In a second embodiment, W represents the 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 not more than 1 O or S atom. In a first aspect of that embodiment, W represents the 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 not more than 1 O or S atom.

[0100] In a third embodiment, W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5-10 carbon atoms, 1 nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but not more than 1 O or S atom. In a first aspect of that embodiment, W represents the 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 not more than 1 O or S atom.

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

[0102] In a 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 azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or hexahydroazepin-1-yl ring). In a 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 a first aspect of that embodiment, the group of formula (Wa) is an optionally substituted morpholin-4-yl moiety. In a 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, of which not more than one is O or S. In a fourth embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and three additional heteroatoms selected from N, O and S, not more than one of which is O or S.

[0103] Exemplary values ​​for groups of formula (Wa) include azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, isothiazolidin-2-yl, imidazolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholin-4-yl, thiomorpholin-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]hexan-3-yl, 2- oxa-5-azabicyclo[2.2.1]heptan-5-yl, 6-azabicyclo[3.2.0]heptan-6-yl, 3-azabicyclo[3.1.1]heptan-3-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[4.1.0]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, 3-azabicyclo[3.2.1]octan-3-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1]octan-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]nonan-3-yl, 3,6-diazabicyclo[3.2.2]nonan-6-yl, 3-oxa-7-azabicyclo[3.3.1]nonan-7-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, 3,9-diazabicyclo[4.2.1]nonan-3-yl, 3,9-diazabicyclo[4.2.1]nonan-9-yl, 5-azaspiro[2.3]hexan-5-yl, 5- Azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxa-6-azaspiro[3.3]heptan-6-yl, 6-thia-2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2,4,8-triazaspiro[4.5]decan-2-yl, 2,4,8-triazaspiro[4.5]decan-4-yl and 2,4,8-triazaspiro[4.5]decan-8-yl, any of which may be optionally substituted with one or more substituents.

[0104] Suitable values ​​for the group of formula (Wa) include azetidin-1-yl and pyrrolidin-1-yl, either of which may be optionally substituted by one or more substituents.

[0105] In a first embodiment, the group of formula (Wa) is unsubstituted. In a second embodiment, the group of formula (Wa) is substituted by one or more substituents, typically 1 to 6 substituents, preferably 2 to 4 substituents. In a first aspect of the embodiment, the group of formula (Wa) is substituted by one substituent. In a second aspect of the embodiment, the group of formula (Wa) is substituted by two substituents. In a third aspect of the embodiment, the group of formula (Wa) is substituted by three substituents. In a fourth aspect of the embodiment, the group of formula (Wa) is substituted by four substituents. In a fifth aspect of the embodiment, the group of formula (Wa) is substituted by five substituents. In a sixth aspect of the embodiment, the group of formula (Wa) is substituted by six substituents.

[0106] Typical examples of optional substituents on the group of formula (Wa) include halogen, 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 Alkyl sulfonyl, 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 Alkyl sulfonyl amino, amino carbonyl, C 1-6 Alkylaminocarbonyl and di(C 1-6 ) alkylaminocarbonyl.

[0107] Selected examples of optional substituents on the group of formula (Wa) include halogen and trifluoromethyl.

[0108] Suitable examples of optional substituents on groups of formula (Wa) include halogen.

[0109] Representative examples of particular 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 particular substituents on the group of formula (Wa) include fluoro and trifluoromethyl.

[0111] Suitable examples of particular substituents on the group of formula (Wa) include fluoro.

[0112] Selected values ​​of the group of formula (Wa) include trifluoromethylazetidin-1-yl and tetrafluoropyrrolidin-1-yl.

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

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

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

[0116] In the first embodiment, R 4a represents hydrogen. In a second embodiment, R 4a represents fluoro. In a third embodiment, R 4a represents hydroxy. In a fourth embodiment, R 4a is C 1-6 In a first aspect of this embodiment, R represents alkyl, in particular methyl or ethyl, which may be optionally substituted by one or more substituents. 4a represents optionally substituted methyl. In a second aspect of that embodiment, R 4a represents optionally substituted ethyl.

[0117] R 4a Typical examples of the above optional substituents include halogen, cyano, nitro, hydroxy, C 1-6Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, 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, Carboxy, 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 ) alkylsulfoximino.

[0118] R 4a Suitable examples of the above optional substituents include 1, 2 or 3 substituents independently selected from halogen.

[0119] R 4a Representative examples of the above specific substituents 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 dimethylsulfoximino.

[0120] R 4a Suitable examples of the above specific substituents include 1, 2 or 3 substituents independently selected from fluoro.

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

[0122] In the first embodiment, R 4b represents hydrogen. In a second embodiment, R 4b represents fluoro. In a third embodiment, R 4b is C 1-6 In a first aspect of this embodiment, R 4b represents methyl. In a second aspect of that embodiment, R 4b represents ethyl.

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

[0124] Or, R 4a and R 4b may be taken together to form an optionally substituted cyclic moiety. Thus, R 4a and R 4b together with the carbon atom to which they are both attached, C 3-7 Cycloalkyl or C 3-7 It can represent a heterocycloalkyl, any of which groups can be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0125] In the first embodiment, R 4a and R 4b together with the carbon atom to which they are both attached, C 3-7Cycloalkyl may suitably be represented, which may be unsubstituted or substituted by one or more substituents, typically one or two. 4a and R 4b together with the carbon atom to which they are both attached may suitably represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two. 4a and R 4b together with the carbon atom to which they are both attached may suitably represent cyclobutyl or cyclohexyl, either of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. 4a and R 4b may be taken together with the carbon atom to which they are both attached to suitably represent a cyclopropyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a second aspect of that embodiment, R 4a and R 4b may be taken together with the carbon atom to which they are both attached to suitably represent a cyclobutyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. 4a and R 4b may suitably represent a cyclopentyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a fourth aspect of that embodiment, R 4a and R 4btaken together with the carbon atom to which they are both attached may suitably represent a cyclohexyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0126] In a second embodiment, R 4a and R 4b together with the carbon atom to which they are both attached, C 3-7 Heterocycloalkyl may suitably be represented, which may be unsubstituted or substituted by one or more substituents, typically one or two. As a general example of this embodiment, R 4a and R 4b may suitably represent, together with the carbon atom to which they are both attached, oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which may be unsubstituted or substituted by one or more substituents, typically one or two. 4a and R 4b may suitably represent pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. 4a and R 4b may suitably represent tetrahydropyranyl or piperidinyl, either of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a first aspect of that embodiment, R 4a and R 4bmay be combined with the carbon atom to which they are both attached to suitably represent an oxetanyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a second aspect of that embodiment, R 4a and R 4b may be combined with the carbon atom to which they are both attached to suitably represent a pyrrolidinyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. 4a and R 4b may be taken together with the carbon atom to which they are both attached to suitably represent a tetrahydropyranyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a fourth aspect of that embodiment, R 4a and R 4b taken together with the carbon atom to which they are both attached may suitably represent a piperidinyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

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

[0128] Appropriately, R 4a and R 4btaken together with the carbon atom to which they are both attached can represent cyclohexyl, tetrahydropyranyl, or piperidinyl, any of which groups can be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0129] Preferably, R 4a and R 4b taken together with the carbon atom to which they are both attached can represent cyclohexyl or tetrahydropyranyl, either of which groups can be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0130] R 4a and R 4b Representative examples of optional substituents on the cyclic moiety formed by 1-6 Alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, hydroxy, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, C 2-6 Alkyl carbonyl, C 2-6 Alkoxycarbonyl, Amino, C 1-6 Alkylamino and di(C 1-6 ) alkylamino. Additional examples include oxetanyl.

[0131] R 4a and R 4b Suitable examples of optional substituents on the cyclic moiety formed by include 1, 2 or 3 substituents independently selected from halogen and oxetanyl.

[0132] R 4a and R 4bSuitable examples of optional substituents on the cyclic moiety formed by include 1, 2 or 3 substituents independently selected from halogen.

[0133] R 4a and R 4b Representative 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. Additional examples include oxetanyl.

[0134] R 4a and R 4b Suitable examples of particular substituents on the cyclic moiety formed by include 1, 2 or 3 substituents independently selected from fluoro and oxetanyl.

[0135] R 4a and R 4b Suitable examples of particular substituents on the cyclic moiety formed by include 1, 2 or 3 substituents independently selected from fluoro.

[0136] R 4a and R 4b Representative examples of the cyclic moiety formed by include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonylpyrrolidinyl, tetrahydropyranyl, piperidinyl, and methoxycarbonylpiperidinyl. Additional examples include oxetanylpiperidinyl.

[0137] R 4a and R 4b Selected examples of the cyclic moiety formed by include difluorocyclohexyl, tetrahydropyranyl, and oxetanylpiperidinyl.

[0138] R 4a and R 4b Suitable examples of the cyclic moiety formed by include difluorocyclohexyl and tetrahydropyranyl.

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

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

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

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

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

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

[0145] Preferably, R 5b represents fluoro or hydroxy, in particular hydroxy.

[0146] Or, R 5a and R 5bmay be taken together to form a spiro bond. Thus, R 5a and R 5b taken together with the carbon atom to which they are both attached can represent cyclopropyl.

[0147] Typically, R 6 -OR 6a Or -NR 6b R 6c or R 6 is C 1-6 Alkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl(C 1-6 ) Alkyl, aryl, aryl (C 1-6 ) alkyl, heteroaryl or heteroaryl (C 1-6 ) alkyl, any of which may be optionally substituted by one or more substituents.

[0148] Appropriately, R 6 -OR 6a Or -NR 6b R 6c or R 6 is C 3-9 It represents cycloalkyl, aryl, or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

[0149] Preferably, R 6 -OR 6a or R 6 is C 3-9 It represents cycloalkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.

[0150] In the first embodiment, R 6 is an optionally substituted C 1-6 In a second embodiment, R 6 is an optionally substituted C 3-9 In a third embodiment, R6 is an optionally substituted C 3-9 Cycloalkyl(C 1-6 ) alkyl. In a fourth embodiment, R 6 represents an optionally substituted aryl. In a fifth embodiment, R 6 is an optionally substituted aryl (C 1-6 ) alkyl. In a sixth embodiment, R 6 is an optionally substituted C 3-7 In a seventh embodiment, R 6 is an optionally substituted C 3-7 Heterocycloalkyl(C 1-6 ) alkyl. In an eighth embodiment, R 6 represents an optionally substituted heteroaryl. In a ninth embodiment, R 6 is an optionally substituted heteroaryl (C 1-6 In a tenth embodiment, R 6 -OR 6a In an eleventh embodiment, R 6 Ha-NR 6a R 6b Represents.

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

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

[0153] R 6 Selected examples of: -OR 6a and cyclopropyl, pyrazolyl, oxadiazolyl or triazolyl, any of which may be optionally substituted by one or more substituents.

[0154] R 6 A suitable example of the group is -OR 6a and cyclopropyl, pyrazolyl, or oxadiazolyl, any of which may be optionally substituted by one or more substituents.

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

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

[0157] R 6 Representative examples include pyrazolyl and oxadiazolyl, either of which may be optionally substituted by one or more substituents.

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

[0159] R 6Typical examples of the above optional substituents include halogen, cyano, nitro, 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 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, amino(C 1-6 ) Alkyl, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C 2-6 Alkylcarbonylamino, C 2-6 Alkylcarbonylamino (C 1-6 ) Alkyl, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonylamino, formyl, C 2-6 Alkylcarbonyl, Carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) alkylaminosulfonyl and di(C 1-6 ) alkylsulfoxyiminyl.

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

[0161] R 6 Suitable examples of the above optional substituents include halogen and C 1-6 There may be one, two or three substituents independently selected from alkyl.

[0162] R 6 Representative examples of the above specific substituents 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 above particular substituents include 1, 2 or 3 substituents independently selected from fluoro, methyl, ethyl, isopropyl and cyclopropyl.

[0164] R 6 Suitable examples of the above specific substituents include 1, 2 or 3 substituents independently selected from fluoro, methyl and isopropyl.

[0165] R 6Illustrative examples of specific values ​​of are 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 6Exemplary values ​​of include fluorocyclopropyl, methylpyrazolyl, ethylpyrazolyl, isopropylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl and isopropyltriazolyl.

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

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

[0169] In the first embodiment, R 6a is an optionally substituted C 1-6 In a second embodiment, R 6a is an optionally substituted C 3-9 In a third embodiment, R 6a is an optionally substituted aryl (C 1-6 ) alkyl.

[0170] Typically, R 6a is C 1-6 It represents alkyl, cyclobutyl, or benzyl, any of which groups may be optionally substituted by one or more substituents.

[0171] R 6a Typical examples of the above optional substituents include halogen, cyano, nitro, C 1-6 Alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 ) Alkyl, oxo, C 1-6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6Alkyl 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, Carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl and di(C 1-6 ) alkylaminosulfonyl.

[0172] R 6a Suitable examples of the above optional substituents include 1, 2 or 3 substituents independently selected from halogen.

[0173] R 6a Representative examples of the above specific substituents 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 6aSuitable examples of the above specific substituents include 1, 2 or 3 substituents independently selected from fluoro.

[0175] R 6a Illustrative 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 a second embodiment, R 6b is C 1-6 It stands for alkyl, especially methyl.

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

[0180] In the first embodiment, R 6c represents hydrogen. In a second embodiment, R 6c is C 1-6 It stands for alkyl, especially methyl.

[0181] Alternatively, partial-NR 6b R 6c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may optionally be substituted by one or more substituents.

[0182] Heterocyclic moiety -NR6b R 6c Selected examples of suitable substituents above include C 1-6 Alkyl, C 1-6 Alkyl sulfonyl, hydroxy, hydroxy(C 1-6 ) Alkyl, Amino (C 1-6 ) Alkyl, cyano, oxo, C 2-6 Alkylcarbonyl, Carboxy, C 2-6 Alkoxycarbonyl, Amino, C 2-6 Alkylcarbonylamino, C 2-6 Alkylcarbonylamino (C 1-6 ) Alkyl, C 2-6 Alkoxycarbonylamino, C 1-6 Alkylsulfonylamino and aminocarbonyl are included.

[0183] Heterocyclic moiety -NR 6b R 6c Selected examples of the above specific substituents include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxycarbonylamino, methylsulfonylamino, and aminocarbonyl.

[0184] In general, R 7 -COR 7a , -CO 2 R 7a Or -SO 2 R 7b or R 7 represents hydrogen; or R 7 is C 1-6 It represents alkyl, which is optionally substituted with one or more fluorine atoms, generally 1, 2 or 3 fluorine atoms, typically 2 fluorine atoms.

[0185] Preferably, R 7 HA-CO 2 R 7a Represents.

[0186] In the first embodiment, R 7 HA-COR 7a In a second embodiment, R 7 HA-CO 2 R 7a In a third embodiment, R 7 HA-CO 2 R 7a In the fourth embodiment, R 7 represents hydrogen. In a fifth embodiment, R 7 is a C optionally substituted by one or more fluorine atoms, typically 1, 2 or 3 fluorine atoms; 1-6 In one aspect of this embodiment, R 7 is unsubstituted C 1-6 In another aspect of this embodiment, R 7 is a C substituted by 1, 2 or 3 fluorine atoms, typically 2 fluorine atoms 1-6 In a sixth embodiment, R represents alkyl. An example of this embodiment is difluoroethyl. 7 is a C optionally substituted by one or more fluorine atoms, typically 1, 2 or 3 fluorine atoms; 3-9 In one aspect of this embodiment, R 7 is unsubstituted C 3-9 In another aspect of this embodiment, R 7 is a C substituted by 1, 2 or 3 fluorine atoms, typically 2 fluorine atoms 3-9 It represents cycloalkyl. An example of this embodiment is difluorocyclobutyl.

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

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

[0189] In the first embodiment, R 7a is C 1-6 In a first aspect of this embodiment, R 7a represents methyl. In a second aspect of that embodiment, R 7a represents ethyl. In a second embodiment, R 7a is difluoro(C 1-6 ) alkyl, in particular difluoroethyl.

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

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

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

[0193] Various subclasses of compounds according to the invention are represented by formulae (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 represents methyl, ethyl, isopropyl or cyclopropyl; R 26 represents fluoro or trifluoromethyl; A is as defined above. and its N-oxides, as well as pharma- ceutically acceptable salts thereof.

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

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

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

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

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

[0199] Specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying examples, as well as pharma- ceutically acceptable salts and solvates thereof.

[0200] The compounds according to the invention are useful in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

[0201] The compounds according to the invention are useful for the treatment and / or prophylaxis of pathological disorders mediated by or associated with increased levels of the proinflammatory IL-17 cytokine. In general, pathological conditions include infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infections, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman's disease, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathy, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, folliculitis, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, The therapeutic agent is selected from the group consisting of type I diabetes, Lyme arthritis, meningoencephalitis, immune-mediated inflammatory diseases of the central and peripheral nervous system, e.g. multiple sclerosis and Guillain-Barre syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrotic disorders, e.g. pulmonary fibrosis, liver fibrosis, kidney 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, in particular acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colon cancer), ischemic diseases such as myocardial infarction and heart diseases, including atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria and pain, in particular pain associated with inflammation.

[0202] WO 2009 / 089036 discloses that modulators of IL-17 activity may be administered to prevent or reduce the severity of ocular inflammatory disorders, particularly ocular surface inflammatory disorders, including dry eye syndrome (DES). As a result, the compounds according to the 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, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness grafts, selective endothelial transplantation, corneal neovascularization, artificial keratoplasty, corneal surface inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjogren's syndrome, Sjogren's syndrome-associated keratoconjunctivitis sicca, non-Sjogren's syndrome-associated keratoconjunctivitis sicca, keratitis sicca, dry eye syndrome, xerophthalmia, tear film disorders, reduced tear volume, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.

[0203] Illustratively, the compounds of the invention may be useful for 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 airways disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathy, cancer, and pain (particularly pain associated with inflammation).

[0204] Suitably, 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 or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers.

[0206] Pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, ocular or rectal administration, or in a form suitable for administration by inhalation or insufflation.

[0207] For oral administration, the pharmaceutical compositions can take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharma- ceutically acceptable excipients, such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavoring agents, coloring agents or sweetening agents, as appropriate.

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

[0209] For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.

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

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

[0212] For administration intranasally or by inhalation, the compounds according to the invention may conveniently be delivered in the form of an aerosol spray presentation for a pressurized pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

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

[0214] For topical administration, the compound according to the present invention can be conveniently formulated into a suitable ointment, which contains 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 compound according to the present invention can be formulated into a suitable lotion, which contains 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-octyl dodecanol and water.

[0215] For ocular administration, the compounds according to the invention may conveniently be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as a bactericidal or fungicidal agent, e.g., phenylmercuric nitrate, benzylalkonium chloride, or chlorhexidine acetate. Alternatively, for ocular administration, the compounds according to the invention may be formulated in an ointment, such as petrolatum.

[0216] For rectal administration, the compound according to the present invention can be conveniently formulated as suppositories.These can be prepared by mixing the active ingredient with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature, and therefore melt in the rectum to release the active ingredient.Such materials include, for example, 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 particular condition may vary depending on the compound selected and the condition of the patient being treated.However, in general, the daily dosage may range from about 10ng / kg body weight to 1000mg / kg body weight, typically 100ng / kg body weight to 100mg / kg body weight, for example, about 0.01mg / kg body weight to 40mg / kg body weight, for oral or buccal administration, about 10ng / kg body weight to 50mg / kg body weight, and about 0.05mg to about 1000mg, for example, about 0.5mg to about 1000mg, for intranasal administration or administration by inhalation or insufflation.

[0218] If desired, the compounds according to the invention may be co-administered with another pharma- ceutically active agent, for example, an anti-inflammatory molecule.

[0219] The compound of formula (I) above has the formula R 6 -CO 2 The compound of formula (III) can be prepared by a process comprising reacting a carboxylic acid of H or a salt thereof (e.g., a lithium salt thereof) with a compound of formula (III): [ka] In the formula, A, E, R 1 and R 6 is as defined above.

[0220] The reaction is conveniently accomplished in the presence of a coupling agent and a base. Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU); and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; and 2-chloro-1-methylpyridinium iodide. Suitable bases include organic amines, such as trialkylamines, such as N,N-diisopropylethylamine; or pyridine. The reaction is conveniently carried out in a suitable solvent, such as a cyclic ether, such as tetrahydrofuran; or a dipolar 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, at ambient or elevated temperature.

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

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

[0223] R 6 -OR 6a When the compound of formula (I) above represents 6aIt can be prepared by a two-step process which comprises reacting a compound of -OH with N,N'-disuccinimidyl carbonate, ideally in the presence of a base, for example an organic amine such as triethylamine; and (ii) reacting the resulting material with a compound of formula (III) as defined above. Steps (i) and (ii) are conveniently carried out at ambient temperature in a suitable solvent, for example a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile.

[0224] The intermediate of formula (III) above can be represented by the formula (IV): [ka] (Wherein, A, E and R 1 is as defined above, and R p represents an N-protecting group) p It can be prepared by removal of

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

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

[0227] In an alternative procedure, the compound of formula (I) above, in which A represents a group of formula (Ad), (i) Formula (V): [ka] (In the formula, E, R 1 , R 4a , R 4b and R 6 is as defined above, and Alk 1 is C 1-4 alkyl, e.g. methyl, ethyl or tert-butyl); and (ii) Compound (III) and formula R 6 -CO 2 under conditions similar to those described above for the reaction between a carboxylic acid of H and the carboxylic acid derivative of formula R 3 Reaction with compounds of -H It can be prepared by a two-step process including:

[0228] Similarly, the intermediate of formula (IV) above, in which A represents a group of formula (Ad), (i) Formula (VI): [ka] (In the formula, E, R 1 , R 4a , R 4b , R p and Alk 1 is as defined above; and (ii) Compound (III) and formula R 6 -CO 2 under conditions similar to those described above for the reaction between a carboxylic acid of H and the carboxylic acid derivative of formula R 3 Reaction with compounds of -H It can be prepared by a two-step process including:

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

[0230] Or, Alk 1 When represents tert-butyl, the saponification reaction in step (i) may generally be effected by treatment with an acid, for example an organic acid such as trifluoroacetic acid. The reaction is conveniently carried out in a suitable organic solvent, for example a chlorinated solvent such as dichloromethane, at ambient temperature.

[0231] The intermediate of formula (V) above can be prepared by reacting compound (III) with compound (III) of formula R 6 -CO 2 Under conditions similar to those described above for the reaction between a carboxylic acid of formula R 6 -CO 2 It can be prepared by reacting a carboxylic acid of H with a compound of formula (VII): [ka] In the formula, E, R 1 , R 4a , R 4b , R 6 and Alk 1 is as defined above.

[0232] The intermediate of formula (VII) above can be prepared by reacting the N-protecting group R p from the compound of formula (VI) as defined above under conditions similar to those described above for the removal of the N-protecting group R P It can be prepared by removing

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

[0234] Leaving group L 1 is typically a halogen atom, for example bromo.

[0235] The reaction is typically accomplished in the presence of a base. Suitably, the base may be an inorganic base, for example a bicarbonate, such as sodium bicarbonate; or an organic base, such as pyridine. The reaction is carried out in a suitable solvent, for example a C 2 O 4 solution, such as ethanol or isopropanol. 1-4 This is conveniently carried out in alkanols or cyclic ethers such as 1,4-dioxane at elevated temperatures.

[0236] In an alternative procedure, the compound of formula (I) above, in which A represents a group of formula (Aa), (Ab) or (Ac), can be reacted with a compound (III) and a compound of formula R 6 -CO 2 Under conditions similar to those described above for the reaction between a carboxylic acid of formula R 2 -CO 2 H to a carboxylic acid of formula (X): [ka] (In the formula, A 1 is represented by the formula (Aa-1), (Ab-1) or (Ac-1): [ka] where the asterisk (*) represents the point of attachment to the remainder of the molecule; E, Y, R 1 , R 2 and R 6 is as defined above) The compound can be prepared by a process comprising reacting the compound with a compound of formula (I).

[0237] The intermediate of formula (X) above may be represented by formula (XI): [ka] (In the formula, A 2 is represented by the formula (Aa-2), (Ab-2) or (Ac-2): [ka] where the asterisk (*) represents the point of attachment to the remainder of the molecule; R z represents an N-protecting group; E, Y, R 1 and R 6 is as defined above) The N-protecting group R from the compound z It can be prepared by removal of

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

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

[0240] In an alternative process, intermediates of formula (IV) above, in which A represents a group of formula (Aa), (Ab) or (Ac), can be prepared by the following steps: (i) Removal of the N-protecting group R from a compound of formula (XII) as defined above under conditions similar to those described above. z Removal of; and (ii) Compound (III) and formula R 6 -CO 2 H under conditions similar to those described above for the reaction between a carboxylic acid of formula R 2 -CO 2 Reaction of H with carboxylic acids It can be prepared by a two-step procedure including:

[0241] The intermediate of formula (XII) above can be reacted with a compound of formula A in the presence of a transition metal catalyst. 2 -CO 2 H with a compound of formula (XIII): [ka] In the formula, E, A 2 , R 1 and R p is as defined above.

[0242] Suitable transition metal catalysts for use 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-phenylpyridinato-C 2 [0,N]iridium(III). The reaction is generally carried out by exposing the reactants to a bright light source. Suitable bright light sources typically include the "integrated photoreactor" described in ACS Cent.Sci., 2017, 3, 647-653; or the Penn Photoreactor M2 system. The reaction is conveniently carried out at ambient temperature in a suitable solvent, for example a dipolar aprotic solvent such as N,N-dimethylformamide, or an organic disulfide such as dimethylsulfoxide.

[0243] In an alternative process, the intermediate of formula (XI) above can be prepared by the following steps: (i) Removal of the N-protecting group R from a compound of formula (XIII) as defined above under conditions similar to those described above. p Removal of; (ii) Compound (III) and formula R 6 -CO 2 under conditions similar to those described above for the reaction between a carboxylic acid of H or a salt thereof (e.g., a lithium salt thereof) and the material obtained thereby with a compound of formula R 6 -CO 2 Reaction of H with a carboxylic acid or a salt thereof (e.g., a lithium salt thereof); and (iii) Compound (XIII) and Formula A 2 -CO 2 and the resulting material under conditions similar to those described above for the reaction between a carboxylic acid of H and a compound of formula A 2 -CO 2 Reaction with compounds of H It can be prepared by a three-step procedure, including:

[0244] In another procedure, the compound of formula (I) above, in which A represents a group of formula (Ad), can be prepared by reacting (i) Removal of the N-protecting group R from a compound of formula (XIII) as defined above under conditions similar to those described above. p Removal of; (ii) Compound (III) and formula R 6 -CO 2 under conditions similar to those described above for the reaction between a carboxylic acid of H or a salt thereof (e.g., a lithium salt thereof) and the material obtained thereby with a compound of formula R 6 -CO 2 Reaction of H with a carboxylic acid or a salt thereof (e.g., a lithium salt thereof); and (iii) Compound (XIII) and Formula A 2 -CO 2 H under conditions similar to those described above for the reaction between the carboxylic acid of formula A-CO 2 Reaction with compounds of H It can be prepared by a three step process including:

[0245] The intermediate of formula (XIII) above can be reacted under conditions similar to those described above for the reaction between compounds (VIII) and (IX) to give a compound of formula (IX) as defined above, of formula (XIV): [ka] (In the formula, R 1 can be prepared by reacting a compound of formula (I) with a compound of formula (II)

[0246] In an alternative procedure, A represents a group of formula (Ae) and Z represents a group of formula (Zt), where R 2z represents hydrogen) is a compound of formula (I) 1z -NH 2 and trialkyl orthoformate HC (O-Alk 1 ) 3 can be prepared by a process comprising reacting a compound of formula (XV): [ka] In the formula, E, R 1 , R 4a , R 4b , R 6 , R 1z and Alk 1 is as defined above.

[0247] The reaction is conveniently carried out in the presence of acetic acid at elevated temperature. The reaction can typically be carried out in a suitable solvent, for example a cyclic ether such as 1,4-dioxane.

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

[0249] The reaction is carried out in a suitable solvent, e.g., C 1-4 This is conveniently carried out in an alkanol at elevated temperature.

[0250] The above intermediate of formula (IV), in which A represents a group of formula (Ae) and Z represents a group of formula (Zu), as defined above, can be prepared by the following steps: (i) saponification of a compound of formula (VI) as defined above by treatment with a base; (ii) Compound (III) and formula R 6 -CO 2 and the carboxylic acid derivative of formula (XVI): [ka] (In the formula, R 2z is as defined above); and (iii) cyclization of the resulting material by treatment with triphenylphosphine in the presence of a base. It can be prepared by a three-step procedure, including:

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

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

[0253] In another procedure, A represents a group of formula (Ae) and Z represents a group of formula (Zw) or (Zx), where R 1z is other than hydrogen), the compound of formula (I) can be prepared by the following steps: (i) reacting an alkali metal azide with an alkali metal azide of formula (XVII): [ka] (In the formula, E, R 1 , R 4a , R 4b and R 6 is as defined above; and (ii) The resulting material is treated with the formula R 1z -L 3 (In the formula, R 1z is as defined above (and is other than hydrogen), and L 3 represents a suitable leaving group, It can be prepared by a two-step procedure including:

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

[0255] Leaving group L 3may suitably be a sulfonyloxy derivative, for example trifluoromethanesulfonyloxy.

[0256] Step (ii) is generally accomplished in the presence of a base. Suitable bases include alkali metal carbonates, such as potassium carbonate. The reaction is conveniently effected at elevated temperature in a suitable solvent, such as a carbonyl-containing solvent, such as acetone.

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

[0258] Step (i) is carried out in a suitable solvent, e.g., C 1-4 This is conveniently carried out in an alkanol at elevated temperature.

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

[0260] A represents a group of formula (Ae) as defined above and Z represents a group of formula (Zq) (wherein 2z is hydrogen), can be reacted in the presence of a transition metal catalyst with an intermediate of formula (IV) 1z -N 3 with an azide derivative of formula (XVIII): [ka] (In the formula, E, R 1 , R 4a , R 4b , R 1z and R p can be prepared by reacting a compound of formula (I) with a compound of formula (II)

[0261] Suitable transition metal catalysts for use in the above reaction include chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II).

[0262] The reaction is conveniently carried out at elevated temperature in a suitable solvent or mixture of solvents. Typical solvents include alkyl ethers, such as tert-butyl methyl ether or 1,2-dimethoxyethane, and cyclic ethers, such as tetrahydrofuran.

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

[0264] The reaction is generally carried out in the presence of a base. Suitably, the base may be an alkali metal carbonate, for example potassium carbonate. The reaction is conveniently carried out at ambient temperature in a suitable solvent or mixture of solvents. Typical solvents include C 1-4 Alkanols, such as methanol; and chlorinated solvents, such as dichloromethane.

[0265] The intermediate of formula (XIX) above can be prepared by the following steps: (i) Formula (XX): [ka] (In the formula, E, R 1 , R 4a , R 4b and R p is as defined above, and R srepresents an O-protecting group) s Removal of; and (ii) treating the compound thus obtained with an oxidizing agent It can be prepared by a two-step procedure including:

[0266] O-protecting group R s is preferably acetyl.

[0267] R s When represents acetyl, its removal in step (i) above may conveniently be effected by treatment with a base. Suitably the base may be an alkali metal carbonate, for example potassium carbonate. The reaction may be carried out in a suitable solvent, for example C 2 O such as methanol. 1-4 It is conveniently carried out in an alkanol at ambient temperature.

[0268] Suitable oxidizing agents for use in step (ii) above include 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane). The reaction is conveniently effected at ambient temperature in a suitable solvent, for example a chlorinated solvent such as dichloromethane.

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

[0270] The intermediate of formula (XX) above can be prepared by reacting a compound of formula (IX) defined above with the compound of formula (XXI): [ka] (In the formula, R 1 , R 4a , R 4b and Rs can be prepared by reacting a compound of formula (I) with a compound of formula (II)

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

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

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

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

[0275] Similarly, compounds containing NH functional groups are typically reacted with a suitable C 1-4 Treatment with an alkylsulfonyl chloride reagent, e.g., methylsulfonyl chloride, affords the NS(O) 2Alk 1 Functional group (in the formula, Alk 1 may be converted to the corresponding compound comprising:

[0276] Similarly, compounds containing NH functional groups may be converted to corresponding compounds containing carbamate or urea moieties, typically by treatment with a suitable chloroformic acid or carbamoyl chloride reagent in the presence of a base, for example, an organic base such as triethylamine or N,N-diisopropylethylamine, respectively. Alternatively, compounds containing NH functional groups may be converted to corresponding compounds containing urea moieties, typically by treatment with a suitable amine-substituted (3-methylimidazol-3-ium-1-yl)methanone iodide derivative in the presence of a base, for example, an organic base such as triethylamine. Alternatively, compounds containing NH functional groups may be converted to corresponding compounds containing urea moieties, typically by treatment with a suitable isocyanate derivative Alk in the presence of a base, for example, an organic base such as triethylamine, 1 Treatment with -N=C=O gives the urea moiety NC(O)N(H)Alk 1 (In the formula, Alk 1 may be converted to the corresponding compound comprising:

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

[0278] C 1-4 Alkoxycarbonyl moiety -CO 2 Alk 1 (In the formula, Alk 1 is as defined above), can be converted to a carboxylic acid (-CO 2 Alternatively, compounds containing a tert-butoxycarbonyl moiety can be converted to the corresponding compounds containing a carboxylic acid (-CO2 H) moiety.

[0279] Carboxylic acid (-CO 2 Compounds containing the moiety H) are represented by the formula (III) and formula R 6 -CO 2 H may be converted to the corresponding compounds containing an amide moiety by treatment with an appropriate amine under conditions similar to those described above for the reaction between a carboxylic acid and H.

[0280] C 1-4 Alkoxycarbonyl moiety -CO 2 Alk 1 (In the formula, Alk 1 is as defined above), can be converted to a hydroxymethyl (-CH 2 may be converted to the corresponding compound containing the moiety OH.

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

[0282] Compounds containing halogen atoms, e.g., bromo, may be converted to the corresponding compounds containing optionally substituted aryl, heterocycloalkenyl or heteroaryl moieties by treatment with appropriately substituted aryl, heterocycloalkenyl or heteroaryl boronic acids, or their cyclic esters formed with organic diols, e.g., pinacol, 1,3-propanediol or neopentyl glycol. The reaction is typically effected in the presence of a transition metal catalyst and a base. The transition metal catalyst may be [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Alternatively, the transition metal catalyst may be tris(dibenzylideneacetone)dipalladium(0), which may be advantageously used in conjunction with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). Suitably, the base may be an inorganic base, such as sodium carbonate or potassium carbonate.

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

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

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

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

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

[0288] When a mixture of products is obtained from any of the above-described processes for preparing compounds according to the invention, the desired products may be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography, for example employing silica and / or alumina in conjunction with a suitable solvent system.

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

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

[0291] Compounds according to the invention potently inhibit IL-17-induced IL-6 release from human dermal fibroblasts. Thus, when tested in the HDF cell line assay described below, compounds of the invention have a pIC of 5.0 or greater, generally 6.0 or greater, usually 7.0 or greater, typically 7.2 or greater, suitably 7.5 or greater, ideally 7.8 or greater, and preferably 8.0 or greater. 50 Values ​​are presented (pIC 50 -log 10 [I C 50 ], and I.C. 50 Since pIC is expressed as a molar concentration, one of skill in the art would recognize that a higher pIC 50 It will be appreciated that a value of 0.1 indicates a more active compound).

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

[0293] HDFs were stimulated with IL-17A (50 pM) in combination with TNF-α (25 pM). The resulting IL-6 response was then measured using a homogeneous time-resolved FRET kit from Cisbio. The kit utilizes two monoclonal antibodies, one labeled with Eu-Cryptate (donor) and the second labeled with d2 or XL665 (acceptor). The intensity of the signal is proportional to the concentration of IL-6 present in the sample (the ratio is calculated by 665 / 620×104).

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

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

[0296] Compounds were serially diluted in DMSO, after which the aqueous dilutions were placed into a 384-well dilution plate (Greiner #781281) and 5 μL from the titration plate was transferred to 45 μL of complete medium and mixed to give a solution containing 10% DMSO.

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

[0298] 10 μL from the aqueous dilution plate was transferred to the reagent plate containing 30 μL of diluted cytokines to give a 2.5% DMSO solution. Compounds were incubated with the cytokine mixture for 5 hours at 37° C. After incubation, 10 μL was transferred to the assay plate to give a 0.5% DMSO solution, then incubated at 37° C. / 5% CO 2 The mixture was incubated at RT for 18 to 20 hours.

[0299] Europium cryptate and Alexa 665 from the Cisbio IL-6 FRET kit (Cisbio#62IL6PEB) were diluted in reconstitution 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 then the supernatant (10 μL) was transferred from the assay plate to the Greiner reagent plate. The mixture was incubated at room temperature with gentle shaking (<400 rpm) for 3 hours before being read on a Synergy Neo2 plate reader (excitation: 330 nm; emission: 615 / 645 nm).

[0300] When tested in the HDF cell line assay described above, the compounds in the attached examples had the following pIC 50 It was found to exhibit value. [Table 1]

[0301] The following examples illustrate the preparation of compounds according to the 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 EtOAc: ethyl acetate TFA: trifluoroacetic acid IPA: Isopropyl alcohol DMAP: 4-(dimethylamino)pyridine TBME: tert-butyl methyl 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®: Propylphosphonic anhydride solution HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 :[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 + 0.1% ammonia solution in water 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: CO 2 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 in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 1.80 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 in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00

[0309] Method 7 MSDXT, pH 10 Stationary phase: Waters Acquity UPLC BEH C18 2.1×50mm, 1.7μm Mobile phase A: 10 mM ammonium formate + 0.1% ammonia solution in water 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 + 0.1% ammonia solution in water 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 an isocratic 7% MeOH (+0.1% NH) elution system with a run time of 14 min on a Waters Prep 100 fractionlynx system in conjunction with a Waters SQD2 mass spectrometer. 4 The separation was performed using SFC on a Lux Cellulose-1 250 × 21.2 mm, 5 μm column eluted with the (OH) method (ABPR 60 bar), at a flow rate of 100 mL / min and a column temperature of 40 °C.

[0312] Method 10 The analysis was performed using a Waters UPC coupled mass spectrometer. 2 Use a run time of 6.5 min on an Acquity system to run a gradient of 3 to 40% MeOH (+0.1% NH 4 The analysis was performed using a Lux Cellulose-C1, 150 x 4.6 mm, 3 μm column eluted with the (OH) method (ABPR 120 bar), flow rate 3 mL / min, column temperature 35 °C.

[0313] Method 11 Purification was performed using a Waters Prep150 fractionlynx system with a 10 min run time in 10–25% MeOH (+0.1% NH 4 The separations were performed using SFC on a Lux Cellulose-4 250 × 21.2 mm, 5 μm column eluted with the OH (ABPR 60 bar) method, with a flow rate of 100 mL / min and a column temperature of 40 °C.

[0314] Method 12 The analysis was performed using a Waters UPC coupled mass spectrometer. 2 Use a run time of 6.5 min on an Acquity system to run a gradient of 3 to 40% MeOH (+0.1% NH 4 The analysis was performed using a Lux Cellulose-C4, 150 x 4.6 mm, 3 μm column eluted with the (OH) method (ABPR 120 bar), with a flow rate of 3 mL / min and a column temperature of 35°C.

[0315] Method 13 Purification was performed using a 7.5 min run time on a Waters Prep150 fractionlynx system in conjunction with a Waters QDa mass spectrometer, with 3–40% MeOH (+0.1% NH 4 The separations were performed using SFC on a Lux Cellulose-2 250 × 21.2 mm, 5 μm column eluted with the OH (ABPR 60 bar) method, with a flow rate of 100 mL / min and a column temperature of 40 °C.

[0316] Method 14 The analysis was performed using a Waters UPC coupled mass spectrometer. 2 Use a run time of 6.5 min on an Acquity system to run a gradient of 3 to 40% MeOH (+0.1% NH 4 The analysis was performed using a Lux Cellulose-C2 150 x 4.6 mm, 3 μm column eluted with the (OH) method (ABPR 120 bar), with a flow rate of 3 mL / min and a column temperature of 35 °C.

[0317] Method 15 SFC purification was performed using a 7.5 min run time on a Waters Prep150 fractionlynx system in conjunction with a Waters QDa mass spectrometer, with 3–40% MeOH (+0.1% NH 4 The analysis was performed using a Chiralpak IB250 x 20 mm, 5 μm column eluted with the 500 MPa (OH) method (ABPR 60 bar), with a flow rate of 100 mL / min and a column temperature of 40°C.

[0318] Method 16 The analysis was performed using a Waters UPC coupled mass spectrometer. 2 Use a run time of 6.5 min on an Acquity system to prepare 3-40% MeOH (+0.1% NH 4 The analysis was performed using a Chiralpak IB, 150 x 4.6 mm, 3 μm column eluted with the (OH) method (ABPR 120 bar), with a flow rate of 3 mL / min and a column temperature of 35°C.

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

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

[0321] Method 19 SFC purification was performed using a 6.5 min run time on a Waters Prep100 fractionlynx system in conjunction with an SQD2 mass spectrometer, with 3–40% MeOH (+0.1% NH 4The analysis was performed using a Chiralpak, 250 x 20 mm, 5 μm column with a flow rate of 100 mL / min, eluting with the (OH) method (ABPR 60 bar), column temperature 40°C.

[0322] method 20 Chiral analysis was performed using the Waters UPC in conjunction with a Waters QDa mass spectrometer. 2 Use a run time of 6.5 min on an Acquity system to prepare 3-40% MeOH (+0.1% NH 4 The analysis was performed using a Chiralpal IC150 x 4.6 mm, 3 μm column eluted with the (OH) method (ABPR 120 bar), flow rate 3 mL / min, column temperature 35°C.

[0323] Method 21 SFC purification was performed using a 7.5 min run time on a Waters Prep150 fractionlynx system in conjunction with a QDa mass spectrometer, with 3–40% MeOH (+0.1% NH 4 The analysis was performed using a Chiralpak, 250 x 20 mm, 5 μm column with a flow rate of 100 mL / min, eluting with the (OH) method (ABPR 60 bar), column temperature 40°C.

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

[0325] Method 23 SFC purification was performed using a 7.5 min run time on a Waters Prep100 fractionlynx system in conjunction with an SQD2 mass spectrometer, with 3–40% MeOH (+0.1% NH 4The analysis was performed using a Regis(R,R)-Whelk-O1, 250 x 21.1 mm, 5 μm column with a flow rate of 100 mL / min, eluting with the (OH) method (ABPR 60 bar), column temperature 40°C.

[0326] Method 24 Chiral analysis was performed using the Waters UPC in conjunction with a Waters QDa mass spectrometer. 2 Use a run time of 6.5 min on an Acquity system to prepare 3-40% MeOH (+0.1% NH 4 The analysis was performed using a Regis(R,R)-Whelk-O1, 150 x 4.6 mm, 5 μm column eluted with a 100 MPa (OH) method (ABPR 120 bar), with a flow rate of 3 mL / min and a column temperature of 35°C.

[0327] Method 25 Chiral analysis was performed in 15% methanol:85% CO 2 The analysis was performed using a Cellulose-4, 4.6×250 mm, 5 μm column with a flow rate of 4 mL / min eluting with an isocratic gradient of 0.01 μm.

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

[0329] Method 27 The analysis was performed using a Waters UPC coupled mass spectrometer. 2 The run was performed on an Acquity system using a 6.5 minute run time using a Regis(R,R)-Whelk-O1, 150 x 4.6 mm, 5 μm column eluting with a 3-40% MeOH (no additives) method (ABPR 120 bar), flow rate 3 mL / min, column temperature 35 °C.

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

[0331] Method 29 The analysis was performed using a Waters UPC coupled mass spectrometer. 2 The run was performed on an Acquity system using a run time of 6.5 min using a Chiralpak IC, 150 × 4.6 mm, 3 μm column eluting with a 3–40% MeOH (no additives) method (ABPR 120 bar), flow rate 3 mL / min, column temperature 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 in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1mL / min Gradient Program: Time A% B% 0.00 95.00 5.00 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® BEH™ 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 on a Gilson System using a Waters Sunfire C18 column (30 × 100 mm, 10 μm) at room temperature with a flow rate of 40 mL / min, uv detection @ 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, a GX-241 autosampler, a 171 / 172 detector and a preparative FC fraction collector. Column: Chiralcel OD-H, 20 x 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 Waters 2795 equipped with a Waters 2998 PDA detector. Purity and / or enantiomeric purity determined by UV (210-400 nm) and identity confirmed by MS. Column: Chiralcel OD-H, 4.6 x 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) in THF (20.7 mL) and DMPU (6.4 mL) at room temperature was added CsF (471 mg, 3.10 mmol) in one portion. The mixture was stirred for 5 min, then (trifluoromethyl)trimethylsilane (3.06 mL, 20.7 mmol) was added dropwise via syringe over 10 min. The reaction mixture was stirred at room temperature for 15 min, then diluted with EtOAc (40 mL) and water (20 mL). The layers were separated and the aqueous layer was re-extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-10% gradient) afforded the title compound (3.12 g, 80%) as a pale yellow oil. δ H (400 MHz, CDCl 3 ) 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:EtOAc, 90:10), non-UV, KMnO 4 .

[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 was added sec-butyllithium (1.3 M, 17.0 mL, 24.0 mmol) dropwise over 10 min. The mixture was stirred at -78°C for 10 min, during which time a dull yellow color developed. After this time, the reaction mixture was warmed to -40°C (replacing the dry ice / acetone bath with a dry ice / acetonitrile bath) and stirred at -40°C for 20 min. The reaction mixture was recooled to -78°C and eluted with CO 2was bubbled through the mixture for 30 min. After this time, the reaction mixture was warmed to room temperature and stirred for 1 h, then saturated NH 4 Aqueous Cl (100 mL) and H 2 The mixture was quenched by the addition of 2×O (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 (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) followed by DCM / MeOH (90:10) afforded the title compound (assumed to be a mixture of two diastereomers, 1 1 H NMR indistinguishable) (2.58 g, 52%) was obtained as a dark yellow oil. H (400 MHz, DMSO-d 6 ) 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) in THF (45 mL) at room temperature was added TBAF (1 M in THF, 6.73 mL, 6.73 mmol) dropwise over 2 min. The mixture was stirred at room temperature for 30 min, after which time TLC analysis showed the appearance of a different acid (100% EtOAc, baseline streaking, but more polar than starting material). The mixture was concentrated in vacuo, then redissolved in diethyl ether (20 mL) and diluted with H 2O (20 mL) was added. The layers were separated and the aqueous layer was re-extracted with diethyl ether (2×20 mL). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated in vacuo. To the crude material was added EtOAc (ca. 1 mL, minimal amount to solubilize) followed by isohexane (ca. 5 mL). The resulting suspension was stirred at room temperature overnight and then filtered under suction using a Büchner funnel. The precipitate was washed with isohexane and then dried under vacuum to give the title compound (assumed to be a mixture of two diastereomers, 1 H NMR indistinguishable) (1.13 g, 80%) was obtained as a beige solid. H (400 MHz, DMSO-d 6 ) 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 was added EDCI.HCl (666 mg, 3.47 mmol) in one portion. The yellow mixture was stirred for 18 h and then concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-60% gradient) afforded the title compound (assumed to be a mixture of two diastereomers, 1 H NMR indistinguishable) (861 mg, 59%) was obtained as a white solid. 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+HH 2 O] + m / z476.2, RT1.40 minutes.

[0341] Intermediate 5 5-(Dicyclopropylmethyl)imidazolidine-2,4-dione A stirred 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 h. To the cooled reaction mixture was added 2N HCl (200 mL) followed by 6N HCl (100 mL) in portions. Additional 2N HCl (60 mL) was added and the mixture was stirred at room temperature for 1 h. Additional 2N HCl (50 mL) was added to the mixture and the solid was filtered off then washed with water (2×200 mL) and dried to give the title compound (95% pure) (32.81 g, 80%) as a white solid. δ H (500 MHz, DMSO-d 6 ) 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 To a stirred solution of intermediate 5 (95%, 1.00 g, 4.89 mmol) in 1,4-dioxane (6 mL) was added 5 M aqueous sodium hydroxide (6.0 mL, 30.0 mmol). The mixture was heated at 100° C. for 18 h, then 1,4-dioxane (6 mL) and water (6 mL) were added and the mixture was heated at 120° C. for 2 days. To the cooled reaction mixture was added TBME (10 mL) and water (10 mL). The biphasic mixture was filtered. To the filtrate was added 6 N HCl (6 mL) and TBME (10 mL). The undissolved solids were filtered off. To the filtrate was added TBME (10 mL). The layers were separated and the aqueous layer was washed with TBME (3×10 mL). To the aqueous layer was added 5 N aqueous NaOH (0.5 mL) and the pH of the solution was adjusted to pH 7 using 6 N HCl / 5 M aqueous NaOH. To the aqueous solution (approximately 40 mL) was added THF (20 mL) followed by NaHCO 3 (1.01 g), then disodium carbonate (1.01 g, 9.53 mmol), 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) was added, followed by water (30 mL). The organic layer was separated. To the aqueous layer was added water (10 mL). The aqueous layer was washed with TBME (10 mL), then filtered and washed with TBME (10 mL). The pH of the aqueous layer was adjusted to pH 3 using 6N HCl (ca. 4 mL). Seeded with crystals from a previous batch, the flask was then cooled externally and left for 2 hours. The contents were filtered off, then washed with water (2×10 mL) and dried to give the title compound (719 mg, 49%) as a white solid. δ H (500 MHz, DMSO-d 6) 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 separation by preparative SFC (column: Daicel Chiralpak AD, 250 mm×50 mm, 10 μm; mobile phase: [Neu-IPA]; B%: 45%-45%, 6 min) and the fractions were concentrated in vacuo at 45° C. to give the title compounds (peak 1, 324 g, 1.07 mol, 100% purity; and peak 2, 351 g, 1.16 mol, 100% purity) as white solids. 1 H NMR and LCMS were consistent with that 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 -sulfanilidene]-2-oxopropyl}carbamate To a suspension of trimethylsulfoxonium iodide (4.57 g, 20.4 mmol) in THF (42 mL) at room temperature, potassium tert-butoxide (2.19 g, 19.1 mmol) was added in portions over a period of 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 give the ylide. Meanwhile, a separate flask was charged sequentially with 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) and stirred at room temperature for 150 minutes. The resulting activated acid mixture was added dropwise to the ylide via cannula over a period of 30 minutes, maintaining the internal temperature of the newly cloudy mixture below 0° C. After the addition, the mixture was stirred for 5 minutes, then H 2 O (15 mL) and saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (15 mL) and stirred for 1 h. The reaction mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with brine (150 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) followed by DCM / MeOH (90:10) afforded the title compound (2.13 g, 86%) as a white solid. δ H (400 MHz, DMSO-d 6 ) 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. was added LiBr (495 mg, 5.64 mmol) in one portion. After about 2 min, the LiBr was completely dissolved and methanesulfonic acid (0.37 mL, 5.70 mmol) was added dropwise over about 30 s. The mixture was stirred for 5 min, turned light yellow and cloudy, then warmed to room temperature (removal of ice / water bath) and stirred for 30 min. The resulting mixture was heated at 65° C. for 2 h and then cooled to room temperature. Saturated NaHCO 3 Aqueous solution (20 mL) was added and the reaction mixture was diluted with H 2 The mixture was further diluted with 2×O (10 mL) and then extracted with EtOAc (2×100 mL). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-20% gradient) afforded the title compound (617 mg, 29%) as a white solid. δ H (400 MHz, DMSO-d 6 ) 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]triazin-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 was added NaHCO 3 (260 mg, 3.10 mmol) was added in one portion. The mixture was stirred at 80° C. for 24 h, then cooled to room temperature and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) afforded the title compound (99% ee) (354 mg, 36%) as a brown solid. δ H (400 MHz, DMSO-d 6 ) 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-Butyl 2-{6-[(1S)-1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (syn isomer) (Intermediate 12) tert-Butyl 2-{6-[(1S)-1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (anti isomer) (Intermediate 13) In a screw-cap vial, add Intermediate 11 (356 mg, 0.94 mmol), Intermediate 4 (649 mg, 1.42 mmol), DMF (18 mL), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (22.0 mg, 0.020 mmol) and TFA (0.11 mL, 1.50 mmol) were sequentially introduced. The vial was capped and the mixture was then flushed with N 2 The mixture was purged with 500 mL of EtOAc for 5 min, then the cap was sealed with parafilm and the mixture was irradiated (450 nm) for 20 h 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 EtOAc (20 mL) and irradiated with 500 mL of H 2 The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-60% gradient) to give intermediate 13 (minor, anti-configuration, two stereoisomers) (56.0 mg, 9%) as a yellow foam along with some additional impurity material. Further purification of the additional material by flash chromatography eluting with diethyl ether / isohexane (0-80% gradient) gave intermediate 12 (syn-configuration, 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)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}ethyl]carbamate trifluoroacetate Intermediate 12 (syn-configuration, 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 h and then washed with saturated NaHCO 3 The mixture was neutralized with aqueous solution (5 mL). EtOAc (10 mL) was added and the layers were separated. The aqueous layer was re-extracted with EtOAc (2×10 mL) and the combined organic layers were then dried (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (mixture of two syn-configured stereoisomers) (236 mg, quantitative) as an orange oil which was used without further purification. LCMS (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]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}ethyl]carbamate To a solution of intermediate 14 (mixture of two syn-configured stereoisomers) (236 mg), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (51.0 mg, 0.39 mmol) and DIPEA (0.25 mL, 1.40 mmol) in DMF (5 mL) at room temperature was added HATU (169 mg, 0.43 mmol) in one portion. The mixture was stirred for 10 min and then diluted with H 2 O (10 mL) was added. The mixture was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (20 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-80% gradient) afforded the title compound (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]triazin-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl](3-fluorobicyclo[1.1.1]pentan-1-yl)methanone To a solution of intermediate 15 (mixture of two stereoisomers) (50.0 mg, 0.076 mmol) in EtOH (2.2 mL) at room temperature was added 4N HCl in 1,4-dioxane (0.02 mL, 0.08 mmol) and 10% Pd / C (10 mg) sequentially. The vessel was evacuated and washed with H 2 The mixture was purged three times with 500 mL of ethyl acetate and then left to stir at room temperature for 210 min. The mixture was evacuated and placed under an atmosphere of Ar and Na 2 CO 3 (16.1 mg, 0.152 mmol) was added. The mixture was stirred for 5 min and then filtered under suction through a pad of Celite® (10 g) with EtOH (20 mL). The filtrate was concentrated in vacuo to give the title compound (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-dioxoisoindolin-2-yl)morpholine-3,4-dicarboxylate 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 at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash column chromatography eluting with a gradient of 0-40% EtOAc in hexanes to give the title compound (812 mg, 99%) as an off-white solid. δ H(400 MHz, DMSO-d 6 ) 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]triazin-6-yl)methyl]carbamate Benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (300 mg, 0.74 mmol), 1,2,4-triazin-3-amine (70.0 mg, 0.74 mmol) and NaHCO 3 A mixture of (75.0 mg, 0.89 mmol) in IPA (5 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated and the residue was purified twice by flash column chromatography eluting with a gradient of 0-60% EtOAc in hexanes to give the title compound (111 mg, 36%) as a brown solid. LCMS (Method 1): [M+H] + m / z402.2, RT1.27 minutes.

[0353] Intermediate 19 tert-Butyl 3-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}morpholine-4-carboxylate Intermediate 17 (190 mg, 0.50 mmol), Intermediate 18 (135 mg, 0.34 mmol), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6A solution of (8.0 mg, 7.1 μmol) and TFA (40.0 μL, 0.53 mmol) in DMF (7 mL) was purged with nitrogen gas for 5 min. The reaction mixture was placed under 450 nm irradiation for 3 h, then diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated. The residue was purified by flash column chromatography eluting with a gradient of 0-40% EtOAc in hexane to give the title compound (156 mg, 79%) as an off-white solid. LCMS (Method 1): [M+H] + m / z587.2, RT1.47 minutes.

[0354] Intermediate 20 (S)-(4,4-Difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazin-6-yl)methanamine To a solution of intermediate 18 (900 mg, 2.02 mmol) in AcOH (6 mL) was added hydrogen bromide in AcOH (35%, 3.3 mL, 20.2 mmol). The solution was stirred at room temperature for 2 h. Diethyl ether (50 mL) was added and the mixture was stirred at room temperature for 30 min. The resulting precipitate was collected by vacuum filtration. The sticky residue was transferred from the filter paper to a separatory funnel by washing with diethyl ether (2×50 mL) and rinsing with water. The aqueous layer was washed with DCM (50 mL) and then with saturated NaHCO 3 The resulting material was extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (50 mL) and MgSO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure to give the title compound (435 mg, 78%). H (500 MHz, CDCl 3) 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]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of 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) in anhydrous DMF (10 mL) was added HATU (720 mg, 1.89 mmol). The mixture was stirred at room temperature for 30 min, then diluted with EtOAc (25 mL) and washed with water (2×25 mL) followed by brine (10 mL). The organic layer was diluted with MgSO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (460 mg, 77%). δ H (500 MHz, CDCl 3 ) 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-Butyl 3-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)morpholine-4-carboxylate Intermediate 17 (1.34 g, 3.55 mmol), intermediate 21 (940 mg, 2.37 mmol) and {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 A solution of (53 mg, 0.047 mmol) in anhydrous DMF (45 mL) was divided equally between two 40 mL vials. To each vial was added TFA (136 μL, 1.79 mmol). The solution was purged for 10 min by bubbling nitrogen while stirring, then sealed under nitrogen with parafilm and irradiated with a blue LED lamp (40 W, Kessil A160WE LED Aquarium Light; Tuna Blue; light set at maximum intensity and greater blue setting) while stirring at approximately 21 °C (temperature maintained with fan). The vial was positioned approximately 5 cm from the nearest light. After 24 h, the solutions were combined and diluted with EtOAc (100 mL), then washed with water (2 × 100 mL), followed by brine (50 mL). The organic fraction was diluted with MgSO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (950 mg, 66%). δ H (400 MHz, CDCl 3) 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-(morpholin-3-yl)imidazo[1,2-b][1,2,4]triazin-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 min and then washed with saturated NaHCO 3 The mixture was neutralized with aqueous solution (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) and the combined organic layers were then dried (Na 2 SO 4 ) and concentrated in vacuo to give the title compound (500 mg, quantitative) as an orange oil which was used without further purification. LCMS (Method 1): [M+H] + m / z 487.2, RT 1.22 minutes.

[0358] Intermediate 24 N-{(S)-(4,4-difluorocyclohexyl)[3-(morpholin-3-yl)imidazo[1,2-b][1,2,4]triazin-6-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride To intermediate 22 (1.00 g, 1.65 mmol) was added 4N HCl in 1,4-dioxane (15 mL) and the solution was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure to give the title compound (1.04 g, 99%). δ H (400 MHz, CDCl 3 ) 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]pentane-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-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 was added HATU (408 mg, 1.04 mmol) in one portion. The mixture was stirred for 45 min and then diluted with H 2 O (30 mL) was added. The mixture was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with brine (100 mL) and then dried (Na 2 SO 4) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) afforded 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]triazin-3-yl}morpholin-4-yl)(3-fluorobicyclo[1.1.1]pentan-1-yl)methanone To a solution of intermediate 25 (444 mg, 0.74 mmol) in EtOH (22 mL) at room temperature was added 4N HCl in 1,4-dioxane (0.23 mL, 0.92 mmol) and 10% Pd / C (85 mg) sequentially. The vessel was evacuated and H 2 The mixture was purged with 3× with ethyl acetate and then left to stir at room temperature for about 5 h. The mixture was filtered through a pad of Celite® (10 g) with EtOH (60 mL) under suction. The filtrate was concentrated in vacuo to give the title compound (71% pure by LC-MS) (405 mg, quantitative), which was used without further purification. LCMS (Method 1): [M+H] + m / z 465.2, RT 1.10 min.

[0361] Intermediate 27 tert-Butyl 3-{6-[(1S)-1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]imidazo[1,2-b][1,2,4]triazin-3-yl}morpholine-4-carboxylate In a screw-cap vial, add Intermediate 11 (355 mg, 0.94 mmol), Intermediate 17 (531 mg, 1.41 mmol), DMF (18 mL), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6(21.0 mg, 0.019 mmol) and TFA (0.11 mL, 1.50 mmol) were sequentially introduced. The vial was capped and the mixture was then flushed with N 2 The mixture was purged with 500 mL of EtOAc for 5 min, then the cap was sealed with parafilm and the mixture was irradiated (450 nm) for 16 h 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 EtOAc (40 mL) and irradiated with 500 mL of H 2 The combined organic fractions were dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) afforded the title compound (mixture of two stereoisomers, 1:1 ratio) (278 mg, 52%) as an orange foam. LCMS (Method 1): [M+H] + m / z563.2, RT1.45 minutes.

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

[0363] Intermediate 29 tert-Butyl 3-(6-{(1S)-2,2-dicyclopropyl-1-[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]ethyl}imidazo[1,2-b][1,2,4]triazin-3-yl)morpholine-4-carboxylate To a solution of intermediate 28 (249 mg, 0.58 mmol), 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) at room temperature was added HATU (274 mg, 0.70 mmol) in one portion. The mixture was stirred for 30 min and then diluted with H 2 O (25 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-75% gradient) afforded the title compound (mixture of two stereoisomers, 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-(morpholin-3-yl)imidazo[1,2-b][1,2,4]triazin-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 min and then washed with saturated NaHCO 3 The mixture was neutralized with aqueous solution (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 (Na 2 SO 4) then concentrated in vacuo to give the title compound (mixture of two stereoisomers, 1:1 ratio) (206 mg, quantitative) as an orange oil which was used without further purification. LCMS (Method 1): [M+H] + m / z439.2, RT1.21 minutes.

[0365] Intermediates 31 and 32 tert-Butyl 2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (syn isomer) (Intermediate 31) tert-Butyl 2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (anti isomer) (Intermediate 32) Intermediate 4 (856 mg, 1.87 mmol), intermediate 18 (500 mg, 1.25 mmol) and {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 To a solution of (28 mg, 0.025 mmol) in anhydrous DMF (20 mL) was added TFA (143 μL, 1.87 mmol). The solution was purged by bubbling nitrogen for 10 min with stirring, then sealed under nitrogen with parafilm and irradiated at 450 nm for 50 h in a Penn M2 photoreactor (LED 100%, stirring 50%, fan 50%). The solution was diluted with EtOAc (50 mL) and washed with water (2×50 mL) followed by brine (25 mL). The organic portion was diluted with MgSO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane to give the title compounds (syn isomer, 390 mg, 44%; and anti isomer, 140 mg, 15%). LCMS (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)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]carbamate hydrochloride To intermediate 31 (syn isomer) (390 mg, 0.55 mmol) was added 4N HCl in 1,4-dioxane (5 mL) and the solution was stirred at room temperature for 30 min. The solvent was removed under reduced pressure to give the title compound (mixture of syn stereoisomers) (415 mg, 89%). δ H (400 MHz, DMSO-d 6 ) 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). Not a single exchangeable proton signal was 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]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]carbamate To a solution of 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) in DCM (5 mL) was added HATU (222 mg, 0.58 mmol). The solution was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was purified twice by column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (mixture of syn stereoisomers) (240 mg, 67%). δ H (400 MHz, DMSO-d 6 ) 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 min.

[0368] Intermediate 35 [2-{6-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidin-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) was added 10% Pd / C (55-65% wet) (5.0%, 70 mg, 0.033 mmol). The mixture was stirred under a balloon of hydrogen at room temperature for 4 h. The flask was flushed with nitrogen three times and then the mixture was filtered through Celite®, washing through with EtOH. The residue was concentrated under reduced pressure to give the title compound (mixture of syn stereoisomers) (180 mg, 90%). δ H (400 MHz, DMSO-d 6 ) 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-thiazinane-3,4-dicarboxylate To a suspension of 4-tert-butoxycarbonyl-1,1-dioxo-1,4-thiazinane-3-carboxylic acid (1.25 g, 4.48 mmol) in DCM (30 mL) at room temperature, 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 portions. The resulting white suspension was stirred and slowly a yellow solution formed which was stirred for 18 h and then concentrated in vacuo. The resulting yellow syrup was partitioned between EtOAc (200 mL) and brine (300 mL). The aqueous phase was extracted with further EtOAc (2 x 200 mL). The combined organic extracts were washed with brine and then washed with anhydrous NaCl. 2 SO 4The mixture was dried at 40° C. and filtered. The volatiles were removed in vacuo. The resulting foamy pale solid was purified by column chromatography on silica eluting with a gradient of 0-80% EtOAc in hexanes to give the title compound (1.62 g, 85%) as a white solid. δ H (400 MHz, DMSO-d 6 ) 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 h, 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°(c1.00, DCM). δ H (300 MHz, CDCl 3 ) 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, CDCl 3 ) 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 h. Saturated aqueous sodium bicarbonate (150 mL) was added and the mixture was stirred for 1 h. The biphasic mixture was separated and the organic layer was concentrated in vacuo. The resulting pale yellow oil was purified by flash column chromatography (0-100% EtOAc / isohexane) and then recrystallized from EtOAc:isohexane (1:2; 90 mL) to give the title compound (single diastereoisomer) (7.20 g, 35%) as a white solid. δ H (400 MHz, CDCl 3 ) 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, CDCl 3 ) 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 in 1,4-dioxane (4N, 12 mL), resulting in a white precipitate. After 4 h, the mixture was concentrated under reduced pressure. To the resulting oily slurry was added isohexane (100 mL). After vigorous stirring, the resulting white solid was filtered off to give the title compound (5.20 g, 95%). δ H (300 MHz, DMSO-d 6) 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 H 2 HCl in O (33%, 50 mL) was added to intermediate 39 (5.20 g, 21.0 mmol). The mixture was heated under reflux for 4 h and then cooled to 20° C. with stirring. After 18 h, the white precipitate was filtered off and dried under airflow to give the title compound (4.40 g, 74%) as a white solid. [α] 25 D +22.1°(c1.0, MeOH). δ H (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -72.33 (s, 3F).

[0374] Intermediate 41 (2S)-2-(Benzyloxycarbonylamino)-2-[4-(trifluoromethyl)cyclohexyl]acetic acid 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. was added N-(benzyloxycarbonyloxy)succinimide (4.47 g, 17.6 mmol) in three portions. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with DCM (10 mL) and washed with 5% hydrochloric acid (2×15 mL) and water (15 mL), then dried (Na 2 SO 4), and concentrated in vacuo to give the title compound (6.34 g, 92%) as a white solid. H (300 MHz, DMSO-d 6 ) 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 -Sulfanilidene]-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 in THF (300 mL, 0.300 mol) was added. The resulting mixture was stirred under nitrogen at 70° C. (external temperature) for 2 h and then cooled to −5° C. under nitrogen in an ice / salt bath to give 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) was added followed by DIPEA (24 mL, 0.137 mol). The reaction mixture was stirred under nitrogen for 150 min and then added dropwise to the cooled solution of ylide over approximately 50 min, maintaining the internal temperature below 1° C. The reaction mixture was stirred under nitrogen at -4°C for 5 min, then water (700 mL) and saturated NaHCO 3The mixture was quenched at -4°C by the addition of 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). Three additional crops were obtained as more solid precipitated from solution in the filtrate each time. The four crops of solid were combined and then water (400 mL) was added. The mixture was sonicated to break up large clumps, then cooled to 0°C, filtered, and washed with water (150 mL). The residue was dried in a vacuum oven overnight to give the title compound (36.15 g, 81%) as a colorless solid. δ H (400 MHz, DMSO-d 6 ) 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 min.

[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 min). Methanesulfonic acid (4.2 mL, 64.7 mmol) was added and the mixture was stirred at 0° C. under nitrogen for 5 min, then warmed to room temperature and stirred under nitrogen for 30 min. The resulting suspension was warmed to 58° C. (internal temperature; 65° C. heating block) over approximately 30 min and stirred at this temperature for 1 h under nitrogen. The reaction mixture was cooled to room temperature and washed with saturated NaHCO 3 The mixture was quenched by the addition of aqueous solution (450 mL). The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (600 mL). The organic layer was washed with saturated aqueous NaBr solution (400 mL) and then dried (Na 2 SO 4 ) and concentrated to dryness under vacuum. The residue was purified by FCC (750 g Biotage KP-Sil cartridge, wet loaded into 150 mL DCM, eluted with 10-20% EtOAc in heptane) and the product fractions were concentrated to dryness under vacuum to give the title compound (19.80 g, 68%) as a colorless solid. The mixed fractions were isolated, concentrated to dryness under vacuum, then re-purified by FCC (100 g Biotage Sfar Duo cartridge, wet loaded into 20 mL DCM, eluted with 10-20% EtOAc in heptane) and the product fractions were concentrated to dryness under vacuum to give a second crop of the title compound (4.90 g, 17%) as a colorless solid. δ H (500 MHz, CDCl 3 ) 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]triazin-6-yl)[4-(trifluoromethyl)cyclohexyl]methyl}carbamate To a suspension of intermediate 43 (5.09 g, 11.67 mmol) in EtOH (75 mL) at ambient temperature was added 3-amino-1,2,4-triazine (recrystallized from acetonitrile) (2.3 g, 23.22 mmol). The resulting suspension was heated to 80° C., whereupon the suspension became a red solution. After 1 h, the reaction mixture was cooled and washed with saturated NaHCO 3 Poured into a mixture of aqueous solution (300 mL) and EtOAc (200 mL). The organic phase was separated. The aqueous phase was diluted with brine (200 mL) and extracted with additional EtOAc (2×200 mL). The combined organic extracts were washed twice with brine and then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and filtered. The volatiles were removed in vacuo. The resulting brown solid was purified by column chromatography on silica eluting with a gradient of EtOAc (0-80%) in hexanes to afford the title compound (1.8 g, 36%) as a red-brown crystalline solid. δ H (400 MHz, DMSO-d 6 ) 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-Butyl 3-(6-{(S)-benzyloxycarbonylamino[4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-1,1-dioxo-1,4-thiazinane-4-carboxylate Intermediate 44 (517 mg, 1.19 mmol), intermediate 36 (777 mg, 1.83 mmol) and {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 To a solution of (35 mg, 0.031 mmol) in anhydrous DMF (12 mL) was added TFA (140 μL, 1.85 mmol) dropwise. The mixture was purged with nitrogen for 5 min and then placed in a photoreactor and irradiated at 450 nm for 20 h at ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and saturated NaHCO 3 The organic phase was separated and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (2×100 mL) and then with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and filtered. The solvent was removed in vacuo. The resulting brown residue was purified by column chromatography on silica (gradient elution 0-80% EtOAc in hexanes) to afford the title compound (402 mg, 51%) as a pale orange solid. δ H (400 MHz, DMSO-d 6) 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-thiazin-3-yl)imidazo[1,2-b][1,2,4]triazin-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 was added TFA (2 mL) slowly. The golden yellow solution was stirred at ambient temperature for 18 h. The volatiles were removed in vacuo and the residue was azeotroped with toluene (2×30 mL). The residue was dissolved in DCM (30 mL) and saturated NaHCO 3 The aqueous phase was extracted with DCM (20 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 After drying at 40° C. and filtration, the solvent was removed in vacuo to give the title compound (450 mg, quantitative) as a golden yellow 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]triazin-3-yl)-1,1-dioxo-1,4-thiazin-4-yl](3-fluorobicyclo[1.1.1]pentan-1-yl)methanone To Example 12 (120 mg, 0.177 mmol) was added HBr (33% solution in AcOH) (5 mL, 30.38 mmol). The resulting yellow suspension was sonicated briefly to ensure solution and the reaction mixture was stirred at ambient temperature. After 10 min, diethyl ether (20 mL) was added. The mixture was stirred at ambient temperature for 5 min, then the solid was collected on a frit, washed with additional diethyl ether and dried under vacuum. The solid was dissolved in MeOH (10 mL) and loaded onto a 2 g SCX column eluting with MeOH (30 mL) followed by 7N ammonia in MeOH (30 mL). The yellow methanolic ammonia portion was concentrated in vacuo to give the title compound (59 mg, 52%) as a yellow film. LCMS (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-difluorocyclohexanecarboxylate (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 min. The reaction mixture was stirred for an additional 30 min, and then acetic anhydride (8.1 mL, 85.8 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 3 h. To the reaction mixture was added water (200 mL) and hexane (200 mL). The organic layer was separated and the aqueous layer was extracted with hexane (2 x 100 mL). The combined organic extracts were washed with Na 2 SO 4 The crude material was purified by column chromatography (Biotage SFAR HC DUO, 350 g, Isolera, 0-20% EtOAc in isohexane) to give the title compound (6.37 g, 48%) as a yellow oil.H (300 MHz, CDCl 3 ) 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 To a solution of intermediate 48 (5.5 g, 23.48 mmol) in DCM (23 mL) was added bromine (2.4 mL, 46.96 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h, then diluted with DCM (200 mL) and washed with saturated Na 2 CO 3 The organic layer was washed with aqueous sodium thiosulfate (200 mL), saturated aqueous sodium thiosulfate (20 mL) and brine (200 mL). 2 SO 4 The crude material was dried at rt, then passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography (Biotage SFAR HC DUO, 250 g, Isolera, 0-20% EtOAc in isohexane) to give the title compound (7.85 g, 85%) as a colorless oil. δ H (300 MHz, CDCl 3 ) 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 To a vial containing a solution of intermediate 49 (7 g, 17.86 mmol) in THF (18 mL) was added morpholine (6.2 mL, 71.42 mmol) dropwise. The reaction mixture was stirred at 65° C. overnight. The resulting suspension was filtered through a pad of Celite®, washing with THF (100 mL). The filtrate was concentrated in vacuo to give an orange oil. To a separate vial containing aminoguanidine bicarbonate (2.48 g, 17.86 mmol) in MeOH (18 mL) was added AcOH (4.1 mL, 71.423 mmol). The suspension was stirred at room temperature for 18 h and then added to a solution of the aforementioned orange oil in MeOH (18 mL). The reaction mixture was stirred at reflux temperature for 4 h and then concentrated in vacuo. The crude residue was dissolved in EtOAc (200 mL) and washed with water (200 mL). The aqueous layer was extracted with further EtOAc (2 x 200 mL). The combined organic extracts were dried and concentrated in vacuo. The crude material was triturated with diethyl ether (3 x 50 mL) and the solid was filtered and dried in vacuo to give the title compound (1.52 g, 30%) as a colourless amorphous solid. δ H (300 MHz, DMSO-d 6 ) 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 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 NaHCO 3To a vial containing (288 mg, 3.43 mmol), IPA (10 mL) was added. The reaction mixture was stirred at 80° C. for 18 h. Additional NaHCO 3 (70 mg, 0.86 mmol) was added and heating at 80° C. was continued for 5 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (20 mL), washed with water (20 mL), and the aqueous layer was then further extracted with EtOAc (2×20 mL). The combined organic extracts were concentrated in vacuo. The crude material was purified by column chromatography (Biotage SFAR HC DUO, 25 g, Isolera, 0-40% EtOAc / Hexanes) to give the title compound (590 mg, 58%). δ H (300 MHz, CDCl 3 ) 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]triazin-3-yl}-4,4-difluorocyclohexanecarboxylic acid sodium salt To a stirred solution of intermediate 51 (200 mg, 0.34 mmol) in THF (4 mL), EtOH (4 mL) and water (2 mL) at room temperature was added aqueous NaOH (2 mol / L, 0.5 mL, 1 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo (water bath, 30° C.) to give the title compound (200 mg, quantitative) as a yellow oil, which was used immediately without further purification. LCMS (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]triazin-6-yl}methyl]carbamate To a solution containing crude intermediate 52 (200 mg, 0.34 mmol) suspended in DMF (2 mL) was added DIPEA (0.15 mL, 0.86 mmol) and 2,2-difluoropropylamine hydrochloride (50 mg, 0.36 mmol), followed by portionwise addition of HATU (155.6 mg, 0.4092 mmol). The reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc (20 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic extracts were concentrated in vacuo. The resulting yellow oil was purified by column chromatography (Biotage SFAR HC DUO, 25 g, Isolera, 0-100% EtOAc / Hexanes) to afford the title compound (impure mixture) (200 mg, 91%) as a clear oil, 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 Exhaust and N 2 To a solution containing crude intermediate 53 (200 mg, 0.31 mmol) in EtOH (3 mL) was added Pd / C (10% by weight) (20 mg, 0.019 mmol). The reaction flask was placed in H 2and stirred at room temperature for 1 h. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo to give the title compound (160 mg, quant.) as a crude brown oil, 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 methyl tetrahydro-2H-pyran-4-carboxylate (0.91 mL, 6.94 mmol) in THF (15 mL) at -75°C (internal temperature) was added 2M LDA in THF (3.9 mL, 7.86 mmol) over 10 min. After 50 min, acetic anhydride (0.98 mL, 10.4 mmol) was added to the reaction mixture over 5 min. The reaction mixture was stirred at room temperature for 75 min and then cooled to 0°C. Heptane (10 mL) and water (5 mL) were added. The biphasic 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 x 30 mL). The combined organic extracts were dried (phase separator) and concentrated in vacuo. The resulting crude yellow oil was purified by automated FCC (Isolera4, Sfar Duo 100 g, 0-100% EtOAc in heptane) to give the title compound (0.85 g, 59%) as a yellow oil. H (500 MHz, CDCl 3 ) 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 To a stirred solution of intermediate 55 (0.84 g, 4.06 mmol) in DCM (6 mL) at room temperature was added bromine (0.52 mL, 10.1 mmol). After 6 h, the mixture was diluted with DCM (30 mL) and saturated NaHCO 3The aqueous phase was re-extracted with DCM (30 mL) and the combined organic extracts were washed with saturated Na 2 S 2 O 3 The organic phase was dried (phase separator) and then concentrated in vacuo to give the title compound (1.46 g, 94%) as a yellow-orange oil. H (500 MHz, CDCl 3 ) 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(morpholin-4-yl)acetyl]tetrahydropyran-4-carboxylate To a stirred solution of intermediate 56 (1.44 g, 3.77 mmol) in THF (15 mL) at room temperature was added morpholine (1.8 mL, 15.2 mmol). The resulting solution was warmed to 55° C. over 45 min and heated at 55° C. for an additional 18 h. Additional morpholine (0.9 mL, 7.6 mmol) was added and heating was continued at 55° C. for 3 h. The reaction mixture was cooled to room temperature and stirred overnight, then the suspension was filtered, washed with THF (20 mL) and concentrated in vacuo. The oily orange residue was azeotroped with heptane (3×30 mL) and then dried in vacuo at room temperature for 3 h to give the title compound ( 1 1.59 g, 77% purity by H NMR (approximately 65%) was obtained as an orange oil which was used without further purification. H (500 MHz, CDCl 3 ) 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-triazin-5-yl)tetrahydropyran-4-carboxylate A round bottom flask was charged with 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). The mixture was stirred at room temperature for 30 min, then heated at 65° C. for 24 h, then cooled to room temperature and left at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in EtOAc (50 mL), H 2 O (50 mL) and saturated Na 2 CO 3 The mixture was diluted with aqueous solution (10 mL) and the phases were then separated. The aqueous phase was re-extracted with EtOAc (2×50 mL). The combined organic extracts were dried (phase separator) and concentrated in vacuo. The residue was purified using automated chromatography (Isolera4, Sfar Duo 50 g, 0-10% MeOH in DCM as eluent) to give the title compound ( 1 65% pure by H NMR (650 mg, 63%) as a yellow-orange solid which was used without further purification. H (400 MHz, DMSO-d 6 ) 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]triazin-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 NaHCO 3A suspension of (0.29 g, 3.48 mmol) in IPA (8.38 mL) was placed under nitrogen and heated at 65° C. for 18 h. After cooling, the mixture was diluted with water (50 mL) and saturated NaHCO 3 It was diluted with aqueous solution (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (50 mL). The phases were separated and the organic phase was then dried (hydrophobic frit) and concentrated in vacuo. The crude residue was purified by automated FCC (Isolera4, Sfar Duo 100 g, 0-100% EtOAc in heptane) to give the title compound (0.64 g, 57%) as a red-brown oil which was used without further purification. δ H (400 MHz, DMSO-d 6 ) 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]triazin-6-yl}methyl]carbamate To a solution of intermediate 59 (200 mg, 0.353 mmol) in DCM (3 mL) at 20° C. was added a 3M solution of NaOH in MeOH (118 μL, 0.353 mmol). The reaction mixture was stirred at room temperature for 30 min, then an additional 3M solution of NaOH in MeOH (118 μL, 0.353 mmol) was added. The reaction mixture was stirred at room temperature for another 25 min. This procedure was repeated three more times, then the reaction mixture was concentrated to dryness under a stream of nitrogen. The resulting carboxylate sodium salt (195 mg) was taken up in DCM (3.8 mL), then 2,2-difluoropropan-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 h, then DMF (3.8 mL) and additional 2,2-difluoropropan-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 rapid succession. The reaction mixture was stirred at room temperature for 10 min, then EtOAc (10 mL), saturated NaHCO 3 The mixture was diluted with aqueous solution (5 mL) and water (5 mL). The biphasic mixture was stirred at room temperature for 20 min. The layers were separated and then the organic phase was dried (hydrophobic frit) and concentrated in vacuo. The crude residue was purified by automated FCC (Isolera4, Sfar Duo 50 g, 0-100% EtOAc in heptane) to give a mixture of the title compound (47%) and an inseparable impurity identified as benzyl N-{(S)-(4,4-difluorocyclohexyl)[3-(tetrahydropyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl]methyl}carbamate (53%) (117 mg, 34%) as a yellow oil 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]triazin-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) was added 10% Pd / C (50% wet) (5.0%, 35 mg, 0.016 mmol) in one portion. The reaction mixture was stirred under hydrogen (3 cycles of vacuum / nitrogen gas, followed by 3 cycles of vacuum / hydrogen gas) for 3 h. The reaction mixture was filtered through Celite®, washing through with additional MeOH. The combined filtrates were concentrated in vacuo and then purified using automated chromatography (Isolera4, Sfar KP Amino D, 11 g, 0-10% MeOH in DCM) to give the title compound (89.0% pure) (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)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]carbamate To a solution of intermediate 33 (a 1:1 ratio 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) in DMF (15 mL) at room temperature was added HATU (242 mg, 0.62 mmol) in one portion. The mixture was stirred for 10 min and then diluted with H 2 O (20 mL) was added. The mixture was extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) afforded the title compound (1:1 ratio mixture of two syn stereoisomers, indistinguishable by LCMS) (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]triazin-3-yl}-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl][(2S)-5,5-difluorotetrahydropyran-2-yl]methanone To a solution of intermediate 62 (a 1:1 ratio mixture of two syn stereoisomers) (246 mg, 0.34 mmol) in EtOH (10 mL) at room temperature was added 10% Pd / C (25 mg). The vessel was evacuated and H 2 The mixture was purged three times with hexanes and then stirred at room temperature for approximately 255 min. The mixture was filtered through a pad of Celite® (10 g) under suction, washing through with EtOH (60 mL). The filtrate was concentrated in vacuo. Purification by flash chromatography (KP-NH column) eluting with EtOAc / isohexane (0-100% gradient) followed by DCM:MeOH (90:10) afforded the title compound (1:1 ratio mixture of two stereoisomers, indistinguishable by LCMS) (85% pure) (162 mg, 69%) as a yellow foam. LCMS (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) in THF (20.7 mL) and DMPU (6.4 mL) at room temperature was added CsF (471 mg, 3.10 mmol) in one portion. The mixture was stirred for 5 min, then (difluoromethyl)trimethylsilane (2.82 mL, 20.7 mmol) was added dropwise via syringe over 2 min. The reaction mixture was stirred at 70° C. overnight, then diluted with EtOAc (20 mL) and H 2 The mixture was diluted with 20 mL of EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-10% gradient) afforded the title compound (2.32 g, 69%) as a white solid. f 0.50 (isohexane:EtOAc, 90:10), non-UV, KMnO 4 . δ H (400 MHz, CDCl 3 ) 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 was added sec-butyllithium (1.3 M in cyclohexane, 12.0 mL, 17.0 mmol) dropwise over 10 min. The mixture was stirred at -78°C for 10 min, during which time a bright orange color developed. After this time the reaction mixture was warmed to -40°C (replacing the dry ice / acetone bath with a dry ice / acetonitrile bath) and stirred at -40°C for 20 min. The reaction mixture was recooled to -78°C and eluted with CO. 2 was bubbled through the mixture for 30 min. After this time, the reaction mixture was warmed to room temperature and stirred for 1 h, then saturated NH 4 Aqueous Cl (30 mL) and H 2 The mixture was quenched by the addition of 2×O (5 mL) (to solubilize the resulting precipitate). The layers were separated and the aqueous layer was then washed with diethyl ether (2×20 mL) and EtOAc (2×20 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) followed by DCM:MeOH (90:10) afforded the title compound (a mixture of two diastereomers, 1 H NMR indistinguishable) (1.97 g, 59%) was obtained as a dark yellow oil. H (400 MHz, CDCl 3 ) 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 signals of carboxylic acids were 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) in THF (50 mL) at room temperature was added TBAF (1 M in THF, 8.04 mL, 8.04 mmol) dropwise over 2 min. The mixture was stirred at room temperature for 30 min, then concentrated to dryness and extracted with SiO 2 Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) followed by DCM:MeOH (90:10) afforded the title compound (a mixture of two diastereomers, 1 H NMR indistinguishable) (1.54 g, 97%) was obtained as a beige foam. H (400 MHz, 373K, DMSO-d 6 ) 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 was added EDCI.HCl (571 mg, 2.98 mmol) in one portion. The yellow mixture was stirred for 18 h and then concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-60% gradient) afforded the title compound (a mixture of two diastereomers, LCMS or1 H NMR indistinguishable) (566 mg, 47%) was obtained as a white foam. H (400 MHz, DMSO-d 6 ) 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, 5.7 Hz, 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-Butyl 2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (syn isomer) (Intermediate 68) tert-Butyl 2-{6-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b][1,2,4]triazin-3-yl}-4-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (anti isomer) (Intermediate 69) In a screw-cap vial, add intermediate 18 (345 mg, 0.86 mmol), intermediate 67 (568 mg, 1.29 mmol), DMF (17 mL), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (20.0 mg, 0.018 mmol) and TFA (0.10 mL, 1.30 mmol) were sequentially introduced. The vial was capped and the mixture was then flushed with N2 The mixture was purged with 500 mL of EtOAc for 5 min, then the cap was sealed with parafilm and the mixture was irradiated (450 nm) for 20 h 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 EtOAc (20 mL) and irradiated with 500 mL of H 2 The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-70% gradient) to give intermediate 68 (syn-configuration, major) (1:1 ratio of two stereoisomers, LCMS or 1 H NMR (indistinguishable) (192 mg, 34%) and intermediate 69 (anti-configuration, minor) (two stereoisomers in a 1:1 ratio, LCMS or 1 H NMR indistinguishable) (56.0 mg, 10%) was obtained as a yellow foam. LCMS (Method 1): [M+H] + m / z 651.2, RT 1.46 min (minor anti diastereomer), RT 1.50 min (major syn diastereomer).

[0402] Intermediate 70 Benzyl N-[(S)-(4,4-difluorocyclohexyl){3-[4-(difluoromethyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]carbamate hydrochloride (syn isomer) To intermediate 68 (a 1:1 ratio mixture of two syn stereoisomers) (192 mg, 0.30 mmol) was added dropwise 4N HCl in 1,4-dioxane (2.70 mL, 11.0 mmol). The mixture was stirred at room temperature for 30 minutes and then washed with saturated NaHCO 3 The mixture was carefully neutralized with aqueous EtOAc (20 mL). EtOAc (20 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na 2 SO 4), then concentrated in vacuo to give the title compound (a 1:1 ratio mixture of two syn stereoisomers, LCMS or 1 H NMR indistinguishable) (169 mg, 98%) was obtained as a yellow foam which was used without further purification. LCMS (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-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]carbamate (syn isomer) To a solution of intermediate 70 (a 1:1 ratio 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) in DMF (10 mL) at room temperature was added HATU (136 mg, 0.35 mmol) in one portion. The mixture was stirred for 45 min and then diluted with H 2 O (20 mL) was added. The mixture was extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) afforded the title compound (1:1 ratio mixture of two syn stereoisomers, indistinguishable by LCMS) (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]triazin-3-yl}-4-(difluoromethyl)-4-hydroxypiperidin-1-yl][(2S)-5,5-difluorotetrahydropyran-2-yl]methanone (syn isomer) To a solution of intermediate 71 (a 1:1 ratio mixture of two syn stereoisomers) (177 mg, 0.25 mmol) in EtOH (10 mL) at room temperature was added 10% Pd / C (17 mg). The vessel was evacuated and H 2 The mixture was purged three times with hexanes and then stirred at room temperature for approximately 90 min. The mixture was filtered through a pad of Celite® (10 g) under suction, washing through with EtOH (60 mL). The filtrate was concentrated in vacuo. Purification by flash chromatography (KP-NH column) eluting with EtOAc / isohexane (0-100% gradient) followed by DCM:MeOH (90:10) afforded the title compound (1:1 ratio mixture of two stereoisomers, indistinguishable by LCMS) (124 mg, 88%) as a yellow foam. LCMS (Method 1): [M+H] + m / z565.2, RT1.14 minutes.

[0405] Intermediate 73 tert-Butyl 3-(6-{(S)-benzyloxycarbonylamino[4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)morpholine-4-carboxylate In a screw-cap vial, add intermediate 44 (99% ee) (400 mg, 0.92 mmol), intermediate 17 (521 mg, 1.38 mmol), DMF (18 mL), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (21.0 mg, 0.019 mmol) and TFA (0.11 mL, 1.50 mmol) were sequentially introduced. The vial was capped and the mixture was then flushed with N 2The mixture was purged with 500 mL of EtOAc for 5 min, then the cap was sealed with parafilm and the mixture was irradiated (450 nm) for 48 h using a Hepatochem "PhotoRedOx Box" photoreactor (US Pat. No. 10,906,022). The mixture was then transferred to an "All-in-One Photoreactor" (ACS Cent. Sci., 2017, 3, 647-653) (settings: fan = 1612 rpm; stirring = 392 rpm; LED = 100%) and irradiated for an additional 5 h. The mixture was diluted with EtOAc (40 mL) and irradiated with H 2 The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) to give the title compound (a 1:1 ratio mixture of two stereoisomers, LCMS or 1 H NMR indistinguishable) (400 mg, 70%) was obtained as an orange foam. LCMS (Method 1): [M+H] + m / z619.2, RT1.48 minutes.

[0406] Intermediate 74 tert-Butyl 3-(6-{(S)-amino[4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)morpholine-4-carboxylate To a solution of intermediate 73 (1:1 ratio of two stereoisomers) (400 mg, 0.65 mmol) in EtOH (22 mL) at room temperature was added 4N HCl in 1,4-dioxane (0.20 mL, 0.80 mmol) and 10% Pd / C (40 mg) sequentially. The vessel was evacuated and washed with H. 2 The mixture was purged three times with hexanes and then stirred at room temperature for approximately 330 minutes. The mixture was filtered through a pad of Celite® (10 g) under suction, washing through with EtOH (60 mL). The filtrate was concentrated in vacuo. Purification by flash chromatography (KP-NH column) eluting with EtOAc / isohexane (0-100% gradient) followed by DCM:MeOH (90:10) gave the title compound (1:1 ratio mixture of two stereoisomers, LCMS or1 H NMR indistinguishable (85% purity) (240 mg, 65%) was obtained as an orange foam. LCMS (Method 1): [M+H] + m / z 485.2, RT 1.31 minutes.

[0407] Intermediate 75 tert-Butyl 3-(6-{(S)-[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino][4-(trifluoromethyl)cyclohexyl]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)morpholine-4-carboxylate To a solution of intermediate 74 (1:1 ratio of two stereoisomers) (85% purity) (240 mg, 0.50 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (64.0 mg, 0.50 mmol) and DIPEA (0.34 mL, 2.00 mmol) in DMF (10 mL) at room temperature was added HATU (233 mg, 0.59 mmol) in one portion. The mixture was stirred for 50 min and then H 2 O (25 mL) was added. The mixture was extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-75% gradient) afforded the title compound (a 1:1 ratio mixture of two stereoisomers, LCMS or 1 H NMR indistinguishable) (159 mg, 54%) was obtained as an orange solid. LCMS (Method 1): [M+H] + m / z595.2, RT1.50 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 (1:1 ratio of two stereoisomers) (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 min and then washed with saturated NaHCO 3 The mixture was neutralized with aqueous solution (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 (Na 2 SO 4 ) and then concentrated in vacuo to give the title compound (a 1:1 ratio mixture of two stereoisomers, LCMS or 1 H NMR indistinguishable) (187 mg, quantitative) was obtained as an orange foam which was used without further purification. LCMS (Method 1): [M+H] + m / z495.2, RT1.25 minutes.

[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)-(-)-pantolactone (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 at room temperature overnight, then diluted with DCM and water and passed through a phase separator. The organic phase was diluted with Na 2 SO 4 It was dried at rt and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 0-5% EtOAc / DCM afforded the title compounds (peak 1, 3.34 g, 42%; peak 2, 2.91 g, 36%). 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-d 6 ) 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 h and then cooled to room temperature. The mixture was adjusted to pH 2 with concentrated HCl and then extracted three times with EtOAc. The combined organic phase was washed with saturated NaHCO 3 After washing twice with aqueous solution, the resulting aqueous layer was adjusted to pH 2 with concentrated HCl. Three extractions with EtOAc and concentration of the organic phase in vacuo afforded the title compound (1.10 g, 63%). H (400 MHz, DMSO-d 6 ) 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-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (syn isomer) (Intermediate 80) tert-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-(difluoromethyl)-4-hydroxypiperidine-1-carboxylate (anti isomer) (Intermediate 81) In a screw-cap vial, add intermediate 21 (500 mg, 1.33 mmol), intermediate 67 (875 mg, 1.99 mmol), DMF (10.5 mL), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (30 mg, 0.026 mmol) and TFA (0.12 mL, 1.9 mmol) were sequentially introduced. The vial was capped and the mixture was then flushed with N 2 The mixture was purged at 400 rpm for 5 min, then the cap was sealed with parafilm and the mixture was irradiated (450 nm) for 20 h 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 DCM (20 mL) and water (20 mL) then washed with brine (2 × 10 mL). The combined organic layers were phase separated through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) afforded intermediate 80 (major syn isomer, 370 mg, 45%) and intermediate 81 (minor anti isomer, 102 mg, 12%) as yellow foams. 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-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (syn isomer) To intermediate 80 (a 1:1 ratio mixture of two syn stereoisomers) (337 mg, 0.54 mmol) was added dropwise 4N HCl in 1,4-dioxane (4.90 mL, 20.0 mmol). The mixture was stirred at room temperature for 25 minutes and then washed with saturated NaHCO 3 The mixture was carefully neutralized with aqueous EtOAc (30 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried (Na 2 SO 4 ), then concentrated in vacuo to give the title compound (a 1:1 ratio mixture of two syn stereoisomers, LCMS or 1 H NMR indistinguishable) (303 mg, quantitative) was obtained as a yellow foam. LCMS (Method 1): [M+H] + m / z527.2, RT1.17 minutes.

[0413] Intermediate 83 N-[(S)-(4,4-Difluorocyclohexyl){3-[4-(difluoromethyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (anti isomer) To intermediate 81 (a 1:1 ratio mixture of the two anti stereoisomers) (104 mg, 0.17 mmol) was added dropwise 4N HCl in 1,4-dioxane (1.51 mL, 6.04 mmol). The mixture was stirred at room temperature for 70 minutes and then washed with saturated NaHCO 3The mixture was carefully neutralized with aqueous EtOAc (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na 2 SO 4 ) and then concentrated in vacuo to give the title compound (a 1:1 ratio mixture of the two anti stereoisomers, LCMS or 1 H NMR indistinguishable) (93.4 mg, quantitative) was obtained as a yellow foam. LCMS (Method 1): [M+H] + m / z527.2, RT1.19 minutes.

[0414] Intermediates 84 and 85 tert-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (syn isomer) (Intermediate 84) tert-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (anti isomer) (Intermediate 85) In a screw-cap vial, add Intermediate 21 (210 mg, 0.56 mmol), Intermediate 4 (383 mg, 0.84 mmol), DMF (10.5 mL), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (13.0 mg, 0.012 mmol) and TFA (0.06 mL, 0.80 mmol) were sequentially introduced. The vial was capped and the mixture was then flushed with N 2The mixture was purged with 500 mL of EtOAc for 5 min, then the cap was sealed with parafilm and the mixture was irradiated (450 nm) for 40 h 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 EtOAc (20 mL) and irradiated with 500 mL of H 2 The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-80% gradient) afforded intermediate 84 (major syn isomer, 250 mg, 70%) and intermediate 85 (minor anti isomer, 43.0 mg, 12%) as a yellow foam. 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)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (anti isomer) To intermediate 85 (a 1:1 ratio mixture of the two anti stereoisomers) (43.0 mg, 0.07 mmol) was added dropwise 4N HCl in 1,4-dioxane (0.61 mL, 2.40 mmol). The mixture was stirred at room temperature for 2 hours and then washed with saturated NaHCO 3 The mixture was carefully neutralized with aqueous EtOAc (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na 2 SO 4 ) and then concentrated in vacuo to give the title compound (a 1:1 ratio mixture of the two anti stereoisomers, LCMS or 1H NMR indistinguishable) (38.8 mg, quantitative) was obtained as a yellow foam. LCMS (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 was added dropwise a 3M solution of methylmagnesium chloride in THF (21 mL, 63 mmol). The mixture was stirred at room temperature overnight, then water was carefully added until no more gas was evolved. An equal volume of EtOAc was added with vigorous stirring. The layers were separated and the aqueous layer was washed with EtOAc. The mixture was adjusted to pH 3 with concentrated HCl, then extracted twice with EtOAc. The combined organic phase was washed with brine and then with Na 2 SO 4 and concentrated in vacuo to give the title compound (3.68 g, 68%). H (400 MHz, 373K, DMSO-d 6 ) 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 OH proton signal was observed.

[0417] Intermediates 88 and 89 tert-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-hydroxy-4-methylpiperidine-1-carboxylate (syn isomer) (Intermediate 88) tert-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-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(CF 3 )ppy] 2 (dtbpy)}PF 6 (15 mg, 0.013 mmol) was dissolved in DMF (25 mL). The solution was purged with nitrogen for 10 min and then irradiated in a Penn Photoreactor M2 system for 3 h (450 nm wavelength; fan = 3000 rpm; stirring = 500 rpm; LED = 100%). The same procedure was carried out three times in batches and the resulting reaction mixtures were combined. The combined mixture was partitioned between EtOAc and brine and the layers were separated. The aqueous phase was extracted with EtOAc and then the combined organic phase was washed with brine and Na 2 SO 4 The mixture was dried at rt and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 20-60% EtOAc / DCM afforded intermediate 88 (syn isomer) (550 mg, 25%) and intermediate 89 (anti isomer) (255 mg, 11%). Intermediate 88 (syn isomer): δ H (400 MHz, DMSO-d 6) 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-d 6 ) 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-methylpiperidin-2-yl)imidazo[1,2-b][1,2,4]triazin-6-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride (syn isomer) Intermediate 88 (665 mg, 1.126 mmol) was dissolved in 4N HCl in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for 1 h and then washed with saturated NaHCO 3 The mixture was neutralized with aqueous solution and diluted with EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc. The combined organic phase was washed with Na 2 SO 4 and concentrated in vacuo to give the title compounds (pair of syn stereoisomers, assumed to be in a 1:1 ratio) (504 mg, 91%). LCMS (Method 1): [M+H] + m / z 491.2, RT 1.09 minutes.

[0419] Intermediate 91 N-{(S)-(4,4-difluorocyclohexyl)[3-(4-hydroxy-4-methylpiperidin-2-yl)imidazo[1,2-b][1,2,4]triazin-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 in 1,4-dioxane (4.5 mL). The mixture was stirred at room temperature for 1 h and then washed with saturated NaHCO 3 The mixture was neutralized with aqueous solution and diluted with EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc. The combined organic phase was washed with Na 2 SO 4 After drying at rt and concentrating in vacuo, the title compounds (anti stereoisomer pair, assumed to be in a 1:1 ratio) were obtained (224 mg, 99%). LCMS (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-water bath was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (5.20 mL, 22.6 mmol). The solution was stirred with cooling for 1 h and then the bath was removed. The solution was allowed to reach room temperature and then stirred for a total of 6 h. DCM (100 mL) and half-saturated Na 2 CO 3 aqueous solution (100 mL) was added. The layers were separated and the organic layer was washed with additional half-saturated Na 2 CO 3 Water (50 mL), then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (5.41 g, 76%). δ H (400 MHz, CDCl 3 ) 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) at −78° C. under nitrogen was added TMEDA (4.6 mL, 30.9 mmol) followed by the dropwise addition of 1.3 M sec-butyllithium in hexanes (24 mL, 30.9 mmol) over 10 min. The mixture was stirred at −78° C. for 2.5 h and then cooled to −78° C. with solid CO. 2(5 medium sized pellets, approximately 10 g) was added. The mixture was stirred at -78 °C for 10 min and then warmed to room temperature. Aqueous HCl (1 M, 100 mL) was carefully added. The organic layer was diluted with EtOAc (100 mL) and the layers were separated. The organic layer was washed with 1 M aqueous HCl (50 mL) and then with MgSO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting material was purified by column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (3.96 g, 57%). δ H (500 MHz, DMSO-d 6 ) 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) was added EDCI.HCl (1:1) (1.17 g, 6.13 mmol). The cloudy mixture became a clear yellow solution and was stirred at room temperature for 2 h. 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 h. The solution was washed with water (50 mL) and passed through a hydrophobic frit, washing through with DCM. The resulting material was concentrated under reduced pressure and purified by column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (1.65 g, 67%). δH (500 MHz, CDCl 3 ) 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-Butyl 4-[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]triazin-3-yl)piperidine-1-carboxylate Intermediate 94 (84%, 1.53 g, 2.54 mmol), intermediate 21 (800 mg, 2.12 mmol) and tris[2-phenylpyridinato-C 2 To a solution of [N]iridium(III) (28 mg, 42.4 μmol) in anhydrous DMSO (24 mL) was added TFA (243 μL, 3.18 mmol). The solution was purged by bubbling nitrogen through it for 10 min while stirring, then sealed under nitrogen with parafilm. The reaction mixture was irradiated in a Penn M2 photoreactor (450 nm; LED 100%; stirring 50%; fan 100%) for 4 h at room temperature. The mixture was diluted with EtOAc (50 mL) and then washed with water (2×50 mL) and brine (20 mL). The resulting material was purified by filtration with MgSO 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane to give 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 (major isomer).

[0424] Intermediate 96 tert-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-hydroxypiperidine-1-carboxylate To a solution of intermediate 95 (56%, 970 mg, 0.79 mmol) in THF (5 mL) was added 1M TBAF in THF (1.0 mL, 1.00 mmol). The solution was stirred at room temperature for 21 h. An additional 1M TBAF in THF (1 mL) was added and stirring was continued for 26 h. An additional 1M TBAF in THF (0.5 mL) was added and stirring was continued for 19 h. The reaction mixture was diluted with EtOAc (20 mL) and half-saturated NaHCO 3 The organic layer was washed with aqueous solution (2×20 mL) followed by brine (20 mL). 4 The mixture was dried at 40° C., then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (unresolved mixture of isomers) (350 mg, 73%). δ H (400 MHz, CDCl 3 ) 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-hydroxypiperidin-2-yl)imidazo[1,2-b][1,2,4]triazin-6-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide hydrochloride To intermediate 96 (94%, 350 mg, 0.57 mmol) was added 4M HCl in 1,4-dioxane (10 mL). The solution was stirred at room temperature for 4 h, then the solvent was removed under reduced pressure and the crude material was left for 16 h. The residue was dissolved in 4M HCl in 1,4-dioxane (10 mL) and stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the title compound (360 mg, 100%). LCMS (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]triazin-6-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide To a stirred solution of 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) in anhydrous DMF (130 mL) was added HATU (15.00 g, 39.4 mmol) in portions. The reaction mixture was stirred at room temperature for 16 h, then diluted with EtOAc (400 mL), washed with brine (4×200 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography (Isolera4, 350 g SFAR HC Duo column) eluting with a gradient of EtOAc (5-65%) in heptane to give the title compound (13.90 g, 93%) as an orange solid. δ H (500 MHz, DMSO-d 6) 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]triazin-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]triazin-3-yl)-4-hydroxypiperidine-1-carboxylate In a screw-cap vial, add 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(CF 3 )ppy] 2 (dtbpy)}PF 6 (25.0 mg, 0.022 mmol) and Cs 2 CO 3(544 mg, 1.67 mmol) were then introduced. The vial was capped and the mixture was then flushed with N 2 The mixture was purged with EtOAc (20 mL) for 10 min, 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 stirred vigorously for 20 h. The mixture was diluted with EtOAc (20 mL) and diluted with H 2 The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) followed by 5% MeOH / DCM afforded the title compound (a mixture of two stereoisomers in approximately 3:1 anti:syn ratio) (237 mg, 35%) as an orange oil / foam. LCMS (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-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide hydrochloride N-[(S)-(4,4-Difluorocyclohexyl){3-[(2R,4S)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-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 approximate ratio of 3:1) (237 mg, 0.39 mmol) was added dropwise 4N HCl in 1,4-dioxane (3.60 mL, 14.0 mmol). The mixture was stirred at room temperature. After 10 min, diethyl ether (25 mL) was added to induce precipitation. The mixture was stirred for 10 min and then filtered under suction. The sticky solid filter cake was washed with copious amounts of diethyl ether. The filtrate was discarded. The solid was redissolved in MeOH and concentrated in vacuo to afford the title compound (a mixture of anti:syn stereoisomers in an approximate ratio of 3:1) (235 mg, quantitative) as an orange oil, which was used without further purification. LCMS (Method 1): [M+H] + m / z504.2, RT1.09 minutes.

[0429] Intermediate 103 tert-Butyl 2-(6-{(S)-(4,4-difluorocyclohexyl)[(2-isopropyl-1,2,4-triazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-hydroxy-4-methylpiperidine-1-carboxylate Intermediate 87 (458 mg, 1.77 mmol), Intermediate 98 (353 mg, 0.804 mmol), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (18 mg, 16.1 μmol) and Cs 2 CO 3 To a mixture of (786 mg, 2.41 mmol) was added anhydrous DMF (16 mL). The mixture was degassed by bubbling nitrogen through it for 10 min with stirring and then irradiated in a Penn M2 photoreactor (450 nm, LED 100%, stirring 100%, fan 100%) for 2×3 h at room temperature. The reaction mixture was diluted with EtOAc (25 mL), washed with water (2×25 mL) and brine (25 mL) and then diluted with MgSO 4The mixture was dried over 1000 ml, filtered and concentrated under reduced pressure. The residue was taken up in DCM (10 mL) and manganese dioxide (1.40 g, 16.1 mmol) was added. The reaction mixture was stirred for 1 h. 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 EtOAc in heptane followed by reverse phase C18 column chromatography eluting with a gradient of acetonitrile in water containing 0.1% formic acid to give the title compound (mixture of syn isomers) (87 mg, 16%). δ H (500 MHz, CDCl 3 ) 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-methylpiperidin-2-yl)imidazo[1,2-b][1,2,4]triazin-6-yl]methyl}-2-isopropyl-1,2,4-triazole-3-carboxamide hydrochloride A solution of intermediate 103 (87 mg, 0.130 mmol) in 4M HCl (0.9 mL) in 1,4-dioxane was stirred for 15 min. The reaction mixture was concentrated under reduced pressure to give the title compound (71 mg, 99%). LCMS (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 To a stirred suspension 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) in DCM (20 mL) at room temperature was added DIPEA (2.0 mL, 11.7 mmol). The reaction mixture was stirred for 64 h, then diluted with DCM (50 mL) and saturated NaHCO 3 Quenched with aqueous solution (50 mL). The phases were separated and the aqueous phase was further extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (frit), then filtered and concentrated in vacuo. The resulting crude material was purified by flash column chromatography eluting with EtOAc / heptane (0-100% gradient) to give the title compound (90% pure) (0.70 g, 42%) as a yellow solid. δ H (500 MHz, DMSO-d 6 ) 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) in THF (15 mL) at room temperature was added 1 M lithium hydroxide (4.6 mL, 4.55 mmol) in one portion. The reaction mixture was stirred for 18 h. Additional 1 M lithium hydroxide (4.6 mL, 4.55 mmol) was added in one portion and the reaction mixture was stirred for 3.5 h. Additional 1 M lithium hydroxide (4.6 mL, 4.55 mmol) was added in one portion and the reaction mixture was stirred for 1 h, then acidified to pH 2 with 1N HCl and extracted with EtOAc (3x30 mL). The combined organic phase was washed with water (30 mL) and brine (30 mL) and then diluted with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give the title compound (0.60 g, 99%) as a white solid. H (500 MHz, DMSO-d 6 ) 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) at room temperature was added EDCI.HCl (0.41 g, 2.14 mmol). The resulting clear yellow solution was cooled to 5° C. for 2 h. 2 The mixture was stirred under reduced pressure for 2 h, then the solvent was concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc / heptane (0-100% gradient) to give the title compound (90% pure) (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-Butyl 4-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)piperidine-1-carboxylate Intermediate 21 (275 mg, 0.73 mmol), intermediate 107 (792 mg, 1.46 mmol) and {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 To a stirred solution of (16.5 mg, 14.7 μmol) in anhydrous DMSO (24.5 mL) was added TFA (84 mL, 1.20 mmol). The mixture was stirred under N 2 Purge by bubbling N for 10 min and then with parafilm. 2 The reaction mixture was sealed under a vacuum and irradiated for 18 h in a Penn M2 photoreactor (450 nm, LED 100%, stirring 50%, fan 100%). The reaction mixture was diluted with water (40 mL) and saturated NaHCO 3 It was quenched with aqueous solution (40 mL) and extracted with EtOAc (5×40 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL) and then washed with MgSO 4 The crude material was purified by flash column chromatography eluting with EtOAc / heptane (0-100% gradient) to give the title compound (77% pure) (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)piperidin-4-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a stirred solution of intermediate 108 (370 mg, 0.390 mmol) in DCM (15 mL) at room temperature was added TFA (3.3 mL). The solution was stirred for 2 h and then passed through a 20 g SCX-2 cartridge, washed with MeOH and purified with 7N NH 3 The latter phase was concentrated in vacuo to give the title compound (90% pure) (285 mg, quantitative) as a yellow-orange oil which solidified on standing. H (500 MHz, DMSO-d 6 ) 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) was added followed by HATU (95 mg, 0.25 mmol) 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 with DCM (25 mL) and diluted with NH 4 The mixture was washed with aqueous Cl (25 mL). The resulting material was passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by flash chromatography (hexanes / EtOAc, 1-50% gradient, 25 g silica cartridge) to give the title compound (1.7 g, 67%) as a pale yellow solid. LCMS (Method 1): [MO t Bu+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. Additional lithium hydroxide monohydrate (30 mg) in water (ca. 0.5 mL) was added, as was MeOH (1 mL) to aid dissolution. The reaction mixture was stirred for a further 5 h, then evaporated in vacuo and azeotroped with MeOH and diethyl ether to give the title compound (985 mg, quantitative) as a white solid. LCMS (Method 1): [MO t Bu+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 EDCI.HCl (720 mg, 3.68 mmol). After 18 h, additional N-hydroxyphthalimide (300 mg) and EDCI.HCl (300 mg) were added. The reaction mixture was left for a further 2 h then diluted with DCM (25 mL) and NH 4 Cl (25 mL) and brine (2×20 mL). The resulting material was passed through a hydrophobic frit and evaporated in vacuo. The residue was purified by flash chromatography on a 25 g silica column eluting with hexanes and EtOAc (1-33% gradient) to give 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-Butyl 4-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-[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), followed by {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (6 mg, 0.0053 mmol). 2was bubbled through the column and the mixture was then placed in a Merck Penn photoreactor and stirred at 450 nm for 7 h. The reaction mixture was partitioned between EtOAc (20 mL) and brine (20 mL). The organic layer was washed with brine (2×10 mL) then passed through a hydrophobic frit and concentrated in vacuo. The resulting yellow solid was purified by flash chromatography (hexanes / EtOAc, 1-100% gradient, 25 g silica column) to give 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]piperidin-4-yl}imidazo[1,2-b][1,2,4]triazin-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 h, then diluted with DCM (20 mL) and washed with water (10 mL) and 0.5 M HCl (5 mL). The combined aqueous layers were washed with saturated NaHCO 3 Basified with aqueous solution and extracted with DCM (3 x 10 mL). The organic layer was passed through a hydrophobic frit and evaporated in vacuo to give the title compound (47 mg, 92%). LCMS (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 To a solution of 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) in DMF (17 mL) was added HATU (1.62 g, 4.18 mmol). The mixture was stirred at room temperature for 10 min, then diluted with water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0-50% EtOAc in isohexane to give 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) was added a solution of lithium hydroxide monohydrate (294 mg, 6.89 mmol) in water (3.5 mL). The reaction mixture was stirred at room temperature for 72 h. A second portion of lithium hydroxide monohydrate (294 mg, 6.89 mmol) was added and the reaction mixture was stirred for 2 h, then acidified to pH 4 with 2.0 M aqueous HCl (7 mL) and diluted with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (1.12 g, 93%) as a colorless amorphous solid. LCMS (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) was added EDCI.HCl (681 mg, 3.52 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0-100% EtOAc in isohexane to give 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-Butyl 4-(6-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b][1,2,4]triazin-3-yl)-4-(2,2-difluoropropylcarbamoyl)piperidine-1-carboxylate N 2 The gas was mixed with intermediate 21 (400 mg, 1.06 mmol), intermediate 117 (1050 mg, 2.12 mmol), {Ir[dF(CF 3 )ppy] 2 (dtbpy)}PF 6 (24 mg, 0.02 mmol) and TFA (121 μL, 1.59 mmol) in DMSO (21 mL) were bubbled for 5 min. The reaction mixture was left at room temperature under 450 nm irradiation for 45 h, then saturated NaHCO 3 It was quenched with aqueous solution (100 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0-50% EtOAc in isohexane to give 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)piperidin-4-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 118 (500 mg, 0.73 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 3.5 h and then added NaHCO 3 Quenched with aqueous 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 in vacuo to give the title compound (316 mg, 74%) as a colorless amorphous solid. LCMS (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]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-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]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 16 (mixture of two stereoisomers) (40.0 mg, 0.076 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (10.0 mg, 0.078 mmol) and DIPEA (0.06 mL, 0.30 mmol) in DMF (4 mL) at room temperature was added HATU (36.0 mg, 0.092 mmol) in one portion. The mixture was stirred for 15 min and then diluted with H 2 O (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with brine (20 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-75% gradient). The resulting material (35.0 mg) was subjected to chiral purification (Method 9) to give, after lyophilization, the title compounds (peak 1, 9.0 mg, 18.7% yield, >99% de; and peak 2, 9.0 mg, 18.7% yield, 82.9% de). Peak 1: δ H( 400 MHz, DMSO-d 6 ) 9.26-9.16 (m, 1H, major and minor rotamers), 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, major rotamer), 5.61 (app.d, J 6.3 Hz, 1H, minor rotamer), 5.57-5.47 (m, 1H), 4.53-4.43 (m, 1H, minor rotamer), 4.14-4.02 (m, 1H, major rotamer), 3.82-3.69 (m, 1H, major rotamer), 3.24-3.11 (m, 1H, minor rotamer), 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-d 6 ) 9.26-9.16 (m, 1H, major and minor rotamers), 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, major rotamer), 5.61 (app.d, J 6.3 Hz, 1H, minor rotamer), 5.56-5.46 (m, 1H), 4.53-4.43 (m, 1H, minor rotamer), 4.14-4.02 (m, 1H, major rotamer), 3.81-3.68 (m, 1H, major rotamer), 3.27-3.14 (m, 1H, minor rotamer), 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]pentane-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(3S)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 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 was added HATU (349 mg, 0.89 mmol) in one portion. The mixture was stirred for 10 min and then diluted with H 2 O (25 mL) was added. The mixture was extracted with EtOAc (3×40 mL) and the combined organic extracts were washed with brine (80 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-75% gradient). The resulting material (244 mg) was subjected to chiral purification (Method 11) to give, after lyophilization, the title compounds (peak 1, 13.0 mg, 3% yield, >97.8% de; and peak 2, 13.0 mg, 3% yield, 89.3% de). Peak 1: δ H (400 MHz, 373K, DMSO-d 6 ) 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 / z 575.2, RT 1.83 min. Chiral analysis (Method 12): RT 2.51 min. Peak 2: δ H (400 MHz, 373K, DMSO-d 6) 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 / z 575.2, RT 1.88 min. Chiral analysis (Method 12): RT 2.61 min.

[0448] Examples 5 and 6 [ka] N-[(1S)-2,2-dicyclopropyl-1-(3-{(3R)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholin-3-yl}imidazo[1,2-b][1,2,4]triazin-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]morpholin-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 30 (97.4 mg, 0.18 mmol), intermediate 79 (29.0 mg, 0.17 mmol) and DIPEA (0.12 mL, 0.69 mmol) in DMF (5 mL) at room temperature was added HATU (83.0 mg, 0.21 mmol) in one portion. The mixture was stirred for 20 h and then diluted with H 2O (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient). The resulting material (91.0 mg) was subjected to chiral purification (Method 13) to give, after lyophilization, the title compounds (peak 1, 26.0 mg, 25.1% yield, 98.0% de; and peak 2, 30.0 mg, 29.0% yield, 95.5% de). Peak 1: δ H (400 MHz, 373K, DMSO-d 6 ) 8.74 (d, J 9.0 Hz, 1H), 8.70-8.57 (br s, 1H), 8.34-8.27 (m, 1H), 5.65-5.49 (m, 2H), 4.71-4.47 (m, 2H), 4.15-3.73 (m, 5H), 3.66-3.51 (m, 1H), 3.07-2.91 (obscured m, 1H), 2.64-2.45 (obscured s, 3H), 2.32-2.18 (m, 1H), 2.18-1.84 (m, 3H), 1.10 (td, J 8.9, 5.5 Hz, 1H), 0.89-0.75 (m, 2H), 0.51-0.38 (m, 2H), 0.38-0.30 (m, 2H), 0.30-0.22 (m, 2H), 0.21-0.07 (m, 2H).LCMS (Method 7): [M+H] + m / z 587.2, RT 2.10 min. Chiral analysis (Method 14): RT 4.46 min. Peak 2: δ H( 400 MHz, 373K, DMSO-d 6)8.73(d,J 8.9 Hz,1H),8.65(s,1H),8.28(s,1H),6.95(br s,3H,ammonium adduct),5.67-5.42(m,2H),4.61(dd,J 8.1,4.0 Hz,1H),4.56(app.d,J 12.5 Hz,1H),4.30-3.34(m,6H),3.09-2.89(Unclear m,1H),2.66-2.42(Unclear s,3H),2.32-2.19(m,1H),2.19-1.92(m,3H),1.09(td,J 9.0,5.5 Hz,1H),0.94-0.73(m,2H),0.52-0.39(m,2H),0.39-0.30(m,2H),0.30-0.22(m,2H),0.20-0.06(m,2H).LCMS(Method 7):[M+H] + m / z 587.4, RT 2.08 min. Chiral analysis (Method 14): RT 5.02 min.

[0449] Examples 7 and 8 [ka] N-[(S)-(4,4-difluorocyclohexyl)(3-{(3R)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholin-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(3S)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholin-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 79 (147 mg, 0.88 mmol), intermediate 24 (500 mg, 0.80 mmol) and DIPEA (420 μL, 2.41 mmol) in DCM (8 mL) was added HATU (366 mg, 0.96 mmol). The mixture was stirred at room temperature for 4 h, then additional intermediate 79 (20 mg, 0.12 mmol) was added, followed by HATU (40 mg, 0.11 mmol). The solution was stirred at room temperature for 2.5 h, then concentrated under reduced pressure. The residue was purified twice by column chromatography eluting with a gradient of EtOAc in heptane to give the first batch (single stereoisomer) (210 mg, 98% purity) as a solid and the second batch (1:1 mixture of stereoisomers) (180 mg, 94% purity) as a solid. The first batch was subjected to HPLC purification (reverse phase HPLC: 5-95% acetonitrile / water (+0.1% formic acid), X-Bridge, 100×30 mm, 5 μm @ 40 mL / min) to give one of the title compounds (diastereomer 1, 92 mg, 19%) as a white solid. The second batch was further purified by reverse phase HPLC (5-95% acetonitrile / water (+0.1% formic acid), X-Bridge, 100×30 mm, 5 μm @ 40 mL / min) to give an additional crop of material consisting of the aforementioned title compound (diastereomer 1, 38 mg, 8%) and the other title compound (diastereomer 2, 38 mg, 8%). Diastereomer 1 (arbitrarily assigned as Example 7): δ H (400 MHz, DMSO-d 6 ) 9.55-9.45 (m, 1H), 8.77-8.62 (m, 1H), 8.35-8.29 (m, 1H), 5.61-5.38 (m, 1H), 5.25-5.14 (m, 1H), 4.63-4.50 (m, 2H), 4.27-3.42 (m, 7H), 2.46 (s, 3H), 2.31-1.68 (m, 10H), 1.67-1.56 (m, 1H), 1.47-1.20 (m, 2H).LCMS (Method 2): [M+H] + 611.3, RT 3.32 min. Diastereomer 2 (arbitrarily assigned as Example 8): δ H (400 MHz, DMSO-d6 ) 9.61-9.48 (m, 1H), 8.93-8.58 (m, 1H), 8.37-8.28 (m, 1H), 5.65-5.43 (m, 1H), 5.26-5.13 (m, 1H), 4.76-4.23 (m, 2H), 4.17-3.02 (m, 7H), 2.46 (s, 3H), 2.31-1.68 (m, 10H), 1.67-1.56 (m, 1H), 1.46-1.25 (m, 2H).LCMS (Method 2): [M+H] + 611.3, RT 3.32 min.

[0450] Examples 9 and 10 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 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) was added T3P® (50 wt % in EtOAc) (176 μL, 0.30 mmol). The solution was stirred at room temperature for 16 h, then diluted with DCM (20 mL) and washed with saturated NaHCO 3The mixture was passed through a hydrophobic frit, washed through with DCM and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane. The resulting material was further purified by chiral HPLC (90:10 heptane:EtOH, Cellulose-4, 21.2×250 mm, 5 μm @ 9 mL / min) to give the title compounds (peak 1, 3.7 mg, 6%; and peak 2, 5.7 mg, 8%). Peak 1: δ H (400 MHz, DMSO-d 6 ) 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, RT 3.57 min.Chiral analysis (Method: 90:10 heptane:EtOH, Cellulose-4, 4.6 x 250 mm, 5 μm @ 0.5 mL / min): RT 20.92 min. Peak 2: δ H (400 MHz, DMSO-d 6 ) 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, RT 3.57 min.Chiral analysis (Method: 90:10 heptane:EtOH, Cellulose-4, 4.6 x 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]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-1-fluorocyclopropanecarboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-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) was added T3P® (50 wt % in EtOAc) (176 μL, 0.30 mmol). The solution was stirred at room temperature for 16 h, then diluted with DCM (20 mL) and washed with saturated Na 2 CO 3 The mixture was passed through a hydrophobic frit, washed through with DCM and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of EtOAc in heptane. The resulting material was further purified by chiral LC (Method: 90:10 heptane:EtOH, Cellulose-4, 21.2×250 mm, 5 μm @ 18 mL / min) to give the title compounds (Peak 1, 6.3 mg, 10%; and Peak 2, 12 mg, 19%) as a white solid. ピーク1:δ H (500 MHz, DMSO-d 6 ) 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, RT3.36 points.キラル analysis (method: 90:10 ヘプタン: EtOH, Cellulose-4, 4.6×250mm, 5μm@0.5mL / min): RT 20.78 minutes. ピーク2:δ H (500 MHz, DMSO-d 6 ) 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, RT3.36 points.キラル analysis (method: 90:10 ヘプタン: EtOH, Cellulose-4, 4.6×250mm, 5μm@0.5mL / min): RT 28.62 minutes.

[0452] Example 13

change

[0453] Examples 14 and 15 [ka] 1-Fluoro-N-[(S)-{3-[(3R)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-1,1-dioxo-1,4-thiazin-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]cyclopropanecarboxamide 1-Fluoro-N-[(S)-{3-[(3S)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-1,1-dioxo-1,4-thiazin-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]cyclopropanecarboxamide To a solution of intermediate 47 (59 mg, 0.108 mmol) in anhydrous DMF (2 mL) were added 1-fluorocyclopropanecarboxylic acid (35 mg, 0.333 mmol), DIPEA (75 μL, 0.431 mmol) and HATU (83 mg, 0.212 mmol) sequentially. The resulting yellow solution was stirred at ambient temperature for 18 h and then diluted with EtOAc (20 mL) and water (20 mL). The organic phase was separated and the aqueous phase was extracted with additional EtOAc (2×50 mL). The combined organic phase was washed with brine (2×100 mL) and anhydrous Na 2 SO 4 The crude residue was purified by column chromatography on silica (gradient elution, 0-80% EtOAc in hexanes) and freeze-dried from acetonitrile / water. The resulting pale yellow solid was subjected to chiral separation (Method 15) to give the title compounds (Peak 1, 17 mg, 25% yield, 82% de; and Peak 2, 15 mg, 22% yield, 85% de). Peak 1: δ H (400 MHz, DMSO-d 6) 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 rotamers in a ratio of approximately 3:2 1 Observed in H NMR spectrum. LCMS (Method 7): [M+H] + 631, RT 1.95 min. Chiral analysis (Method 16): RT 3.97 min. Peak 2: δ H (400 MHz, DMSO-d 6 ) 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 rotamers in a ratio of approximately 3:2 is 1 Observed in H NMR spectrum. LCMS (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]triazin-6-yl}methyl]-2-isopropylpyrazole-3-carboxamide To a solution 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) in DMF (2 mL) was added HATU (140 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with EtOAc (15 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3×15 mL) and the combined organic extracts were concentrated in vacuo. The crude material was purified by SFC preparative chromatography (Method 17) to give the title compound (41 mg, 21.5%) as a white solid. δ H (400 MHz, DMSO-d 6 ) 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]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide DIPEA (33 μL, 0.186 mmol) was added 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) at room temperature. The reaction mixture was stirred at room temperature for 45 min, then diluted with EtOAc (7 mL) and washed with saturated NaHCO 3 The biphasic mixture was stirred at room temperature for 20 min. The layers were separated and the aqueous phase was extracted with EtOAc (2×7 mL). The combined organic extracts were washed with MgSO 4 The residue was dried at 4° C., then filtered and concentrated in vacuo. 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) over 10 min; flow rate: 40 mL / min; UV: 215 and 254 nm) to give the title compound (19 mg, 52%) as a white solid after freeze-drying. δ H (400 MHz, DMSO-d 6) 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 min.

[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)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 63 (1:1 ratio of two stereoisomers) (85% purity) (82.0 mg, 0.14 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (18.0 mg, 0.14 mmol) and DIPEA (0.10 mL, 0.58 mmol) in DMF (5 mL) at room temperature was added HATU (67.0 mg, 0.17 mmol) in one portion. The mixture was stirred for 20 min and then H 2 O (20 mL) was added. The mixture was extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient). Further chiral purification of the resulting white foam (77.0 mg) was carried out by SFC (3-40% MeOH (+0.1% NH) using a 10 min run time on a Waters Prep150 fractionlynx system in conjunction with a Waters QDa mass spectrometer). 4 Purification was performed on a Lux Cellulose-1 250 × 21.2 mm, 5 μm column eluted with the 500 MPa (OH) method (ABPR 60 bar), flow rate 100 mL / min, column temperature 40 °C) to give, after lyophilization, the isolated title compounds (peak 1, 15.0 mg, 15.4% yield, 96.7% de; and peak 2, 14.0 mg, 14.4% yield, 95.7% de). Peak 1 ( 1 H NMR shows a 2.2:1 ratio of rotamer mixture): δ H( 400 MHz, DMSO-d 6) 9.51 (d,J 9.3 Hz,1H, minor rotamer), 9.48 (d,J 9.0 Hz,1H, main rotamer), 8.81 (s,1H, main rotamer), 8.71 (s,1H, minor rotamer), 8.28 (s,1H), 5.94-5.89 (m,1H, main rotamer), 6.11-5.81 (v br s,1H), 5.65-5.60 (m,1H, minor rotamer), 5.20 (unclear t,J 8.8 Hz,1H, minor rotamer), 5.18 (t,J 8.7 Hz,1H, main rotamer), 4.75-4.68 (m,1H, main rotamer), 4.61-4.52 (m,2H,2 x minor rotamer), 4.15-4.05 (m, 1H, major rotamer), 4.02-3.82 (m, 1H and 1H, major rotamers), 3.74-3.63 (m, 1H, major rotamer), 3.58-3.43 (m, 2H, 2 x minor rotamers), 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 H NMR shows a mixture of rotamers in a ratio of 1.4:1): δ H( 400 MHz, DMSO-d 6) 9.51 (d,J 8.9 Hz,1H, minor rotamer), 9.50 (d,J 8.9 Hz,1H, main rotamer), 8.87 (s,1H, minor rotamer), 8.71 (s,1H, main rotamer), 8.28 (s,1H, minor rotamer), 8.26 (s,1H, main rotamer), 6.11-5.84 (v br s,1H), 5.94 (d,J 6.9 Hz,1H, main rotamer), 5.73 (d,J 6.2 Hz,1H, minor rotamer), 5.19 (t,J 8.5 Hz, 2H, major and minor rotamers), 4.72-4.66(m, 1H, major rotamer), 4.51-4.42(m, 1H, minor rotamer), 4.33-4.25(m, 1H, minor rotamer), 4.16-3.99(m, 2H, 2 x major rotamers), 3.98-3.69(m, 1H and 2H, major and minor rotamers), 3.25-3.12(m, 1H, minor rotamer), 2.79(app d, J 14.4 Hz, 1H, minor rotamer), 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)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-1-fluorocyclopropanecarboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-1-fluorocyclopropanecarboxamide To a solution of intermediate 63 (1:1 ratio of two stereoisomers) (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) at room temperature was added HATU (65.0 mg, 0.17 mmol) in one portion. The mixture was stirred for 20 min and then diluted with H 2 O (20 mL) was added. The mixture was extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient). Further chiral purification of the resulting white foam (77 mg) was carried out by SFC (3-40% MeOH (+0.1% NH) using a 10 min run time on a Waters Prep150 fractionlynx system in conjunction with a Waters QDa mass spectrometer). 4 Purification was performed on a Lux Cellulose-1 250 × 21.2 mm, 5 μm column eluted with the 5% CO2 (ABPR 60 bar) (flow rate 100 mL / min, column temperature 40 °C) to give, after lyophilization, the isolated title compounds (peak 1, 20.0 mg, 21.8% yield, 98.6% de; and peak 2, 17.0 mg, 18.5% yield, 98.5% de). Peak 1 ( 1 H NMR shows a mixture of rotamers in a ratio of 2.6:1):δ H( 400 MHz, DMSO-d 6) 8.81 (s,1H, main rotamer), 8.70 (s,1H, minor rotamer), 8.56 (d,J 9.0 Hz, minor rotamer), 8.53 (d,J 9.5 Hz, main rotamer), 8.24 (s,1H), 5.92 (app d,J 6.8 Hz,1H, main rotamer), 5.94-5.81 (v br s,1H), 5.63 (app d,J 6.3 Hz,1H, minor rotamer), 5.07 (unclear t,J 9.0 Hz,1H, minor rotamer), 5.05 (t,J 8.9 Hz,1H, main rotamer), 4.72 (t,J 6.4 Hz, 1H, major rotamer), 4.62-4.52(m, 2H, 2 x minor rotamers), 4.15-4.05(m, 1H, major rotamer), 4.02-3.82(m, 1H and 1H, major rotamers), 3.76-3.65(m, 1H, major rotamer), 3.60-3.42(m, 2H, 2 x minor rotamers), 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 H NMR shows a mixture of rotamers in a ratio of 1.3:1): δ H( 400 MHz, DMSO-d 6) 8.86 (s,1H, minor rotamer), 8.70 (s,1H, main rotamer), 8.54 (app t,J 8.7 Hz, 2H, main and minor rotamers), 8.24 (s,1H, minor rotamer), 8.23 ​​(s,1H, main rotamer), 5.97-5.91 (m,1H, main rotamer), 5.92-5.85 (v br s,1H), 5.76-5.70 (m,1H, minor rotamer), 5.06 (t,J 8.5 Hz,1H, main rotamer), 5.05 (t,J 8.9 Hz, 1H, minor rotamer), 4.73-4.66(m, 1H, main rotamer), 4.52-4.42(m, 1H, minor rotamer), 4.34-4.26(m, 1H, minor rotamer), 4.17-4.00(m, 2H, 2 x main rotamers), 3.97-3.68(m, 1H and 2H, main and minor rotamers), 3.27-3.16(m, 1H, minor rotamer), 2.78(app d, J 14.4 Hz, 1H, minor rotamer), 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-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 72 (1:1 ratio of two stereoisomers) (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 was added HATU (104 mg, 0.27 mmol) in one portion. The mixture was stirred for 45 min and then H 2 O (20 mL) was added. The mixture was extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient). Further chiral purification of the resulting white foam (140 mg) was carried out by SFC (3-40% MeOH (+0.1% NH) using a 10 min run time on a Waters Prep150 fractionlynx system in conjunction with a Waters QDa mass spectrometer). 4 Purification was performed on a Lux Cellulose-1 250 × 21.2 mm, 5 μm column eluted with the 5% CO2 (ABPR 60 bar) (flow rate 100 mL / min, column temperature 40 °C) to give, after lyophilization, the isolated title compounds (peak 1, 37.0 mg, 25% yield, 98.9% de; and peak 2, 27.0 mg, 18.2% yield, 94.2% de). Peak 1 ( 1 H NMR shows a mixture of rotamers in a ratio of 2.8:1): δ H( 400 MHz, DMSO-d 6) 9.50 (d,J 9.4 Hz, 1H, minor rotamer), 9.47 (d,J 8.9 Hz, 1H, major rotamer), 8.76 (s,1H, major rotamer), 8.65 (s,1H, minor rotamer), 8.26 (s,1H), 5.90-5.84 (m,1H, major rotamer), 5.78 (t,J 56.0 Hz, 1H, major rotamer), 5.75 (t,J 56.1 Hz, 1H, minor rotamer), 5.60-5.55 (m,1H, minor rotamer), 5.26-5.07 (unclear v br s,1H), 5.18 (app t,J 8.8 Hz, 2H, major and minor rotamers), 4.70 (app t,J 6.3 Hz, 1H, major rotamer), 4.61-4.44(m, 2H, 2 x minor rotamers), 4.11-3.80(m, 1H and 2H, 2 x major rotamers), 3.73-3.60(m, 1H, major rotamer), 3.59-3.40(m, 2H, 2 x minor rotamers), 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 H NMR shows a mixture of rotamers in a ratio of 1.3:1): δ H( 400 MHz, DMSO-d 6) 9.51 (d,J 8.9 Hz, 1H, minor rotamer), 9.50 (d,J 9.0 Hz, 1H, main rotamer), 8.80 (s,1H, minor rotamer), 8.65 (s,1H, main rotamer), 8.27 (s,1H, minor rotamer), 8.25 (s,1H, main rotamer), 5.91-5.86 (m,1H, main rotamer), 5.78 (t,J 55.7 Hz, 1H, minor rotamer), 5.77 (t,J 56.0 Hz, 1H, main rotamer), 5.69-5.65 (m,1H, minor rotamer), 5.28-5.10 (unclear v br s,1H), 5.19 (t,J 8.6 Hz, 1H, major rotamer), 5.19 (t, J 8.8 Hz, 1H, minor rotamer), 4.72-4.65 (m, 1H, major rotamer), 4.46-4.36 (m, 1H, minor rotamer), 4.31-4.23 (m, 1H, minor rotamer), 4.11-3.98 (m, 2H, 2 x major rotamer), 3.94-3.67 (m, 1H and 2H, major and minor rotamers), 3.22-3.10 (m, 1H, minor rotamer), 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]morpholin-3-yl}imidazo[1,2-b][1,2,4]triazin-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]morpholin-3-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)[4-(trifluoromethyl)cyclohexyl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 76 (1:1 ratio of two stereoisomers) (91.0 mg, 0.15 mmol), intermediate 79 (25.0 mg, 0.15 mmol) and DIPEA (0.10 mL, 0.58 mmol) in DMF (5 mL) at room temperature was added HATU (71.0 mg, 0.18 mmol) in one portion. The mixture was stirred for 16 h and then H 2 O (20 mL) was added. The mixture was extracted with EtOAc (3x20 mL). The combined organic extracts were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient). Further chiral purification of the resulting white foam (57.0 mg) (using a UV-directed Agilent 1100 / 1200 hybrid system with a run time of 19 minutes, using a (R,R) Whelk-O1 250 x 10 mm, 5 μm column eluting with 40% EtOH:60% n-heptane (+0.1% diethylamine) isocratic method, flow rate 4.7 mL / min, column temperature ambient) afforded the isolated title compounds after lyophilization (peak 1, 7.3 mg, 7.6% yield, >99% de; and peak 2, 12.0 mg, 12.5% ​​yield, 99% de). Peak 1: δ H (400 MHz, 373K, DMSO-d 6) 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-d 6 ) 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

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[0461] Examples 28 and 29 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4S)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4R)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 83 (a 1:1 ratio mixture of two anti stereoisomers) (93.4 mg, 0.17 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (25.0 mg, 0.18 mmol) and DIPEA (0.12 mL, 0.69 mmol) in DMF (5 mL) at room temperature was added HATU (78.0 mg, 0.20 mmol) in one portion. The mixture was stirred for 80 min and then HCl was added to HCl. 2 O (10 mL) was added. The mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were washed with brine (20 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient). The resulting white foam (42.0 mg) was subjected to chiral purification (Method 19) to give, after lyophilization, the title compounds (peak 1, 10.0 mg, 9.4% yield, >99% de; and peak 2, 9.0 mg, 8.5% yield, 98.0% de). Peak 1: δ H (400 MHz, DMSO-d 6 ) 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-d 6) 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-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 83 (a 1:1 ratio mixture of two anti stereoisomers) (73.7 mg, 0.13 mmol), intermediate 79, and DIPEA (0.09 mL, 0.50 mmol) in DMF (5 mL) at room temperature was added HATU (62.0 mg, 0.16 mmol) in one portion. The mixture was stirred for 35 min and then diluted with H 2 O (20 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (40 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient) to give the crudely resolved anti diastereomers. Diastereomer 1 was subjected to chiral purification (Method 21) to give peak 1 (8 mg, 9%). Diastereomer 2 was subjected to chiral purification (Method 22) to give peak 2 (8 mg, 9%). Peak 1: δ H (400 MHz, DMSO-d 6 ) 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-d 6) 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]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 86 (a 1:1 ratio mixture of two anti stereoisomers) (38.8 mg, 0.067 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (10.0 mg, 0.073 mmol) and DIPEA (0.05 mL, 0.30 mmol) in DMF (5 mL) at room temperature was added HATU (32.0 mg, 0.08 mmol) in one portion. The mixture was stirred for 30 min and then diluted with H 2O (10 mL) was added. The mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were washed with brine (20 mL) and then dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc / isohexane (0-100% gradient). The resulting white foam (35.0 mg) was subjected to chiral purification (Method 23) to give, after lyophilization, the title compounds (peak 1, 11.0 mg, 25.1% yield, >99% de; and peak 2, 9.0 mg, 20.6% yield, 92.6% de). Peak 1: δ H (400 MHz, DMSO-d 6 ) 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-d 6) 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-methylpiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 90 (277 mg, 0.473 mmol), intermediate 79 (100 mg, 0.602 mmol) and DIPEA (220 μL, 1.3 mmol) in DMF (5 mL) was added HATU (240 mg, 0.612 mmol). The solution was stirred at room temperature overnight and then partitioned between EtOAc and brine. The aqueous phase was extracted twice with EtOAc and the combined organic phase was washed with brine and then added Na 2 SO 4 The mixture was dried at rt and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 30-100% EtOAc / isohexane followed by chiral purification (Method 19) afforded, after lyophilization, the title compounds (peak 1, 45 mg, 15% yield, 100.0% de; and peak 2, 37 mg, 12% yield, 96.1% de). Peak 1: δ H (400 MHz, 373K, DMSO-d 6 ) 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-d 6) 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]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 90 (220 mg, 0.376 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (62 mg, 0.45 mmol) and DIPEA (160 μL, 0.94 mmol) in DMF (5 mL) was added HATU (177 mg, 0.452 mmol). The solution was stirred at room temperature overnight and then partitioned between EtOAc and brine. The aqueous phase was extracted twice with EtOAc and the combined organic phase was washed with brine and then diluted with Na 2 SO 4 The residue was dried at rt and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 20-100% EtOAc / isohexane followed by chiral purification (Method 19) afforded, after lyophilization, the title compounds (peak 1, 18 mg, 8% yield, 100.0% de; and peak 2, 17 mg, 7% yield, 97.4% de). Peak 1: δ H (400 MHz, 373K, DMSO-d 6 ) 9.03 (d, J 8.2 Hz, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 5.68 (br s, 1H), 5.24 (t, J 8.1 Hz, 1H), 3.93 (s, 1H), 3.81-3.51 (m, 1H), 2.49 (s, 3H), 2.49-2.33 (m, 6H), 2.31-2.20 (m, 2H), 2.11-1.94 (m, 4H), 1.91-1.67 (m, 4H), 1.60-1.54 (m, 2H), 1.49-1.33 (m, 2H), 1.19 (s, 3H).LCMS (Method 7): [M+H] + m / z 603.4, RT 1.85 min. Chiral analysis (Method 20): RT 3.41 min. Peak 2: δ H (400 MHz, 373K, DMSO-d 6) 9.02 (d, J 8.7 Hz, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 5.66 (br s, 1H), 5.24 (t, J 7.9 Hz, 1H), 3.93 (s, 1H), 3.81-3.51 (m, 1H), 2.49 (s, 3H), 2.49-2.31 (m, 6H), 2.31-2.19 (m, 2H), 2.13-1.91 (m, 4H), 1.92-1.68 (m, 4H), 1.59-1.52 (m, 2H), 1.50-1.32 (m, 2H), 1.19 (s, 3H).LCMS (Method 7): [M+H] + m / z 603.4, RT 1.85 min. Chiral analysis (Method 20): RT 3.83 min.

[0466] Examples 38 and 39 [ka] N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 91 (100 mg, 0.123 mmol), intermediate 79 (25 mg, 0.15 mmol) and DIPEA (54 μL, 0.31 mmol) in DMF (2.5 mL) was added HATU (60 mg, 0.15 mmol). The solution was stirred at room temperature overnight and then partitioned between EtOAc and brine. The aqueous phase was extracted twice with EtOAc and the combined organic phase was washed with brine and then added Na2 SO 4 The mixture was dried at rt and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 50-100% EtOAc / isohexane followed by chiral purification (Method 19) afforded, after lyophilization, the title compounds (peak 1, 4.6 mg, 6% yield, 100.0% de; and peak 2, 6.3 mg, 8% yield, 98.9% de). Peak 1: δ H (400 MHz, 373K, DMSO-d 6 ) 9.06-8.99 (m, 1H), 8.57-8.52 (m, 1H), 8.19 (s, 1H), 5.41-5.33 (m, 1H), 5.25 (t, J 8.3 Hz, 1H), 4.52-4.46 (m, 1H), 4.35 (s, 1H), 4.04-3.72 (m, 4H), 3.60-3.50 (m, 1H), 2.63-2.57 (m, 2H), 2.49 (s, 3H), 2.29-2.16 (m, 3H), 2.13-1.65 (m, 8H), 1.54-1.35 (m, 3H), 1.09 (s, 3H).LCMS(Method 7):[M+H] + m / z 639.2, RT 1.84 min. Chiral analysis (Method 20): RT 4.39 min. Peak 2: δ H (400 MHz, 373K, DMSO-d 6 ) 9.05-8.99 (m, 1H), 8.59-8.53 (m, 1H), 8.18 (s, 1H), 5.41-5.33 (m, 1H), 5.25 (t, J 8.3 Hz, 1H), 4.60-4.53 (m, 1H), 4.34 (s, 1H), 4.10-3.87 (m, 2H), 3.82-3.66 (m, 2H), 3.62-3.44 (m, 1H), 2.57-2.54 (m, 2H), 2.49 (s, 3H), 2.28-2.19 (m, 3H), 2.14-1.65 (m, 8H), 1.55-1.34 (m, 3H), 1.09 (s, 3H).LCMS (Method 7): [M+H] +m / z 639.2, RT 1.82 min. Chiral analysis (Method 20): RT 4.70 min.

[0467] Examples 40 and 41 [ka] N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 91 (100 mg, 0.123 mmol), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (20 mg, 0.15 mmol) and DIPEA (54 μL, 0.31 mmol) in DMF (2.5 mL) was added HATU (60 mg, 0.15 mmol). The solution was stirred at room temperature overnight and then partitioned between EtOAc and brine. The aqueous phase was extracted twice with EtOAc and the combined organic phase was washed with brine and then diluted with Na 2 SO 4 The mixture was dried at rt and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 50-100% EtOAc / isohexane followed by chiral purification (Method 19) afforded, after lyophilization, the title compounds (peak 1, 6.1 mg, 8% yield, 100.0% de; and peak 2, 5.5 mg, 7% yield, 99.4% de). Peak 1: δ H (400 MHz, 373K, DMSO-d 6) 9.05-8.99 (m, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 5.33-5.20 (m, 2H), 4.35 (s, 1H), 3.98-3.88 (m, 1H), 3.60-3.48 (m, 1H), 2.49 (s, 3H), 2.43-2.34 (m, 6H), 2.28-2.16 (m, 2H), 2.11-2.02 (m, 3H), 1.98-1.92 (m, 1H), 1.87-1.65 (m, 5H), 1.53-1.43 (m, 1H), 1.41-1.31 (m, 1H), 1.10 (s, 3H).LCMS (method 7): [M+H] + m / z603.4, RT1.81 points.キラル analysis (method 20): RT4.10 points. ピーク2:δ H (400 MHz, 373K, DMSO-d 6 ) 9.02 (d, J 9.0 Hz, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 5.33-5.20 (m, 2H), 4.35 (s, 1H), 4.02-3.84 (m, 1H), 3.62-3.43 (m, 1H), 2.49 (s, 3H), 2.42-2.35 (m, 6H), 2.28-2.14 (m, 2H), 2.12-2.01 (m, 3H), 1.99-1.91 (m, 1H), 1.88-1.66 (m, 5H), 1.55-1.44 (m, 1H), 1.43-1.32 (m, 1H), 1.10 (s, 3H).LCMS(Method 7):[M+H] + m / z603.4, RT1.82 points.キラル analysis (method 20): RT5.52 points.

[0468] Examples 42~45

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Claims

1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 in the formula E represents a group of formula (Ea), (Eb), (Ec), (Ed) or (Ee): 【Chemical 2】 (wherein the asterisk (*) represents the point of attachment to the remainder of the molecule) ; A represents a group of formula (Aa), (Ab), (Ac), (Ad) or (Ae): 【Chemical Formula 3】 (wherein the asterisk (*) represents the point of attachment to the remainder of the molecule) ; Y represents -O-, -N(R ７ ), -, -C(R ５ａ )(R ５ｂ ), -, -S-, -S(O)-, -S(O) ２ - or -S(O)(N-R ８ )-; Z represents heteroaryl, which group may optionally be substituted by one or more substituents; R １ represents hydrogen, fluoro, chloro, methyl, difluoromethyl or trifluoromethyl; R ２ represents -OR ２ａ or; or R ２ represents C ３－９ cycloalkyl, C ４－１２ bicycloalkyl, C ３－７ heterocycloalkyl or C ４－９ heterobicycloalkyl, any of these groups may optionally be substituted by one or more substituents; R ２ａ represents C １－６ alkyl; or R ２ａ represents C ３－９ cycloalkyl, which group may optionally be substituted by one or more substituents; R ３ represents -NR ３ａ R ３ｂ or R ３ is of the formula (Wa): 【Chemical Formula 4】 (wherein the asterisk (*) represents the point of attachment to the remainder of the molecule) ; W represents the residue of a saturated monocyclic ring which contains 3 to 6 carbon atoms, 1 nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but contains 1 or fewer O or S atoms, and which may be optionally substituted; or W represents the residue of a saturated bicyclic ring system which contains 4 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but contains 1 or fewer O or S atoms, and which may be optionally substituted; or W represents the residue of a saturated spirocyclic ring system which contains 5 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but contains 1 or fewer O or S atoms, and which may be optionally substituted; R ３ａ represents hydrogen or C １－６ alkyl; R ３ｂ represents C １－６ alkyl, C ３－７ cycloalkyl, C ３－７ cycloalkyl(C １－６ )alkyl, C ４－１２ bicycloalkyl, aryl, aryl(C １－６ )alkyl, C ３－７ heterocycloalkyl, C ３－７ heterocycloalkyl(C １－６ )alkyl, heteroaryl or heteroaryl(C １－６ )alkyl, and any of these groups may optionally be substituted by one or more substituents; R ４ａ represents hydrogen, fluoro or hydroxy; or R ４ａ represents C １－６ alkyl, which group may optionally be substituted by one or more substituents; R ４ｂ represents hydrogen, fluoro or C １－６ alkyl; or R ４ａ and R ４ｂ together with the carbon atom to which they are both attached form a C ３－９ cycloalkyl or a C ３－７ heterocycloalkyl, either of which groups may optionally be substituted by one or more substituents; R ５ａ represents hydrogen, fluoro, methyl, difluoromethyl or trifluoromethyl; R ５ｂ represents hydrogen, fluoro, methyl or hydroxy; or R ５ａ and R ５ｂ together with the carbon atom to which they are both attached represent cyclopropyl; R ６ represents -OR ６ａ or -NR ６ｂ R ６ｃ ; or R ６ represents C １－６ alkyl, C ３－９ cycloalkyl, C ３－９ cycloalkyl(C １－６ )alkyl, aryl, aryl(C １－６ )alkyl, C ３－７ heterocycloalkyl, C ３－７ heterocycloalkyl(C １－６ )alkyl, heteroaryl or heteroaryl(C １－６ )alkyl, and any of these groups may optionally be substituted by one or more substituents; R ６ａ represents C １－６ alkyl, C ３－９ cycloalkyl or aryl(C １－６ ), and any of these groups may optionally be substituted by one or more substituents; R ６ｂ represents hydrogen or C １－６ alkyl; R ６ｃ represents hydrogen or C １－６ alkyl; or R ６ｂ and R ６ｃ together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of these groups optionally being substituted by one or more substituents; R ７ represents -COR ７ａ , -CO ２ R ７ａ or -SO ２ R ７ｂ ; or R ７ represents hydrogen; or R ７ represents C １－６ alkyl or C ３－９ cycloalkyl, and any of these groups may optionally be substituted by one or more fluorine atoms; R ７ａ represents C optionally substituted by one or more fluorine atoms; １－６ alkyl; R ７ｂ represents C １－６ alkyl; R ８ represents C １－６ alkyl A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

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

3. R ６ is C ３－９ cycloalkyl, aryl or heteroaryl, any of these groups optionally being substituted by one or more substituents, a compound according to claim 1 or claim 2.

4. Formula (IIA-1): 【Chemical Formula 5】 (wherein X represents CH or N, R １６ represents methyl, ethyl, isopropyl or cyclopropyl, and A is as defined in claim 1) A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, represented by.

5. Formula (IIA-2): [Chemical Formula 6] (wherein A is as defined in claim 1, X and R １６ is as defined in claim 4) A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, represented by.

6. Formula (IIA-3): [Chemical Formula 7] (wherein A is as defined in claim 1, X and R １６ are as defined in claim 4) A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, represented by.

7. Formula (IIB-1): 【Chemical 8】 (wherein A is as defined in claim 1, X and R １６ are as defined in claim 4) a compound according to claim 1 represented by, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

8. Formula (IIC-1): 【Chemical Formula 9】 (wherein A is as defined in claim 1, R ２６ (which represents fluoro or trifluoromethyl) a compound according to claim 1 represented by, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

9. Formula (IIC-2): 【Chemical Formula 10】 (wherein A is as defined in claim 1, R ２６ is as defined in claim 8) a compound according to claim 1 represented by, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 9, wherein A represents a group of formula (Ab) or (Ad) according to claim 1.

11. N-[(1S)-2,2-dicyclopropyl-1-{3-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-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]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(3R)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(3S)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-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]morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-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]morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-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]morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl)(3-{[(3S)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){3-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-1-fluorocyclopropanecarboxamide, Benzyl N-[(S)-{3-[4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-1,1-dioxo-1,4-thiazinan-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]carbamate, 1-Fluoro-N-[(S)-{3-[(3R)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-1,1-dioxo-1,4-thiazinan-3-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}[4-(trifluoromethyl)cyclohexyl]methyl]cyclopropanecarboxamide, 1-Fluoro-N-[(S)-{3-[(3S)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-1,1-dioxo-1,4-thiazinan-3-yl]imidazo[1,2-b][1,2,4]triazin-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]triazin-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]triazin-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)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl)(3-{ (2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl)(3-{ (2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-Difluorocyclohexyl)(3-{ (2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-Difluorocyclohexyl)(3-{ (2S,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl)(3-{[(2R,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-{[(S)-(3-{[(3R)-4-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-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]morpholin-3-yl]imidazo[1,2-b][1,2,4]triazin-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]pentane-1-carbonyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){3-[(2R,4S)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){3-[(2S,4S)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4R)-4-(difluoromethyl)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2S,4S)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{(2R,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-(trifluoromethyl)piperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2S,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2R,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-difluorocyclohexyl){3-[(2S,4S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){3-[(2R,4R)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-4-hydroxy-4-methylpiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2S,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2R,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2S,4S)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2R,4R)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2S,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-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-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-6-yl)-methyl]-2-methyl-pyrazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{[(2S,4R)-4-(difluoromethyl)-1-[(2S)-5,5-difluorotetrahydropyran-2-carbonyl]-4-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-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-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-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-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-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-hydroxypiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-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-methylpiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-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-methylpiperidin-2-yl}imidazo[1,2-b][1,2,4]triazin-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)piperidin-4-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(3-{1-(oxetan-3-yl)-4-[3-(trifluoromethyl)azetidine-1-carbonyl]piperidin-4-yl}imidazo[1,2-b][1,2,4]triazin-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)piperidin-4-yl]imidazo[1,2-b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide The compound according to claim 1, selected from

12. A pharmaceutical composition comprising the compound of formula (I) according to claim 1 or its N-oxide, 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 a modulator of IL-17 function is indicated.

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

15. A pharmaceutical composition comprising the compound of formula (I) according to claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

16. Use of the compound of formula (I) according to claim 1, or an N-oxide thereof, 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 a modulator of IL-17 function is indicated.

17. Use of the compound of formula (I) according to claim 1, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of an inflammatory disorder or an autoimmune disorder.

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