Difluorocyclohexyl derivatives as IL-17 modulators

Abstract

The series of substituted 4,4-difluorocyclohexyl derivatives defined herein are potent modulators of human IL-17 activity and are therefore useful in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

Description

Technical Field

[0001] The present invention relates to heterocyclic compounds and their use in therapy. More particularly, the present invention relates to pharmacologically active substituted 4,4-difluorocyclohexyl derivatives. These compounds act as modulators of IL-17 activity and are thus useful as pharmaceuticals for treating and / or preventing pathological conditions including harmful inflammatory and autoimmune disorders.

Background Art

[0002] IL-17A (originally called CTLA-8 and also known as IL-17) is a pro-inflammatory cytokine and an early member of the IL-17 family (Rouvier et al., J. Immunol., 1993, 150, 5445-5456). Subsequently, five further members of the family (IL-17B - IL-17F), including the most closely related IL-17F, were identified, which share approximately 55% amino acid sequence homology with IL-17A (ML-1) (Moseley et al., Cytokine Growth Factor Rev., 2003, 14, 155-174). IL-17A and IL-17F are expressed by a recently defined subset of autoimmune-related T helper cells, Th17, which also express the IL-21 and IL-22 signaling cytokines (Korn et al., Ann. Rev. Immunol., 2009, 27, 485-517). IL-17A and IL-17F are expressed as homodimers but also as IL-17A / F heterodimers (Wright et al., J. Immunol., 2008, 181, 2799-2805). IL-17A and F signal via the receptors IL-17R, IL-17RC or the IL-17RA / RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F are associated with a number of autoimmune diseases.

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

[0004] Furthermore, the compounds according to the invention can be useful as pharmacological criteria for the development of new biological tests and the search for new pharmacological agents. Thus, the compounds of the invention can be useful as radioactive ligands in assays for detecting pharmacologically active compounds.

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

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

[0007] WO 2019 / 138017 describes a class of fused bicyclic imidazole derivatives, including benzimidazole derivatives and their analogs, that act as modulators of IL-17 activity and are thus stated to be beneficial in the treatment of pathological conditions, including harmful inflammatory and autoimmune disorders.

[0008] WO 2019 / 223718 describes heterocyclic compounds, including benzimidazole derivatives, that inhibit IL-17A and are stated to be useful as immunomodulators.

[0009] The co-pending international patent applications PCT / EP2019 / 082774 and PCT / EP2019 / 082779 (both published on June 18, 2020 as International Publication Nos. 2020 / 120140 and 2020 / 120141 respectively), the specification of the co-pending international patent application PCT / IB2020 / 055970, the specifications of PCT / EP2020 / 067758 and PCT / EP2020 / 067759 (both published on December 30, 2020 as International Publication Nos. 2020 / 261141, 2020 / 260425 and 2020 / 260426 respectively, claiming priority from UK patent applications Nos. 1909190.9, 1909191.7 and 1909194.1 respectively), and the co-pending international patent applications PCT / EP2021 / 054519 and PCT / EP2021 / 054523 (claiming the earliest priority from the specifications of UK patent applications Nos. 2002635.7 and 2002636.5 respectively) describe distinct classes of chemical compounds that act as modulators of IL-17 activity and are thus stated to be useful in the treatment of pathological conditions including harmful inflammatory and autoimmune disorders.

[0010] However, none of the prior art available to date has disclosed or suggested the exact structural class of the substituted 4,4-difluorocyclohexyl derivatives provided by the present invention. SUMMARY OF THE INVENTION

[0011] The compounds according to the present invention are not only potent modulators of human IL-17 activity but also have other significant advantages. In particular, the compounds of the present invention exhibit valuable metabolic stability as determined by either microsomal or hepatocyte incubation.

[0012] The present invention provides a compound of formula (I) or an N-oxide thereof or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

[0013] The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0014] The present invention also provides a compound of formula (I) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0015] The present invention also provides a compound of formula (I) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disorder in which administration of a modulator of IL-17 function is indicated.

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

[0017] The present invention also provides a method for the treatment and / or prevention of a disorder in which administration of a modulator of IL-17 function is indicated, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0018] When it is stated that any of the groups in the compounds of formula (I) above may be optionally substituted, the group may be unsubstituted or may be substituted by one or more substituents. Generally, such a group is unsubstituted or substituted by 1, 2, 3 or 4 substituents. Typically, such a group is unsubstituted or substituted by 1, 2 or 3 substituents. Suitably, such a group is unsubstituted or substituted by 1 or 2 substituents.

[0019] When used in pharmaceuticals, the salts of the compounds of formula (I) are pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the compounds of formula (I) or their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P. H. Stahl & C. G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include, for example, acid addition salts that can be formed by mixing a solution of the compound of formula (I) with a solution of a pharmaceutically acceptable acid.

[0020] 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 a situation where neutral molecular components are present within a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modification of the crystalline form of a pharmaceutically active ingredient, thereby allowing its physicochemical properties to be changed without compromising the intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0021] Suitable alkyl groups that may be present in the compounds used in the present invention include straight-chain and branched C 1-6 alkyl groups, for example C 1-4An alkyl group may be mentioned. Typical examples include a methyl group, an ethyl group, and a linear or branched propyl group, butyl group, and pentyl group. Specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, and 3-methylbutyl. "C 1-6 alkoxy", "C 1-6 alkylthio", "C 1-6 alkyl-sulfonyl", and "C 1-6 alkylamino" and other derivative expressions should be interpreted accordingly.

[0022] As used herein, the term "C 3-9 cycloalkyl" refers to a monovalent group of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon and may include its benzo-fused analogs. Suitable C 3-9 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononanyl.

[0023] As used herein, the term "aryl" refers to a monovalent carbocyclic aromatic group derived from a single aromatic ring or a plurality of fused aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

[0024] Suitable aryl(C 1-6 )alkyl groups include benzyl, phenylethyl, phenylpropyl, and naphthylmethyl.

[0025] As used herein, "C 3-7The term "heterocycloalkyl" refers to a saturated monocyclic ring containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur, and nitrogen, and may include its benzo-fused analogs. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl, and azocanyl.

[0026] As used herein, the term "heteroaryl" refers to a monovalent aromatic group containing at least 5 atoms derived from a single ring or multiple fused rings, wherein one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b]-[1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]-pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 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[3,4-a]pyridinyl, 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.

[0027] As used herein, the term "halogen" is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.

[0028] If the compound of formula (I) has one or more asymmetric centers, it may exist as enantiomers accordingly. If the compound according to the invention has two or more asymmetric centers, they may further exist as diastereomers. It should be understood that the present invention extends to the use of all such enantiomers and diastereomers, and to any proportion of mixtures thereof including racemates. Formulas (I) and the formulas shown below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise specified or indicated. Further, the compounds of formula (I) may exist as tautomers, for example keto (CH2C=O) ⇔ enol (CH=CHOH) tautomers or amide (NHC=O) ⇔ hydroxyimine (N=COH) tautomers. Formulas (I) and the formulas shown below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise specified or indicated.

[0029] It should be understood that each of the individual atoms present in formula (I) or the formulas shown later herein may actually exist in any form of its naturally occurring isotopes, and the most abundant isotope(s) is / are preferred. Thus, by way of example, the individual hydrogen atoms present in formula (I) or the formulas shown below may be 1 H, 2 H (deuterium) or 3 H (tritium) atoms, preferably 1 H. Similarly, by way of example, the individual carbon atoms present in formula (I) or the formulas shown below may be 12 C, 13 C or 14 C atoms, preferably 12 C.

[0030] In one embodiment, A represents C-R 1 In another embodiment, A represents N.

[0031] In one embodiment, E represents C-R 2 In another embodiment, E represents N.

[0032] In certain embodiments, A represents C-R 1 or N, and E represents C-R 2 In one aspect of that embodiment, A represents C-R 1 and E represents C-R 2 In particular embodiments, A represents C-R

[0033] Suitably, the present invention provides a compound of formula (I-1) or (I-2), or an N-oxide thereof, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0034] In a first embodiment, R 1 represents hydrogen. In a second embodiment, R 1 represents fluoro.

[0035] In a first embodiment, R 2 represents hydrogen. In a second embodiment, R 2 represents fluoro.

[0036] In a first embodiment, R 3 represents -NR 3a R 3b In a second embodiment, R 3 represents a group of formula (Wa) as defined above.

[0037] In a first embodiment, R 3a represents hydrogen. In a second embodiment, R 3a represents C 1-6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R 3arepresents methyl. In a second aspect of that embodiment, R 3a represents ethyl.

[0038] Typically, R 3b is C 1-6 alkyl, C 3-7 cycloalkyl(C 1-6 )alkyl or heteroaryl, and any of these groups may be substituted by one or more substituents.

[0039] Suitably, R 3b is C 1-6 alkyl or C 3-7 cycloalkyl(C 1-6 )alkyl, and any of these groups may be substituted by one or more substituents.

[0040] In a first embodiment, R 3b represents optionally substituted C 1-6 alkyl. In a second embodiment, R 3b represents optionally substituted C 3-7 cycloalkyl. In a third embodiment, R 3b represents optionally substituted C 3-7 cycloalkyl(C 1-6 )alkyl. In a fourth embodiment, R 3b represents optionally substituted aryl. In a fifth embodiment, R 3b represents optionally substituted aryl(C 1-6 )alkyl. In a sixth embodiment, R 3b represents optionally substituted C 3-7 heterocycloalkyl. In a seventh embodiment, R 3b represents optionally substituted C 3-7 heterocycloalkyl(C 1-6 )alkyl. In an eighth embodiment, R 3b represents optionally substituted heteroaryl. In a ninth embodiment, R 3b represents optionally substituted heteroaryl(C 1-6 )alkyl.

[0041] R 3b Typical values of R include ethyl, n-propyl, isopropyl, 2-methylpropyl, cyclopropylmethyl, and pyridinyl, and any of these groups may be substituted with one or more substituents.

[0042] R 3b Exemplary values of R include ethyl, n-propyl, isopropyl, 2-methylpropyl, and cyclopropylmethyl, and any of these groups may be substituted by one or more substituents.

[0043] R 3b Typical examples of any of the above substituents include halogen, cyano, nitro, C 1-6 alkyl, trifluoro-methyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, 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 one, two, or three substituents independently selected therefrom.

[0044] R 3b Suitable examples of any of the above substituents include halogen, C 1-6Alkyl, trifluoromethyl, C 1-6 One, two or three substituents independently selected from alkylaminocarbonyl and di(C 1-6 )alkylaminocarbonyl are exemplified.

[0045] R 3b Suitable examples of the above optional substituents include halogen, C 1-6 One, two or three substituents independently selected from alkylaminocarbonyl and di-(C 1-6 )alkylaminocarbonyl are exemplified.

[0046] R 3b Typical examples of the above specific substituents include 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 one, two or three substituents independently selected from dimethylsulfoximino.

[0047] R 3b Suitable examples of the above specific substituents include one, two or three substituents independently selected from fluoro, methyl, trifluoromethyl, methylamino-carbonyl and dimethylaminocarbonyl.

[0048] R 3b Suitable examples of the above specific substituents include one, two or three substituents independently selected from fluoro, methylaminocarbonyl and dimethyl-aminocarbonyl.

[0049] R 3bSuitable values for

[0050] R 3b include difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, trifluoroisopropyl, (fluoro)(methyl)propyl, methylaminocarbonyl-2-methylpropyl, dimethylaminocarbonyl-2-methylpropyl, (cyclopropyl)(trifluoromethyl)-methyl, and difluorocyclopropylmethyl.

[0051] R 3b Typical values for

[0052] R 3b Preferred values for

[0053] In the first embodiment, W represents a 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 no more than 1 O or S atom. In the first aspect of that embodiment, W represents a 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 containing no more than 1 O or S atom.

[0054] In the second embodiment, W represents a residue of an optionally substituted saturated bicyclic ring system containing 4 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing no more than 1 O or S atom. In the first aspect of that embodiment, W represents a residue of an optionally substituted saturated bicyclic ring system containing 5, 6, or 7 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing no more than 1 O or S atom.

[0055] In the third embodiment, W represents a residue of an optionally substituted saturated spiro 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 no more than 1 O or S atom. In the first aspect of that embodiment, W represents a residue of an optionally substituted saturated spiro ring system containing 5, 6, or 7 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing no more than 1 O or S atom.

[0056] Suitably, W represents a residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms, 1 nitrogen atom, and 0 or 1 oxygen atom. In the first embodiment, W represents a residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms and 1 nitrogen atom. In the first aspect of that embodiment, W represents a residue of an optionally substituted saturated monocyclic ring containing 3 carbon atoms and 1 nitrogen atom. In the second aspect of the embodiment, W represents a residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms and 1 nitrogen atom. In the second embodiment, W represents a residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms, 1 nitrogen atom, and 1 oxygen atom.

[0057] In the first embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing 1 nitrogen atom and no further heteroatoms (i.e., it is an optionally substituted azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or hexahydroazepin-1-yl ring). In the second embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing 1 nitrogen atom and 1 additional heteroatom selected from N, O and S. In the first aspect of that embodiment, the group of formula (Wa) is an optionally substituted morpholin-4-yl moiety. In the third embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing 1 nitrogen atom and 2 additional heteroatoms selected from N, O and S, with no more than 1 of them being O or S. In the fourth embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing 1 nitrogen atom and 3 additional heteroatoms selected from N, O and S, with no more than 1 of them being O or S.

[0058] Typical values for the group 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-aza-spiro[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]dec-2-yl, 2,4,8-triazaspiro[4.5]dec-4-yl and 2,4,8-triazaspiro[4.5]dec-8-yl, and any of these groups may be substituted by one or more substituents.

[0059] Suitable values for the group of formula (Wa) include azetidin-1-yl, pyrrolidin-1-yl and morpholin-4-yl, and any of these rings may be substituted by one or more substituents.

[0060] Suitable values for the group of formula (Wa) include azetidin-1-yl and pyrrolidin-1-yl, and either of these rings may be substituted by one or more substituents.

[0061] In the first embodiment, the group of formula (Wa) is unsubstituted. In the second embodiment, the group of formula (Wa) is substituted by one or more substituents, typically 1 to 6 substituents, suitably 2 to 4 substituents. In the first aspect of that embodiment, the group of formula (Wa) is substituted by one substituent. In the second aspect of that embodiment, the group of formula (Wa) is substituted by two substituents. In the third aspect of that embodiment, the group of formula (Wa) is substituted by three substituents. In the fourth aspect of that embodiment, the group of formula (Wa) is substituted by four substituents. In the fifth aspect of that embodiment, the group of formula (Wa) is substituted by five substituents. In the sixth aspect of that embodiment, the group of formula (Wa) is substituted by six substituents.

[0062] 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, difluoro-methoxy, trifluoromethoxy, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6Alkylsulfonyl, cyano, oxo, formyl, C 2-6 Alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 Alkoxycarbonyl, C 2-6 Alkoxycarbonyl(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6 Alkylamino, di(C 1-6 )alkylamino, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkylsulfonylamino, aminocarbonyl, C 1-6 Alkylaminocarbonyl and di(C 1-6 )alkylaminocarbonyl may be mentioned.

[0063] Suitable examples of optional substituents on the group of formula (Wa) include halogen.

[0064] Typical examples of specific substituents on the group of formula (Wa) include fluoro, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulfonyl, cyano, oxo, formyl, acetyl, ethylcarbonyl, tert-butylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino, aminomethyl, methylamino, ethylamino, dimethylamino, acetylamino, tert-butoxycarbonylamino, methylsulfonylamino, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.

[0065] Suitable examples of specific substituents on the group of formula (Wa) include fluoro.

[0066] Suitable values for the group of formula (Wa) include difluoroazetidin-1-yl, tetrafluoropyrrolidin-1-yl, and tetrafluoromorpholin-4-yl.

[0067] Typical values for the group of formula (Wa) include difluoroazetidin-1-yl and tetrafluoropyrrolidin-1-yl.

[0068] Generally, R 4a represents hydrogen or fluoro, or R 4a represents C 1-6 alkyl, and this group may be substituted with one or more substituents.

[0069] Typically, R 4a represents hydrogen, or R 4a represents C 1-6 alkyl, and this group may be substituted with one or more substituents.

[0070] Suitably, R 4a represents C 1-6 alkyl, and this group may be substituted by one or more substituents.

[0071] In the first embodiment, R 4a represents hydrogen. In the second embodiment, R 4a represents fluoro. In the third embodiment, R 4a represents hydroxy. In the fourth embodiment, R 4a represents C 1-6 alkyl, especially methyl or ethyl, and these groups may be substituted by one or more substituents. In the first aspect of that embodiment, R 4a represents optionally substituted methyl. In the second aspect of that embodiment, R 4a represents optionally substituted ethyl. In the third aspect of that embodiment, R 4a represents optionally substituted propyl.

[0072] R 4aTypical examples of any substituent above include halogen, cyano, nitro, hydroxy, C 1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkyl-carbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkyl-carbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di-(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 )alkylamino-sulfonyl and di(C 1-6 )alkylsulfoximino, and one, two or three substituents independently selected therefrom.

[0073] R 4a Selected examples of any substituent above include halogen, C 1-6 alkoxy and C 1-6 alkylsulfonyl, and one, two or three substituents independently selected therefrom.

[0074] R 4a Suitable examples of any substituent above include halogen, and C 1-6 alkylsulfonyl, and one, two or three substituents independently selected therefrom.

[0075] R 4aTypical examples of the specific substituents above include 1, 2, or 3 substituents independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoro-ethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino-sulfonyl, and dimethylsulfoximino.

[0076] R 4a Selected examples of the specific substituents above include 1, 2, or 3 substituents independently selected from fluoro, methoxy, and ethylsulfonyl.

[0077] R 4a Selected examples of the suitable substituents above include 1, 2, or 3 substituents independently selected from fluoro and ethylsulfonyl.

[0078] R 4a Exemplary values of include hydrogen, fluoro, hydroxy, methyl, difluoroethyl, trifluoroethyl, and ethylsulfonylethyl. Further values include methoxymethyl and difluoropropyl.

[0079] R 4a Selected values of include methyl, methoxymethyl, difluoroethyl, trifluoro-ethyl, ethylsulfonylethyl, and difluoropropyl.

[0080] R 4a Typical values of include methyl, difluoroethyl, trifluoroethyl, and ethylsulfonylethyl.

[0081] In the first embodiment, R 4b represents hydrogen. In the second embodiment, R 4b represents fluoro. In the third embodiment, R 4b represents C 1-6 alkyl, particularly methyl or ethyl. In the first aspect of that embodiment, R 4b represents methyl. In the second aspect of that embodiment, R 4b represents ethyl.

[0082] Typical values of R 4b include hydrogen and fluoro, particularly hydrogen.

[0083] Alternatively, R 4a and R 4b may together form an optionally substituted spiro bond. Thus, R 4a and R 4b , when taken together with the carbon atom to which both are attached, can represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, and any of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0084] In the first embodiment, R 4a and R 4b , when taken together with the carbon atom to which both are attached, can suitably represent C 3-7 cycloalkyl, and this group may be unsubstituted or substituted with one or more substituents, typically one or two substituents. As a general exemplification of that embodiment, R 4a and R 4b , when taken together with the carbon atom to which both are attached, can suitably represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and any of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents. As a specific exemplification of that embodiment, R 4a and R 4bWhen taken together with the carbon atom to which both are attached, can suitably represent cyclobutyl or cyclohexyl, and either of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a first aspect of that embodiment, R 4a and R 4b When taken together with the carbon atom to which both are attached, can suitably represent a cyclopropyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a second aspect of that embodiment, R 4a and R 4b When taken together with the carbon atom to which both are attached, can suitably represent a cyclobutyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a third aspect of that embodiment, R 4a and R 4b When taken together with the carbon atom to which both are attached, can suitably represent a cyclopentyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents. In a fourth aspect of that embodiment, R 4a and R 4b When taken together with the carbon atom to which both are attached, can suitably represent a cyclohexyl ring, which may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0085] In a second embodiment, R 4a and R 4b When taken together with the carbon atom to which both are attached, can suitably represent C 3-7 heterocycloalkyl, and this group may be unsubstituted or substituted with one or more substituents, typically one or two substituents. As a general exemplification of that embodiment, R 4a and R 4bWhen combined with the carbon atom to which both are attached, can suitably represent oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of these groups may be unsubstituted, or may be substituted with one or more substituents, typically one or two substituents. As specific exemplifications of that embodiment, R 4a and R 4b When combined with the carbon atom to which both are attached, can suitably represent pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of these groups may be unsubstituted, or may be substituted with one or more substituents, typically one or two substituents. In a first aspect of that embodiment, R 4a and R 4b When combined with the carbon atom to which both are attached, can suitably represent an oxetanyl ring, which may be unsubstituted, or may be substituted with one or more substituents, typically one or two substituents. In a second aspect of that embodiment, R 4a and R 4b When combined with the carbon atom to which both are attached, can suitably represent a pyrrolidinyl ring, which may be unsubstituted, or may be substituted with one or more substituents, typically one or two substituents. In a third aspect of that embodiment, R 4a and R 4b When combined with the carbon atom to which both are attached, can suitably represent a tetrahydropyranyl ring, which may be unsubstituted, or may be substituted with one or more substituents, typically one or two substituents. In a fourth aspect of that embodiment, R 4a and R 4b When combined with the carbon atom to which both are attached, can suitably represent a piperidinyl ring, which may be unsubstituted, or may be substituted with one or more substituents, typically one or two substituents.

[0086] Typically, R 4a and R 4bWhen taken together with the carbon atom to which both are attached, can represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0087] Suitably, R 4a and R 4b When taken together with the carbon atom to which both are attached, can represent cyclobutyl, cyclohexyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of these groups may be unsubstituted or substituted with one or more substituents, typically one or two substituents.

[0088] R 4a and R 4b Typical examples of optional substituents on the spiro ring formed by R 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 alkylcarbonyl, C 2-6 alkoxycarbonyl, amino, C 1-6 alkylamino and di(C 1-6 )alkylamino may be mentioned.

[0089] R 4a and R 4b Suitable examples of any substituents on the spiro ring formed by R 1-6 alkyl, halogen, trifluoroethyl and C 2-6 alkoxycarbonyl, especially halogen may be mentioned.

[0090] R 4a and R 4bSuitable examples of any substituent on the spiro ring formed by include halogen and C 2-6 and alkoxycarbonyl.

[0091] R 4a and R 4b Typical examples of specific substituents on the spiro ring formed by include methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, methoxycarbonyl, ethoxy-carbonyl, amino, methylamino and dimethylamino.

[0092] R 4a and R 4b Suitable examples of specific substituents on the spiro ring formed by include methyl, fluoro, trifluoroethyl and methoxycarbonyl, particularly fluoro.

[0093] R 4a and R 4b Suitable examples of specific substituents on the spiro ring formed by include fluoro and methoxycarbonyl.

[0094] R 4a and R 4b Typical examples of the spiro ring formed by include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonyl-pyrrolidinyl, tetrahydropyranyl, piperidinyl and methoxycarbonylpiperidinyl.

[0095] R 4a and R 4b Suitable examples of the spiro ring formed by include difluoro-cyclobutyl, difluorocyclohexyl, methoxycarbonylpyrrolidinyl, tetrahydropyranyl, piperidinyl and methoxycarbonylpiperidinyl.

[0096] Typically, R 6 is -OR6a or -NR 6b R 6c represents, 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, and any of these groups may be substituted by one or more substituents.

[0097] More specifically, R 6 is -OR 6a or -NR 6b R 6c represents, or R 6 is C 3-9 cycloalkyl, aryl or heteroaryl, and any of these groups may be substituted by one or more substituents.

[0098] R 6 is -OR 6a or -NR 6b R 6c represents, or R 6 is aryl or heteroaryl, and any of these groups may be substituted by one or more substituents.

[0099] Suitably, R 6 is -OR 6a represents, or R 6 is heteroaryl, and this group may be substituted by one or more substituents.

[0100] In a first embodiment, R 6 represents optionally substituted C 1-6 alkyl. In a second embodiment, R 6 represents optionally substituted C 3-9 cycloalkyl. In a third embodiment, R 6 represents optionally substituted C 3-9 cycloalkyl(C1-6 ) represents alkyl. In the fourth embodiment, R 6 represents optionally substituted aryl. In the fifth embodiment, R 6 represents optionally substituted aryl(C 1-6 )alkyl. In the sixth embodiment, R 6 represents optionally substituted C 3-7 heterocycloalkyl. In the seventh embodiment, R 6 represents optionally substituted C 3-7 heterocycloalkyl(C 1-6 )alkyl. In the eighth embodiment, R 6 represents optionally substituted heteroaryl. In the ninth embodiment, R 6 represents optionally substituted heteroaryl(C 1-6 )alkyl. In the tenth embodiment, R 6 represents -OR 6a . In the eleventh embodiment, R 6 represents -NR 6a R 6b .

[0101] R 6 Typical values of R 6a include -OR 6a R 6b , and methyl, ethyl, propyl, 2-methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl or pyridinylmethyl. Any of these groups may be substituted with one or more substituents. Further values of R 6 include triazolyl, and this group may be substituted with one or more substituents.

[0102] R 6 Typical examples of R 6a include -OR 6a R 6band cyclopropyl, phenyl, pyrazolyl, isoxazolyl, oxadiazolyl or triazolyl, any of these groups may be substituted with one or more substituents.

[0103] R 6 Representative values for are -OR 6a or -NR 6a R 6b and phenyl, pyrazolyl, isoxazolyl or oxadiazolyl, any of these groups may be substituted with one or more substituents.

[0104] R 6 Exemplary values for are -OR 6a and pyrazolyl, isoxazolyl or oxadiazolyl, any of these groups may be substituted with one or more substituents.

[0105] R 6 Representative examples for are cyclopropyl, phenyl, pyrazolyl, isoxazolyl, oxadiazolyl and triazolyl, any of these groups may be substituted with one or more substituents.

[0106] R 6 Selected examples for are cyclopropyl, phenyl, pyrazolyl, oxadiazolyl and triazolyl, any of these groups may be substituted by one or more substituents.

[0107] R 6 Suitable values for are phenyl, pyrazolyl, isoxazolyl and oxadiazolyl, any of these groups may be substituted by one or more substituents.

[0108] R 6 More suitable values for are phenyl, pyrazolyl and oxadiazolyl, any of these groups may be substituted with one or more substituents.

[0109] R6 Suitable values for

[0110] R 6 include pyrazolyl, isoxazolyl and oxadiazolyl, and any of these groups may be substituted by one or more substituents.

[0111] R 6 A specific value for

[0112] R 6 Typical examples of any of the above substituents include halogen, cyano, nitro, C 1-6 alkyl, trifluoro-methyl, phenyl, fluorophenyl, hydroxy, hydroxy(C 1-6 )alkyl, oxo, C 1-6 alkoxy, difluoro-methoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, 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 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylamino-carbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C1-6 ) One, two, or three substituents independently selected from alkylaminosulfonyl and di(C 1-6 ) alkylsulfoximinyl are exemplified. As a further example, cyclopropyl is exemplified.

[0113] R 6 Examples of the above optional substituents selected include one, two or three substituents independently selected from halogen, C 1-6 alkyl and cyclopropyl.

[0114] R 6 Suitable examples of any of the above substituents include halogen, and 1-6 one, two or three substituents independently selected from C

[0115] R 6 Suitable examples of any of the above substituents include 1-6 one, two or three substituents independently selected from C

[0116] R 6Typical 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, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl-amino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonyl-amino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonylmethylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximinyl. Further examples include cyclopropyl.

[0117] R 6 Selected examples of the above specific substituents include one, two or three substituents independently selected from fluoro, methyl, ethyl, isopropyl and cyclopropyl.

[0118] R 6 Suitable examples of the above specific substituents include one, two or three substituents independently selected from fluoro, methyl and ethyl.

[0119] R 6 Suitable examples of the above specific substituents include one, two or three substituents independently selected from methyl and ethyl.

[0120] R 6Exemplary examples of specific values include methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxyethyl, difluoropropyl, 2-methylpropyl, butyl, cyanocyclopropyl, methylcyclopropyl, ethyl-cyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chloro-phenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethyl-sulfoximinylphenyl, benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, (chloro)(fluoro)-benzyl, dichlorobenzyl, (chloro)(difluoro)benzyl, bromobenzyl, cyanobenzyl, methyl-benzyl, dimethylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, hydroxymethylbenzyl, benzoyl, methoxybenzyl, dimethoxybenzyl, trifluoromethoxy-benzyl, methylsulfonylbenzyl, aminomethylbenzyl, aminoethylbenzyl, dimethylamino-benzyl, pyrrolidinylbenzyl, (dimethyl)(pyrrolidinyl)benzyl, morpholinylbenzyl, (dimethyl)(morpholinyl)benzyl, piperazinylbenzyl, acetylaminoethylbenzyl, phenylethyl, chlorophenylethyl, methylpyrazolyl, ethylpyrazolyl, (methyl)(tetrahydropyranyl)-pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, pyridinylmethyl and aminopyridinyl-methyl. Further examples include fluorocyclopropyl, cyclopropyloxadiazolyl and isopropyltriazolyl.

[0121] R 6Preferred values thereof include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl.

[0122] R 6 Selected values thereof include methylpyrazolyl, ethylpyrazolyl, methyloxadiazolyl and ethyloxadiazolyl.

[0123] R 6 Selected examples of specific values thereof include fluorocyclopropyl, fluorophenyl, methylpyrazolyl, methyloxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl and isopropyltriazolyl.

[0124] R 6 Typical examples of specific values thereof include fluorophenyl, methyl-pyrazolyl, methyloxadiazolyl and ethyloxadiazolyl.

[0125] R 6 Notable values thereof include methylpyrazolyl, methyloxadiazolyl and ethyl-oxadiazolyl.

[0126] R 6 Specific examples of selected values thereof include methyloxadiazolyl and ethyloxadiazolyl.

[0127] In the first embodiment, R 6a represents C 1-6 alkyl. In the second embodiment, R 6a represents optionally substituted C 3-9 cycloalkyl.

[0128] Typically, R 6a represents C 1-6 alkyl, or R 6a represents cyclobutyl, and this group may be substituted with one or more substituents.

[0129] R 6a Typical examples of the above-mentioned optional substituents include halogen, cyano, nitro, C 1-6 alkyl, trifluoro-methyl, hydroxy, hydroxy(C 1-6 )alkyl, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoro-methoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, amino(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, 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, independently selected from 1, 2 or 3 substituents.

[0130] R 6a Suitable examples of the above-mentioned optional substituents include 1, 2 or 3 substituents independently selected from halogen.

[0131] R 6aTypical 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.

[0132] R 6a Suitable examples of the above specific substituents include one, two or three substituents independently selected from fluoro.

[0133] R 6a Exemplary examples of specific values of include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl and difluorocyclobutyl.

[0134] Typically, R 6a represents cyclobutyl.

[0135] Typically, R 6b represents hydrogen or methyl.

[0136] In the first embodiment, R 6b represents hydrogen. In the second embodiment, R 6b represents C 1-6 alkyl, particularly methyl.

[0137] Typically, R 6c represents hydrogen or methyl.

[0138] In the first embodiment, R 6c represents hydrogen. In the second embodiment, R 6c represents C 1-6 alkyl, particularly methyl.

[0139] Alternatively, the moiety -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, and any of these groups may be substituted by one or more substituents.

[0140] For the heterocyclic moiety -NR 6b R 6c Examples of suitable substituents selected thereon include C 1-6 alkyl, C 1-6 alkylsulfonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, cyano, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, C 2-6 alkylcarbonyl - amino, C 2-6 alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonyl - amino and aminocarbonyl.

[0141] For the heterocyclic moiety -NR 6b R 6cSelected examples of the above specific substituents include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy-carbonylamino, methylsulfonylamino, and aminocarbonyl.

[0142] One subclass of the compounds according to the invention is represented by the compounds of formula (IIA) and their N-oxides, as well as their pharmaceutically acceptable salts,

Chemical formula

[0143] Generally, R 16 represents methyl (-CD 3 including) or ethyl.

[0144] In a first embodiment, R 16 represents methyl. In a first aspect of that embodiment, R 16 represents -CH 3 In a second aspect of that embodiment, R 16 represents -CD 3 In a second embodiment, R 16 represents ethyl. In a third embodiment, R 16 represents isopropyl. In a fourth embodiment, R 16 represents cyclopropyl.

[0145] Another subclass of the compounds according to the invention is represented by the compounds of formula (IIB) and their N-oxides, as well as their pharmaceutically acceptable salts,

Chemical formula

[0146] In the first embodiment, X represents CH. In the second embodiment, R 16 represents N.

[0147] Another subclass of the compounds according to the present invention is represented by the compounds of formula (IIC) and their N-oxides, and their pharmaceutically acceptable salts,

Chemical formula

[0148] Suitably, R 26 represents fluoro or chloro, especially fluoro.

[0149] In the first embodiment, R 26 represents fluoro. In the second embodiment, R 26 represents chloro.

[0150] Another subclass of the compounds according to the present invention is represented by the compounds of formula (IID) and their N-oxides, and their pharmaceutically acceptable salts,

Chemical formula

[0151] Suitably, R 36 represents fluoro or chloro, especially fluoro.

[0152] In the first embodiment, R 36 represents fluoro. In the second embodiment, R 36 represents chloro.

[0153] The specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying examples, as well as their pharmaceutically acceptable salts and solvates.

[0154] The compounds according to the present invention are useful for the treatment and / or prevention of various human diseases including inflammatory and autoimmune disorders.

[0155] The compounds according to the invention are useful for the treatment and / or prevention of pathological disorders mediated by pro-inflammatory IL-17 cytokines or associated with an increase in the level of pro-inflammatory IL-17 cytokines. In general, the pathological conditions are infections (viruses, bacteria, fungi and parasites), endotoxin 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 spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, pyoderma gangrenosum, celiac disease, gallbladder disease, folliculitis, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, type I diabetes, Lyme arthritis, meningoencephalitis, immune-mediated inflammatory disorders of the central and peripheral nervous systems, such as multiple sclerosis and Guillain-Barré syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, scleroderma or systemic sclerosis, fibrotic disorders including cancer (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 disorders such as myocardial infarction and heart diseases including atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria and pain (in particular pain associated with inflammation), selected from the group consisting of.

[0156] International Publication No. WO 2009 / 089036 discloses that a modulator of IL-17 activity can be administered to inhibit 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 present invention are useful for the treatment and / or prevention of IL-17-mediated ocular inflammatory disorders, particularly IL-17-mediated ocular surface inflammatory disorders including dry eye syndrome. Ocular surface inflammatory disorders include dry eye syndrome, full-thickness corneal transplantation, corneal transplantation, lamellar or partial-thickness transplantation, selective endothelial transplantation, corneal neovascularization, artificial cornea surgery, corneal ocular surface inflammatory conditions, conjunctival scarring disorders, autoimmune conditions of the eye, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye diseases, conjunctivitis and bacterial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjogren's syndrome, Sjogren's syndrome-related keratoconjunctivitis sicca, non-Sjogren's syndrome-related keratoconjunctivitis sicca, keratitis sicca, xerosis syndrome, xerophthalmia, tear film disorders, reduced tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.

[0157] Exemplarily, the compounds of the present invention may be useful for the treatment and / or prevention of pathological disorders selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer and pain (particularly pain associated with inflammation).

[0158] Suitably, the compounds of the present invention are useful for the treatment and / or prevention of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis or ankylosing spondylitis.

[0159] The present invention also provides a pharmaceutical composition comprising the compound according to the present invention as described above or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable carriers.

[0160] The pharmaceutical composition according to the present invention can 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.

[0161] In the case of oral administration, the pharmaceutical composition can be in the form of tablets, troches or capsules prepared by conventional means using pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc or silica), disintegrants (e.g., potato starch or sodium glycolate), or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can be in the form of, for example, solutions, syrups or suspensions, or can be provided as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations can also contain buffering salts, flavoring agents, coloring agents or sweetening agents, as required.

[0162] Preparations for oral administration can be suitably formulated to provide controlled release of the active compound.

[0163] In the case of buccal administration, the composition can be in the form of tablets or troches formulated in a conventional manner.

[0164] The compounds according to the invention can be formulated for parenteral administration by injection, for example by bolus injection or infusion. Injectable formulations can be provided in unit dosage forms, for example glass ampoules, or in multi-dose containers, for example glass vials. The injectable composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and can contain formulations such as suspending agents, stabilizers, preservatives and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example sterile pyrogen-free water, before use.

[0165] In addition to the above formulations, the compounds according to the invention can also be formulated as depot formulations. Such long-acting formulations can be administered by implantation or intramuscular injection.

[0166] In the case of nasal administration or administration by inhalation, the compounds according to the invention can be conveniently delivered in the form of a pressurized pack or aerosol spray for a nebulizer using a suitable propellant, for example dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

[0167] The composition can, if desired, be provided in a pack or dispenser device which can contain one or more unit dosage forms containing the active ingredient. The pack or dispenser device can be accompanied by instructions for administration.

[0168] For topical administration, the compounds according to the invention can be conveniently formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, liquid petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds according to the invention can be formulated as suitable lotions containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.

[0169] For ocular administration, the compounds according to the invention can be conveniently formulated as a micronized suspension in isotonic pH-adjusted sterile physiological saline, which may or may not contain a preservative, such as a bactericide or a fungicide, such as phenylmercuric nitrate, benzalkonium chloride or chlorhexidine acetate. Alternatively, for ocular administration, the compounds according to the invention can be formulated as an ointment, such as petrolatum.

[0170] For rectal administration, the compounds according to the invention can be conveniently formulated as suppositories. These can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the active ingredient. Such materials include, for example, cocoa butter, beeswax and polyethylene glycol.

[0171] The amount of the compound according to the invention required for the prevention or treatment of a particular condition will vary depending on the compound selected and the condition of the patient being treated. However, generally, the daily dosage will be, for oral or buccal administration, depending on body weight, from about 10 ng / kg to 1000 mg / kg, typically from 100 ng / kg to 100 mg / kg, for example about 0.01 mg / kg to 40 mg / kg; for parenteral administration, depending on body weight, from about 10 ng / kg to 50 mg / kg; and for nasal administration or administration by inhalation or insufflation, from about 0.05 mg to about 1000 mg, for example about 0.5 mg to about 1000 mg.

[0172] If desired, the compounds according to the invention can be co-administered with another pharmaceutically active agent, such as an anti-inflammatory molecule.

[0173] The compound of formula (I) is 6 -CO 2 a carboxylic acid of H or a salt thereof, such as its lithium salt, can be prepared by a process comprising reacting it with a compound of formula (III),

Chemical formula

[0174] The reaction is conveniently achieved in the presence of a coupling agent and a base. Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. Suitable bases include organic amines, such as trialkylamines like N,N-diisopropylethylamine, or pyridine. The reaction is conveniently carried out at ambient temperature or elevated temperature in a suitable solvent, such as a cyclic ether like tetrahydrofuran; or an aprotic dipolar solvent like N,N-dimethylformamide or N,N-dimethylacetamide; or a chlorinated solvent like dichloromethane; or an organic ester solvent like ethyl acetate.

[0175] R 6 When represents C 1-6 alkyl, such as methyl, the compound of formula (I) above can be prepared by a process comprising reacting a compound of formula R 6 -COCl, such as acetyl chloride, with a compound of formula (III) as defined above. The reaction is conveniently achieved in the presence of a base. Suitable bases include organic amines, such as trialkylamines like N,N-diisopropylethylamine. The reaction is conveniently carried out at ambient temperature in a suitable solvent, such as a cyclic ether like tetrahydrofuran.

[0176] R 6 When represents -OR 6a the compound of formula (I) above can be prepared by a two-step process comprising (i) reacting a compound of formula R 6a -OH, preferably in the presence of a base, such as an organic amine like triethylamine, with N,N'-disuccinimidyl carbonate, 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, such as a chlorinated solvent like dichloromethane, or an organic nitrile solvent like acetonitrile.

[0177] The intermediate of formula (III) can be prepared by removing the N-protecting group R from the compound of formula (IV), p [Chemical formula] wherein A, E, R 3 , R 4a and R 4b are as defined above, and R p represents an N-protecting group.

[0178] The N-protecting group R p is preferably tert-butoxycarbonyl (BOC), in which case its removal can be conveniently carried out by treatment with an acid, such as a mineral acid like hydrochloric acid, or an organic acid like trifluoroacetic acid.

[0179] Alternatively, the N-protecting group R p may be benzyloxycarbonyl, in which case its removal can be conveniently carried out by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of a hydrogenation catalyst, such as palladium on charcoal or palladium hydroxide on charcoal.

[0180] In another procedure, the compound of formula (I) above is (i) saponifying the compound of formula (V) and [Chemical formula] (wherein A, E, R 4a , R 4b and R 6 are as defined above, and Alk 1 represents C 1-4 alkyl, such as methyl, ethyl or tert-butyl), (ii) under the same conditions as described above for the reaction between the compound (III) and a carboxylic acid of formula R 6 -CO 2 H, and then reacting the resulting carboxylic acid derivative with a formula R 3 ​Reaction with a compound of -H, and can be prepared by a two-step process including

[0181] Alk 1 When represents methyl or ethyl, the saponification reaction in step (i) is generally carried out by treatment with a base. Suitable bases include inorganic hydroxides such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. The reaction is conveniently carried out at ambient temperature or elevated temperature in water and a suitable organic solvent such as a cyclic ether such as tetrahydrofuran, or C 1-4 alkanols such as methanol.

[0182] Alternatively, when Alk 1 represents tert-butyl, the saponification reaction in step (i) can generally be carried out by treatment with an acid such as an organic acid such as trifluoroacetic acid. The reaction is conveniently carried out at ambient temperature in a suitable organic solvent such as a chlorinated solvent such as dichloromethane.

[0183] An alternative coupling agent that can be usefully used in step (ii) includes 2-chloro-1-methylpyridinium iodide.

[0184] In another procedure, the compound of formula (I) above can be prepared by a process including cyclizing a compound of formula (VIA) or (VIB),

Chemical formula

[0185] The cyclization of the compound (VIA) or (VIB) is conveniently carried out by heating in a suitable medium such as acetic acid or trifluoroacetic acid.

[0186] The intermediate of the above formula (VIA) or (VIB) can be prepared by reacting a compound of formula (VII) with a carboxylic acid of formula (VIII) or a salt thereof, such as its lithium salt.

Chemical formula

[0187] The intermediate of formula (VIII) can be prepared by a two-step procedure involving (i) reacting a carboxylic acid of formula R 6 -CO 2 H with a compound of formula (IX)

Chemical formula

[0188] and (ii) saponification of the material obtained under the same conditions as described above for the saponification of compound (V). Alternative coupling agents that can be usefully employed in step (i) include N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU).

[0189] The intermediate of the above formula (IV) is prepared by the following steps, (i) reacting a compound of formula (VII) as defined above with a compound of formula (X), [Chemical formula] (wherein R p is as defined above, and the reaction between compounds (VII) and (VIII) is under the same conditions as described above) (ii) cyclization of the material obtained under conditions similar to those described above for the cyclization of compound (VIA) or (VIB), and can be prepared by a two-step procedure involving

[0190] Alternatively, the intermediate of formula (III) above can be prepared by the following steps: (i) reacting a compound of formula (XI) with a compound of formula (XII) to obtain [Chemical formula] (wherein A, E, R 3 , R 4a and R 4b are as defined above, and R q represents an N-protecting group) a compound of formula (XIII), and [Chemical formula] (wherein A, E, R 3 , R 4a , R 4b and R q are as defined above) (ii) removal of the tert-butylsulfinyl group and the N-protecting group R q from compound (XIII), and can be prepared by a procedure involving

[0191] The N-protecting group R q is suitably 2-(trimethylsilyl)ethoxymethyl.

[0192] Step (i) is suitably carried out by treating compound (XI) with a base, such as an organic base like n-butyllithium, and subsequently reacting it with compound (XII). The reaction is conveniently achieved in a suitable solvent, such as a cyclic ether like tetrahydrofuran.

[0193] N-protecting group R q When is 2-(trimethylsilyl)ethoxymethyl, the removal of the tert-butylsulfinyl group and the N-protecting group R from compound (XIII) in step (ii) q can both be achieved by treatment with an acid, such as a mineral acid like hydrochloric acid, or an organic acid like trifluoroacetic acid.

[0194] N-protecting group R q When is 2-(trimethylsilyl)ethoxymethyl, the intermediate of formula (XI) above is prepared by the following steps, (i) the reaction of the compound of formula (VII) defined above with formic acid, and (ii) the reaction of the material thus obtained with 2-(trimethylsilyl)ethoxymethyl chloride, and can be prepared by a procedure comprising.

[0195] Step (i) is conveniently carried out at an elevated temperature.

[0196] Step (ii) is suitably carried out by treating the reactant with a base, such as an inorganic base like sodium hydride, or an organic amine like N,N-diisopropylethylamine.

[0197] The intermediate of formula (XII) above can be prepared by reacting 4,4-difluorocyclohexylcarboxaldehyde with 2-methyl-2-propanesulfinamide. The reaction is suitably carried out in the presence of pyridinium p-toluenesulfonate and magnesium sulfate. The reaction is conveniently carried out at ambient temperature in a suitable solvent, such as a chlorinated solvent like dichloromethane.

[0198] The intermediate of formula (V) above is of the formula R 6 -CO2 It can be prepared by reacting a carboxylic acid of H with a compound of formula (XIV),

Chemical formula

[0199] The above intermediate of formula (XIV) is prepared by the following steps, (i) Reacting a compound of formula (X) as defined above with a compound of formula (XV),

Chemical formula

[0200] In an alternative method, the above intermediate of formula (IV) is prepared by the following steps, (i) Reacting a compound of formula (X) as defined above with a compound of formula (XV) under the same conditions as described above for the reaction between compound (VII) and (VIII), (ii) cyclization of the materials obtained under conditions similar to those described above for the cyclization of compound (VIA) or (VIB), and (iii) saponification of the materials obtained under the same conditions as those described above for the saponification of compound (V), and (iv) the carboxylic acid derivative thus obtained and a compound of formula R 3 -H, and the reaction between compound (III) and a carboxylic acid of formula R 6 -CO 2 H under the same conditions as those described above, and can be prepared by a four-step procedure including.

[0201] If they are not commercially available, the starting materials of formula (VII), (IX), (X) and (XV) can be prepared by methods similar to those described in the accompanying examples or by standard methods well known in the art.

[0202] It will be understood that any compound of formula (I) initially obtained from any of the above processes can, where appropriate, subsequently be synthesized into further compounds of formula (I) by techniques known in the art. By way of example, a compound containing an N-BOC moiety (BOC is an abbreviation for tert-butoxy-carbonyl) can be converted to the corresponding compound containing an N-H moiety by treatment with an acid, such as a mineral acid, such as hydrochloric acid, or an organic acid, such as trifluoroacetic acid.

[0203] Compounds containing an N-H functional group can typically be alkylated, such as methylated, by treatment with a suitable alkyl halide, such as iodomethane, in the presence of a base, such as an inorganic carbonate, such as sodium carbonate.

[0204] Compounds containing an N-H functional group can typically be acylated, for example acetylated, by treatment with a suitable acyl halide, such as acetyl chloride, in the presence of a base, such as an organic base like N,N-diisopropylethylamine or triethylamine. Similarly, compounds containing an N-H functional group can typically be acylated, for example acetylated, by treatment with a suitable acyl anhydride, such as acetic anhydride, in the presence of a base, such as an organic base like triethylamine.

[0205] Similarly, compounds containing an N-H functional group can typically be, in the presence of a base, such as an organic base, such as triethylamine, with a suitable 1-4 alkylsulfonyl chloride reagent, such as methylsulfonyl chloride, to convert to the corresponding compound containing an N-S(O) 2 Alk 1 functional group (wherein Alk 1 is as defined above).

[0206] Similarly, compounds containing an N-H functional group can typically be converted to the corresponding compounds containing a carbamate or urea moiety, respectively, by treatment with a suitable chloroformate or carbamoyl chloride reagent in the presence of a base, such as an organic base like triethylamine or N,N-diisopropylethylamine. Alternatively, compounds containing an N-H functional group can typically be converted to the corresponding compounds containing a urea moiety by treatment with a suitable amine-substituted (3-methylimidazol-3-ium-1-yl)methanone iodide derivative in the presence of a base, such as an organic base like triethylamine. Alternatively, compounds containing an N-H functional group can typically be, in the presence of a base, such as an organic base like triethylamine, with a suitable isocyanate derivative Alk 1 -N=C=O to convert to the corresponding compound containing a urea moiety N-C(O)N(H)Alk 1 (wherein Alk 1 is as defined above).

[0207] Compounds containing an N-H functional group can be converted to the corresponding compounds containing an N-C(H) functional group by treatment with a suitable aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride.

[0208] C 1-4 Alkoxycarbonyl moiety -CO 2 Alk 1 (wherein Alk 1 is as defined above) can be converted to the corresponding compound containing a carboxylic acid (-CO 2 H) moiety by treatment with a base such as an alkali metal hydroxide salt like lithium hydroxide. Alternatively, a compound containing a tert-butoxy-carbonyl moiety can be converted to the corresponding compound containing a carboxylic acid (-CO 2 H) moiety by treatment with trifluoroacetic acid.

[0209] A compound containing a carboxylic acid (-CO 2 H) moiety can be converted to the corresponding compound containing an amide moiety by treatment with a suitable amine under the same conditions as described above for the reaction between compound (III) and a carboxylic acid of the formula R 6 -CO 2 H.

[0210] C 1-4 Alkoxycarbonyl moiety -CO 2 Alk 1 (wherein Alk 1 is as defined above) can be converted to the corresponding compound containing a hydroxymethyl (-CH 2 OH) moiety by treatment with a reducing agent such as lithium aluminum hydride.

[0211] C 1-4 Alkylcarbonyloxy moiety -OC(O)Alk 1 (wherein Alk 1Compounds containing (as defined above), for example acetoxy, can be converted to the corresponding compounds containing a hydroxy (-OH) moiety by treatment with a base, such as an alkali metal hydroxide salt like sodium hydroxide.

[0212] Compounds containing a halogen atom, for example bromo, can be converted to the corresponding compounds containing an optionally substituted aryl, heterocycloalkenyl or heteroaryl moiety by treatment with an appropriately substituted aryl, heterocycloalkenyl or heteroaryl boronic acid or its cyclic ester formed from an organic diol, such as pinacol, 1,3 - propanediol or neopentyl glycol. The reaction is typically carried out in the presence of a transition metal catalyst and a base. The transition metal catalyst can be [1,1’ - bis(diphenylphosphino)ferrocene]dichloropalladium(II). Alternatively, the transition metal catalyst may be tris(dibenzylideneacetone)dipalladium(0), which may be advantageously used in combination with 2 - dicyclohexylphosphino - 2’,4’,6’ - triisopropylbiphenyl (XPhos). Preferably, the base can be an inorganic base such as sodium carbonate or potassium carbonate.

[0213] Compounds containing a halogen atom, for example bromo, can be converted to the corresponding compounds containing an optionally substituted aryl or heteroaryl moiety by a two - step procedure involving (i) reaction with bis(pinacolato)diboron and (ii) reaction of the resulting compound with an appropriately substituted bromoaryl or bromoheteroaryl derivative. Step (i) is conveniently carried out in the presence of a transition metal catalyst such as [1,1’ - bis(diphenylphosphino)ferrocene] - dichloropalladium(II) and potassium acetate. Step (ii) is conveniently carried out in the presence of a transition metal catalyst such as [1,1’ - bis(diphenylphosphino)ferrocene] - dichloropalladium(II) and a base, such as an inorganic base like sodium carbonate or potassium carbonate.

[0214] Compounds containing a cyano (-CN) moiety can be converted to the corresponding compounds containing a 1-aminoethyl moiety by a two-step process comprising (i) reaction with methylmagnesium chloride, preferably in the presence of titanium(IV) isopropoxide, and (ii) treatment of the resulting material with a reducing agent such as sodium borohydride. When an excess of methylmagnesium chloride is used in step (i), the corresponding compounds containing a 1-amino-1-methylethyl moiety are obtained.

[0215] Compounds containing a moiety-S-can be converted to the corresponding compounds containing a moiety-S(O)(NH)-by treatment with (diacetoxyiodo)benzene and ammonium carbamate.

[0216] Compounds containing a C=C double bond can be converted to the corresponding compounds containing a CH-CH single bond by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst, such as palladium on charcoal.

[0217] Compounds containing an aromatic nitrogen atom can be converted to the corresponding compounds containing an N-oxide moiety by treatment with a suitable oxidizing agent, such as 3-chloroperbenzoic acid.

[0218] If a mixture of products is obtained from any of the above processes for the preparation of the compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography using silica and / or alumina in combination with a suitable solvent system, for example.

[0219] When a mixture of stereoisomers is produced by the above-described methods for preparing the compounds according to the invention, these isomers can be separated by conventional techniques. In particular, if it is desired to obtain a specific enantiomer of a compound of formula (I), this can be prepared from the corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, such as salts, can be produced by reaction of a mixture of enantiomers of formula (I), such as a racemate, with a suitable chiral compound, such as a chiral base. The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer can be recovered, for example, by treatment with an acid if the diastereomer is a salt. In another resolution process, the racemate of formula (I) can be separated using chiral HPLC. Further, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the above processes. Alternatively, a specific enantiomer can be obtained by performing enantioselective enzymatic biotransformation, such as ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolyzed acid from the unreacted ester enantiomer. Chromatography, recrystallization, and other conventional separation procedures can also be used with the intermediates or final products if it is desired to obtain specific geometric isomers of the invention.

[0220] During any of the above synthetic sequences, it may be necessary and / or desirable to protect any sensitive or reactive groups of any of the molecules involved. This can be achieved by conventional protecting group means, for example, as described in Greene’s Protective Groups in Organic Synthesis, ed. P.G.M. Wuts, John Wiley & Sons, 5 th edition, 2014. The protecting groups can be removed at any convenient subsequent stage using methods known in the art.

[0221] The compounds according to the present invention potently inhibit the ability of IL-17A to bind to IL-17RA. Thus, when tested in the following IL-17 FRET assay, the compounds of the present invention have a pIC 50 value of 5.0 or greater, generally 6.0 or greater, usually 7.0 or greater, typically 7.2 or greater, suitably 7.5 or greater, ideally 7.8 or greater, and preferably 8.0 or greater (pIC 50 is equal to -log 10 [IC 50 , and since IC 50 is expressed as a molar concentration, those skilled in the art will understand that the higher the numerical value of pIC 50 , the more active the compound).

[0222] Furthermore, certain compounds according to the present invention potently inhibit the IL-6 release of IL-17 induction from human dermal fibroblasts. Indeed, when tested in the HDF cell line assay described below, the compounds of the present invention have a pIC 50 value of 5.0 or greater, generally 6.0 or greater, usually 7.0 or greater, typically 7.2 or greater, suitably 7.5 or greater, ideally 7.8 or greater, and preferably 8.0 or greater (as described above, those skilled in the art will understand that the higher the numerical value of pIC 50 , the more active the compound).

[0223] IL-17 FRET assay The purpose of this assay is to test the ability of a compound to disrupt the interaction between IL-17A and the soluble IL-17 receptor A (IL-17RA). In this assay, the ability of a compound to inhibit the binding of IL-17A to IL-17RA is measured.

[0224] The IL-17AA-TEV-human Fc construct was expressed in the CHO SXE cell line and purified by protein A chromatography and size exclusion. The protein was labeled with an amine-reactive AlexaFluor647 dye (Thermo Fisher #A20006) according to the manufacturer's instructions.

[0225] Soluble IL-17RA(33-317)-HKH-TEV-Fc was expressed in the Expi HEK293 cell line and purified by protein A chromatography and size exclusion. The Fc tag was cleaved by TEV to produce IL-17RA(33-317)-HKH, and the protein was labeled with amine-reactive terbium (Thermo Fisher #PV3581).

[0226] The following solutions were prepared in assay buffer [Dulbecco's PBS (Sigma #14190-094), 0.05% P20 (Thermo Scientific #28320), 1 mg / mL BSA (Sigma #A2153-500G)]. For IL-17A assay · 5 nM IL-17A-Fc-AF647 · 5 nM IL-17RA-HKH-Tb

[0227] The compound was serially diluted with DMSO, and then an aqueous diluent was added to a 384-well dilution plate (Greiner #781281) to obtain a 25% DMSO solution.

[0228] IL-17A (10 μL) was added to a black low-volume assay plate (Costar #4511), and the diluted compound (5 μL) was transferred from the aqueous dilution plate. The cytokine and the compound were incubated for 1 hour, and then IL-17RA (10 μL) was added. The plate was wrapped with foil and incubated at room temperature for 18 - 20 hours with gentle shaking (<400 rpm), and then read on a Perkin Elmer Envision plate reader (excitation: 330 nm; emission 615 / 645 nm).

[0229] The final assay concentrations were 2 nM IL-17A-AF647 and 2 nM IL-17RA-Tb, 5% DMSO.

[0230] When tested in the IL-17 FRET assay as described above, the compounds of the attached examples were found to exhibit the following pIC 50 values.

Table 1

[0231] Inhibition of IL-17A-induced IL-6 release from skin fibroblast cell lines The purpose of this assay is to test the neutralizing ability against IL-17 protein in human primary cell lines. Stimulation of normal human dermal fibroblasts (HDF) with IL-17 alone results in a very weak signal, but in combination with certain other cytokines such as TNFα, a synergistic effect can be observed in the production of the inflammatory cytokine, namely IL-6.

[0232] HDF was stimulated with IL-17A (50 pM) in combination with TNF-α (25 pM). The resulting IL-6 response was then measured using a homogeneous time-resolved FRET kit from Cisbio. The kit utilizes two monoclonal antibodies, one labeled with Eu-cryptate (donor) and the other labeled with d2 or XL665 (acceptor). The intensity of the signal is proportional to the concentration of IL-6 present in the sample (the ratio is calculated by 665 / 620×104).

[0233] In this assay, the ability of compounds to inhibit IL-17-induced IL-6 release from human skin fibroblasts is measured.

[0234] HDF cells (Sigma#106-05n) were cultured in complete medium (DMEM + 10% FCS + 2 mM L-glutamine) and maintained in tissue culture flasks using standard techniques. Cells were harvested from tissue culture flasks in the morning of the assay using TrypLE (Invitrogen#12605036). TrypLE was neutralized using complete medium (45 mL), and the cells were centrifuged at 300×g for 3 minutes. The cells were resuspended in complete medium (5 mL), counted, and adjusted to a concentration of 3.125×10 4 cells / mL, and then added to a 384-well assay plate (Corning#3701) at 40 μL / well. The cells were incubated at 37°C / 5% CO 2It was left standing for at least 3 hours and adhered to the plate.

[0235] After the compound was serially diluted with DMSO, the aqueous diluent was placed in a 384-well dilution plate (Greiner #781281), 5 μL from the titration plate was transferred to 45 μL of complete medium, and mixed to obtain a solution containing 10% DMSO.

[0236] A mixture of TNFα and IL-17 cytokines was prepared in complete medium at a final concentration of TNFα 25 pM / IL-17A 50 pM, and then 30 μL of the solution was added to a 384-well reagent plate (Greiner #781281).

[0237] 10 μL from the aqueous dilution plate was transferred to the reagent plate containing 30 μL of diluted cytokine to obtain a 2.5% DMSO solution. The compound was incubated with the cytokine mixture at 37 °C for 1 hour or 5 hours (the incubation times of specific test compounds are shown in the following table). After incubation, 10 μL was transferred to the assay plate to obtain a 0.5% DMSO solution, and then incubated at 37 °C / 5% CO 2 for 18 - 20 hours.

[0238] From the Cisbio IL-6 FRET kit (Cisbio #62IL6PEB), europium cryptate and Alexa665 were diluted in the reconstitution buffer and mixed 1:1 according to the kit instructions. 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 for 3 hours with gentle shaking (<400 rpm) and then read on a Synergy Neo2 plate reader (excitation: 330 nm; emission: 615 / 645 nm).

[0239] When tested in the HDF cell line assay as described above, the compounds in the attached examples were found to show the following pIC 50 values.

Table 2

Example

[0240] The following examples illustrate the preparation of the compounds according to the present invention.

[0241] 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 TBME: tert-Butyl methyl ether DAST: (Diethylamino)sulfur trifluoride IPA: Isopropyl alcohol DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene LiHMDS: Lithium bis(trimethylsilyl)amide T3P®: 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate XPhos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium(0) h: hour r.t.: room temperature M: mass RT: retention time HPLC: High performance liquid chromatography LCMS: Liquid chromatography mass spectrometry SFC: Supercritical Fluid Chromatography

[0242] Analysis and preparation method Method 1 Agilent, pH 3, run for 3 minutes. Stationary phase: X-Bridge C18 Waters (2.1×20 mm, 2.5 μm column) Column temperature: 40 °C Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water Mobile phase B: Acetonitrile + 5% water + 0.1% formic acid Flow rate: 1 mL / 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

[0243] Method 2 Agilent, pH 3, run for 6 minutes. Stationary phase: X-Bridge C18 Waters (2.1×20 mm, 2.5 μm column) Column temperature: 40 °C Mobile phase A: 10 mM ammonium formate + 0.1% formic acid in water Mobile phase B: Acetonitrile + 5% water + 0.1% formic acid Flow rate: 1 mL / 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

[0244] Method 3 Agilent, pH 10, run for 3 minutes. Stationary phase: X-Bridge C18 Waters (2.1×20 mm, 2.5 μm column) 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: Pump 1: 1 mL / 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

[0245] Method 4 MSQ1 / MSQ2 low pH uPLC-MET-uHPLC-AB-101, run for 7 minutes. Stationary phase: Phenomenex Kinetix-XB C18 (2.1×100 mm, 1.7 μm column) Column temperature: 40 °C Mobile Phase A: Water + 0.1% formic acid Mobile Phase B: Acetonitrile + 0.1% formic acid Flow rate: 0.6 mL / min Gradient program: Time A% B% 0.00 95.00 5.00 5.30 0.00 100.00 5.80 0.00 100.00 5.82 95.00 5.00 7.00 95.0 5.00

[0246] Method 5 Gilson low pH fractionation method (Early Elute method). Stationary phase: Waters Sunfire C18 (30x100 mm, 10 μm column) (Part No. 186003971) Mobile Phase A: Water + 0.1% formic acid Mobile Phase B: Acetonitrile + 0.1% formic acid Flow rate: 40 mL / min Gradient program: Time A% B% 0.00 90 10 0.55 90 10 14.44 5 95 16.55 5 95 16.75 90 10

[0247] Method 6 MET / CR / 1602 - uPLC IPC high pH method; injection volume of 1 μL. Stationary phase: Waters BEH C18 (30 × 2.1 mm, 1.7 μm column) (Section 186002349) Column temperature: 40 °C Mobile phase A: 2 mM ammonium bicarbonate buffered to pH 10 Mobile phase B: Acetonitrile Flow rate: 1 mL / min Gradient program: Time A% B% 0.00 95 5 0.75 0 100 0.85 0 100 0.90 95 5 1.00 95 5

[0248] Method 7 pH 10. Stationary phase: Phenomenex Gemini NmX - C18 (2 × 20 mm, 3 μm column) Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1 mL / 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

[0249] Method 8 MSDXT, pH 10. Stationary phase: Waters Acquity UPLC BEH C18 (2.1×50 mm, 1.7 μm column) 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: 1.5 mL / 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

[0250] Method 9 pH 10. Stationary phase: Phenomenex Gemini NX-C18 (2×20 mm, 3 μm column) 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 mL / 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

[0251] Method 10 Chiral HPLC conditions: Chiralpak AD-H (4.6 x 250 mm, 5 μm column) 85:15 heptane:EtOH (1 mL / min)

[0252] Method 11 Purification was carried out by SFC using a Chiralpak IB (250×20 mm, 5 μm column) eluting with an isocratic 5% MeOH (+0.1% NH 4 OH) method (ABPR 60 bar) at a flow rate of 100 mL / min for 16 minutes using a Waters Prep 100 fractionation system in conjunction with a Waters SQD2 mass spectrometer.

[0253] Method 12 Purification was carried out by SFC using a Chiralcel OJ (250×20 mm, 5 μm column) eluting with an isocratic 3% MeOH (+0.1% NH 4 OH) method (ABPR 120 bar) at a flow rate of 100 mL / min for 16 minutes using a Waters Prep 100 fractionation system in conjunction with a Waters SQD2 mass spectrometer.

[0254] Method 13 Chiral purification was performed using a Waters FractionLynx automated purification system linked to a Waters SQD2 mass spectrometer with an XBridge Prep Phenyl OBD (19×150 mm, 5 μm column) at a flow rate of 20 mL / min with a focus gradient of 45 - 60% over 15 minutes. Solvent A: 10 mM ammonium bicarbonate + 0.1% ammonia solution in water Solvent B: Acetonitrile + 5% water + 0.1% ammonia solution

[0255] Method 14 Gilson high pH fractionation method 1500 μL injection using UV detection (215 nM). Stationary phase: Waters Xbridge C18 (30×100 mm, 10 μm column) (Section 186003930) Mobile phase A: Water + 0.2% ammonium hydroxide Mobile phase B: Acetonitrile + 0.2% ammonium hydroxide Flow rate: 40 mL / min Gradient program: Time A% B% 0.00 70 30 0.55 70 30 11.00 5 95 13.10 5 95 13.31 70 30

[0256] Method 15 Chiral purification was carried out using a Waters Prep100 fractionlynx system in conjunction with a Waters SQD2 mass spectrometer, with a run time of 14 minutes, eluting with 5% MeOH (+0.1% NH 4 OH) isocratic method (ABPR 60 bar) using a Chiralpak-IB (250×21.2 mm, 5 μm column) at a flow rate of 100 mL / min.

[0257] Method 16 Chiral analysis was carried out using a Waters UPC2 system in conjunction with a Waters QDa mass spectrometer, with a run time of 8 minutes, eluting with 5% MeOH (+0.1% NH 4 OH) isocratic method (ABPR 120 bar) using a Chiralpak-IB (150×4.6 mm, 3 μm column) at a flow rate of 3 mL / min.

[0258] Method 17 Chiral purification was carried out using a Waters Prep100 fractionlynx system in conjunction with a Waters SQD2 mass spectrometer, with a run time of 7.5 minutes, eluting with isocratic 10% MeOH (+0.1% NH 4 OH) method (ABPR 120 bar) using a Chiralpak IC (250×20 mm, 5 μm column) at a flow rate of 100 mL / min.

[0259] Method 18 Chiral analysis was performed using a Waters UPC2 system in conjunction with a Waters QDa mass spectrometer with a run time of 6.5 minutes, eluting with 10% MeOH(+0.1% NH 4 OH) isocratic method (ABPR 120 bar) using a Chiralpak-IB (150×4.6 mm, 3 μm column) at a flow rate of 3 mL / min.

[0260] Method 19 Waters Prep SFC80, with a Pirkle (R,R) Whelk-01 (5 mm, 250×21.1 mm column) as the stationary phase and CO 2 / MeOH (70 / 300) as the mobile phase, a flow rate of 50 mL / min (100 bar), and 40 °C.

[0261] Method 20 Preparative chiral LC was performed on a Gilson system equipped with 321 / 322 pumps, a GX-241 autosampler, 171 / 172 detectors, and a preparative FC fraction collector. The purity and / or enantiomeric purity and identity determined by UV (210 - 400 nm) were confirmed by MS. Stationary phase: CSH: 100×30 mm, 5 μm column Flow rate: 40 mL / min Gradient: Over 20 minutes, from 95:5 acetonitrile / H 2 O(+0.1% formic acid) to 5:95 acetonitrile / H 2 O(+0.1% formic acid).

[0262] Method 21 Gilson low pH preparative method. Stationary phase: Waters Sunfire C18 (30x100 mm, 10 μm column) (Part No. 186003971) Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% formic acid Flow rate: 40 mL / min Gradient program: Time A% B% 0.00 70 30 0.55 70 30 11.00 5 95 13.10 5 95 16.31 70 30

[0263] Method 22 The chiral LC fraction collection was performed on a Gilson system equipped with 321 / 322 pumps, a GX-241 autosampler, 171 / 172 detectors, and a fraction collection FC. The purity and / or enantiomeric purity and identity determined by UV (210 - 400 nm) were confirmed by MS. Stationary phase: Chiralpak AD-H, 4.6 x 250 mm, 5 μm column Flow rate: 40 mL / min Gradient: 90:10 heptane:ethanol

[0264] Method 23 Purification was carried out using a Chiralpak IB, 250 x 21.2 mm, 5 μm column, with a flow rate of 100 mL / min, eluting in an isocratic 5% EtOH (+10 mM ammonium formate) method (ABPR 60 bar) for 20 minutes of run time using a Waters Prep100 fractionlynx system in conjunction with a Waters SQD2 mass spectrometer.

[0265] Method 24 Stationary phase: Phenomenex Gemini NX-C18 (2 x 20 mm, 3 μm column) Mobile phase A: 10 mM ammonium formate + 0.1% formic acid solution in water Mobile phase B: Acetonitrile + 5% water + 0.1% formic acid solution Flow rate: 1 mL / 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

[0266] Method 25 In cooperation with a Waters QDa mass spectrometer, chiral purification was performed by HPLC using a Regis (R,R)-Whelk-1 250x21.1 mm, 5 μm column (temperature 40 °C) eluting with a 3 - 40% MeOH (+0.1% NH 4 OH) gradient (ABPR 60 bar) on a Waters Prep150 fractionlynx system with a run time of 7.5 minutes.

[0267] Method 26 In cooperation with a Waters QDa mass spectrometer, chiral analysis was performed by HPLC using a Regis (R,R)-Whelk-1 250x4.6 mm, 5 μm column (temperature 40 °C) eluting with a 3 - 40% MeOH (+0.1% NH 4 OH) method (ABPR 120 bar) on a Waters UPC2 Acquity system with a run time of 6.5 minutes.

[0268] Method 27 In cooperation with a Waters QDa mass spectrometer, chiral purification was performed by HPLC using a Regis (R,R)-Whelk-1 250x21.1 mm, 5 μm column (temperature 40 °C) eluting with a 3 - 40% EtOH (+0.1% NH 4 OH) gradient (ABPR 60 bar) on a Waters Prep150 fractionlynx system with a run time of 7.5 minutes.

[0269] Method 28 In cooperation with a Waters QDa mass spectrometer, chiral analysis was performed by HPLC using a Regis (R,R)-Whelk-1 250x4.6 mm, 5 μm column (temperature 40 °C) eluting with a 3 - 40% EtOH (+0.1% NH 4 OH) method (ABPR 120 bar) on a Waters UPC2 Acquity system with a run time of 6.5 minutes.

[0270] Method 29 Chiral purification was performed by SFC using a Chiralpak AD-H, 10×250 mm, 5 μm column, a flow rate of 15 mL / min, and eluting with 5% MeOH and 95% CO 2 in the mobile phase.

[0271] Method 30 Chiral analysis was performed by SFC using a Chiralpak AD-H, 4.6x250 mm, 5 μm column, a flow rate of 4 mL / min, and eluting with 5% MeOH and 95% CO 2 in the mobile phase.

[0272] Method 3 1 Chiral purification was carried out by preparative SFC using a Kromasil 2EP column with a gradient of 3 - 40% MeOH + 0.1% NH 4 OH.

[0273] Method 32 In conjunction with a Waters QDa mass spectrometer, chiral analysis by HPLC was performed on a Waters UPC2 Acquity system with a run time of 6.5 minutes using a Regis (R,R)-Whelk-1 250×4.6 mm, 5 μm column (temperature 35 °C, 3 - 40% MeOH (+0.1% NH 4 OH) method (ABPR 120 bar) for elution.

[0274] Method 33 Chiral purification was performed by SFC using a Chiralpak AD-H, 10×250 mm, 5 μm column, eluting with 10% EtOH and 90% CO 2 in the mobile phase at a flow rate of 15 mL / min.

[0275] Method 34 Chiral analysis was performed by SFC using a Chiralpak AD-H, 4.6×250 mm, 5 μm column, eluting with 15% EtOH and 85% CO 2 in the mobile phase at a flow rate of 4 mL / min.

[0276] Method 35 Chiral purification was performed by SFC using a Chiralpak AD-H, 10×250 mm, 5 μm column eluting with 5% EtOH and 95% CO 2 at a flow rate of 10 mL / min and a run time of 15 minutes.

[0277] Method 36 Chiral analysis was performed by SFC using a Chiralpak AD-H, 4.6×250 mm, 5 μm column eluting with 5% EtOH and 95% CO 2 at a flow rate of 4 mL / min over a run time of 15 minutes.

[0278] Method 37 Chiral purification was performed by SFC using a Chiralpak AD-H, 10×250 mm, 5 μm column eluting with 5% EtOH and 95% CO 2 at a flow rate of 15 mL / min and a run time of 10 minutes.

[0279] Method 38 Chiral analysis was performed by SFC using a Chiralpak AD-H, 4.6×250 mm, 5 μm column eluting with 5% EtOH and 95% CO 2 at a flow rate of 4 mL / min over a run time of 10 minutes.

[0280] Method 39 Chiral purification was performed by HPLC using a Chiralpak AD-H, 20×250 mm, 5 μm column with a flow rate of 18 mL / min, eluting with 15% EtOH and 85% heptane.

[0281] Method 40 Chiral analysis was performed by HPLC using a Chiralpak AD-H, 4.6×250 mm, 5 μm, with a flow rate of 1 mL / min, eluting with 15% EtOH and 85% heptane.

[0282] Method 41 Chiral analysis was performed by SFC using a Chiralpak AD-H, 4.6 × 250 mm, 5 μm column, eluting with 10% EtOH and 90% CO 2 at a flow rate of 4 mL / min.

[0283] Intermediate 1 (2S)-2-(Benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid To a stirred solution of (2S)-2-amino-2-(4,4-difluorocyclohexyl)acetic acid hydrochloride (1.61 g, 6.66 mmol) and triethylamine (3.25 mL, 23.3 mmol) in DCM (26.6 mL) at 0 °C was added N-(benzyloxycarbonyloxy)succinimide (1.61 g, 6.33 mmol). The reaction mixture was warmed to room temperature and stirred for 4 h, then diluted with DCM (25 mL) and washed with 5% hydrochloric acid (50 mL) and water (50 mL). The combined organic extracts were passed through a phase separator and concentrated. Trituration with hexane (50 mL) gave the title compound (1.99 g, 91%) as a white solid. δ H( 300 MHz, DMSO-d 6 ) 12.70 (s, 1H), 7.09 (d, J 8.7 Hz, 1H), 7.43 - 7.26 (m, 5H), 5.04 (s, 2H), 4.00 (dd, J 8.7, 6.0 Hz, 1H), 2.12 - 1.55 (m, 7H), 1.52 - 1.19 (m, 2H).

[0284] Intermediate 2 (2S)-2-(tert-Butoxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid To a stirred solution of (2S)-2-amino-2-(4,4-difluorocyclohexyl)acetic acid hydrochloride (2.0 g, 8.71 mmol) in DCM (10 mL) were added triethylamine (4.3 mL, 30.5 mmol) and N-(tert-butoxycarbonyloxy)succinimide (1.72 g, 7.83 mmol). The resulting mixture was stirred at room temperature for 24 h, then diluted with DCM (200 mL), 5% hydrochloric acid (2 × 100 mL) and water (100 mL). The combined organic extracts were passed through a phase separator and concentrated. Trituration with hexane (100 mL) gave the title compound (2.0 g, 78%) as a white solid. δH( 300 MHz, DMSO-d 6 ) 12.60 (s, 1H), 7.09 (d, J 8.7 Hz, 1H), 3.91 (dd, J 8.5, 6.2 Hz, 1H), 2.08 - 1.92 (m, 2H), 1.92 - 1.54 (m, 5H), 1.51 - 1.16 (m, 11H).

[0285] Intermediate 3 Bromo(2-tert-butoxy-2-oxoethyl)zinc tert-Butyl 2-bromoacetate (45.0 mL, 0.31 mol) was added dropwise to a slurry of activated zinc (30.2 g, 0.46 mol) in THF (400 mL) at 60 °C over 1 hour. Exotherm was observed. The reaction mixture was stirred at 65 °C for 1 hour, then cooled to room temperature, and the excess zinc was allowed to settle. Assuming 100% conversion and that the resulting yellow solution is a 0.77 M solution in THF.

[0286] Intermediate 4 N,N-Dibenzyl-3-bromo-2-fluoro-6-nitroaniline To a stirred suspension of 1-bromo-2,3-difluoro-4-nitrobenzene (23.0 g, 96.6 mmol) and potassium carbonate (16.0 g, 116 mmol) in acetonitrile (250 mL) was added N-benzyl-1-phenylmethanamine (20.0 mL, 106 mmol). The suspension was stirred at 80 °C for 16 hours, then re-treated with N-benzyl-1-phenylmethanamine (2.0 mL, 10.4 mmol) and stirred at 80 °C for 1 hour. The mixture was filtered and then concentrated. The residue was purified by flash column chromatography eluting with a gradient of ethyl acetate in heptane to give the title compound (40.9 g, 85%) as an orange solid. δ H( 400 MHz, DMSO-d 6 ) 7.64 (dd, J 8.8, 6.5 Hz, 1H), 7.54 (dd, J 8.8, 1.6 Hz, 1H), 7.33 - 7.18 (m, 10H), 4.15 (s, 4H). LCMS (Method 1) [M + H] + m / z 415, 417, RT 2.25 minutes.

[0287] Intermediate 5 tert-Butyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]acetate Under nitrogen, to a stirred solution of intermediate 4 (63.0 g, 0.15 mol), XPhos (4.17 g, 8.74 mmol) and allyl(chloro)palladium dimer (1.61 g, 4.37 mmol) in THF (400 mL) was added intermediate 3 (0.77 M, 378 mL, 0.29 mol) dropwise. The mixture was stirred at 50 °C for 45 minutes, then cooled to 30 °C and quenched with saturated NH 4 Cl aqueous solution (200 mL) while maintaining the temperature at 20 °C - 30 °C. The combined mixture was diluted with EtOAc (200 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (50 mL). The organic fractions were combined, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of DCM in heptane to afford the title compound (65 g, 94%) as a yellow powder. δ H( 400 MHz, DMSO-d 6 ) 7.47 (dd, J 8.3, 1.1 Hz, 1H), 7.30 - 7.18 (m, 11H), 4.11 (s, 4H), 3.68 (d, J 1.3 Hz, 2H), 1.41 (s, 9H). LCMS (Method 1): [M+H] + m / z 451, RT 2.27 minutes.

[0288] Intermediate 6 tert-Butyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]prop-2-enoate To a solution of intermediate 5 (5.00 g, 11.1 mmol) in DMSO (25 mL) was added N,N,N’,N’-tetramethylmethanediamine (2.3 mL, 16.7 mmol), followed by acetic anhydride (3.5 mL, 36.6 mmol). The reaction mixture was stirred at room temperature for 21 hours, then diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic fractions were washed with water (3 × 50 mL), saturated NaHCO 3 aqueous solution (50 mL) and brine (50 mL), then dried over Na 2 SO 4It was dried and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (4.97 g, 97%) as a pale yellow solid. LCMS (Method 1): [M+H] + m / z 463.0, RT 2.32 minutes.

[0289] Intermediate 7 tert-Butyl 1-benzyl-3-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]pyrrolidine-3-carboxylate To a solution of Intermediate 6 (4.97 g, 10.7 mmol) and N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (4.1 mL, 16.1 mmol) in DCM (99 mL) was added TFA (81 μL, 1.09 mmol) at 0 °C. The mixture was warmed to room temperature, stirred for 16 h, and then concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (6.30 g, 98%) as a pale yellow solid. LCMS (Method 1): [M+H] + m / z 596, RT 2.05 minutes.

[0290] Intermediate 8 tert-Butyl 3-[4-amino-3-(dibenzylamino)-2-fluorophenyl]pyrrolidine-3-carboxylate To a stirred solution of Intermediate 7 (3.00 g, 5.04 mmol) in EtOH (40 mL) was added 10% Pd / C (50% wet, 2.0 g, 0.94 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 10 mL) and concentrated in vacuo to afford the title compound (1.60 g, 53%) as a pale orange solid. δ H( 400 MHz, DMSO-d 6)7.35 - 7.13(m, 10H), 6.78(t, J 8.5 Hz, 1H), 6.31(d, J 8.5 Hz, 1H), 5.06(br s, 2H), 4.13 - 3.88(m, 4H), 3.57(s, 1H), 3.09 - 2.81(m, 3H), 2.43 - 2.31(m, 1H), 2.08 - 1.92(m, 1H), 1.33 - 1.24(m, 9H). LCMS(Method 1): [M + H] + m / z 476, RT 1.80 minutes.

[0291] Intermediate 9 Di-tert-butyl 3-[4-amino-3-(dibenzylamino)-2-fluorophenyl]pyrrolidine-1,3-dicarboxylate To a stirred solution of Intermediate 8 (1.56 g, 2.62 mmol) in DCM (31 mL) was added DIPEA (884 μL, 5.06 mmol), followed by di - tert - butyldicarbonate (572 mg, 2.62 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with DCM (30 mL) and washed with saturated aqueous NH 4 Cl (30 mL). The organic fraction was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (1.33 g, 88%) as a pale orange solid. LCMS(Method 1): [M + H] + m / z 576, RT 2.27 minutes.

[0292] Intermediate 10 Di-tert-butyl 3-(3,4-diamino-2-fluorophenyl)pyrrolidine-1,3-dicarboxylate To a stirred solution of Intermediate 9 (1.33 g, 2.26 mmol) in EtOH (30 mL) was added 10% Pd / C (50% wet, 0.78 g, 0.366 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 10 mL) and concentrated in vacuo to afford the title compound (0.769 g, 86%) as an off - white solid. δ H( 500 MHz, DMSO - d6 ) 6.29 (t, J 3.7 Hz, 2H), 4.80 (s, 2H), 4.41 (s, 2H), 4.14 (t, J 10.4 Hz, 1H), 3.29 (s, 1H), 3.26 - 3.14 (m, 2H), 2.55 - 2.51 (m, 1H), 2.20 - 2.10 (m, 1H), 1.40 (d, J 6.6 Hz, 9H), 1.31 (s, 9H). LCMS (Method 1): [M - BOC - t Bu + H] + m / z 240.2, RT 1.86 minutes.

[0293] Intermediate 11 Di-tert-butyl 3-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyrrolidine-1,3-dicarboxylate A stirred solution of Intermediate 1 (697 mg, 2.13 mmol) and HATU (810 mg, 2.16 mmol) in DCM (20 mL) was added with DIPEA (1.0 mL, 5.73 mmol) and Intermediate 10 (766 mg, 1.94 mmol) at room temperature. The reaction mixture was stirred for 3 hours and then diluted with DCM (50 mL), and successively washed with saturated NH 4 Cl aqueous solution (50 mL), saturated NaHCO 3 aqueous solution (50 mL) and water (50 mL). The organic fractions were combined, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane. The obtained beige solid was dissolved in acetic acid (15 mL) and heated at 60 °C for 12 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to give the title compound (1.10 g, 83%) as a beige solid. δ H( 500 MHz, CD 3OD) 7.50 - 6.86 (m, 7H), 5.24 - 4.99 (m, 2H), 4.80 (d, J 8.0 Hz, 1H), 4.46 (d, J 10.9 Hz, 1H), 3.61 - 3.37 (m, 3H), 2.86 (d, J 22.6 Hz, 1H), 2.48 - 2.31 (m, 1H), 2.24 - 2.09 (m, 1H), 2.09 - 1.89 (m, 3H), 1.89 - 1.66 (m, 2H), 1.50 (d, J 7.9 Hz, 11H), 1.38 (s, 10H). LCMS (Method 1): [M + H] + m / z 687.1, RT 2.09 minutes.

[0294] Intermediate 12 Di-tert-butyl 3-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}pyrrolidine-1,3-dicarboxylate To a stirred solution of Intermediate 11 (1.10 g, 1.60 mmol) in EtOH (20 mL) was added 10% Pd / C (50% wet, 0.33 g, 0.155 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature for 1.5 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 20 mL) and concentrated in vacuo to afford the title compound (0.88 g, 99%) as an off-white solid. δ H( 500 MHz, CD 3 OD) 7.34 (d, J 8.5 Hz, 1H), 7.23 - 7.17 (m, 1H), 4.51 - 4.42 (m, 1H), 3.95 (d, J 7.3 Hz, 1H), 3.57 - 3.36 (m, 3H), 2.94 - 2.81 (m, 1H), 2.46 - 2.34 (m, 1H), 2.16 - 1.97 (m, 3H), 1.97 - 1.87 (m, 1H), 1.87 - 1.62 (m, 3H), 1.50 (d, J 7.9 Hz, 10H), 1.37 (d, J 1.3 Hz, 11H). LCMS (Method 1): [M + H] + m / z 553.0, RT 1.76 minutes.

[0295] Intermediate 13 Di-tert-butyl 3-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1,3-dicarboxylate A stirred suspension of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (128 mg, 0.99 mmol) and HATU (404 mg, 1.06 mmol) in DCM (10 mL) was added with DIPEA (44 μL, 0.25 mmol) at room temperature, followed by the addition of Intermediate 12 (500 mg, 0.91 mmol). The reaction mixture was stirred for 2 hours and then successively diluted with saturated NH 4 Cl aqueous solution (25 mL) and water (25 mL). The residue was extracted with EtOAc (2 × 50 mL). The combined organic fractions were washed with brine (50 mL) and dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (411 mg, 69%) as an off-white solid. δ H( 500 MHz, CD 3 OD) 7.41 - 7.32 (m, 1H), 7.26 - 7.19 (m, 1H), 5.27 (d, J 8.7 Hz, 1H), 4.46 (d, J 11.4 Hz, 1H), 3.55 - 3.38 (m, 3H), 2.93 - 2.83 (m, 1H), 2.53 (s, 3H), 2.44 - 2.28 (m, 2H), 2.19 - 1.99 (m, 3H), 1.94 - 1.70 (m, 3H), 1.50 (d, J 8.0 Hz, 11H), 1.37 (s, 9H). LCMS (Method 1): [M + H] + m / z 663.0, RT 2.06 minutes.

[0296] Intermediate 14 tert-Butyl 3-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-3-carboxylate To a stirred solution of Intermediate 13 (400 mg, 0.60 mmol) in DCM (8 mL) was added 4 M HCl in 1,4-dioxane (700 μL, 2.80 mmol). The mixture was stirred at room temperature for 3.5 hours and then quenched with saturated NaHCO 3 aqueous solution (25 mL) and extracted with 10% MeOH in DCM (3 × 20 mL). The organic fractions were combined and then dried over Na 2 SO 4It was dried and concentrated in vacuo to afford the title compound (335 mg, 99%) as an off-white solid. δ H( 500 MHz, CD 3 OD) 7.34 (d, J 8.5 Hz, 1H), 7.30 - 7.22 (m, 1H), 5.27 (d, J 8.7 Hz, 1H), 3.95 - 3.86 (m, 1H), 3.17 - 3.06 (m, 3H), 2.81 - 2.68 (m, 1H), 2.53 (s, 3H), 2.42 - 2.26 (m, 2H), 2.18 - 2.00 (m, 3H), 1.95 - 1.66 (m, 2H), 1.62 - 1.40 (m, 3H), 1.37 (d, J 1.3 Hz, 9H). LCMS (Method 1): [M + H] + m / z 563.0, RT 1.66 minutes.

[0297] Intermediate 15 3-tert-Butyl 1-methyl 3-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)pyrrolidine-1,3-dicarboxylate To a stirred solution of Intermediate 14 (167 mg, 0.30 mmol) and DIPEA (104 μL, 0.59 mmol) in DCM (4 mL) at 0 °C was added dropwise a solution of methyl chloroformate (21 μL, 0.27 mmol) in DCM (2 mL). The reaction mixture was stirred for 15 minutes. Additional methyl chloroformate (2.0 μL, 0.03 mmol) in DCM (0.2 mL) was added. The reaction mixture was stirred at 0 °C for 20 minutes and then diluted with DCM (5 mL) and washed with saturated NaHCO 3 aqueous solution (5 mL). The combined organic extracts were dried over Na 2 SO 4 and then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (140 mg, 76%) as an off-white solid. LCMS (Method 1): [M + H] + m / z 621.0, RT 1.94 minutes.

[0298] Intermediate 16 3-(2-{(S)-(4,4-Difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}-4-fluoro-1H-benzimidazol-5-yl)-1-(methoxycarbonyl)pyrrolidine-3-carboxylic acid, trifluoroacetate Intermediate 15 (130 mg, 0.21 mmol) was stirred in DCM (0.7 mL) and TFA (0.7 mL) at room temperature for 2.5 h. The reaction mixture was concentrated in vacuo to afford the title compound (130 mg, 91%) as a beige solid. δ H( 500 MHz, CD 3 OD) 7.38 - 7.31 (m, 1H), 7.31 - 7.22 (m, 1H), 5.19 (d, J 8.5 Hz, 1H), 4.47 - 4.38 (m, 1H), 3.66 - 3.57 (m, 3H), 3.54 - 3.43 (m, 2H), 3.42 - 3.35 (m, 1H), 2.89 - 2.78 (m, 1H), 2.40 (s, 3H), 2.38 - 2.31 (m, 1H), 2.31 - 2.18 (m, 1H), 2.08 - 1.90 (m, 3H), 1.83 - 1.62 (m, 2H), 1.55 - 1.28 (m, 3H). LCMS (Method 1): [M + H] + m / z 565.0, RT 1.74 minutes.

[0299] Intermediate 17 tert-Butyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluorobutanoate To a stirred solution of Intermediate 5 (1.00 g, 2.22 mmol) in THF (10 mL) was added NaH (60%, 98 mg, 2.45 mmol) in one portion at 5 °C. The reaction mixture was stirred for 15 min and then 2,2 - difluoroethyl trifluoromethanesulfonate (308 μL, 2.33 mmol) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 2 h, then treated with additional 2,2 - difluoroethyl trifluoromethanesulfonate (30 μL, 0.14 mmol) and stirred for 30 min. The resulting mixture was quenched with saturated NH 4 Cl aqueous solution (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 and then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 10% EtOAc in heptane to afford the title compound (1.00 g, 79%) as a pale oil. δ H( 500 MHz, CDCl 3)7.39 - 7.16(m, 11H), 7.04(dd, J 8.5, 6.7 Hz, 1H), 5.64(tt, J 56.4, 4.6 Hz, 1H), 4.22(s, 4H), 3.98(t, J 7.5 Hz, 1H), 2.70 - 2.54(m, 1H), 2.19 - 2.00(m, 1H), 1.42(s, 9H). LCMS(Method 2): [M + H] + m / z 515.0, RT 4.03 minutes.

[0300] Intermediate 18 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluorobutanoic acid Intermediate 17 (1.00 g, 1.94 mmol) was stirred in DCM (3.7 mL) and TFA (7.7 mL) at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound (0.89 g, 100%) as a pale orange oil. LCMS(Method 1): [M + H] + m / z 459.0, RT 2.05 minutes.

[0301] Intermediate 19 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-1-(3,3-difluoroazetidin-1-yl)-4,4-difluoro-butan-1-one To a stirred solution of Intermediate 18 (1.00 g, 1.96 mmol) and HATU (895 mg, 2.35 mmol) in DCM (10 mL) was added DIPEA (1.6 mL, 9.16 mmol) at room temperature. The reaction mixture was stirred for 5 minutes and then 3,3 - difluoroazetidine hydrochloride (305 mg, 2.35 mmol) was added. The reaction mixture was stirred for 1 hour and then diluted with DCM (50 mL) and washed with saturated NH 4 Cl aqueous solution (25 mL). The organic layer was dried over Na 2 SO 4 and then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to give the title compound (700 mg, 67%) as an orange solid. δ H( 500 MHz, CDCl 3)7.39(dd, J 8.5, 1.4 Hz, 1H), 7.26(s, 10H), 7.09(dd, J 8.5, 6.6 Hz, 1H), 5.69(tt, J 56.3, 4.3 Hz, 1H), 4.42 - 4.08(m, 7H), 3.96 - 3.88(m, 1H), 3.51(q, J 11.1 Hz, 1H), 2.73 - 2.55(m, 1H), 2.15 - 1.97(m, 1H). LCMS(Method 1): [M + H] + m / z 534.0, RT 2.12 minutes.

[0302] Intermediate 20 2-(3,4-Diamino-2-fluorophenyl)-1-(3,3-difluoroazetidin-1-yl)-4,4-difluorobutan-1-one To a stirred solution of Intermediate 19 (700 mg, 1.31 mmol) in EtOH (10 mL) was added 10% Pd / C (50% wet, 0.28 g, 0.132 mmol) all at once. The reaction mixture was purged and stirred vigorously at room temperature for 18 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 20 mL) and concentrated in vacuo to afford the title compound (420 mg, 99%) as a light pink solid. LCMS(Method 1): [M + H] + m / z 324.0, RT 1.40 minutes.

[0303] Intermediate 21 tert-Butyl N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]carbamate To a stirred solution of Intermediate 2 (424 mg, 1.45 mmol) and HATU (555 mg, 1.45 mmol) in DCM (10 mL) was added DIPEA (0.46 mL, 2.61 mmol) at room temperature, followed by Intermediate 20 (420 mg, 1.30 mmol). The reaction mixture was stirred for 1 h and then diluted with DCM (50 mL) and washed with saturated NH 4 Cl aqueous solution (50 mL). The combined organic phases were washed with Na 2 SO 4It was dried, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane. The resulting peach-colored solid was dissolved in acetic acid (6 mL) and heated at 60 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (395 mg, 52%) as an off-white solid. δ H( 500 MHz, CD 3 OD) 7.35 (br s, 1H), 7.27 - 7.16 (m, 1H), 5.87 (tt, J 56.6, 4.5 Hz, 1H), 4.78 - 4.51 (m, 2H), 4.49 - 4.15 (m, 3H), 4.15 - 3.90 (m, 1H), 2.80 - 2.66 (m, 1H), 2.38 - 2.19 (m, 1H), 2.16 - 1.89 (m, 4H), 1.89 - 1.63 (m, 2H), 1.59 - 1.04 (m, 12H). LCMS (Method 1): [M+H] + m / z 581.0, RT 1.93 minutes.

[0304] Intermediate 22 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-1-(3,3-difluoroazetidin-1-yl)-4,4-difluorobutan-1-one Intermediate 21 (395 mg, 0.680 mmol) was stirred in DCM (2 mL) and TFA (2 mL) at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO 3 aqueous solution and extracted with 10% MeOH in DCM (4 × 10 mL). The combined organic phases were dried over Na 2 SO 4 and then filtered and concentrated in vacuo to afford the title compound (325 mg, 99%) as an off-white solid. LCMS (Method 1): [M+H] + m / z 481.0, RT 1.54 minutes.

[0305] Intermediate 23 tert-Butyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4,4-trifluorobutanoate To a stirred mixture of KOH (0.12 g, 2.09 mmol), aqueous KOH solution (60%, 24 mL, 0.12 mol), Intermediate 5, and tetrabutylammonium bromide (0.67 g, 2.09 mmol) was added 1,1,1-trifluoro-2-iodoethane (0.41 mL, 4.17 mmol) all at once. The reaction mixture was stirred at 40 °C for 6 h, then cooled to room temperature and partitioned between water (40 mL) and DCM (40 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (1.04 g, 61%) as a yellow-orange solid. LCMS (Method 1): [M+H] + m / z 533, RT 2.33 minutes.

[0306] Intermediate 24 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4,4-trifluorobutanoic acid Intermediate 23 (65%, 1.00 g, 1.22 mmol) was stirred in DCM (3 mL) and TFA (2.7 mL) at room temperature for 18 h. The reaction mixture was concentrated in vacuo to afford the title compound (1.77 g, 100%, purity 60%) as a yellow-orange gum. LCMS (Method 1): [M+H] + m / z 477, RT 2.05 minutes.

[0307] Intermediate 25 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-1-(3,3-difluoroazetidin-1-yl)-4,4,4-trifluorobutan-1-one To a stirred solution of Intermediate 24 (purity 60%, 1.70 g, 2.14 mmol) and HATU (1.06 g, 2.80 mmol) in DCM (20 mL) was added DIPEA (5.6 mL, 32.1 mmol) at room temperature. The reaction mixture was stirred for 15 min, then 3,3-difluoroazetidine hydrochloride (0.37 g, 2.89 mmol) was added. The reaction mixture was stirred for 18 h, then diluted with saturated NaHCO 3 aqueous solution (40 mL) and DCM (40 mL). The phases were separated and the aqueous phase was extracted with DCM (2 × 40 mL). The combined organic phases were dried over Na 2 SO 4It was dried, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 30% EtOAc in heptane to afford the title compound (0.56 g, 47%) as an orange solid. δ H( 500 MHz, DMSO-d 6 ) 7.57 (d, J 8.5 Hz, 1H), 7.34 - 7.16 (m, 11H), 4.68 (q, J 11.8 Hz, 1H), 4.33 (q, J 12.6 Hz, 1H), 4.28 - 4.10 (m, 6H), 3.57 (q, J 11.4 Hz, 1H), 3.08 - 2.91 (m, 1H), 2.73 - 2.59 (m, 1H). LCMS (Method 1): [M+H] + m / z 552, RT 2.16 minutes.

[0308] Intermediate 26 2-(3,4-Diamino-2-fluorophenyl)-1-(3,3-difluoroazetidin-1-yl)-4,4,4-trifluorobutan-1-one To a stirred solution of Intermediate 25 (550 mg, 1 mmol) in EtOH (10 mL) was added 10% Pd / C (50% wet, 1.63 g, 0.80 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature for 3 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2×20 mL) and concentrated in vacuo to afford the title compound (0.34 g, 81%) as a clear purple oil. δ H( 500 MHz, DMSO-d 6 ) 6.37 - 6.21 (m, 2H), 4.84 (s, 2H), 4.74 (q, J 11.7 Hz, 1H), 4.45 (s, 2H), 4.39 - 4.14 (m, 2H), 4.03 - 3.81 (m, 2H), 3.08 - 2.90 (m, 1H), 2.60 - 2.39 (m, 1H). LCMS (Method 1): [M+H] + m / z 342, RT 1.55 minutes.

[0309] Intermediate 27 Benzyl N-[(1S)-2-{2-Amino-4-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3,3-trifluoropropyl]-3-fluoroanilino}-1-(4,4-difluorocyclohexyl)-2-oxoethyl]carbamate A stirred suspension of Intermediate 1 (338 mg, 1.03 mmol) and HATU (393 mg, 1.03 mmol) in DCM (3.5 mL) was added with DIPEA (0.35 mL, 1.99 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and then Intermediate 26 (333 mg, 0.80 mmol) in DCM (3.5 mL) was added. The reaction mixture was stirred for 18 hours and then diluted with saturated NaHCO 3 aqueous solution (30 mL) and DCM (30 mL). The phases were separated and the aqueous phase was extracted with DCM (2 × 30 mL). The combined organic phases were dried over Na 2 SO 4 and then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (0.51 g, 99%) as a reddish brown oil. δ H( 400 MHz, DMSO-d 6 ) 9.51 (d, J 4.5 Hz, 1H), 7.68 (d, J 7.9 Hz, 1H), 7.45 - 7.24 (m, 5H), 7.13 - 7.03 (m, 1H), 6.53 (t, J 8.0 Hz, 1H), 5.05 (s, 2H), 4.97 (s, 2H), 4.82 (q, J 11.9 Hz, 1H), 4.47 - 4.17 (m, 2H), 4.18 - 4.08 (m, 2H), 4.06 - 3.91 (m, 1H), 3.13 - 2.93 (m, 1H), 2.77 - 2.59 (m, 1H), 2.15 - 1.97 (m, 2H), 1.94 - 1.63 (m, 5H), 1.53 - 1.27 (m, 2H). LCMS (Method 1): [M + H] + m / z 651, RT 1.97 minutes.

[0310] Intermediate 28 Benzyl N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]carbamate Intermediate 27 (0.513 g, 0.79 mmol) was stirred in acetic acid (10 mL) at 75 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo and then saturated NaHCO 3Aqueous solution (30 mL) was carefully added. The aqueous phase was extracted with DCM (3 × 30 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 20% MeOH in DCM to afford the title compound (0.41 g, 82%) as a red solid. δ H( 400 MHz, DMSO-d 6 ) 12.70 (br s, 1H), 8.14 - 7.80 (m, 1H), 7.47 - 7.23 (m, 5H), 7.22 - 7.03 (m, 1H), 5.15 - 4.96 (m, 2H), 4.85 (q, J 12.3 Hz, 1H), 4.73 (t, J 8.2 Hz, 1H), 4.46 - 4.27 (m, 2H), 4.22 (q, J 11.8 Hz, 1H), 4.10 - 3.93 (m, 1H), 3.51 - 3.20 (m, 1H, obs.), 3.18 - 2.99 (m, 1H), 2.86 - 2.63 (m, 1H), 2.20 - 1.63 (m, 6H), 1.58 - 1.44 (m, 1H), 1.43 - 1.18 (m, 2H). LCMS (Method 1): [M + H] + m / z 633, RT 1.96 minutes.

[0311] Intermediate 29 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-1-(3,3-difluoroazetidin-1-yl)-4,4,4-trifluorobutan-1-one To a stirred solution of Intermediate 28 (0.41 g, 0.65 mmol) in EtOH (5 mL) and THF (5 mL) was added 10% Pd / C (50% wet, 0.207 g, 0.19 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature for 2 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 10 mL) and concentrated in vacuo to afford the title compound (0.35 g, 100%) as a purple oil. δ H( 400 MHz, DMSO-d 6)12.53(s,1H),7.30(d,J 8.3 Hz,1H),7.10(ddd,J 8.7,6.6,2.7 Hz,1H),4.84(q,J 11.7 Hz,1H),4.53 - 4.28(m,2H),4.30 - 4.14(m,1H),4.04 - 3.89(m,1H),3.88(d,J 5.9 Hz,1H),3.14 - 2.98(m,1H),2.84 - 2.63(m,1H),2.11 - 1.92(m,2H),1.94 - 1.65(m,4H),1.61 - 1.47(m,1H),1.42 - 1.24(m,2H).LCMS(Method 1):[M + H] + m / z 499,RT 1.59 minutes.

[0312] Intermediate 30 tert-Butyl 2-(3,4-diamino-2-fluorophenyl)-4,4,4-trifluorobutanoate To a stirred solution of Intermediate 23 (3.05 g, 5.27 mmol) in EtOH (50 mL) was added 10% Pd / C (50% wet, 1.12 g, 1.05 mmol) all at once. The reaction mixture was purged and stirred vigorously at room temperature for 18 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 50 mL) and concentrated in vacuo to afford the title compound (1.91 g, 97%) as a purple - brown oil. δ H( 500 MHz,DMSO - d 6 )6.31(s,2H),4.81(s,2H),4.44(s,2H),3.83(dd,J 8.2,5.9 Hz,1H),3.07 - 2.90(m,1H),2.51(dt,J 3.6,1.8 Hz,1H),1.34(s,9H).LCMS(Method 1):[M + H] + m / z 323,RT 1.84 minutes.

[0313] Intermediate 31 tert-Butyl 2-(3-amino-4-{[(2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)-acetyl]amino}-2-fluorophenyl)-4,4,4-trifluorobutanoate To a stirred solution of Intermediate 1 (2.16 g, 6.59 mmol) and HATU (2.51 g, 6.59 mmol) in DCM (25 mL) was added DIPEA (2.2 mL, 12.7 mmol) at room temperature. The reaction mixture was stirred for 15 minutes. Intermediate 30 (1.90 g, 5.07 mmol) was added as a solution in DCM (25 mL). The reaction mixture was stirred for 36 hours and then diluted with saturated NaHCO 3 aqueous solution (30 mL) and DCM (30 mL). The phases were separated and the aqueous phase was extracted with DCM (2 × 30 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (3.4 g, 99%) as an orange-brown solid. δ H( 500 MHz, DMSO-d 6 ) 9.51 (s, 1H), 7.76 - 7.63 (m, 1H), 7.51 - 7.18 (m, 5H), 7.08 (d, J 8.4 Hz, 1H), 6.53 (t, J 7.9 Hz, 1H), 5.06 (s, 2H), 4.96 (s, 2H), 4.19 - 4.09 (m, 1H), 3.99 (t, J 7.3 Hz, 1H), 3.16 - 2.95 (m, 1H), 2.74 - 2.56 (m, 1H), 2.14 - 1.95 (m, 2H), 1.95 - 1.58 (m, 5H), 1.53 - 1.22 (m, 11H). LCMS (Method 1): [M+H] + m / z 632, RT 2.10 minutes.

[0314] Intermediate 32 tert-Butyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4,4-trifluorobutanoate Intermediate 31 (3.35 g, 4.93 mmol) was stirred in DCM (30 mL) and TFA (0.73 mL, 9.87 mmol) at 40 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with DCM (50 mL) and then washed with 1 M aqueous NaOH solution (50 mL). The layers were separated using a phase separator and the organic phase was concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (3.1 g, 93%) as a reddish-brown solid. δ H(500 MHz, DMSO-d 6 ) 12.69 (s, 1H), 7.99 (s, 1H), 7.46 - 7.25 (m, 6H), 7.21 - 7.11 (m, 1H), 5.07 (d, J 12.6 Hz, 1H), 5.01 (d, J 12.6 Hz, 1H), 4.74 (t, J 8.1 Hz, 1H), 4.18 (t, J 7.1 Hz, 1H), 3.23 - 3.06 (m, 1H), 2.83 - 2.67 (m, 1H), 2.20 - 2.08 (m, 1H), 2.08 - 1.93 (m, 2H), 1.92 - 1.84 (m, 1H), 1.84 - 1.68 (m, 2H), 1.68 - 1.56 (m, 1H), 1.48 (d, J 10.5 Hz, 1H), 1.44 - 1.30 (m, 10H). LCMS (Method 1): [M + H] + m / z 614, RT 2.10 minutes.

[0315] Intermediate 33 tert-Butyl 2-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4,4-trifluorobutanoate To a stirred solution of Intermediate 32 (2.40 g, 3.56 mmol) in EtOH (36 mL) was added 10% Pd / C (50% wet, 1.52 g, 0.1712 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature for 18 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 20 mL) and concentrated in vacuo to afford the title compound (1.92 g, 100%) as a light brown foam. δ H( 500 MHz, DMSO-d 6 ) 12.46 (br s, 1H), 7.30 (d, J 8.3 Hz, 1H), 7.19 - 6.92 (m, 1H), 4.17 (t, J 6.5 Hz, 1H), 3.90 (d, J 5.9 Hz, 1H), 3.21 - 3.05 (m, 1H), 2.82 - 2.66 (m, 1H), 2.12 - 1.93 (m, 2H), 1.94 - 1.66 (m, 4H), 1.60 - 1.49 (m, 1H), 1.42 - 1.26 (m, 11H). LCMS (Method 1): [M + H] + m / z 480, RT 1.72 minutes.

[0316] Intermediate 34 tert-Butyl 2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4,4-trifluorobutanoate A stirred suspension of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (0.63 g, 4.9 mmol) and HATU (1.87 g, 4.93 mmol) in DCM (20 mL) was added with DIPEA (1.87 mL, 10.71 mmol) at room temperature. The reaction mixture was stirred for 15 minutes and then intermediate 33 (1.90 g, 3.61 mmol) in DCM (20 mL) was added. The reaction mixture was stirred for 18 hours and then quenched with saturated NaHCO 3 aqueous solution (40 mL) and stirred at room temperature for 20 minutes. The phases were separated using a phase separator and the organic phase was concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (2.0 g, 87%) as a yellow-orange oil. δ H( 500 MHz, DMSO-d 6 ) 12.79 (s, 1H), 9.68 (s, 1H), 7.60 - 7.26 (m, 1H), 7.25 - 7.00 (m, 1H), 5.20 (t, J 7.1 Hz, 1H), 4.18 (t, J 7.2 Hz, 1H), 3.22 - 3.04 (m, 1H), 2.84 - 2.67 (m, 1H), 2.49 (s, 3H), 2.39 - 2.24 (m, 1H), 2.16 - 1.93 (m, 3H), 1.91 - 1.72 (m, 2H), 1.69 - 1.54 (m, 1H), 1.49 - 1.21 (m, 11H). LCMS (Method 1): [M+H] + m / z 590, RT 2.16 minutes.

[0317] Intermediate 35 2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4,4-trifluorobutanoic acid, trifluoroacetate Intermediate 34 (1.99 g, 3.11 mmol) was stirred in DCM (10 mL) and TFA (10 mL) at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to afford the title compound (2.52 g, 100%) as a light brown foam. δ H( 500 MHz, DMSO-d 6)9.60(d, J 8.4 Hz, 1H), 7.28(d, J 8.4 Hz, 1H), 7.21 - 7.06(m, 1H), 5.11(t, J 8.3 Hz, 1H), 4.17 - 4.11(m, 1H), 3.14 - 2.99(m, 1H), 2.79 - 2.63(m, 1H), 2.39(s, 3H), 2.30 - 2.17(m, 1H), 2.05 - 1.85(m, 3H), 1.82 - 1.60(m, 2H), 1.55 - 1.41(m, 1H), 1.39 - 1.10(m, 3H). LCMS(Method 1): [M + H] + m / z 534, RT 1.89 minutes.

[0318] Intermediate 36 Methyl (2R)-2-{[2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4,4trifluorobutanoyl]-amino}-3-methylbutanoate To a stirred suspension of Intermediate 35 (200 mg, 0.29 mmol) and HATU (145 mg, 0.38 mmol) in DCM (2 mL) was added DIPEA (256 μL, 1.47 mmol) at room temperature. The reaction mixture was stirred for 15 minutes and then methyl D-valinate hydrochloride (64 mg, 0.38 mmol) in DCM (2 mL) was added. The reaction mixture was stirred for 18 hours and then quenched with saturated NaHCO 3 aqueous solution (4 mL) and stirred at room temperature for 20 minutes. The phases were separated using a phase separator and the organic phase was concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (a 1:1 mixture of diastereomers, 139 mg, 63%) as a white solid. δ H( 500 MHz, DMSO-d 6)12.73(s,1H),9.68(s,1H),8.58(dd,J 16.5,8.1 Hz,1H),7.49-7.26(m,1H),7.25-7.15(m,1H),5.18(d,J 6.4 Hz,1H),4.44(ddd,J 16.5,8.6,5.1 Hz,1H),4.27-4.09(m,1H),3.67-3.49(m,3H),3.17-2.98(m,1H),2.70-2.54(m,1H),2.49-2.41(m,3H),2.36-2.25(m,1H),2.12-1.91(m,4H),1.90-1.71(m,2H),1.58-1.50(m,1H),1.45-1.35(m,1H),1.35-1.22(m,2H),0.88(d,J 6.9 Hz,1H),0.87(d,J 6.9 Hz,1H),0.75-0.66(m,3H).LCMS(Method 4):[M+H] + m / z 647,RT 3.59,3.70 minutes.

[0319] Intermediate 37 (2R)-2-{[2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4,4-trifluorobutanoyl]amino}-3-methylbutanoic acid Intermediate 36 (135 mg, 0.18 mmol) was dissolved in THF (2.3 mL) and water (0.6 mL), and lithium hydroxide monohydrate (18.5 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then concentrated in vacuo, diluted with water (10 mL), and acidified to pH 2 with 1 M HCl. The aqueous phase was extracted with DCM:isopropanol (4:1, 3 × 15 mL). The combined organic phases were dried over MgSO 4 and then filtered and concentrated in vacuo to afford the title compound (1:1 mixture of diastereomers, 125 mg, 100%) as an off-white foam. δ H( 500 MHz, DMSO-d 6)12.51(br s,1H),9.68(dd,J 8.4,3.9 Hz,1H),8.45(dd,J 8.6,5.9 Hz,1H),7.36 - 7.23(m,2H),5.25 - 5.16(m,1H),4.53 - 4.42(m,1H),4.21 - 4.11(m,1H),3.15 - 3.00(m,1H),2.73 - 2.55(m,1H),2.48(s,3H),2.40 - 2.24(m,1H),2.13 - 1.93(m,4H),1.90 - 1.68(m,2H),1.61 - 1.49(m,1H),1.48 - 1.21(m,2H),0.88(d,J 6.8 Hz,3H),0.70(dd,J 6.8,3.7 Hz,3H).LCMS(Method 1):[M + H] + m / z 633,RT 1.88,1.92 minutes.

[0320] Intermediate 38 1-Benzyl-4-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]piperidine-4-carboxylate, sodium salt To a stirred mixture of KOH (4.21 g, 75.1 mmol), aqueous KOH (60%, 120 mL, 0.57 mol), Intermediate 5 (10 g, 20.90 mmol) and tetrabutylammonium bromide (10.12 g, 31.3 mmol) was added N - benzyl - 2 - chloro - N - (2 - chloroethyl)ethanamine hydrochloride (16.81 g, 62.6 mmol) in one portion. The reaction mixture was stirred at 50 °C for 18 h, then cooled to room temperature and partitioned between water (50 mL) and DCM (50 mL). The aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phases were dried over Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane. The resulting yellow - orange oil was stirred in DCM (10 mL) and TFA (20 mL) at room temperature for 96 h. The reaction mixture was concentrated in vacuo and saturated aqueous NaHCO 3 was carefully added. The aqueous phase was extracted with DCM (3 × 50 mL). The resulting off - white precipitate was filtered and then dried in vacuo at 40 °C for 1 h to give the title compound (2.15 g, 18%) as an off - white solid. δ H(500 MHz, DMSO-d 6 ) 7.45 (d, J 8.5 Hz, 1H), 7.37 - 7.15 (m, 16H), 4.12 (s, 4H), 3.49 (s, 2H), 2.91 (d, J 11.3 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.47 - 2.41 (m, 1H), 2.40 - 2.29 (m, 1H), 2.11 - 2.01 (m, 1H), 1.96 - 1.83 (m, 1H), 1.75 - 1.52 (m, 2H). LCMS (Method 1): [M + H] + m / z 554, RT 1.83 minutes.

[0321] Intermediate 39 {1-Benzyl-4-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]piperidin-4-yl}(3,3-difluoro-azetidin-1-yl)methanone A solution of Intermediate 38 (2.14 g, 3.72 mmol) and HATU (1.85 g, 4.86 mmol) in DCM (20 mL) was stirred, and DIPEA (3.2 mL, 18.6 mmol) was added at room temperature. The reaction mixture was stirred for 15 minutes, then 3,3 - difluoroazetidine hydrochloride (0.65 g, 5.02 mmol) was added. The reaction mixture was stirred for 18 hours, then diluted with saturated NaHCO 3 aqueous solution (30 mL) and DCM (50 mL). The phases were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phases were dried over Na 2 SO 4 and then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a 0 - 100% gradient of EtOAc in heptane to give the title compound (2.15 g, 89%) as an orange foam. δ H( 500 MHz, DMSO-d 6 ) 7.58 (d, J 8.6 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.35 - 7.15 (m, 15H), 4.85 - 4.18 (m, 2H), 4.16 (s, 4H), 3.72 (s, 2H), 3.39 (s, 2H), 2.58 - 2.41 (m, 2H), 2.32 - 2.20 (m, 2H), 2.20 - 2.08 (m, 2H), 1.96 - 1.80 (m, 2H). LCMS (Method 1): [M + H] + m / z 629, RT 1.84 minutes.

[0322] Intermediate 40 {4-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]piperidin-4-yl}(3,3-difluoroazetidin-1-yl)-methanone To a stirred solution of Intermediate 39 (2.04 g, 3.15 mmol) in anhydrous toluene (50 mL) was added methyl chloroformate (0.85 mL, 7.87 mmol). The reaction mixture was stirred at 100 °C for 18 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and heated at 85 °C for 2 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was partitioned between saturated NaHCO 3 aqueous solution (50 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were dried over Na 2 SO 4 then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 20% MeOH in DCM to afford the title compound (0.45 g, 24%) as a yellow oil. δ H( 500 MHz, DMSO-d 6 ) 8.26 (br s, 1H), 7.65 (d, J 8.5 Hz, 1H), 7.42 - 7.30 (m, 1H), 7.33 - 7.12 (m, 10H), 4.56 - 4.24 (m, 2H), 4.17 (s, 4H), 3.94 - 3.61 (m, 2H), 3.20 - 3.10 (m, 2H), 3.06 - 2.95 (m, 2H), 2.38 - 2.23 (m, 2H), 2.07 - 1.92 (m, 2H). LCMS (Method 1): [M + H] + m / z 539, RT 1.79 minutes.

[0323] Intermediate 41 tert-Butyl 4-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-4-(3,3-difluoroazetidine-1-carbonyl)piperidine-1-carboxylate To a stirred solution of Intermediate 40 (91%, 400 mg) in DCM (10 mL) were added di-tert-butyl dicarbonate (148 mg, 0.68 mmol), followed by triethylamine (0.19 mL, 1.35 mmol). The reaction mixture was stirred at room temperature for 40 minutes and then concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (474 mg, 99%) as a yellow-orange gum. δ H( 400 MHz, DMSO-d 6 )7.58 (d, J 8.0 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.32 - 7.15 (m, 10H), 4.57 - 4.11 (m, 6H), 3.98 - 3.51 (m, 2H), 3.47 - 3.24 (m, 1H, obs.), 2.21 - 2.04 (m, 2H), 1.86 - 1.73 (m, 2H), 1.69 - 1.56 (m, 1H), 1.39 (s, 9H), 0.98 - 0.77 (m, 2H). LCMS (Method 1): [M+H] + m / z 639, RT 2.20 minutes.

[0324] Intermediate 42 tert-Butyl 4-(3,4-diamino-2-fluorophenyl)-4-(3,3-difluoroazetidine-1-carbonyl)piperidine-1-carboxylate To a stirred solution of Intermediate 41 (470 mg, 0.66 mmol) in EtOH (10 mL) was added 10% Pd / C (50% wet, 0.141 g, 0.13 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 20 mL) and concentrated in vacuo to afford the title compound (0.3 g, 92%) as a brown solid. δ H( 500 MHz, DMSO-d 6 )6.43 - 6.29 (m, 2H), 4.87 (s, 2H), 4.46 (s, 2H), 4.29 - 4.03 (m, 2H), 3.70 (s, 2H), 3.56 - 3.48 (m, 2H), 3.38 - 3.20 (m, 2H, obs.), 2.20 - 2.06 (m, 2H), 1.82 - 1.71 (m, 2H), 1.39 (s, 9H). LCMS (Method 1): [M - tBu+H] + m / z 373, RT 1.71 minutes.

[0325] Intermediate 43 tert-Butyl 4-(3-amino-4-{[(2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetyl]amino}-2-fluorophenyl)-4-(3,3-difluoroazetidine-1-carbonyl)piperidine-1-carboxylate A stirred suspension of Intermediate 1 (255 mg, 0.779 mmol) and HATU (296 mg, 0.779 mmol) in DCM (3 mL) was added with DIPEA (0.26 mL, 1.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, and then Intermediate 42 (295 mg, 0.60 mmol) in DCM (3 mL) was added. The reaction mixture was stirred for 18 hours and then diluted with saturated NaHCO 3 aqueous solution (30 mL) and DCM (30 mL). The phases were separated, and the aqueous phase was extracted with DCM (2×30 mL). The combined organic phases were separated using a phase separator and then concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to give the title compound (0.44 g, 75%) as a reddish-brown oil. LCMS (Method 1): [M-BOC+H] + m / z 638, RT 2.02 minutes.

[0326] Intermediate 44 tert-Butyl 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4-(3,3-difluoroazetidine-1-carbonyl)piperidine-1-carboxylate Intermediate 43 (0.44 g, 0.45 mmol) was stirred in acetic acid (7.8 mL) at 75 °C for 3 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and then saturated NaHCO 3 aqueous solution (30 mL) was carefully added until foaming subsided. The aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were dried over Na 2 SO 4 and then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to give the title compound (0.32 g, 70%) as a light brown solid. δ H( 500 MHz, DMSO-d 6)12.71 (broad singlet, 1H), 7.99 (broad singlet, 1H), 7.48 - 7.24 (multiplet, 6H), 7.24 - 7.15 (multiplet, 1H), 5.06 (doublet, J = 12.6 Hz, 1H), 5.01 (doublet, J = 12.6 Hz, 1H), 4.74 (triplet, J = 8.2 Hz, 1H), 4.43 - 4.08 (multiplet, 2H), 3.93 - 3.45 (multiplet, 4H), 2.34 - 2.22 (multiplet, 2H), 2.21 - 2.08 (multiplet, 1H), 2.08 - 1.61 (multiplet, 9H), 1.57 - 1.44 (multiplet, 1H), 1.44 - 1.31 (multiplet, 11H). LCMS (Method 1): [M - t Bu + H] + m / z 664, RT 2.01 minutes.

[0327] Intermediate 45 tert-Butyl 4-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4-(3,3-difluoroazetidine-1-carbonyl)piperidine-1-carboxylate To a stirred solution of Intermediate 44 (0.31 g) in EtOH (5 mL) was added 10% Pd / C (50% wet, 0.129 g, 0.122 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature for 3.5 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 20 mL) and concentrated in vacuo to afford the title compound (0.28 g, 100%) as a pale brown oil. δ H( 500 MHz, DMSO-d 6 )12.57 (broad singlet, 1H), 7.31 (doublet, J = 8.5 Hz, 1H), 7.22 - 7.10 (multiplet, 1H), 4.57 - 4.00 (multiplet, 3H), 3.87 (doublet, J = 6.2 Hz, 1H), 3.80 - 3.52 (multiplet, 4H), 2.34 - 2.19 (multiplet, 2H), 2.10 - 1.62 (multiplet, 9H), 1.58 - 1.48 (multiplet, 1H), 1.40 (singlet, 11H). LCMS (Method 1): [M - t Bu + H] + m / z 530, RT 1.35 minutes.

[0328] Intermediate 46 tert-Butyl 4-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-piperidine-1-carboxylate A stirred suspension of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (76 mg, 0.59 mmol) and HATU (227 mg, 0.60 mmol) in DCM (2.5 mL) was added with DIPEA (226 μL, 1.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, and then intermediate 45 (275 mg, 0.44 mmol) in DCM (2.5 mL) was added. The reaction mixture was stirred for 2 hours and then diluted with saturated NaHCO 3 aqueous solution (20 mL) and DCM (20 mL). The phases were separated and the aqueous phase was extracted with DCM (2 × 20 mL). The combined organic phases were dried over Na 2 SO 4 and then filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to give the title compound (0.24 g, 73%) as a yellow oil. δ H( 500 MHz, DMSO-d 6 ) 12.90 (br s, 1H), 9.65 (br s, 1H), 7.36 (br s, 1H), 7.21 (t, J 7.6 Hz, 1H), 5.20 (d, J 8.1 Hz, 1H), 4.47 - 4.10 (m, 2H), 3.95 - 3.54 (m, 4H), 3.50 - 3.34 (m, 1H), 2.48 (s, 3H), 2.38 - 2.19 (m, 3H), 2.15 - 1.88 (m, 5H), 1.89 - 1.73 (m, 2H), 1.64 - 1.53 (m, 1H), 1.48 - 1.35 (m, 11H), 1.34 - 1.25 (m, 1H). LCMS (Method 1): [M - t Bu + H] + m / z 640, RT 1.97 minutes.

[0329] Intermediate 47 N,N-Dibenzyl-2,3-difluoro-6-nitroaniline To a stirred solution of 2,3,4-trifluoronitrobenzene (200 g, 1.13 mol) in acetonitrile (2 L) were added DIPEA (296 g, 2.29 mol) and dibenzylamine (245 g, 1.20 mol). The reaction mixture was stirred at 65 °C for 18 h, then TBME (2 L) and water (1 L) were added. The phases were separated and the organic fraction was washed with water (1 L), 5% HCl solution (1.6 L), 50% brine (1 L) and brine (600 mL). The organic fraction was dried over Na 2 SO 4 and concentrated in vacuo. The residue was dissolved in TBME (500 mL) while heating and isooctane (700 mL) was added. The mixture was cooled to room temperature and the title compound (310 g, 77%) was obtained by crystallization. δ H( 300 MHz, DMSO-d 6 ) 7.69 (m, 1H), 7.45 - 7.20 (m, 11H), 4.20 (s, 4H). LCMS (Method 9): [M+H] + m / z 355.0, RT 3.03 minutes.

[0330] Intermediate 48 1-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-3,3-difluorocyclobutanecarbonitrile To a stirred solution of 3,3-difluorocyclobutanecarbonitrile (700 mg, 5.98 mmol) in THF (15 mL) in an ice bath was added 1 M LiHMDS in THF (6.0 mL, 5.98 mmol), followed by intermediate 47 (1.41 g, 3.99 mmol). The mixture was warmed to room temperature and stirred for 16 h, then quenched with saturated NH 4 Cl aqueous solution and extracted with EtOAc (2 × 20 mL). The organic fractions were combined and dried over Na 2 SO 4 . The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to give the title compound (242 mg, 12%) as a yellow oil. δ H( 400 MHz, DMSO-d 6)7.66(dd, J 8.5, 1.3 Hz, 1H), 7.45(dd, J 8.4, 7.4 Hz, 1H), 7.31 - 7.19(m, 10H), 4.16(s, 4H), 3.56(tt, J 13.3, 5.9 Hz, 2H), 3.47 - 3.34(m, 2H). LCMS(Method 4): [M + H] + m / z 452.1, RT 4.5 minutes.

[0331] Intermediate 49 1-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-3,3-difluorocyclobutanoic acid An aqueous sodium hydroxide solution (5M, 0.77 mL, 3.86 mmol) and Intermediate 48 (242 mg, 0.48 mmol) were stirred in EtOH (5 mL) at 70 °C for 4 hours and then at room temperature for 40 hours. The solution was concentrated in vacuo, adjusted to pH 1 with 1M HCl (5 mL), and extracted with DCM (3 × 5 mL). The organic fractions were combined, passed through a phase separator, and concentrated in vacuo to give the title compound (226 mg, 95%) as an orange solid. δ H( 500 MHz, DMSO-d 6 )7.47(d, J 8.4 Hz, 1H), 7.33 - 7.17(m, 11H), 4.09(s, 4H), 3.00 - 2.88(m, 2H). LCMS(Method 3): [M + H] + m / z 471, RT 1.74 minutes.

[0332] Intermediate 50 [1-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-3,3-difluorocyclobutyl](3,3-difluoro-azetidin-1-yl)methanone At room temperature, HATU (208 mg, 0.55 mmol) was added to a stirred solution of DIPEA (239 μL, 1.37 mmol), Intermediate 49 (226 mg, 0.46 mmol), and 3,3-difluoroazetidine hydrochloride (65 mg, 0.50 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 45 minutes and then washed with water (1 × 5 mL). The aqueous layer was extracted with DCM (2 × 5 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (247 mg, 86%) as a yellow oil. δ H( 400 MHz, DMSO-d 6 )7.64 - 7.53 (m, 2H), 7.32 - 7.15 (m, 10H), 4.41 - 4.25 (m, 2H), 4.15 (s, 4H), 3.84 - 3.68 (m, 2H), 3.54 - 3.40 (m, 2H), 3.10 - 2.97 (m, 2H). LCMS (Method 1): [M + H] + m / z 546, RT 2.11 minutes.

[0333] Intermediate 51 [1-(3,4-Diamino-2-fluorophenyl)-3,3-difluorocyclobutyl](3,3-difluoroazetidin-1-yl)-methanone To a stirred solution of Intermediate 50 (247 mg, 0.45 mmol) in EtOH (4 mL) was added 10% Pd / C (50% wet with water, 80 mg, 0.04 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 10 mL) and concentrated in vacuo to afford the title compound (129 mg, 85%) as a brown solid. δ H( 400 MHz, DMSO-d 6 )6.52 (t, J 8.4 Hz, 1H), 6.35 (d, J 8.3 Hz, 1H), 4.92 (s, 2H), 4.49 (s, 2H), 4.35 - 4.19 (m, 2H), 3.98 - 3.80 (m, 2H), 3.45 - 3.34 (m, 2H), 3.00 - 2.85 (m, 2H). LCMS (Method 1): [M + H] +m / z 336, RT 1.45 minutes.

[0334] Intermediate 52 Benzyl N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3-difluorocyclobutyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]carbamate HATU (176 mg, 0.46 mmol) was added to a stirred solution of Intermediate 51 (129 mg, 0.39 mmol), Intermediate 1 (150 mg, 0.46 mmol), and DIPEA (134 μL, 0.77 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred for 2 hours and then washed with water (5 mL). The aqueous layer was extracted with DCM (5 mL). The organic layers were combined, passed through a phase separator, and concentrated in vacuo. The resulting crude oil was stirred in acetic acid (2.5 mL) at 50 °C for 16 hours. The solution was concentrated in vacuo and then diluted with EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed with saturated brine (1 × 5 mL), then dried over 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (180 mg, 67%) as a brown solid. δ H( 400 MHz, DMSO-d 6 ) 13.11 - 12.52 (m, 1H), 8.04 - 7.89 (m, 1H), 7.41 - 7.27 (m, 6H), 5.09 - 4.96 (m, 2H), 4.72 (t, J 8.2 Hz, 1H), 4.38 - 4.20 (m, 2H), 4.01 - 3.88 (m, 2H), 3.63 - 3.47 (m, 2H), 3.24 - 3.07 (m, 2H), 2.17 - 1.92 (m, 3H), 1.91 - 1.56 (m, 4H), 1.52 - 1.28 (m, 3H). LCMS (Method 1): [M+H] + m / z 627, RT 1.94 minutes.

[0335] Intermediate 53 (1-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-3,3-difluorocyclobutyl)(3,3-difluoroazetidin-1-yl)methanone To a stirred solution of intermediate 52 (180 mg, 0.26 mmol) in EtOH (4 mL) was added 10% Pd / C (50% wet with water, 46 mg, 0.02 mmol) in one portion. The reaction mixture was purged and stirred vigorously at room temperature for 18 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 10 mL) and concentrated in vacuo. The resulting brown glass was purified by flash column chromatography (KP-NH) eluting with a gradient of MeOH in DCM to afford the title compound (64 mg, 43%) as a colorless glass. LCMS (Method 1): [M+H] + m / z 493, RT 1.54 minutes.

[0336] Intermediate 54 tert-Butyl 4-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]tetrahydropyran-4-carboxylate To a stirred solution of NaH (purity 60%, 9.23 g, 0.23 mol) in DMA (400 mL) was added intermediate 5 (40 g, 88.8 mmol) portionwise at 5 °C. The mixture was stirred for 10 min and then 1-iodo-2-(2-iodoethoxy)ethane (14 mL, 0.10 mol) was added dropwise. The resulting mixture was stirred at room temperature for 16 h and then cooled in an ice bath and quenched with saturated NH 4 Cl aqueous solution. The mixture was extracted with TBME (2 × 300 mL). The organic fractions were combined, washed with saturated brine (50 mL) and then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of EtOAc in heptane to afford the title compound (37.6 g, 67%) as a yellow solid. δ H( 500 MHz,CDCl 3 )7.36(dd,J 8.7,1.4 Hz,1H),7.30-7.17(m,10H),7.15-7.10(m,1H),4.21-4.15(m,4H),3.86-3.76(m,4H),2.33(d,J 13.5 Hz,2H),2.01-1.92(m,2H),1.44(s,9H).LCMS(Method 1):[M+H] +m / z 521, RT 2.26 minutes.

[0337] Intermediate 55 tert-Butyl 4-[4-amino-3-(dibenzylamino)-2-fluorophenyl]tetrahydropyran-4-carboxylate Intermediate 54 (36.9 g, 65.9 mmol) was dissolved in EtOH (700 mL) and EtOAc (300 mL), and 10% Pd / C (50% wet, 21.1 g, 9.89 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature for 20 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 100 mL) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of EtOAc in heptane to give the title compound (21.6 g, 67%) as an off-white solid. δ H( 400 MHz, DMSO-d 6 ) 7.28 - 7.16 (m, 10H), 6.78 (t, J 8.6 Hz, 1H), 6.32 (d, J 8.5 Hz, 1H), 5.03 (s, 2H), 4.11 - 3.90 (m, 4H), 3.70 - 3.49 (m, 4H), 2.15 - 2.05 (m, 2H), 1.86 - 1.75 (m, 2H), 1.33 (s, 9H). LCMS (Method 1): [M+H] + m / z 491, RT 2.19 minutes.

[0338] Intermediate 56 tert-Butyl 4-(3,4-diamino-2-fluorophenyl)tetrahydropyran-4-carboxylate Intermediate 55 (21.6 g, 44.0 mmol) was dissolved in EtOH (300 mL), and 10% Pd / C (50% wet, 9.37 g, 4.40 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature for 16 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 100 mL) and concentrated in vacuo to give the title compound (12.93 g, 90%) as a pale pink powder. δ H( 400 MHz, DMSO-d 6)6.38 - 6.27 (m, 2H), 4.59 (s, 4H), 3.71 (dt, J 11.5, 3.9 Hz, 2H), 3.59 - 3.48 (m, 2H), 2.23 - 2.11 (m, 2H), 1.92 - 1.78 (m, 2H), 1.35 (s, 9H). LCMS (Method 1): [M - t Bu + H] + m / z 255, RT 1.63 minutes.

[0339] Intermediate 57 tert-Butyl 4-(3-amino-4-{[(2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)-acetyl]amino}-2-fluorophenyl)tetrahydropyran-4-carboxylate HATU (6.89 g, 18.1 mmol) was added portionwise at room temperature to a stirred solution of Intermediate 1 (5.19 g, 15.8 mmol), Intermediate 56 (4.93 g, 15.1 mmol) and DIPEA (5.3 mL, 30.2 mmol) in DCM (50 mL). The reaction mixture was stirred for 2 h and then washed with water (25 mL). The aqueous layer was extracted with DCM (15 mL). The combined organic layers were passed through a phase separator and evaporated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of EtOAc in heptane to afford the title compound (9.5 g, 91%) as a pale pink solid. δ H( 500 MHz, DMSO - d 6 )9.49 (s, 1H), 7.68 (d, J 8.1 Hz, 1H), 7.39 - 7.29 (m, 5H), 7.07 (d, J 8.5 Hz, 1H), 6.57 (t, J 8.4 Hz, 1H), 5.05 (s, 2H), 4.84 (s, 2H), 4.14 (t, J 8.0 Hz, 1H), 3.77 - 3.69 (m, 2H), 3.64 - 3.56 (m, 2H), 2.20 (d, J 13.5 Hz, 2H), 2.10 - 1.99 (m, 2H), 1.97 - 1.67 (m, 7H), 1.46 - 1.30 (m, 11H). LCMS (Method 1): [M + H] + m / z 620, RT 2.03 minutes.

[0340] Intermediate 58 tert-Butyl 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-carboxylate Intermediate 57 (17.08 g, 27.6 mmol) was stirred in acetic acid (170 mL) at 75 °C for 4 h, then the mixture was cooled to room temperature and concentrated in vacuo. The resulting gum was partitioned between saturated NaHCO 3 aqueous solution (150 mL) and EtOAc (200 mL). The phases were separated and the aqueous layer was further extracted with EtOAc (200 mL). The organic fractions were combined, washed with saturated brine (50 mL) and concentrated in vacuo. The residue was suspended in 1:1 EtOAc:heptane, filtered and washed with heptane. The filtrate was concentrated in vacuo and purified by flash column chromatography eluting with a gradient of EtOAc in heptane to afford the title compound (13.29 g, 80%) as a white powder. δ H( 400 MHz, DMSO-d 6 ) 12.79 (s, 1H), 7.96 (d, J 8.3 Hz, 1H), 7.44 - 7.24 (m, 5H), 7.23 - 7.14 (m, 1H), 5.10 - 4.97 (m, 2H), 4.72 (t, J 8.2 Hz, 1H), 3.82 - 3.72 (m, 2H), 3.61 (t, J 10.2 Hz, 2H), 2.32 (d, J 12.4 Hz, 2H), 2.16 - 1.64 (m, 8H), 1.54 - 1.42 (m, 1H), 1.36 (s, 10H), 1.27 - 1.21 (m, 1H). LCMS (Method 4): [M+H] + m / z 602.3, RT 3.82 minutes.

[0341] Intermediate 59 tert-Butyl 4-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-carboxylate To a stirred solution of Intermediate 58 (2.0 g, 3.32 mmol) in EtOH (40 mL) and EtOAc (60 mL) was added 10% Pd / C (50% wet with water, 700 mg, 0.33 mmol). The reaction mixture was purged and stirred vigorously at room temperature under a hydrogen atmosphere for 1 h. The reaction mixture was filtered through a pad of Celite® then washed with EtOH (2 × 20 mL) and concentrated in vacuo to afford the title compound (1.65 g, 100%) as a white solid. δ H( 400 MHz, DMSO-d 6)7.27(d, J 8.4 Hz, 1H), 7.18 - 7.09(m, 1H), 3.86(d, J 6.1 Hz, 1H), 3.82 - 3.72(m, 2H), 3.66 - 3.56(m, 2H), 2.31(d, J 11.3 Hz, 2H), 2.08 - 1.91(m, 4H), 1.91 - 1.62(m, 4H), 1.52(d, J 10.2 Hz, 1H), 1.35(br s, 11H). LCMS(Method 1): [M + H] + m / z 468, RT 1.59 minutes.

[0342] Intermediate 60 tert-Butyl 4-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydropyran-4-carboxylate DIPEA (1.5 mL, 8.43 mmol) was added to a stirred solution of 4 - methyl - 1,2,5 - oxadiazole - 3 - carboxylic acid (0.49 g, 3.86 mmol) and HATU (1.48 g, 3.88 mmol) in DCM (26 mL) at room temperature. The reaction mixture was stirred for 15 minutes and then intermediate 59 (1.60 g, 2.84 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then quenched with saturated NaHCO 3 aqueous solution and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO 4 and filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 70% EtOAc in heptane to afford the title compound (1.20 g, 66%) as a yellow oil. δ H( 500 MHz, DMSO - d 6 )12.69(s, 1H), 9.66(s, 1H), 7.30(d, J 7.0 Hz, 1H), 7.20(t, J 7.7 Hz, 1H), 5.29 - 5.08(m, 1H), 3.84 - 3.68(m, 2H), 3.61(t, J 10.9 Hz, 2H), 2.47(s, 3H), 2.31(d, J 12.8 Hz, 2H), 2.10 - 1.90(m, 5H), 1.88 - 1.70(m, 2H), 1.62 - 1.50(m, 1H), 1.45 - 1.21(m, 12H). LCMS(Method 1): [M + H] + m / z 578, RT 1.98 minutes.

[0343] Intermediate 61 4-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydropyran-4-carboxylic acid, trifluoroacetate Intermediate 60 (1.20 g, 1.87 mmol) was stirred in DCM (9 mL) and TFA (9 mL) at room temperature for 18 h. The reaction mixture was concentrated in vacuo to afford the title compound (1.46 g, 100%) as an off-white solid. LCMS (Method 1): [M+H] + m / z 522.0, RT 1.75 minutes.

[0344] Intermediate 62 tert-Butyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]propanoate A mixture of Intermediate 4 (7.00 g, 16.2 mmol), XPhos (2.31 g, 4.85 mmol) and Pd 2 (dba) 3 (2.22 g, 2.43 mmol) in dry THF (150 mL) was degassed under nitrogen at room temperature for 2 min. A solution of bromo(2-tert-butoxy-1-methyl-2-oxoethyl)zinc in THF (0.5 M, 97 mL, 48.5 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h, then cooled to room temperature, quenched with saturated aqueous ammonium chloride (30 mL) and extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography eluting with a gradient of 0 - 10% EtOAc in heptane, followed by acidic reverse-phase column chromatography eluting with a gradient of 70 - 85% acetonitrile (containing 0.1% formic acid) in water to afford the title compound (7.24 g, 96%) as an orange oil. δ H( 500 MHz,CDCl 3 )7.31(dd,J 8.5,1.5 Hz,1H),7.28 - 7.25(m,8H),7.25 - 7.20(m,2H),7.07(dd,J 8.5,6.7 Hz,1H),4.22 - 4.17(m,4H),3.89(q,J 7.2 Hz,1H),1.45 - 1.39(m,12H).LCMS(Method 1):[M+H] + m / z 465,RT 2.32 minutes.

[0345] Intermediate 63 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-1-(3,3-difluoroazetidin-1-yl)propan-1-one Intermediate 62 (7.20 g, 15.5 mmol) was stirred in DCM (30 mL) and TFA (30 mL) for 18 h. The reaction mixture was concentrated in vacuo. The resulting brown oil was dissolved in DCM (100 mL). 3,3-Difluoroazetidine hydrochloride (2.40 g, 18.6 mmol), DIPEA (11 mL, 61.9 mmol) and HATU (7.06 g, 18.6 mmol) were added. The reaction mixture was stirred for 2 h and then washed with water (2 × 50 mL) and brine (30 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 40% EtOAc in heptane to afford the title compound (7.7 g, 99%) as an orange oil. δ H( 400 MHz, DMSO-d 6 ) 7.52 (dd, J 8.5, 1.2 Hz, 1H), 7.31 - 7.13 (m, 11H), 4.65 (q, J 11.8 Hz, 1H), 4.38 - 4.20 (m, 2H), 4.17 (s, 4H), 3.96 (q, J 6.9 Hz, 1H), 3.74 (q, J 11.4 Hz, 1H), 1.25 (d, J 7.0 Hz, 3H). LCMS (Method 1): [M+H] + m / z 484.0, RT 2.11 minutes.

[0346] Intermediate 64 2-(3,4-Diamino-2-fluorophenyl)-1-(3,3-difluoroazetidin-1-yl)propan-1-one Intermediate 63 (7.7 g, 15.29 mmol) was dissolved in EtOH (100 mL) and 10% Pd / C (50% wet, 1.63 g, 0.80 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature under a hydrogen atmosphere for 16 h. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 100 mL) and concentrated in vacuo to afford the title compound (3.82 g, 88%) as a purple solid. δ H( 400 MHz, DMSO-d6 )6.36 - 6.15 (m, 2H), 4.77 - 4.59 (m, 3H), 4.38 (s, 2H), 4.36 - 4.13 (m, 2H), 4.05 - 3.91 (m, 1H), 3.76 (q, J 6.9 Hz, 1H), 1.22 (d, J 7.0 Hz, 3H). LCMS (Method 1): [M+H] + m / z 274.0, RT 0.93 minutes.

[0347] Intermediate 65 tert-Butyl N-[(S)-{5-[2-(3,3-difluoroazetidin-1-yl)-1-methyl-2-oxoethyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]carbamate To a solution of Intermediate 64 (2.32 g, 7.90 mmol) and Intermediate 2 (2.66 g, 9.06 mmol) in DCM (50 mL) were added DIPEA (2.9 mL, 16.5 mmol), followed by HATU (3.44 g, 9.06 mmol). The mixture was stirred at room temperature for 45 minutes, then diluted with DCM (50 mL) and washed with water (2 × 50 mL). The combined organic fractions were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane. The resulting peach-colored solid was stirred in acetic acid (50 mL, 0.873 mol) at 60 °C for 9 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with saturated NaHCO 3 aqueous solution (3 × 50 mL) and brine (30 mL), then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 90% EtOAc in heptane and subsequently further purified by flash column chromatography (KP-NH) eluting with a gradient of 0 - 100% EtOAc in heptane to give the title compound (3.3 g, 78%) as a white solid. δ H( 400 MHz, DMSO-d 6)12.95 - 12.27 (m, 1H), 7.46 - 7.17 (m, 2H), 7.17 - 6.88 (m, 1H), 4.89 - 4.71 (m, 1H), 4.71 - 4.49 (m, 1H), 4.41 - 3.90 (m, 4H), 2.14 - 1.91 (m, 3H), 1.91 - 1.63 (m, 3H), 1.56 - 1.09 (m, 15H). LCMS (Method 1): [M + H] + m / z 531.1, RT 1.86 minutes.

[0348] Intermediate 66 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-1-(3,3-difluoroazetidin-1-yl)propan-1-one Intermediate 65 (3.30 g, 5.60 mmol) was stirred in DCM (30 mL) and TFA (10 mL) at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (150 mL) and carefully washed with saturated NaHCO 3 aqueous solution (3 × 50 mL). The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (2.6 g, 97%) as a white solid. δ H( 400 MHz, DMSO - d 6 )7.27 (d, J 8.3 Hz, 1H), 7.11 - 6.95 (m, 1H), 4.77 (q, J 11.9 Hz, 1H), 4.32 (q, J 13.0, 12.3 Hz, 1H), 4.21 (q, J 12.7 Hz, 1H), 4.10 (q, J 6.9 Hz, 1H), 4.07 - 3.91 (m, 1H), 3.87 (d, J 5.9 Hz, 1H), 2.08 - 1.91 (m, 2H), 1.91 - 1.63 (m, 4H), 1.57 - 1.45 (m, 1H), 1.42 - 1.21 (m, 5H). LCMS (Method 1): [M + H] + m / z 431.5, RT 0.84 minutes.

[0349] Intermediate 67 tert-Butyl 8-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-1,4-dioxaspiro[4.5]decane-8-carboxylate To KOH pellets (785 mg, 14 mmol), aqueous KOH solution (60%, 20 mL), intermediate 5 (900 mg, 2 mmol) and tetrabutylammonium bromide (1.95 g, 6 mmol), 2,2-bis(2-bromoethyl)-1,3-dioxolane (3.45 g, 12 mmol) was added all at once. The reaction mixture was stirred at 50 °C for 24 h, then diluted with DCM (30 mL) and washed with water (10 mL). The organic fractions were combined, passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in hexane to afford the title compound (550 mg, 48%) as a yellow oil. LCMS (Method 7): [M+H] + m / z 577.0, RT 1.73 minutes.

[0350] Intermediate 68 8-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid, trifluoroacetate Intermediate 67 (550 mg, 0.954 mmol) was stirred in DCM (6 mL) and TFA (5 mL) at room temperature for 3 h. The reaction mixture was concentrated in vacuo to afford the title compound (450 mg, 100%) as a brown oil. LCMS (Method 7): [M+H] + m / z 521.0, RT 1.11 minutes.

[0351] Intermediate 69 4-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]4-(3,3-difluoroazetidine-1-carbonyl)-cyclohexanone To intermediate 68 (450 mg, 0.864 mmol), HATU (395 mg, 1.04 mmol) and DIPEA (0.82 mL, 4.72 mmol) in DCM (5 mL), 3,3-difluoroazetidine hydrochloride (147 mg, 1.13 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in hexane to afford the title compound (370 mg, 78%) as a cream solid. LCMS (Method 7): [M+H] + m / z 552.0, RT 1.51 minutes.

[0352] Intermediate 70 {1-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluorocyclohexyl}(3,3-difluoro-azetidin-1-yl)methanone To a solution of intermediate 69 (370 mg, 0.67 mmol) in DCM (6 mL) was added dropwise DAST (0.24 mL, 1.76 mmol). The reaction mixture was stirred at room temperature for 18 h, then poured into ice and neutralized with saturated Na 2 CO 3 aqueous solution (1 mL). The mixture was extracted with DCM (2 × 30 mL). The combined organic fractions were dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in hexanes to afford the title compound (200 mg, 52%) as a yellow oil. LCMS (Method 7): [M+H] + m / z 574.0, RT 1.62 minutes.

[0353] Intermediate 71 [1-(3,4-Diamino-2-fluorophenyl)-4,4-difluorocyclohexyl](3,3-difluoroazetidin-1-yl)-methanone Intermediate 70 (200 mg, 0.35 mmol) was dissolved in EtOH (5 mL) and 10% Pd / C (74 mg, 0.070 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature for 18 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite (registered trademark), then washed with MeOH (2 × 20 mL) and concentrated in vacuo to afford the title compound (90 mg, 71%) as a brown solid. LCMS (Method 7): [M+H] + m / z 364.0, RT 1.07 minutes.

[0354] Intermediate 72 Benzyl N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-4,4-difluorocyclohexyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]carbamate To a solution of intermediate 71 (90 mg, 0.25 mmol) and intermediate 1 (97 mg, 0.297 mmol) in DCM (5 mL) at room temperature, DIPEA (0.13 mL, 0.743 mmol) was added, followed by HATU (113.0 mg, 0.297 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with DCM (40 mL) and washed with water (10 mL). The aqueous fraction was extracted with DCM (2×20 mL). The organic fractions were combined, dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in acetic acid (8 mL), heated at 70 °C for 4 h, then cooled to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in hexanes to afford the title compound (160 mg, 99%) as a pale yellow solid. LCMS (Method 7): [M+H] + m / z 655.0, RT 1.41 minutes.

[0355] Intermediate 73 (1-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4-difluorocyclohexyl)(3,3-difluoroazetidin-1-yl)methanone Intermediate 72 (160 mg, 0.24 mmol) was dissolved in EtOH (8 mL) and 10% Pd / C (52 mg, 0.05 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2×20 mL) and concentrated in vacuo to afford the title compound (125 mg, 98%) as a purple solid. LCMS (Method 7): [M+H] + m / z 521.0, RT 1.20 minutes.

[0356] Intermediate 74 N,N-Dibenzyl-6-chloro-3-nitropyridin-2-amine To a stirred solution of 2,6-dichloro-3-nitropyridine (3.00 g, 15.5 mmol) in DCM (50 mL) were added triethylamine (4.3 mL, 31.1 mmol) and dibenzylamine (3.1 mL, 15.5 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with DCM (50 mL), washed with water (2 × 50 mL) and brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo. The resulting yellow oil was purified by flash column chromatography eluting with a gradient of 0 - 28% EtOAc / heptane to afford the title compound (6 g, 100%) as a yellow oil. LCMS (Method 1): [M+H] + m / z 354.0, RT 2.19 minutes.

[0357] Intermediate 75 Methyl 2-[6-(dibenzylamino)-5-nitropyridin-2-yl]acetate To a solution of Intermediate 74 (19.9 g, 54.0 mmol) and dimethyl malonate (9.45 mL, 81.0 mmol) in DMF (110 mL) was added K 2 CO 3 (18.7 g, 135 mmol). The mixture was heated at 70 °C for 20 h, then cooled to room temperature, poured into water (400 mL) and acidified with 10% HCl solution (<pH 4). The mixture was extracted with TBME (400 mL). The organic fraction was washed with water (300 mL) and brine (300 mL), then passed through a phase separator and concentrated in vacuo. The residue was dissolved in DMSO (216 mL) and water (21.6 mL), then lithium chloride (6.9 g, 160 mmol) was added. The mixture was heated at 120 °C for 18 h, cooled to room temperature, then diluted with water (600 mL) and extracted with TBME (2 × 300 mL). The combined organic fractions were washed with water (200 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 25% EtOAc in isohexane to afford the title compound (8.44 g, 34%). LCMS (Method 9): [M+H] +m / z 392.0, RT 2.81 minutes.

[0358] Intermediate 76 Methyl 4-[6-(dibenzylamino)-5-nitropyridin-2-yl]tetrahydropyran-4-carboxylate To a stirred suspension of NaH (60%, 1.04 g, 26.0 mmol) in DMF (25 mL) at 0 °C was added dropwise intermediate 75 (4.24 g, 10.8 mmol) in DMF (15 mL). The red mixture was stirred for 5 minutes and then 1-iodo-2-(2-iodoethoxy)ethane (2.3 mL, 16.3 mmol) was added dropwise. The reaction mixture was stirred for 3 hours while warming to room temperature and then diluted with EtOAc (50 mL) and poured into saturated NH 4 Cl aqueous solution (50 mL). Water (50 mL) and EtOAc (150 mL) were added and the mixture was separated. The organic fraction was washed successively with water (100 mL), saturated NH 4 Cl aqueous solution (100 mL), water (100 mL) and brine (50 mL). The organic fraction was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 30% EtOAc in heptane to give the title compound (5.9 g, 100%) as a yellow oil. δ H( 400 MHz, CDCl 3 ) 8.11 (d, J 8.4 Hz, 1H), 7.26 (s, 6H), 7.21 - 7.10 (m, 4H), 6.76 (d, J 8.4 Hz, 1H), 4.59 (s, 4H), 3.79 (t, J 4.2 Hz, 1H), 3.76 (t, J 4.2 Hz, 1H), 3.64 (s, 3H), 3.62 - 3.49 (m, 2H), 2.38 - 2.27 (m, 2H), 2.09 (ddd, J 14.0, 10.2, 4.1 Hz, 2H). LCMS (Method 2): [M + H] + m / z 462.0, RT 3.43 minutes.

[0359] Intermediate 77 Methyl 4-[5-amino-6-(benzylamino)pyridin-2-yl]tetrahydropyran-4-carboxylate Intermediate 76 (5.90 g, 10.9 mmol) was dissolved in EtOH (40 mL), and 10% Pd / C (50% wet, 2.32 g, 1.10 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature for 23 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOAc (2 × 50 mL) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane. The resulting orange oil (nitro reduction intermediate, 4.6 g) was redissolved in EtOH (40 mL), and 10% Pd / C (50% wet, 2.39 g, 1.12 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature for 21 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with EtOH (2 × 50 mL) and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with saturated NaHCO 3 aqueous solution (20 mL). The aqueous fraction was extracted with 20% MeOH in DCM (2 × 40 mL). The organic fractions were combined and then dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound (2.8 g, 52%) as a red / brown solid. LCMS (Method 6): [M + H] + m / z 342.3, RT 0.56 minutes.

[0360] Intermediate 78 Methyl 4-(5,6-diaminopyridin-2-yl)tetrahydropyran-4-carboxylate Intermediate 77 (2.80 g, 8.20 mmol) was dissolved in MeOH (100 mL), and 10% Pd / C (50% wet, 1.75 g, 0.82 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature for 18 h under a hydrogen atmosphere. HCl aqueous solution (6 M, 1.4 mL, 8.20 mmol) was added, and the reaction mixture was stirred for 20 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and then washed with MeOH (2 × 50 mL) and concentrated in vacuo. The residue was dissolved in 20% MeOH in DCM (50 mL) and then saturated NaHCO 3It was washed with an aqueous solution (20 mL). The aqueous layer was extracted with 20% MeOH (50 mL) in DCM. The combined organic layers were dried over Na 2 SO 4 and then concentrated in vacuo to give the title compound (1.98 g, 72%) as a red / brown solid. δ H( 500 MHz, DMSO-d 6 ) 6.66 (d, J 7.8 Hz, 1H), 6.35 (d, J 7.8 Hz, 1H), 5.32 (s, 2H), 4.62 (s, 2H), 3.75 - 3.63 (m, 2H), 3.57 (s, 3H), 3.47 - 3.36 (m, 2H), 2.21 - 2.10 (m, 2H), 1.96 (ddd, J 13.7, 10.0, 3.9 Hz, 2H). LCMS (Method 6): [M+H] + m / z 252.1, RT 0.34 minutes.

[0361] Intermediate 79 Methyl 4-[6-amino-5-(tert-butoxycarbonylamino)pyridin-2-yl]tetrahydropyran-4-carboxylate Intermediate 78 (1.98 g, 7.88 mmol), di-tert-butyl dicarbonate (2.06 g, 9.46 mmol) and guanidine hydrochloride (1:1) (150 mg, 1.58 mmol) were stirred in EtOH (40 mL) at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (50 mL). The aqueous fraction was extracted with EtOAc (50 mL). The combined organic fractions were washed with brine (30 mL) and dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 60% EtOAc in heptane to give the title compound (2.41 g, 82%) as a white solid. δ H( 500 MHz, DMSO-d 6)8.40(s,1H),7.55(d,J 8.0 Hz,1H),6.54(d,J 8.1 Hz,1H),5.70(s,2H),3.70(dt,J 11.5,4.1 Hz,2H),3.60(s,3H),3.48-3.39(m,2H),2.24-2.14(m,2H),2.05-1.92(m,2H),1.46(s,9H).LCMS(Method 1):[M+H] + m / z 352.0,RT 1.62 minutes.

[0362] Intermediate 80 Methyl 4-[6-{[(2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetyl]-amino}-5-(tert-butoxycarbonylamino)pyridin-2-yl]tetrahydropyran-4-carboxylate To a stirred solution of Intermediate 79 (3.00 g, 8.11 mmol) and Intermediate 1 (2.92 g, 8.92 mmol) in EtOAc (50 mL) was added pyridine (3.0 mL, 36.5 mmol) at 0 °C. T3P® in EtOAc (50%, 12 mL, 20.3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 h and then quenched with water (50 mL). The aqueous fraction was extracted with EtOAc (50 mL). The combined organic fractions were washed with saturated NH 4 Cl aqueous solution (50 mL) and water (50 mL), then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 30% EtOAc in heptane to afford the title compound (5.65 g, 95%) as a white solid. δ H( 400 MHz, DMSO-d 6 )10.67(s,1H),8.03(d,J 8.4 Hz,1H),7.87(s,1H),7.74(d,J 8.0 Hz,1H),7.42-7.24(m,6H),5.06(s,2H),4.41(t,J 6.2 Hz,1H),3.77-3.65(m,2H),3.62(s,3H),3.55-3.42(m,2H),2.31-2.23(m,2H),2.18-1.96(m,4H),1.96-1.65(m,5H),1.42(s,11H).LCMS(Method 1):[M+H] + m / z 661.0,RT 2.08 minutes.

[0363] Intermediate 81 Methyl 4-(5-amino-6-{[(2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)-acetyl]amino}pyridin-2-yl)tetrahydropyran-4-carboxylate The intermediate 80 (5.65 g, 7.70 mmol) was stirred in 1,4-dioxane (25 mL) and 4 M HCl in 1,4-dioxane (25 mL, 0.10 mol) for 5 h, then the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO 3 aqueous solution (2 × 50 mL) and brine (20 mL), then dried over Na 2 SO 4 and concentrated in vacuo to give the title compound (4.79 g, 94%) as a white foam. δ H( 400 MHz, DMSO-d 6 ) 10.17 (s, 1H), 7.61 (d, J 8.3 Hz, 1H), 7.43 - 7.25 (m, 5H), 7.17 (d, J 8.3 Hz, 1H), 7.08 (d, J 8.3 Hz, 1H), 5.05 (s, 2H), 4.91 (s, 2H), 4.39 - 4.20 (m, 1H), 3.77 - 3.64 (m, 2H), 3.59 (s, 3H), 3.52 - 3.37 (m, 2H), 2.29 - 2.15 (m, 2H), 2.15 - 1.94 (m, 4H), 1.94 - 1.61 (m, 5H), 1.60 - 1.30 (m, 2H). LCMS (Method 1): [M + H] + m / z 561.0, RT 1.87 minutes.

[0364] Intermediate 82 Methyl 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-1H-imidazo-[4,5-b]pyridin-5-yl}tetrahydropyran-4-carboxylate The intermediate 81 (4.70 g, 7.13 mmol) was stirred in acetic acid (34 mL, 0.59 mol) at 50 °C for 2 h, then the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (150 mL) and washed with saturated NaHCO 3 aqueous solution (2 × 100 mL) and brine (20 mL), then dried over Na 2 SO 4It was dried and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 80% EtOAc in heptane to afford the title compound (4.15 g, 97%) as a white solid foam. δ H( 500 MHz, DMSO-d 6 ) 13.27 - 12.36 (m, 1H), 8.03 - 7.76 (m, 2H), 7.39 - 7.28 (m, 5H), 7.25 (d, J 8.3 Hz, 1H), 5.11 - 4.94 (m, 2H), 4.78 - 4.67 (m, 1H), 3.80 - 3.71 (m, 2H), 3.60 (s, 3H), 3.55 - 3.45 (m, 2H), 2.41 - 2.32 (m, 2H), 2.21 - 2.07 (m, 2H), 2.07 - 1.91 (m, 3H), 1.91 - 1.66 (m, 3H), 1.57 - 1.47 (m, 1H), 1.44 - 1.31 (m, 1H), 1.31 - 1.20 (m, 1H). LCMS (Method 4): [M + H] + m / z 543.3, RT 3.12 minutes.

[0365] Intermediate 83 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-1H-imidazo[4,5-b]-pyridin-5-yl}tetrahydropyran-4-carboxylic acid Intermediate 82 (0.50 g, 0.92 mmol) was stirred in MeOH (10 mL) and 1 M aqueous NaOH (6.0 mL, 6.00 mmol) at 50 °C for 7 h, then at room temperature for 16 h, and then at 50 °C for 4 h. The reaction mixture was concentrated in vacuo. The remaining aqueous residue was washed with diethyl ether (2 × 20 mL), then acidified to pH 2 - 3 with 1 M aqueous HCl and extracted with EtOAc (2 × 50 mL). The combined organic fractions were then dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound (494 mg, 98%) as a yellow foam. LCMS (Method 1): [M + H] + m / z 529.0, RT 1.76 minutes.

[0366] Intermediate 84 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(5-{4-[(2,2-difluorocyclopropyl)methyl-carbamoyl]tetrahydropyran-4-yl}-1H-imidazo[4,5-b]pyridin-2-yl)methyl]carbamate A stirred solution of intermediate 83 (100.0 mg, 0.19 mmol) and (2,2-difluoro-cyclopropyl)methanamine hydrochloride (33.0 mg, 0.23 mmol) in DCM (3 mL) and DMF (2 mL) was treated with DIPEA (0.13 mL, 0.76 mmol), followed by HATU (86 mg, 0.23 mmol). The reaction mixture was stirred for 15 minutes and washed successively with water (2 mL), saturated NH 4 Cl aqueous solution (2 mL), water (2 mL) and brine (2 mL), then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (172 mg, 68%) as a clear oil. LCMS (Method 1): [M+H] + m / z 618.0, RT 1.85 minutes.

[0367] Intermediate 85 4-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-1H-imidazo[4,5-b]pyridin-5-yl}-N-[(2,2-difluorocyclopropyl)methyl]tetrahydropyran-4-carboxamide Intermediate 84 (172 mg, 0.19 mmol) was dissolved in EtOH (5 mL) and 10% Pd / C (50% wet, 40 mg, 0.019 mmol) was added. The reaction mixture was purged and stirred vigorously at room temperature for 2 h under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite (registered trademark), then washed with EtOH (2×10 mL) and concentrated in vacuo to afford the title compound (102 mg) as a clear oil. LCMS (Method 1): [M+H] + m / z 484.0, RT 1.43 minutes.

[0368] Intermediate 86 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]acetic acid Intermediate 5 (2.00 g, 4.44 mmol) was dissolved in DCM (10 mL) and TFA (5 mL, 64.6 mmol) was added. The mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo. The residue was azeotroped with EtOAc and then placed under high vacuum overnight to afford the title compound (1.74 g, 99.4%) as a yellow powder. δ H(300 MHz, DMSO-d 6 ) 12.70 (br s, 1H), 7.50 - 7.20 (m, 12H), 4.15 (s, 4H), 3.76 (s, 2H). LCMS (Method 9): [M+H] + m / z 395, RT 1.28 minutes.

[0369] Intermediate 87 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-1-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-ethanone Intermediate 86 (1.74 g, 4.41 mmol) and DIPEA (1.60 mL, 9.20 mmol) were stirred in DCM (20 mL) at room temperature, then HATU (1.73 g, 4.41 mmol) and 3,3,4,4 - tetrafluoropyrrolidine hydrochloride (832 mg, 4.63 mmol) were added. The mixture was stirred at room temperature for 18 hours, then diluted with DCM (50 mL) and washed with saturated NaHCO 3 aqueous solution (50 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo, then purified by chromatography (silica, DCM, 0 - 10% MeOH gradient). The relevant fractions were concentrated in vacuo. The resulting yellow oil was azeotroped with DCM / isohexane (ca. 1:2) to give the title compound (2.17 g, 95%) as a yellow solid. δ H( 300 MHz, DMSO-d 6 ) 7.50 - 7.20 (m, 12H), 4.50 (m, 2H), 4.18 (s, 4H), 4.13 (m, 2H), 3.83 (s, 2H). LCMS (Method 9): [M+H] + m / z 520, RT 2.69 minutes.

[0370] Intermediate 88 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-butan-1-one Intermediate 87 (1.00 g, 1.92 mmol) was dissolved in dry DMF (5 mL), then NaH (81 mg, 2.02 mmol, 60% dispersion in oil) was added. The mixture was stirred at room temperature for 10 minutes, then ethyl vinyl sulfone (0.21 mL, 2.00 mmol) was added. The mixture was stirred at room temperature for 2 hours, then saturated NH4 It was quenched with an aqueous solution of Cl (20 mL) and extracted with TBME (20 mL). The organic layer was concentrated in vacuo and purified by chromatography (silica, 0 - 15% EtOAc gradient in DCM) to give the title compound (590 mg, 48%) as a yellow solid. δ H( 300 MHz, DMSO-d 6 ) 7.42 (d, J 8 Hz, 1H), 7.35 - 7.20 (m, 10H), 7.07 (t, J 8 Hz, 1H), 4.35 - 4.30 (m, 1H), 4.27 (s, 4H), 4.20 - 3.80 (m, 3H), 3.23 (m, 1H), 3.11 - 2.96 (m, 4H), 2.47 (m, 1H), 2.21 (m, 1H), 1.43 (t, J 7.4 Hz, 3H). LCMS (Method 9): [M + H] + m / z 640, RT 2.68 minutes.

[0371] Intermediate 89 2-(3,4-Diamino-2-fluorophenyl)-4-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-butan-1-one Intermediate 88 (580 mg, 0.91 mmol) was dissolved in EtOH (15 mL) and EtOAc (15 mL), and 10% Pd / C (80 mg) was added. The reaction mixture was degassed under vacuum and placed under a hydrogen atmosphere (balloon) with vigorous stirring for 18 h. The mixture was filtered through a Celite® plug and washed with EtOH (20 mL). The combined organic fractions were concentrated in vacuo and then azeotroped twice with DCM / isohexane to give the title compound (289 mg, 97.8%) as a foamy off - white solid. δ H( 300 MHz, DMSO-d 6 ) 6.34 (d, J 8.2 Hz, 1H), 6.21 (t, J 8.0 Hz, 1H), 4.86 (s, 2H), 4.46 (m, 3H), 4.20 - 3.88 (m, 3H), 3.55 (q, J 13.7 Hz, 1H), 3.08 (q, J 7.4 Hz, 2H), 3.02 - 2.80 (m, 2H), 2.33 - 2.08 (m, 1H), 1.95 (tt, J 12.1, 10.7, 4.2 Hz, 1H), 1.18 (t, J 7.4 Hz, 3H). LCMS (Method 9): [M + H] +m / z 430, RT 1.24 / 1.27 minutes.

[0372] Intermediate 90 Benzyl N-[(S)-(4,4-difluorocyclohexyl){5-[3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]carbamate Intermediate 1 (292 mg, 0.89 mmol) and HATU (350 mg, 0.89 mmol) were dissolved in dry DCM (50 mL), and DIPEA (0.31 mL, 1.785 mmol) was added, followed by Intermediate 89 (365 mg, 0.85 mmol). The mixture was stirred at room temperature for 6 hours and then washed with saturated NaHCO 3 aqueous solution (50 mL). The organic fraction was dried over Na 2 SO 4 and then concentrated in vacuo. The residue was dissolved in DCM (40 mL), and TFA (0.2 mL, 3.0 mmol) was added. The mixture was stirred at 40 °C for 2 hours, then cooled to room temperature and washed with saturated NaHCO 3 aqueous solution (2 × 50 mL). The organic layer was separated and concentrated in vacuo. The residue was purified by chromatography (silica, DCM, 0 - 60% EtOAc gradient) to give the title compound (417 mg, 68%) as an off - white solid. δ H( 300 MHz, DMSO - d 6 ) 13.00 - 12.70 (s, 1H), 7.95 (m, 1H), 7.57 - 7.21 (m, 5H), 7.06 (m, 1H), 5.16 - 4.86 (m, 2H), 4.86 - 4.26 (m, 4H), 4.26 - 3.83 (m, 3H), 3.67 (t, J 13.8 Hz, 1H), 3.20 - 2.80 (m, 3H), 2.70 (s, 2H), 2.43 - 2.20 (m, 1H), 2.22 - 1.61 (m, 3H), 1.57 - 1.01 (m, 5H), 0.99 - 0.63 (m, 3H). LCMS (Method 9): [M + H] + m / z 721, RT 2.30 minutes.

[0373] Intermediate 91 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidin-1-yl)butan-1-one Intermediate 90 (410 mg, 0.57 mmol) was dissolved in EtOH (15 mL) and EtOAc (10 mL), and 10% Pd / C (50 mg) was added. The mixture was degassed and refilled with a hydrogen atmosphere (balloon), and then stirred vigorously at room temperature for 4 hours. The mixture was filtered through a Celite® pad and washed with EtOH (3 × 5 mL). The combined organic fractions were concentrated in vacuo to afford the title compound (334 mg, 100%) as an off-white solid. LCMS (Method 9): [M+H] + m / z 587, RT 1.72 minutes.

[0374] Intermediate 92 Dimethyl 1-[6-(dibenzylamino)-5-nitropyridin-2-yl]-4-oxocyclohexane-1,3-dicarboxylate To a solution of Intermediate 75 (5 g, 12.39 mmol) in THF (25 mL) were added methyl acrylate (2.5 mL, 27 mmol) and DBU (9.5 mL, 62 mmol). The resulting mixture was stirred at room temperature for 3.5 hours, and then magnesium bromide (11.6 g, 61.7 mmol) was added portionwise. A cooling bath was introduced during the addition to control the exothermic effect. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 20 hours, then diluted with DCM (80 mL) and washed with 1N HCl (80 mL). The aqueous washings were re-extracted with DCM (50 mL). The combined organic extracts were washed with brine (50 mL), passed through a hydrophobic frit, and concentrated in vacuo. Purification by flash chromatography (SNAP 100 g, 0 - 40% EtOAc in hexanes) afforded the title compound (6.5 g, 90%) as a yellow oil. LCMS (Method 9): [M+H] + m / z 564, RT 2.94 minutes.

[0375] Intermediate 93 Methyl 1-[6-(dibenzylamino)-5-nitropyridin-2-yl]-4-oxocyclohexanecarboxylate To a solution of Intermediate 92 (6.5 g, 10 mmol) in DMSO (51 mL) were added NaCl (890 mg, 15.22 mmol) and water (5.1 mL). The resulting mixture was stirred at 110 °C for 2 days, then cooled to room temperature, diluted with TBME (250 mL), and washed with water (250 mL) mixed with brine (20 mL). The aqueous washings were re-extracted with TBME (250 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. Purification by flash chromatography (SNAP 100 g, 0 - 50% EtOAc in hexanes) afforded the title compound (3.0 g, 58%) as a yellow oil. LCMS (Method 7): [M+H] + m / z 474, RT 2.43 minutes.

[0376] Intermediate 94 Methyl 1-[6-(dibenzylamino)-5-nitropyridin-2-yl]-4,4-difluorocyclohexanecarboxylate To a solution of Intermediate 93 (2.5 g, 5.3 mmol) in dry DCM (26.4 mL) was added N 2 -bis(2-methoxyethyl)aminosulfur trifluoride (6.7 mL, 16 mmol) was added dropwise at -78 °C. The cooling bath was removed and the mixture was stirred at room temperature for 21 hours, then diluted with DCM (150 mL) and NaHCO 3It was washed with an aqueous solution (150 mL). The organic extract was passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in acetone (53 mL) and water (5.3 mL), and then potassium osmate(VI) dihydrate (100 mg, 0.26 mmol) and 4-methylmorpholine N-oxide (1 g, 8.28 mmol) were added. The resulting mixture was stirred at room temperature for 22 h, and then further potassium osmate(VI) dihydrate (50 mg) was added. Stirring was continued at room temperature for 1.5 h, and then further 4-methylmorpholine N-oxide (300 mg) was added. After 1 h, the mixture was concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with water (100 mL). The aqueous washings were re-extracted with DCM (100 mL). The organic extracts were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography (SNAP 100 g, 0–50% EtOAc in hexane) gave a mixture of the title compound and vinyl fluoride, which was again dissolved in acetone (53 mL) and water (5.3 mL), to which potassium osmate(VI) dihydrate (100 mg, 0.26 mmol) and 4-methylmorpholine N-oxide (1 g, 8.28 mmol) were added. Stirring was continued at room temperature for 24 h, and then the mixture was concentrated in vacuo. The residue was dissolved in DCM (100 mL) and washed with water (100 mL). The aqueous washings were re-extracted with DCM (100 mL). The organic extracts were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography (SNAP 100 g, 0–60% EtOAc in hexane) gave the title compound (1.27 g, 48.5%) as a yellow oil, which solidified on standing. LCMS (Method 7): [M+H] + m / z 496, RT 2.66 minutes.

[0377] Intermediate 95 Methyl 1-(5,6-diaminopyridin-2-yl)-4,4-difluorocyclohexanecarboxylate To a stirred solution of Intermediate 94 (305 mg, 0.62 mmol) in a mixture of EtOH (4.6 mL) and DCM (4.6 mL) was added 6 M HCl (0.21 mL) and 10% palladium on charcoal (50% wet) (64 mg, 0.30 mmol). The reaction mixture was evacuated with nitrogen gas (3 times) and then placed under a hydrogen gas atmosphere. The reaction mixture was stirred at ambient temperature for 20 h under 1 atm of hydrogen gas (balloon), then filtered through a pad of Celite® and the filter cake was rinsed with EtOH (2 x 5 mL). The filtrates were combined and the solvent was removed in vacuo. The residue was diluted with EtOAc (10 mL) and washed with saturated NaHCO 3 aqueous solution (5 mL) and brine (5 mL), then dried over anhydrous Na 2 SO 4 and filtered. The solvent was removed in vacuo to afford the title compound (179 mg, 91%) as a purple oil, which was used without further purification. δ H( 400 MHz, CDCl 3 ) 6.85 (d, J 7.8 Hz, 1H), 6.63 (d, J 7.8 Hz, 1H), 4.18 (s, 2H), 3.67 (s, 3H), 3.25 (s, 2H), 2.47 - 2.36 (m, 2H), 2.26 - 2.16 (m, 2H), 2.09 - 1.83 (m, 4H).

[0378] Intermediate 96 Methyl 1-[6-amino-5-(tert-butoxycarbonylamino)pyridin-2-yl]-4,4-difluorocyclohexane-carboxylate To a stirred solution of Intermediate 95 (170 mg, 0.54 mmol) in EtOH (2.8 mL) was added di-tert-butyl dicarbonate (129 mg, 0.59 mmol) and guanidine hydrochloride (1:1) (11 mg, 0.11 mmol) portionwise. The reaction mixture was stirred at 50 °C for 16 h and then cooled to ambient temperature. The solvent was removed in vacuo. Water (5 mL) was added and the mixture was extracted with EtOAc (2 x 5 mL). The organic extracts were combined and washed with saturated NaHCO 3 aqueous solution (5 mL) and brine (5 mL), then dried over anhydrous Na 2 SO 4It was dried and filtered. The solvent was concentrated in vacuo. The residue was purified using automated chromatography (Isolera 4, 10 g SFAR Duo column) eluting with a gradient of EtOAc (5 - 50%) in heptane to afford the title compound (170 mg, 77%) as a clear gum. δ H( 400 MHz, CDCl 3 ) 7.51 (d, J 8.0 Hz, 1H), 6.72 (d, J 8.1 Hz, 1H), 6.00 (s, 1H), 4.51 (s, 2H), 3.67 (s, 3H), 2.47 - 2.37 (m, 2H), 2.28 - 2.15 (m, 2H), 2.08 - 1.85 (m, 4H), 1.51 (s, 9H).

[0379] Intermediate 97 Methyl 1-[6-{[(2S)-2-(Benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetyl]-amino}-5-(tert-butoxycarbonylamino)pyridin-2-yl]-4,4-difluorocyclohexanecarboxylate To a stirred solution of Intermediate 96 (170 mg, 0.44 mmol), Intermediate 1 (159 mg, 0.49 mmol) and pyridine (0.16 mL, 2.03 mmol) in EtOAc (1.5 mL), cooled in an ice - bath beforehand, T3P® (50% in EtOAc) (0.65 mL, 1.10 mmol) was added dropwise while maintaining the temperature below 10 °C. The reaction mixture was stirred at ambient temperature for 2 h, then diluted with EtOAc (4 mL), cooled to 0 °C and quenched with 1 M HCl (2 mL). The aqueous phase was separated. The organic phase was washed with water (3 mL) and brine (2 mL), then dried over anhydrous Na 2 SO 4 and filtered. The solvent was concentrated in vacuo to afford the title compound (315 mg, 95%) as a yellow foam. δ H( 400 MHz, CDCl 3 ) 8.48 (s, 1H), 8.17 (d, J 8.4 Hz, 1H), 7.83 (s, 1H), 7.40 - 7.30 (m, 5H), 7.26 - 7.21 (m, 1H), 5.48 (d, J 8.7 Hz, 1H), 5.14 (s, 2H), 4.46 (s, 1H), 3.65 (s, 3H), 2.45 (dd, J 12.9, 5.0 Hz, 2H), 2.23 - 2.10 (m, 4H), 2.06 - 1.62 (m, 11H), 1.48 (s, 9H).

[0380] Intermediate 98 Methyl 1-{2-[(S)-Benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-1H-imidazo-[4,5-b]pyridin-5-yl}-4,4-difluorocyclohexanecarboxylate To a stirred solution of Intermediate 97 (310 mg, 0.45 mmol) in DCM (2 mL) was added TFA (0.33 mL, 4.46 mmol) portionwise. The reaction mixture was heated at 40 °C for 16 h and then cooled to ambient temperature and washed with saturated NaHCO 3 aqueous solution (2 mL). The organic phase was collected and the aqueous phase was extracted with DCM (2 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography (Isolera 4, 10 g KP-Sil column) eluting with a gradient of EtOAc (5 - 50%) in heptane to afford the title compound (137 mg, 51%) as a beige solid. δ H( 400 MHz, CD 3 OD) 7.90 (d, J 8.2 Hz, 1H), 7.40 - 7.26 (m, 5H), 7.08 - 6.85 (m, 1H), 5.12 (d, J 12.5 Hz, 1H), 5.06 (d, J 12.5 Hz, 1H), 4.95 (d, J 20.1 Hz, 1H), 3.68 (s, 3H), 2.58 - 2.48 (m, 2H), 2.44 - 2.34 (m, 2H), 2.12 - 1.93 (m, 6H), 1.88 - 1.63 (m, 3H), 1.61 - 1.30 (m, 4H) (two NH signals exchanged with solvent).

[0381] Intermediate 99 Benzyl N-[(S)-(4,4-Difluorocyclohexyl){5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)cyclohexyl]-1H-imidazo[4,5-b]pyridin-2-yl}methyl]carbamate To a stirred solution of Intermediate 98 (130 mg, 0.23 mmol) in MeOH (1 mL) was added 2 M aqueous NaOH solution (0.56 mL, 1.13 mmol) portionwise. The reaction mixture was heated at 50 °C for 16 h and then cooled to ambient temperature. 1 M HCl was added slowly to adjust the pH to about 2 - 3. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (2 × 2 mL) and then with anhydrous Na 2 SO 4It was dried and filtered. The solvent was removed in vacuo. The resulting beige solid was dissolved in EtOAc (0.7 mL) containing 2,2,2-trifluoroethanamine (0.013 mL, 0.163 mmol) and pyridine (0.055 mL, 0.680 mmol). T3P® (50% in EtOAc) (0.22 mL, 0.37 mmol) was added dropwise at ambient temperature and stirring was continued for a further 4.5 h. The reaction mixture was diluted with EtOAc (4 mL), cooled to 0 °C and then quenched with 1 M HCl (2 mL). The aqueous phase was separated. The organic phase was washed with water (2 mL) and brine (2 mL) and then dried over anhydrous Na 2 SO 4 and filtered. The solvent was concentrated in vacuo. The residue was purified using automated chromatography (Isolera 4, 10 g SFAR Duo column) eluting with a gradient of EtOAc in heptane (5 - 100%) to give the title compound (29.3 mg, 19%) as a grey solid. δ H( 400 MHz, CD 3 OD) 7.99 - 7.80 (m, 1H), 7.40 - 7.21 (m, 5H), 7.17 - 6.90 (m, 1H), 5.12 (d, J 12.4 Hz, 1H), 5.06 (d, J 12.4 Hz, 1H), 4.80 - 4.75 (m, 1H), 3.83 (q, J 9.3 Hz, 2H), 2.59 - 2.35 (m, 4H), 2.10 - 1.93 (m, 6H), 1.87 - 1.65 (m, 3H), 1.58 - 1.36 (m, 4H) (three NH signals exchanged with solvent).

[0382] Intermediate 100 Methyl 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]acetate To a solution of intermediate 47 (15.0 g, 42.3 mmol) and dimethyl malonate (7.4 mL, 63 mmol) in DMF (85 mL) was added K 2 CO 3(14.6 g, 106 mmol) was added. The mixture was heated at 60 °C for 24 h, then diluted with TBME (450 mL) and water (300 mL). The pH was adjusted to about 7 using 10% aqueous HCl. The organic layer was washed with water (2 × 300 mL), separated, and concentrated in vacuo. The residue was dissolved in a mixture of DMSO (170 mL) and water (17 mL). Lithium chloride (5.4 g, 130 mmol) was added to the solution and the mixture was heated at 115 °C for 20 h. Water (400 mL) was added to the mixture. The resulting yellow suspension was extracted with TBME (2 × 300 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over Na 2 SO 4 , and concentrated. The residue was recrystallized from TBME and isohexane to afford the title compound (11.26 g, 65%). LCMS (Method 8): [M+H] + m / z 409, RT 2.95 minutes.

[0383] Intermediate 101 Methyl 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluorobutanoate To a stirred solution of Intermediate 100 (10.60 g, 26.0 mmol) in THF was added NaH (60%, 1.15 g, 28.6 mmol) in one portion at -10 °C. The mixture was stirred for 15 min, then a solution of 2,2-difluoroethyl trifluoromethanesulfonate (3.6 mL, 27.2 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 18 h, then quenched with saturated NH 4 Cl aqueous solution (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over MgSO 4 , filtered, and concentrated in vacuo. The resulting crude material was separated by flash column chromatography eluting with EtOAc / heptane (0 - 100% gradient) to afford the title compound (7.4 g, 59%) as a yellow-orange solid. δ H( 500 MHz, DMSO-d 6)7.53 (dd, J 8.4, 0.9 Hz, 1H), 7.38 - 7.13 (m, 11H), 5.97 (tt, J 56.1, 4.4 Hz, 1H), 4.21 - 4.06 (m, 5H), 3.63 (s, 3H), 2.77 - 2.55 (m, 1H), 2.23 (dtdd, J 19.2, 15.2, 8.2, 4.4 Hz, 1H). LCMS (Method 2): [M+H] + m / z 473, RT 3.66 minutes.

[0384] Intermediate 102 Methyl 2-(3,4-Diamino-2-fluorophenyl)-4,4-difluorobutanoate To a stirred solution of Intermediate 101 (7.3 g, 14.99 mmol) in EtOH (50 mL) was added 10% palladium on carbon (50% wet) (1.60 g, 1.50 mmol) in one portion. The reaction mixture was stirred at 1 atm of H 2 for 18 h, then filtered through Celite® and concentrated in vacuo to afford the title compound (4.25 g, 85%) as a purple oil. δ H( 400 MHz, DMSO-d 6 )6.38 - 6.24 (m, 2H), 5.96 (tt, J 56.4, 4.6 Hz, 1H), 4.81 (s, 2H), 4.44 (s, 2H), 3.88 (t, J 7.4 Hz, 1H), 3.59 (s, 3H), 2.66 - 2.52 (m, 1H), 2.24 - 2.06 (m, 1H). LCMS (Method 1): [M+H] + m / z 263, RT 1.50 minutes.

[0385] Intermediate 103 Methyl 2-(3-Amino-4-{[(2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)-acetyl]amino}-2-fluorophenyl)-4,4-difluorobutanoate To a stirred solution of Intermediate 1 (5.48 g, 16.74 mmol) and HATU (6.36 g, 16.74 mmol) in DCM (30 mL) was added DIPEA (5.62 mL, 32.19 mmol) at room temperature. The reaction mixture was stirred for 15 min, then Intermediate 102 (4.22 g, 12.87 mmol) was added as a solution in DCM (30 mL). The reaction mixture was stirred for 18 h, then saturated NaHCO 3It was diluted with aqueous solution (50 mL) and DCM (50 mL). The phases were separated, and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic phases were separated using a hydrophobic frit and then concentrated in vacuo. The residue was separated by flash column chromatography eluting with EtOAc / heptane (0 - 100% gradient) to afford the title compound (8.78 g, quantitative) as a pale pink solid. δ H( 500 MHz, DMSO-d 6 ) 9.51 (s, 1H), 7.70 (d, J 8.0 Hz, 1H), 7.42 - 7.27 (m, 5H), 7.07 (d, J 8.4 Hz, 1H), 6.52 (t, J 8.0 Hz, 1H), 6.04 (tt, J 56.3, 4.4 Hz, 1H), 5.06 (s, 2H), 4.96 (s, 2H), 4.14 (t, J 7.9 Hz, 1H), 4.08 - 3.99 (m, 1H), 3.62 (s, 3H), 2.72 - 2.58 (m, 1H), 2.32 - 2.17 (m, 1H), 2.14 - 1.96 (m, 2H), 1.95 - 1.56 (m, 5H), 1.50 - 1.28 (m, 2H). LCMS (Method 1): [M + H] + m / z 572, RT 2.02 minutes.

[0386] Intermediate 104 Methyl 2-{2-[(S)-Benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4-difluorobutanoate Intermediate 103 (8.77 g, 13.66 mmol) was stirred in DCM (150 mL) and TFA (2.02 mL, 27.31 mmol) at 40 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with DCM (50 mL), and washed with 1 M aqueous NaOH solution (50 mL). The layers were separated using a hydrophobic frit, and the organic phase was concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc / heptane (0 - 100% gradient) to afford the title compound (7.25 g, 87%) as a pale pink solid. δ H( 500 MHz, DMSO-d 6)12.68(s,1H),8.01(d,J 6.8 Hz,1H),7.40 - 7.24(m,6H),7.16 - 7.08(m,1H),6.18 - 5.88(m,1H),5.06(d,J 12.6 Hz,1H),5.01(d,J 12.6 Hz,1H),4.71(t,J 8.0 Hz,1H),4.23(t,J 7.3 Hz,1H),3.60(s,3H),2.85 - 2.60(m,1H),2.40 - 2.23(m,1H),2.17 - 2.07(m,1H),2.07 - 1.93(m,2H),1.92 - 1.85(m,1H),1.85 - 1.61(m,2H),1.54 - 1.43(m,1H),1.42 - 1.31(m,1H),1.31 - 1.20(m,1H).LCMS(Method 1):[M + H] + m / z 554,RT 2.00 minutes.

[0387] Intermediate 105 Methyl 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4-difluorobutanoate Method 1 To a stirred solution of Intermediate 104 (2.50 g, 4.11 mmol) in EtOH (40 mL) was added 10% palladium on carbon (50% wet) (0.87 g, 0.41 mmol) in one portion. The reaction mixture was stirred at 1 atm of H 2 for 18 h, then filtered through Celite® and concentrated in vacuo to afford the title compound (2.02 g, quantitative) as a pale brown foam. δ H( 500 MHz, DMSO - d 6 )12.37(br s,1H),7.30(d,J 8.3 Hz,1H),7.08(dd,J 8.2,6.6 Hz,1H),6.03(tt,J 56.3,4.5 Hz,1H),4.22(t,J 7.4 Hz,1H),3.97 - 3.80(m,1H),3.60(s,3H),2.81 - 2.63(m,1H),2.40 - 2.22(m,1H),2.08 - 1.92(m,2H),1.93 - 1.63(m,4H),1.61 - 1.48(m,1H),1.42 - 1.22(m,2H)(NH 2protons not observed in NMR spectrum). LCMS(Method 1): [M+H] + m / z 420, RT 1.55 minutes.

[0388] Method 2 To a stirred solution of Intermediate 104 (15.00 g, 27.1 mmol) in 1,4-dioxane (150 mL) was added 10% Pd / C (50% wet) (5.0%, 1.73 g, 0.81 mmol). The reaction mixture was circulated three times under vacuum and nitrogen, then stirred at room temperature for 16 h under a hydrogen atmosphere. The mixture was filtered through a pad of Celite® and washed with 1,4-dioxane (50 mL). The solvent was removed in vacuo to afford the title compound (12.8 g, quantitative) as a purple / brown foam. LCMS(Method 2): [M+H] + m / z 420, RT 2.07 minutes.

[0389] Intermediate 106 Methyl 2-(2-{(S)-(4,4-Difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4-difluorobutanoate To a stirred suspension of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (0.67 g, 5.25 mmol) and HATU (2.00 g, 5.28 mmol) in DCM (20 mL) was added DIPEA (2.00 mL, 11.47 mmol) at room temperature. The reaction mixture was stirred for 15 min, then Intermediate 105 (2.00 g, 3.86 mmol) in DCM (20 mL) was added. The reaction mixture was stirred for 18 h, then quenched with saturated NaHCO 3 aqueous solution (40 mL) and stirred at room temperature for 20 min. The phases were separated using a hydrophobic frit and the organic phase was concentrated in vacuo. The residue was separated by flash column chromatography eluting with EtOAc / heptane (0 - 100% gradient) to afford the title compound (1.71 g, 79%) as a white solid. δ H( 500 MHz, DMSO-d 6)12.78(s,1H),9.68(s,1H),7.51 - 7.23(m,1H),7.20 - 7.06(m,1H),6.17 - 5.90(m,1H),5.23 - 5.13(m,1H),4.24(t,J 7.4 Hz,1H),3.60(s,3H),2.80 - 2.63(m,1H),2.48(s,3H),2.41 - 2.24(m,2H),2.14 - 1.92(m,3H),1.91 - 1.71(m,2H),1.68 - 1.52(m,1H),1.48 - 1.23(m,2H).LCMS(Method 1):[M + H] + m / z 530, RT 1.96 minutes.

[0390] Intermediate 107 2-(2-{(S)-(4,4-Difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4-difluorobutanoic acid A stirred suspension of Intermediate 106 (1.7 g, 3.05 mmol) in THF (40 mL) and water (10 mL) was added LiOH·H 2 O (0.32 g, 7.32 mmol) all at once. The reaction mixture was stirred at room temperature for 18 h. Further LiOH·H 2 O (0.070 g, 1.62 mmol) was added and stirring was continued at room temperature for an additional 2 h. The solvent was concentrated in vacuo, water (30 mL) was added, then the suspension was acidified to pH 2 with 1 N HCl and extracted with DCM / IPA (4:1) (3 × 30 mL). The combined organic phases were dried over MgSO 4 and then filtered and concentrated in vacuo and dried at 40 °C in vacuo for 18 h to afford the title compound (1.60 g, 99%) as a white solid. δ H( 500 MHz, DMSO-d 6)9.68(d, J 8.4 Hz, 1H), 7.36(d, J 8.4 Hz, 1H), 7.16(dd, J 8.3, 6.6 Hz, 1H), 6.19 - 5.88(m, 1H), 5.20(t, J 8.4 Hz, 1H), 4.12(t, J 7.4 Hz, 1H), 2.68(dtdd, J 24.6, 16.7, 8.4, 4.8 Hz, 1H), 2.48(s, 3H), 2.38 - 2.19(m, 2H), 2.12 - 1.93(m, 3H), 1.90 - 1.71(m, 2H), 1.55(d, J 12.5 Hz, 1H), 1.47 - 1.20(m, 2H)(CO 2 H and benzimidazole NH protons not observed). LCMS(Method 1): [M + H] + m / z 516, RT 1.84 minutes.

[0391] Intermediate 108 Methyl 2-(2-{(S)-(4,4-difluorocyclohexyl)[(2-fluorobenzoyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4-difluorobutanoate To a stirred solution of Intermediate 105 (164 mg, 0.36 mmol), 2-fluorobenzoic acid (65 mg, 0.463 mmol) and DIPEA (186 μL, 1.07 mmol) in DMF (3 mL) was added HATU (176 mg, 0.463 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in EtOAc (15 mL) and washed successively with saturated NaHCO 3 aqueous solution (10 mL) and brine (3 × 10 mL). The organic phase was dried over MgSO 4 and then filtered and concentrated in vacuo. The residue was separated by flash column chromatography eluting with EtOAc / heptane (0 - 100% gradient) to afford the title compound (165 mg, 81%) as a white solid. δ H( 400 MHz, DMSO-d 6)13.08 - 12.71(m, 1H), 9.00 - 8.76(m, 1H), 7.62(t, J 6.7 Hz, 1H), 7.59 - 7.50(m, 1H), 7.35 - 7.22(m, 3H), 7.20 - 7.08(m, 1H), 6.22 - 5.86(m, 1H), 5.20(t, J 8.3 Hz, 1H), 4.23(t, J 7.3 Hz, 1H), 3.60(s, 3H), 3.48 - 2.21(m, 1H, obs.), 2.83 - 2.63(m, 1H), 2.39 - 2.18(m, 1H), 2.15 - 1.93(m, 3H), 1.94 - 1.69(m, 2H), 1.60 - 1.50(m, 1H), 1.48 - 1.22(m, 2H). LCMS(Method 1): [M + H] + m / z 542, RT 1.97 minutes.

[0392] Intermediate 109 2-(2-{(S)-(4,4-Difluorocyclohexyl)[(2-fluorobenzoyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4-difluorobutanoic acid A stirred suspension of Intermediate 108 (165 mg, 0.305 mmol) in THF (4 mL) and water (1 mL) was added LiOH·H 2 O (31.4 mg, 0.731 mmol) in one portion. The reaction mixture was stirred at room temperature for 18 h. Further LiOH·H 2 O (10 mg, 0.233 mmol) was added and stirring was continued at room temperature for an additional 2.5 h. The solvent was concentrated in vacuo, water (30 mL) was added, then the suspension was acidified to pH 2 with 1 N HCl and extracted with DCM / IPA (4:1) (3 × 30 mL). The combined organic phases were dried over MgSO 4 and then filtered and concentrated in vacuo and dried at 40 °C in vacuo for 18 h to give the title compound (191 mg, quantitative) as a white solid. δ H( 400 MHz, DMSO-d 6)8.91(d, J 6.5 Hz, 1H), 7.63(t, J 7.6 Hz, 1H), 7.58 - 7.51(m, 1H), 7.36(d, J 8.4 Hz, 1H), 7.35 - 7.26(m, 2H), 7.20 - 7.13(m, 1H), 6.19 - 5.86(m, 1H), 5.22(t, J 8.4 Hz, 1H), 4.12(t, J 7.4 Hz, 1H), 3.94 - 3.02(m, 1H, obs.), 2.78 - 2.60(m, 1H), 2.37 - 2.18(m, 1H), 2.15 - 1.94(m, 3H), 1.91 - 1.68(m, 2H), 1.60 - 1.50(m, 1H), 1.47 - 1.21(m, 2H). LCMS(Method 1): [M + H] + m / z 528, RT 1.85 minutes.

[0393] Intermediate 110 2-{2-[(S)-Benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4-difluorobutanoic acid Lithium hydroxide monohydrate (0.26 g, 6.08 mmol) in water (8 mL) was added to a solution of Intermediate 104 (1.54 g, 2.53 mmol) in THF (33 mL). The reaction mixture was stirred at room temperature for 64 hours and then the solvent was concentrated in vacuo. The residue was diluted with water (50 mL) and the pH was adjusted to 2 using 1 M HCl. The resulting material was extracted with DCM:IPA (4:1) (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and then dried over MgSO 4 and filtered. The solvent was concentrated in vacuo. The residue was dried in vacuo at 40 °C for 18 hours to afford the title compound (1.57 g, quantitative) as a yellow foam. LCMS(Method 1): [M + H] + m / z 540, RT 1.88 minutes.

[0394] Intermediate 111 Benzyl N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]carbamate HATU (202 mg, 0.53 mmol) was added to a stirred solution of Intermediate 110 (250 mg, 0.41 mmol) and 2,2-difluoropropan-1-amine hydrochloride (70 mg, 0.53 mmol). The mixture was stirred for 15 minutes, then DIPEA (356 μL, 2.04 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with EtOAc (30 mL) and quenched with saturated NaHCO 3 aqueous solution (30 mL) and water (30 mL). The biphasic mixture was stirred at room temperature for 10 minutes, then the phases were separated. The aqueous phase was washed with EtOAc (2 × 30 mL), the combined organic phases were washed with brine (3 × 30 mL), then dried over MgSO 4 and filtered, and concentrated in vacuo. The resulting crude material was purified by normal-phase flash column chromatography (Isolera 4, Sfar Duo 50 g, eluting with 0 - 100% EtOAc in heptane) to afford the title compound (207 mg, 80%) as a yellow solid. LCMS (Method 1): [M+H] + m / z 617, RT 1.97 minutes.

[0395] Intermediate 112 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N-(2,2-difluoropropyl)-4,4-difluorobutanamide To a stirred solution of Intermediate 111 (200 mg, 0.32 mmol) in 1,4-dioxane (4 mL) placed under nitrogen (3 cycles of vacuum / nitrogen gas), 10% Pd / C (50% wet) (5.0%, 134 mg, 0.06 mmol) was added 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 21 hours, then filtered through Celite®. The plug was washed with additional MeOH. The combined filtrate was concentrated in vacuo to afford the title compound (182 mg, quantitative) as a brown foam. LCMS (Method 1): [M+H] + m / z 483, RT 1.60 minutes.

[0396] Intermediate 113 Me Methyl 2-(2-{(S)-(4,4-difluorocyclohexyl)[(2-isopropyl-1,2,4-triazole-3-carbonyl)amino]-methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4-difluorobutanoate To a stirred solution of Intermediate 105 (12.58 g, 27.0 mmol) and lithium 2-isopropyl-1,2,4-triazole-3-carboxylate (4.78 g, 29.7 mmol) in DMF (100 mL) was added HATU (12.32 g, 32.4 mmol), followed by DIPEA (10 mL, 56.7 mmol). The resulting mixture was stirred at room temperature for 1.5 h under a nitrogen atmosphere, then partitioned between EtOAc (50 mL) and water (50 mL) and stirred for 10 min. The layers were separated and the aqueous layer was further extracted with EtOAc (50 mL). The combined organic extracts were washed with saturated NH 4 Cl aqueous solution (20 mL), water (15 mL), saturated NH 4 Cl aqueous solution (15 mL), water (15 mL), saturated NaHCO 3 aqueous solution (15 mL), water (15 mL) and brine (15 mL), then dried over MgSO 4 filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Isolera 4, Sfar Duo 350 g) eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (9.8 g, 65%) as a yellow solid. LCMS (Method 2): [M+H] + m / z 557, RT 3.03 minutes.

[0397] Intermediate 114 2-(2-{(S)-(4,4-Difluorocyclohexyl)[(2-isopropyl-1,2,4-triazole-3-carbonyl)amino]-methyl}-4-fluoro-1H-benzimidazol-5-yl)-4,4-difluorobutanoic acid To a solution of Intermediate 113 (9.82 g, 17.6 mmol) in THF (150 mL) was added 1 M aqueous lithium hydroxide solution (53 mL, 52.9 mmol). The reaction mixture was stirred at room temperature for 20 h under a nitrogen atmosphere. THF was removed in vacuo. The aqueous phase was washed with TBME (20 mL), then acidified with 1 N HCl aqueous solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), then dried over MgSO 4 filtered and concentrated in vacuo to afford the title compound (9 g, 61% over 2 steps) as a yellow solid. LCMS (Method 2): [M+H] + m / z 543, RT 2.75 minutes.

[0398] Intermediate 115 2-{2-[(S)-Benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4,4-trifluorobutanoic acid To a stirred solution of intermediate 32 (1 g, 1.71 mmol) in a mixture of THF (4 mL) and MeOH (4 mL) was added portionwise 2 M aqueous NaOH solution (4.0 mL, 8.00 mmol). The reaction mixture was stirred at ambient temperature for 3 h, then 1 M HCl (9 mL) was added dropwise and the resulting material was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (20 mL), then dried over anhydrous Na 2 SO 4 and filtered. The solvent was concentrated in vacuo to afford the title compound (932 mg, 98%) as a peach-colored solid. LCMS (Method 2): [M+H] + m / z 558, RT 2.96 minutes.

[0399] Intermediate 116 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{3,3,3-trifluoro-1-[(2-fluoro-2-methyl-propyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]carbamate To a solution of intermediate 115 (1.18 g, 2.00 mmol) and 2-fluoro-2-methyl-propan-1-amine hydrochloride (0.28 g, 2.20 mmol) in DMF (6 mL) was added DIPEA (1.0 mL, 6.01 mmol), followed by HATU (0.91 g, 2.40 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The resulting brown oil was dissolved in EtOAc (50 mL). The organic layer was washed with saturated aqueous NaHCO 3 solution (25 mL) and brine (3 × 25 mL), then dried over MgSO 4 and filtered. The solvent was evaporated. The resulting brown foam was purified by flash column chromatography (Biotage Isolera Sfar Duo 50 g, eluting with a gradient of 0 - 55% EtOAc in heptane) to afford the title compound (1.37 g, quantitative) as a light brown solid. LCMS (Method 2): [M+H] + m / z 631.2, RT 3.22 minutes.

[0400] Intermediate 117 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4,4-trifluoro-N-(2-fluoro-2-methylpropyl)butanamide To a stirred solution of intermediate 116 (1.37 g, 2.05 mmol) in 1,4-dioxane (45 mL) placed under nitrogen (3 cycles of vacuum / nitrogen gas), 10% Pd / C (50% wet) (5.0%, 0.87 g, 0.41 mmol) was added all at once. The reaction mixture was stirred under hydrogen (3 cycles of vacuum / nitrogen gas, followed by 3 cycles of vacuum / hydrogen gas) for 22 h, then filtered through Celite® while washing with MeOH. The filtrate was concentrated in vacuo and then azeotroped with DCM to afford the title compound (1.16 g, 99.7%) as a grey / brown foam. LCMS (Method 1): [M+H] + m / z 497.2, RT 1.62 minutes.

[0401] Intermediate 118 Benzyl N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]carbamate To a solution of intermediate 115 (1.10 g, 1.87 mmol) and 2,2-difluoropropan-1-amine hydrochloride (1:1) (0.27 g, 2.05 mmol) in DMF (6 mL) was added DIPEA (0.98 mL, 5.60 mmol), followed by HATU (0.85 g, 2.24 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature and then concentrated in vacuo. The resulting brown oil was dissolved in EtOAc (50 mL). The organic layer was washed with saturated NaHCO 3 aqueous solution (25 mL) and brine (3×25 mL), then dried over MgSO 4 and filtered. The solvent was evaporated. The resulting light brown foam was purified by flash column chromatography (Biotage Isolera Sfar Duo50g, eluting with a gradient of 0 - 60% EtOAc in heptane) to afford the title compound (1.23 g, quantitative) as a light brown foam. LCMS (Method 2): [M+H] + m / z 635.2, RT 3.22 minutes.

[0402] Intermediate 119 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N-(2,2-difluoropropyl)-4,4,4-trifluorobutanamide To a stirred solution of intermediate 118 (1.23 g, 1.86 mmol) in 1,4-dioxane (40 mL) placed under nitrogen (3 cycles of vacuum / nitrogen gas), 10% Pd / C (50% wet) (5.0%, 0.79 g, 0.37 mmol) was added all at once. The reaction mixture was stirred under hydrogen (3 cycles of vacuum / nitrogen gas, followed by 3 cycles of vacuum / hydrogen gas) for 20 h, then filtered through Celite® while washing with MeOH. The filtrate was concentrated in vacuo and then azeotroped with DCM to afford 1.02 g (quantitative) of the title compound as a grey / brown foam. LCMS (Method 1): [M+H] + m / z 501.2, RT 1.63 minutes.

[0403] Intermediate 120 Methyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]prop-2-enoate To a stirred solution of intermediate 100 (1 g, 2.45 mmol) in DMSO (4.8969 mL), acetic anhydride (0.69 mL, 7.35 mmol) was added, followed by N,N,N’,N’-tetramethyl-methanediamine (0.50 mL, 3.67 mmol). The resulting solution was stirred at room temperature for 2 h, then partitioned between EtOAc (15 mL) and water (10 mL) and stirred for 10 min. The layers were separated, the organic phase was washed with brine (10 mL), dried over MgSO 4 and filtered, concentrated and dried. The crude material was purified by flash column chromatography (Isolera4, Sfar Duo25 g) eluting with a gradient of 0 - 20% EtOAc in heptane to afford 860 mg (84%) of the title compound as a yellow oil which crystallized to a yellow solid on standing.

[0404] Intermediate 121 Methyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-3-methoxypropanoate To a stirred solution of intermediate 120 (850 mg, 2.02 mmol) in anhydrous MeOH (20 mL), sodium methoxide (109 mg, 2.02 mmol) was added. The resulting solution was stirred at room temperature for 16 h under a nitrogen atmosphere. The volume was reduced to approximately 5 mL, then the resulting material was diluted with DCM (15 mL) and saturated NH4 It was quenched with an aqueous Cl solution (10 mL). After stirring for 5 minutes, the layers were separated, and the aqueous layer was extracted with DCM (10 mL). The combined organic extracts were washed with brine (10 mL) and dried over MgSO 4 , then filtered, concentrated to dryness, and the title compound (950 mg, quantitative) was obtained as a yellow oil. LCMS (Method 1): [M+H] + m / z 453, RT 2.15 minutes.

[0405] Intermediate 122 Methyl 2-(3,4-diamino-2-fluorophenyl)-3-methoxypropanoate To a stirred solution of Intermediate 121 (500 mg, 1.11 mmol) in EtOH (10 mL) was added 10% Pd / C (50% wet) (5.0%, 470 mg, 0.22 mmol). The reaction mixture was cycled three times between vacuum and nitrogen, then stirred at room temperature for 16 hours under a hydrogen atmosphere. The mixture was filtered through a pad of Celite® and washed with EtOAc (10 mL). The solvent was removed in vacuo. The crude material (260 mg) was purified by FCC (Isolera4, Sfar Duo10 g) eluting with a 0 - 100% EtOAc gradient in heptane to give the title compound (215 mg, 80%) as a purple oil which crystallized on standing. LCMS (Method 1): [M+H] + m / z 243, RT 0.98 minutes.

[0406] Intermediate 123 Methyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-3-methoxypropanoate To a stirred solution of Intermediate 122 (190 mg, 0.784 mmol) and Intermediate 1 (257 mg, 0.78 mmol) in DMF (2.8 mL) were added HATU (328 mg, 0.86 mmol), followed by DIPEA (0.29 mL, 1.65 mmol). The resulting mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere, then partitioned between EtOAc (20 mL) and water (10 mL) and stirred for 10 minutes. The layers were separated and the aqueous layer was further extracted with EtOAc (10 mL). The combined organic extracts were washed with saturated NH 4 Cl aqueous solution (10 mL), water (10 mL), saturated NaHCO3 Washed with aqueous solution (10 mL) and brine (10 mL), then dried over MgSO 4 and filtered, and concentrated in vacuo. The crude material (550 mg) was purified by FCC (Isolera 4, Sfar Duo 25 g) eluting with a 0 - 100% gradient of EtOAc in heptane, and the isolated material was dissolved in DCM (10 mL), to which TFA (0.20 mL, 2.72 mmol) was added. The reaction mixture was stirred at 40 °C for 18 h under a nitrogen atmosphere, then cooled to room temperature and diluted with DCM (20 mL). Saturated NaHCO 3 aqueous solution was added until foaming ceased. The layers were separated, and the aqueous layer was extracted with DCM (15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO 4 and then filtered and concentrated in vacuo to afford the title compound (350 mg, 84%) as a beige solid. LCMS (Method 1): [M + H] + m / z 534, RT 1.94 minutes.

[0407] Intermediate 124 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-3-methoxypropanoic acid To a stirred solution of Intermediate 123 (150 mg, 0.28 mmol) in THF (5 mL) was added 1 M aqueous lithium hydroxide solution (1.1 mL, 1.12 mmol). The reaction mixture was stirred at room temperature for 40 h under a nitrogen atmosphere, then diluted with water and acidified to pH 2 with 1 N aqueous HCl solution and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO 4 and then filtered and concentrated in vacuo to afford the title compound (150 mg, quantitative) as a white solid. LCMS (Method 1): [M + H] + m / z 520, RT 1.83 minutes.

[0408] Intermediate 125 Benzyl N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[1-(methoxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzimidazol-2-yl}methyl]carbamate To a stirred solution of Intermediate 124 (150 mg, 0.289 mmol) and 2,2,2-trifluoroethanamine (34 mg, 0.346 mmol) in DMF (3 mL) was added HATU (132 mg, 0.346 mmol), followed by DIPEA (0.11 mL, 0.606 mmol). The resulting mixture was stirred at room temperature for 15 h under a nitrogen atmosphere, then partitioned between EtOAc (10 mL) and water (5 mL) and stirred for 10 min. The layers were separated and the aqueous layer was further extracted with EtOAc (10 mL). The combined organic extracts were washed with saturated NH 4 Cl aqueous solution (10 mL), water (10 mL), saturated NaHCO 3 aqueous solution (10 mL) and brine (10 mL), then dried over MgSO 4 , filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolera 4, Sfar Duo 10 g) eluting with a 0 - 100% gradient of EtOAc in heptane to afford the title compound (120 mg, 60%) as a white solid. LCMS (Method 2): [M+H] + m / z 601, RT 2.98 minutes.

[0409] Intermediate 126 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-3-methoxy-N-(2,2,2-trifluoroethyl)propanamide To a stirred solution of Intermediate 125 (120 mg, 0.20 mmol) in EtOH (4 mL) was added 10% Pd / C (50% wet) (5.0%, 85 mg, 0.04 mmol). The reaction mixture was evacuated and backfilled with nitrogen three times, then stirred at room temperature for 1.5 h under a hydrogen atmosphere. The mixture was filtered through a pad of Celite® and washed with EtOAc (10 mL) and EtOH (10 mL). The solvent was removed in vacuo to afford the title compound (106 mg, quantitative) as a colorless film. LCMS (Method 2): [M+H] + m / z 467, RT 1.97 minutes.

[0410] Intermediate 127 1-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-1H-imidazo[4,5-b]pyridin-5-yl}-4,4-difluoro-N-(2,2,2-trifluoroethyl)cyclohexanecarboxamide To a nitrogen-purged solution of intermediate 99 (2 g, 3.05 mmol) in EtOH (20 mL), Pd / C (0.15 g) was added. The flask was evacuated, purged with hydrogen, and then stirred overnight. The reaction mixture was filtered through Celite®, and the plug was washed with DCM. The resulting material was concentrated in vacuo. The resulting dark gum was purified using silica gel chromatography eluting with a gradient of 100% EtOAc and MeOH (0 - 10%) to give the title compound (1.2 g, 70%) as a purple / grey foam. LCMS (Method 3): [M+H] + m / z 510, RT 1.19 minutes.

[0411] Intermediate 128 2,2-Difluoropropyl trifluoromethanesulfonate To a solution of 2,2-difluoropropanol (85 mL, 1050 mmol) and triethylamine (290 mL, 2080 mmol) in DCM (2 L) at -15 °C (internal temperature), trifluoromethanesulfonic anhydride (200 mL, 1200 mmol) was added over 40 minutes while maintaining the temperature below 10 °C. The colorless solution turned dark brown during the addition. After 1 hour, the material was washed with 10% HCl solution and 1 analyzed by 1H NMR, which showed complete conversion. 10% HCl solution (1 L) was added and the mixture was warmed to 20 °C. The organic layer was washed with water (2 × 1 L), then passed through a hydrophobic frit and concentrated in vacuo to give the title compound (80 wt%) (231 g, 77%) as a dark brown oil.

[0412] Intermediate 129 Diethyl 2-(2,2-difluoropropyl)propanedioate A solution of diethyl malonate (61 mL, 400 mmol) in THF (800 mL) at 0 °C was added potassium tert-butoxide (55 g, 480 mmol) in three portions (exothermic). A thick suspension formed. After 30 minutes, intermediate 128 (80 wt%) (231 g, 810 mmol) in THF (150 mL) was added. The mixture was warmed to 25 °C. After 92 hours, isohexane (200 mL) was added, followed by 10% HCl solution (400 mL). The aqueous layer was extracted with TBME (300 mL). The combined organic phases were washed with saturated NaHCO 3 aqueous solution (2 × 500 mL) (foaming was observed), then with Na 2 SO 4 and dried over Na H( SO 3 and concentrated under reduced pressure. The resulting dark brown oil was purified by flash chromatography (gradient elution of 0 - 20% TBDME in isohexane) to give the title compound (90.0 g, 86%) as a pale yellow oil. δ

[0413] Intermediate 130 Diethyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-2-(2,2-difluoropropyl)propane-dioate To a solution of intermediate 4 (20 g, 56 mmol) and intermediate 129 (90 wt%) (26 g, 98 mmol) in DMF (110 mL) was added K 2 CO 3 (24 g, 174 mmol). The mixture was heated at 90 °C (external temperature) for 30 hours. The resulting dark brown / black mixture was cooled to ambient temperature and poured into water (200 mL). The aqueous phase was extracted with TBME (2 × 200 mL). The combined extracts were dried over Na 2 SO 4It was dried and concentrated under reduced pressure. The resulting dark brown oil slowly crystallized. The residue was recrystallized from isohexane:TBME (3:2) (150 mL). The crystals were collected on a sintered body, then washed with isohexane (200 mL) and dried to obtain the title compound (22.3 g, 69%) as a yellowish brown solid. δ H( 300 MHz, DMSO-d 6 ) 7.82 - 7.68 (m, 1H), 7.55 (dd, J 8.8, 1.4 Hz, 1H), 7.38 - 7.12 (m, 10H), 4.34 - 4.12 (m, 4H), 4.10 (s, 4H), 2.96 (t, J 16.6 Hz, 2H), 1.52 (t, J 19.3 Hz, 3H), 1.17 (t, J 7.1 Hz, 6H).

[0414] Intermediate 131 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluoropentanoic acid To a solution of Intermediate 130 (4.1 g, 7.2 mmol) in THF (30 mL) was added LiOH·H 2 O (1.2 g, 29 mmol) dissolved in H 2 O (10 mL). The mixture was stirred at 35 °C for 12 h, then diethyl ether (50 mL) was added and the layers were separated. The aqueous layer was acidified using 0.5 M HCl solution. The material was extracted with EtOAc (2 × 50 mL), then passed through a hydrophobic frit and evaporated in vacuo to obtain the title compound (3.3 g, 95%) as an orange rubber. LCMS (Method 3): [M + H] + m / z 573, RT 1.55 minutes.

[0415] Intermediate 132 Methyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluoropentanoate To a solution of Intermediate 131 (10.0 g, 21.2 mmol) in MeOH (21 mL) was added H 2 SO 2 O (18.18 M) in H 4 O (4.4 mL). The reaction mixture was heated at reflux temperature (75 °C) for 18 h, then concentrated in vacuo and dissolved in EtOAc (100 mL). The organic layer was washed with saturated NaHCO 3It was washed with an aqueous solution (100 mL), and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over Na 2 SO 4 and then passed through a phase separator and concentrated in vacuo to give the title compound (9.09 g, 88%) as an orange oil. LCMS (Method 3): [M+H] + m / z 487.2, RT 1.48 minutes.

[0416] Intermediate 133 Methyl 2-(3,4-diamino-2-fluorophenyl)-4,4-difluoropentanoate N 2 Under, to a solution of intermediate 132 (9.0 g, 18.7 mmol) in EtOH (187 mL) was added Pd / C (10% by mass) (909 mg, 0.85 mmol). The reaction flask was placed under an H 2 atmosphere. After 18 hours, the reaction mixture was filtered through a pad of Celite® and then concentrated in vacuo to give the title compound (5.3 g, quantitative) as an orange oil. LCMS (Method 9): [M+H] + m / z 277.2, RT 1.31 minutes.

[0417] Intermediate 134 Methyl 2-(3-amino-4-{[(2S)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)-acetyl]amino}-2-fluorophenyl)-4,4-difluoropentanoate To a mixture of intermediate 133 (5.16 g, 18.7 mmol), intermediate 1 (7.34 g, 22.4 mmol) and HATU (8.70 g, 22.4 mmol) in DCM (190 mL) was added DIPEA (6.0 g, 46.7 mmol). The reaction mixture was stirred at room temperature for 2.5 hours and then washed with water (200 mL). The aqueous layer was extracted with DCM (2 × 100 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography (Biotage SFAR HC DUO, 200 g, Isolera) eluting with a gradient of 0 - 80% EtOAc in isohexane to give the title compound (10.86 g, 99%) as a peach-colored amorphous solid. LCMS (Method 3): [M+H] + m / z 586.2, RT 1.22 minutes.

[0418] Intermediate 135 Methyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4-difluoropentanoate To a solution of Intermediate 134 (10.9 g, 18.54 mmol) in DCM (185 mL) was added TFA (5.6 mL, 74.16 mmol). The reaction mixture was heated at 40 °C overnight and then quenched with saturated NaHCO 3 aqueous solution (200 mL). The aqueous layer was extracted with DCM (2 × 100 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography (Biotage SFAR HC DUO, 200 g, Isolera) eluting with a gradient of 0 - 80% EtOAc in isohexane, followed by crystallization from hot TBME to give the title compound (7.18 g, 68%) as a colorless amorphous solid. LCMS (Method 3): [M+H] + m / z 568.2, RT 1.21 minutes.

[0419] Intermediate 136 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4-difluoropentanoic acid To a solution of Intermediate 135 in 1,4 - dioxane (50 mL) was added LiOH·H 2 O (880 mg, 21 mmol) dissolved in H 2 O (20 mL). MeOH (10 mL) was also added to facilitate dissolution of the starting material and the reaction mixture was left stirring overnight. Additional LiOH·H 2 O (0.5 g, 12 mmol) in water (10 mL) was added. After leaving the reaction mixture overnight, the volatile materials were removed in vacuo and the residue was lyophilized overnight to give the title compound (lithium salt) (purity ca. 80%) (3.9 g, 79%) as a white solid. LCMS (Method 3): [M+H] + m / z 544.2, RT 1.44 minutes.

[0420] Intermediate 137 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(5-{(1S)-3,3-difluoro-1-[(2-fluoro-2-methyl-propyl)carbamoyl]butyl}-4-fluoro-1H-benzimidazol-2-yl)methyl]carbamate To a stirred solution of intermediate 136 (2 g, 3.25 mmol) in DCM (50 mL) and DIPEA (1.7 mL, 9.7 mmol), 2-fluoro-2-methylpropan-1-amine hydrochloride (622 mg, 4.88 mmol) was added, followed by HATU (1.6 g, 4.1 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with DCM (100 mL) and brine (10 mL). The layers were separated and the aqueous layer was re-extracted with DCM (100 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The resulting off-white solid was purified by flash column chromatography on silica eluting with 1 - 80% EtOAc / hexane to give a white solid (mixture of stereoisomers) (1.65 g). A portion of the material (300 mg) was subjected to chiral purification (Method 25) to give Peak 1 (100 mg) and Peak 2 (the latter was arbitrarily designated as the title compound (100 mg)). LCMS (Method 8): [M+H] + m / z 672.4, RT 2.05 minutes. Chiral analysis (Method 26): RT 5.140 min, 100% d.e.

[0421] Intermediate 138 (2S)-2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-4,4-difluoro-N-(2-fluoro-2-methylpropyl)pentanamide Intermediate 137 (420 mg, 0.67 mmol) was dissolved in EtOH (10 mL) and ammonium formate (0.9 g, 13.56 mmol) was added. The reaction flask was degassed and flushed with nitrogen, then Pd / C (70 mg, 0.07 mmol) was added. The reaction mixture was stirred for 5 h and then filtered through a pad of Celite® and washed with DCM. The filtrate was washed with water (10 mL) and then re-extracted with DCM (10 mL). The combined organic extracts were washed with water (10 mL) once more, then passed through a hydrophobic frit and concentrated in vacuo to give the title compound (330 mg, 90%) as a white solid. LCMS (Method 9): [M+H] + m / z 493.2, RT 1.69 minutes.

[0422] Intermediate 139 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluorobutanoic acid To a stirred solution of Intermediate 101 (10.00 g, 21.2 mmol) in THF (100 mL) was added portionwise at ambient temperature a solution of LiOH·H 2 2O (2.20 g, 51.2 mmol) in water (25 mL). The reaction mixture was stirred for 16 h and then cooled in an ice bath. 6 M HCl (10 mL) was added dropwise. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (2 × 50 mL) and brine (50 mL), then dried over anhydrous Na 2 2 4 SO + 4 and filtered. The solvent was concentrated in vacuo to afford the title compound (9.77 g, 96%) as a yellow solid. LCMS (Method 1): [M+H]

[0423] Intermediate 140 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluoro-N-(2,2,2-trifluoroethyl)-butanamide To a stirred solution of Intermediate 139 (800 mg, 1.75 mmol) in DCM (8 mL) was added DIPEA (0.46 mL, 2.62 mmol). To the resulting solution were added 2,2,2-trifluoroethylamine (0.17 mL, 2.10 mmol) and subsequently HATU (821 mg, 2.09 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with DCM (50 mL) and washed with brine. The aqueous layer was re-extracted with DCM (50 mL). The combined organic extracts were washed with saturated aqueous NH 4 4Cl (50 mL) and concentrated in vacuo. The resulting orange oil was purified by silica column chromatography (25G SFar column) eluting with 1 - 100% EtOAc in hexane to afford the title compound (900 mg, 96%) as a yellow oil. LCMS (Method 3): [M+H] + m / z 540, RT 1.55 minutes.

[0424] Intermediate 141 2-(3,4-Diamino-2-fluorophenyl)-4,4-difluoro-N-(2,2,2-trifluoroethyl)butanamide To a stirred solution of Intermediate 140 (1.5 g, 2.78 mmol) in EtOH (20 mL) was added Pd / C (592 mg, 0.56 mmol) at room temperature. The reaction mixture was placed under a hydrogen gas atmosphere (3 cycles of vacuum / nitrogen gas, followed by 3 cycles of vacuum / hydrogen gas) and stirred at room temperature for 18 h. The material was filtered through a plug of Celite® and concentrated in vacuo. The resulting dark brown oil was purified by column chromatography (25 g Si cartridge preconditioned with hexanes and eluted with 0 - 60% EtOAc / hexanes) to afford the title compound (717 mg, 78%) as a light brown solid. LCMS (Method 3): [M+H] + m / z 330, RT 1.10 minutes.

[0425] Intermediates 142 and 143 ( (2R)-2-(3,4-Diamino-2-fluorophenyl)-4,4-difluoro-N-(2,2,2-trifluoroethyl)butanamide (Intermediate 142) (2S)-2-(3,4-Diamino-2-fluorophenyl)-4,4-difluoro-N-(2,2,2-trifluoroethyl)butanamide (Intermediate 143) Intermediate 141 (717 mg) was subjected to chiral HPLC (Method 27) to afford the title compound (Peak 1, 270 mg, 38%, and Peak 2, 270 mg, 38%). Chiral analysis (Method 28): Peak 1, RT 3.96 min (100%), and Peak 2, RT 4.93 min (100%).

[0426] Intermediate 144 Benzyl N-[(1S)-2-{2-amino-4-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-3-fluoroanilino}-1-(4,4-difluorocyclohexyl)-2-oxoethyl]carbamate To a stirred solution of Intermediate 143 (50.00 g, 0.152 mol) and Intermediate 1 (49.71 g, 0.152 mol) in DMF (500 mL), HATU (69.00 g, 0.181 mol) was added portionwise, followed by the addition of DIPEA (53 mL, 0.304 mol). The reaction mixture was stirred at ambient temperature for 2.5 h and then poured into water (3 L). The resulting suspension was stirred for an additional 20 min. The solid was collected by filtration and the filter cake was washed with water (2 × 400 mL) and diethyl ether (400 mL). The wet solid was transferred to a 5 L flask and MeOH (3 L) was added. The slurry was heated at 50 °C for 1 h (complete dissolution was never achieved, but partial crystallization of the product was effected). The solid (wet cake) was collected by filtration and further dried in a vacuum oven to afford a fluffy solid. The MeOH filtrate was concentrated in vacuo to give a brown solid. Both solids were recombined and dissolved in EtOAc (6 L) (with gentle heating). The solvent was removed in vacuo and the solid was further dried in a vacuum oven (40 °C) for 16 h to give the title compound (85.34 g, 86%) as a dark beige solid. LCMS (Method 2): [M+H] + m / z 639, RT 3.24 minutes.

[0427] Intermediate 145 Benzyl N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]carbamate To a stirred solution of Intermediate 144 (85.00 g, 0.133 mol) in DCM (3400 mL), TFA (40 mL, 0.539 mol) was added dropwise. The reaction mixture was stirred at 40 °C for 20 h and then cooled to ambient temperature. 1 M aqueous NaOH (0.5 L) was added portionwise. Then saturated aqueous NaOH (200 mL) was carefully added portionwise. The organic phase was recovered, washed with water (1 L), then dried over anhydrous Na 2 SO 4 and filtered. The solvent was concentrated in vacuo. The residue was purified by dry flash chromatography (1 kg of silica) eluting with a 10 - 40% gradient of EtOAc in heptane to give the title compound (100% e.e.) (74.36 g, 88%) as a pale pink solid. LCMS (Method 2): [M+H]+ m / z 621, RT 3.19 minutes.

[0428] Intermediate 146 (2S)-2-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N-(2,2,2-difluoroethyl)-4,4-difluorobutanamide To a stirred solution of intermediate 145 (0.7 g, 1 mmol) in EtOH (10 mL) that had been degassed and was flowing with nitrogen, Pd / C (100 mg, 0.09 mmol) was added. The material was further degassed and hydrogen was added via a balloon. The reaction mixture was stirred overnight and then filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give the title compound (0.6 g, quantitative) as a gray solid. LCMS (Method 3): [M+H] + m / z 487.0, RT 1.22 minutes.

[0429] Intermediate 147 Benzyl N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3-difluoro-butyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]carbamate Intermediate 136 (150 mg, 0.27 mmol), 2,2-difluoro-propan-1-amine hydrochloride (53 mg, 0.41 mmol), DIPEA (0.14 mL, 0.81 mmol) and DMF (3 mL) were introduced into a vial under N at room temperature, and then HATU (155 mg, 0.41 mmol) was added. The reaction mixture was stirred for 2 h and then quenched with water (12 mL) and brine (6 mL). The mixture was extracted with EtOAc (12 mL). The organic layer was washed with brine (6 mL) and then dried over MgSO 4 and filtered and concentrated in vacuo. The crude material obtained was purified by silica flash column chromatography eluting with a gradient between 10% EtOAc:90% heptane and 70% EtOAc:30% heptane to give the title compound (141 mg, 83%) as a white solid. LCMS (Method 1): [M+H] + 631.2, RT 1.96 minutes.

[0430] Intermediate 148 2-{2-[(S)-Amino(4,4-difluorocyclohexyl)methyl]-4-fluoro-1H-benzimidazol-5-yl}-N-(2,2-difluoropropyl)-4,4-difluoropentanamide An intermediate 147 (141 mg, 0.203 mmol) and EtOH (6 mL) were introduced into a round-bottom flask at room temperature. The mixture was stirred, evacuated, and purged with N 2 and the cycle was repeated 3 times. Pd / C (10 wt%, 50% wet) (5.0%, 43 mg, 0.02 mmol) was added. The mixture was stirred, evacuated, and purged with N 2 and the cycle was repeated 3 times. The evacuation-purging cycle was repeated 3 times with H 2 and the reaction mixture was left for 2 hours. The reaction mixture was evacuated, purged with N 2 and the cycle was repeated 3 times. The reaction mixture was filtered through a glass fiber filter paper and the filter cake was washed with MeOH (about 10 mL). The filtrate was concentrated in vacuo to give the title compound (106 mg, 95%) as a grey solid. LCMS (Method 1): [M+H] + 497.2, RT 1.61 minutes.

[0431] Examples 1 and 2

Chemical formula

[0432] Peak 1 (arbitrarily assigned 3S with pyrrolidine): δ H( 500 MHz, DMSO - d 6 )12.79 (br s, 1H), 9.61 (br s, 1H), 7.33 (br s, 1H), 7.24 - 7.12 (m, 1H), 5.21 - 5.10 (m, 1H), 4.13 - 3.84 (m, 3H), 3.75 - 3.55 (m, 2H), 3.55 - 3.49 (m, 3H), 3.48 - 3.29 (m, 3H), 2.65 - 2.50 (m, 1H), 2.41 (s, 3H), 2.30 - 2.18 (m, 1H), 2.06 - 1.84 (m, 3H), 1.83 - 1.65 (m, 2H), 1.51 (d, J 12.2 Hz, 1H), 1.41 - 1.14 (m, 3H). LCMS (Method 4): [M + H] + m / z 690.3, RT 3.31 minutes.

[0433] Peak 2 (arbitrarily assigned 3R with pyrrolidine): δ H( 500 MHz, DMSO - d 6 )12.80 (br s, 1H), 9.59 (br s, 1H), 7.34 (br s, 1H), 7.23 - 7.13 (m, 1H), 5.15 (d, J 7.9 Hz, 1H), 4.16 - 3.87 (m, 3H), 3.77 - 3.55 (m, 2H), 3.53 (d, J 2.9 Hz, 3H), 3.48 - 3.31 (m, 3H), 2.65 - 2.50 (m, 1H), 2.41 (s, 3H), 2.29 - 2.19 (m, 1H), 2.06 - 1.84 (m, 3H), 1.83 - 1.66 (m, 2H), 1.56 - 1.46 (m, 1H), 1.41 - 1.14 (m, 3H). LCMS (Method 4): [M + H] + m / z 690.3, RT 3.31 minutes.

[0434] Example 3

Chem.

[0435] Examples 4 and 5

Chem.

[0436] Peak 1 (arbitrarily assigned S): δ H( 400 MHz, DMSO-d 6 ) 12.93 (s, 1H), 9.69 (s, 1H), 7.34 (d, J 8.4 Hz, 1H), 7.09 (d, J 7.6 Hz, 1H), 5.98 (tt, J 56.4, 4.5 Hz, 1H), 5.19 (d, J 8.0 Hz, 1H), 4.80 (q, J 11.9 Hz, 1H), 4.56 - 4.11 (m, 3H), 3.98 (q, J 11.8 Hz, 1H), 3.33 (br s, 3H), 2.67 (d, J 1.9 Hz, 1H), 2.42 - 2.13 (m, 3H), 2.13 - 1.90 (m, 2H), 1.78 (dd, J 31.8, 13.4 Hz, 1H), 1.58 (d, J 13.4 Hz, 1H), 1.50 - 1.15 (m, 2H), 1.03 - 0.73 (m, 1H). LCMS (Method 8): [M+H] + m / z 591.4, RT 1.89 minutes.

[0437] Peak 2 (arbitrarily assigned R): δ H( 400 MHz, DMSO-d 6 ) 13.05 (s, 1H), 9.73 (s, 1H), 7.33 (d, J 8.4 Hz, 1H), 7.08 (s, 1H), 6.34 - 5.49 (m, 1H), 5.19 (d, J 8.1 Hz, 1H), 4.80 (q, J 11.9 Hz, 1H), 4.46 - 4.10 (m, 3H), 3.97 (q, J 11.4 Hz, 1H), 3.33 (br s, 3H), 2.84 - 2.56 (m, 1H), 2.40 - 2.14 (m, 2H), 2.14 - 1.91 (m, 2H), 1.91 - 1.67 (m, 1H), 1.58 (d, J 13.4 Hz, 1H), 1.48 - 1.09 (m, 3H), 0.85 (d, J 7.7 Hz, 1H). LCMS (Method 8): [M+H] + m / z 591.2, RT 1.89 minutes.

[0438] Example 6

Chemical Structure

[0439] Example 7

Chemical Structure

[0440] Example 8

Chem.

[0441] Examples 9 and 10

Chem.

[0442] Peak 1 (arbitrarily designated as S): δ H( 500 MHz, DMSO-d 6)12.70(s,1H),9.67(d,J 8.5 Hz,1H),8.13(d,J 9.0 Hz,1H),7.92 - 7.79(m,1H),7.46 - 7.20(m,2H),5.25 - 5.14(m,1H),4.40(t,J 6.8 Hz,1H),4.10 - 4.01(m,1H),3.19 - 3.02(m,1H),2.72 - 2.61(m,1H),2.59(d,J 4.5 Hz,3H),2.48(s,3H),2.36 - 2.23(m,1H),2.14 - 1.93(m,3H),1.90 - 1.70(m,3H),1.61 - 1.50(m,1H),1.47 - 1.35(m,1H),1.36 - 1.22(m,1H),0.70 - 0.53(m,6H).LCMS(Method 4):[M + H] + m / z 646,RT 3.13 minutes.

[0443] Peak 2 (arbitrarily designated as R): δ H( 500 MHz,CD 3 OD)7.54 - 7.19(m,2H),5.26(d,J 8.5 Hz,1H),4.55 - 4.42(m,1H),4.09(d,J 8.1 Hz,1H),3.28 - 3.11(m,1H),2.61(s,3H),2.58 - 2.44(m,4H),2.42 - 2.25(m,1H),2.19 - 1.96(m,4H),1.96 - 1.70(m,2H),1.69 - 1.36(m,3H),1.01 - 0.86(m,6H).LCMS(Method 4):[M + H] + m / z 646,RT 3.26 minutes.

[0444] Examples 11 and 12

Chemical Structure

[0445] Peak 1 (arbitrarily assigned S): δ H( 500 MHz, DMSO-d 6 ) 12.77 (s, 1H), 9.69 (s, 1H), 8.43 (d, J 8.8 Hz, 1H), 7.52 - 7.09 (m, 2H), 5.24 - 5.10 (m, 1H), 4.56 (t, J 8.4 Hz, 1H), 4.43 (dd, J 8.7, 4.9 Hz, 1H), 3.18 - 3.02 (m, 1H), 2.97 (s, 3H), 2.72 (s, 3H), 2.64 - 2.53 (m, 1H), 2.48 (s, 3H), 2.36 - 2.21 (m, 1H), 2.15 - 1.91 (m, 4H), 1.90 - 1.66 (m, 2H), 1.62 - 1.48 (m, 1H), 1.47 - 1.20 (m, 2H), 0.87 (d, J 6.7 Hz, 3H), 0.83 (d, J 6.7 Hz, 3H). LCMS (Method 4): [M + H] + m / z 646, RT 3.46 minutes.

[0446] Peak 2 (arbitrarily R): δ H( 500 MHz, DMSO-d 6)12.72(s,1H),9.78 - 9.64(m,1H),8.39(d,J 8.3 Hz,1H),7.47 - 7.22(m,2H),5.25 - 5.15(m,1H),4.49(t,J 8.5 Hz,1H),4.43 - 4.31(m,1H),3.20 - 3.01(m,4H),2.84(s,3H),2.73 - 2.57(m,1H),2.48(s,3H),2.36 - 2.25(m,1H),2.13 - 1.92(m,3H),1.92 - 1.71(m,3H),1.61 - 1.51(m,1H),1.47 - 1.35(m,1H),1.36 - 1.21(m,1H),0.70(d,J 6.7 Hz,3H),0.64 - 0.50(m,3H).LCMS(Method 4):[M + H] + m / z 660,RT 3.32 minutes.

[0447] Example 13

Chem.

[0448] Example 14

Chem.

[0449] Example 15

Chem.

[0450] Example 16

Chem.

[0451] Example 17

Chem.

[0452] Example 18

Chem.

[0453] Example 19

Chem.

[0454] Example 20

Chem.

[0455] Examples 21 and 22

Chemical Structure

[0456] Peak 1 (arbitrarily assigned S): δ H( 400 MHz, DMSO-d 6 ) 12.82 (s, 1H), 8.97 (d, J 8.5 Hz, 1H), 7.48 (d, J 2.1 Hz, 1H), 7.31 (d, J 8.3 Hz, 1H), 7.18 - 6.82 (m, 2H), 5.15 (t, J 8.6 Hz, 1H), 4.78 (q, J 12.1 Hz, 1H), 4.43 - 4.11 (m, 2H), 4.03 (s, 3H), 3.33 (s, 2H), 2.51 (p, J 1.9 Hz, 3H), 2.30 (q, J 10.5, 10.1 Hz, 1H), 2.19 - 1.96 (m, 2H), 1.54 (d, J 13.3 Hz, 1H), 1.46 - 1.04 (m, 5H). LCMS (Method 8): [M+H] + m / z 539.2, RT 1.61 minutes.

[0457] Peak 2 (arbitrarily assigned R): δ H( 400 MHz, DMSO-d 6 ) 12.82 (s, 1H), 8.97 (d, J 8.5 Hz, 1H), 7.47 (d, J 2.1 Hz, 1H), 7.31 (d, J 8.4 Hz, 1H), 7.18 - 6.80 (m, 2H), 5.15 (t, J 8.6 Hz, 1H), 4.79 (d, J 12.1 Hz, 1H), 4.49 - 3.77 (m, 6H), 3.33 (s, 2H), 2.51 (s, 1H), 2.30 (q, J 10.9, 10.5 Hz, 1H), 2.15 - 1.91 (m, 2H), 1.91 - 1.66 (m, 1H), 1.66 - 1.46 (m, 1H), 1.46 - 0.97 (m, 5H). LCMS (Method 8): [M+H] + m / z 539.2, RT 1.60 minutes.

[0458] Example 23

Chemical Structure

[0459] Example 24

Chemical Structure

[0460] Examples 25 and 26

Chem.

[0461] Peak 1 (arbitrarily assigned S): δ H(400 MHz, DMSO-d 6 ) 12.80 (br s, 1H), 9.63 (br s, 1H), 8.78 (d, J 8.8 Hz, 1H), 7.29 (d, J 8.0 Hz, 1H), 7.14 (t, J 7.4 Hz, 1H), 5.18 (d, J 8.1 Hz, 1H), 4.62 (dt, J 15.5, 7.7 Hz, 1H), 4.31 (dd, J 8.4, 5.4 Hz, 1H), 3.12 (m, 1H), 2.74 - 2.56 (m, 1H), 2.48 (s, 3H), 2.34 - 2.25 (m, 1H), 2.09 - 1.90 (m, 3H), 1.90 - 1.68 (m, 2H), 1.56 (d, J 13.4 Hz, 1H), 1.46 - 1.27 (m, 2H), 1.23 (d, J 7.0 Hz, 3H). LCMS (Method 8): [M + H] + m / z 629.4, RT 2.06 minutes. Chiral LC (Method 16): RT 3.52 minutes, 100%.

[0462] Peak 2 (arbitrarily assigned R): δ H( 400 MHz, DMSO-d 6 ) 9.67 (br s, 1H), 8.88 (d, J 8.9 Hz, 1H), 7.31 (br s, 1H), 7.23 (m, 1H), 5.18 (t, J 7.7 Hz, 1H), 4.57 (dq, J 15.6, 7.5 Hz, 1H), 4.28 (dd, J 9.1, 4.7 Hz, 1H), 3.12 (dt, J 15.0, 11.1 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.48 (s, 3H), 2.36 - 2.23 (m, 1H), 2.09 - 1.96 (m, 3H), 1.88 - 1.70 (m, 2H), 1.55 (d, J 13.5 Hz, 1H), 1.47 - 1.18 (m, 2H), 1.11 (d, J 7.1 Hz, 3H). LCMS (Method 8): [M + H] + m / z 629.4, RT 2.08 minutes. Chiral LC (Method 16): RT 4.22 minutes, 100%.

[0463] Example 27 [Chemistry] N-[(S)-(4,4-Difluorocyclohexyl){5-[3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide 4-Methyl-1,2,5-oxadiazole-3-carboxylic acid (40 mg, 0.30 mmol) and HATU (117 mg, 0.30 mmol) were dissolved in DCM (3 mL), and DIPEA (0.10 mL, 0.58 mmol) was then added, followed by the addition of Intermediate 91 (167 mg, 0.28 mmol) in DCM (4 mL). The mixture was stirred overnight at room temperature and then washed with saturated aqueous NH 4 Cl (10 mL) and concentrated in vacuo. The residue was purified by chromatography (silica, DCM, 0 - 65% EtOAc gradient) to give the title compound (187 mg, 94%) as an off-white solid. δ H( 300 MHz, DMSO-d 6 ) 13.05 (d, J 4.4 Hz, 0.25H), 12.80 (s, 0.75H), 9.68 (d, J 8.4 Hz, 0.75H), 9.59 (d, J 8.6 Hz, 0.25H), 7.47 (d, J 8.4 Hz, 0.25H), 7.36 (d, J 8.4 Hz, 0.75H), 7.09 (ddd, J 8.6, 6.4, 2.8 Hz, 1H), 5.21 (q, J 8.3 Hz, 1H), 4.56 (q, J 13.5 Hz, 1H), 4.36 (q, J 6.1, 5.1 Hz, 1H), 4.25 - 3.86 (m, 2H), 3.86 - 3.50 (m, 1H), 3.22 - 2.81 (m, 4H), 2.50 (s, 3H), 2.32 (q, J 11.1, 10.5 Hz, 2H), 2.15 - 1.00 (m, 13H). LCMS (Method 9): [M + H] + m / z 697, RT 2.11 minutes.

[0464] Examples 28 and 29 [Chemistry] N-[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 28) N-[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide (Example 29) Example 27 (120 mg) was subjected to chiral preparative HPLC (Method 17), and the title compound (Peak 1, 37 mg, and Peak 2, 32 mg) was obtained as a white solid.

[0465] Peak 1 (arbitrarily assigned S): δ H( 400 MHz, DMSO-d 6 ) 13.04 (s, 0.2H), 12.92 - 12.68 (m, 0.8H), 9.68 (d, J 8.5 Hz, 0.8H), 9.59 (d, J 8.6 Hz, 0.2H), 7.47 (d, J 8.4 Hz, 0.2H), 7.36 (d, J 8.4 Hz, 0.8H), 7.07 (dt, J 8.2, 6.0 Hz, 1H), 5.29 - 5.06 (m, 1H), 4.56 (q, J 13.2 Hz, 1H), 4.37 (t, J 7.2 Hz, 1H), 4.05 (dt, J 47.6, 14.4 Hz, 2H), 3.65 (p, J 13.5, 13.0 Hz, 1H), 3.22 - 2.81 (m, 4H), 2.50 (s, 3H), 2.43 - 2.16 (m, 1H), 2.17 - 1.67 (m, 6H), 1.67 - 1.02 (m, 7H). LCMS (Method 9): [M+H] + m / z 697, RT 2.11 minutes. Chiral LC (Method 18): RT 3.48 minutes, 100%.

[0466] Peak 2 (arbitrarily assigned R): δ H( 400 MHz, DMSO-d 6 ) 12.86 (s, 1H), 9.64 (s, 1H), 7.36 (d, J 8.3 Hz, 1H), 7.05 (t, J 7.4 Hz, 1H), 5.19 (s, 1H), 4.56 (q, J 13.5 Hz, 1H), 4.36 (t, J 7.2 Hz, 1H), 4.07 (dq, J 46.8, 14.3 Hz, 2H), 3.65 (q, J 13.5 Hz, 1H), 3.17 - 2.80 (m, 4H), 2.49 (s, 3H), 2.42 - 2.15 (m, 1H), 2.18 - 1.24 (m, 8H), 1.17 (t, J 7.4 Hz, 5H). LCMS (Method 9): [M+H] +m / z 697, RT 2.11 minutes. Chiral LC (Method 18): RT 5.09 minutes, 99.7%.

[0467] Example 30

Chem.

[0468] Examples 31 and 32

Chem.

[0469] Peak 1 (arbitrarily assigned S): δ H( 400 MHz, DMSO-d 6 ) 13.06 (s, 0.2H), 12.82 (s, 0.8H), 9.71 (d, J 8.4 Hz, 0.8H), 9.63 (d, J 8.4 Hz, 0.2H), 7.47 - 7.35 (m, 1H), 7.18 - 6.97 (m, 1H), 5.29 - 5.12 (m, 1H), 4.56 (q, J 13.3 Hz, 1H), 4.37 (t, J 7.2 Hz, 1H), 4.20 - 3.90 (m, 2H), 3.63 (q, J 13.6 Hz, 1H), 3.20 - 2.83 (m, 7H), 2.44 - 2.22 (m, 1H), 2.14 - 1.48 (m, 6H), 1.49 - 1.07 (m, 9H). LCMS (Method 9): [M+H] + m / z 711, RT 2.37 minutes. Chiral LC (Method 18): RT 3.31 minutes, 100%.

[0470] Peak 2 (arbitrarily assigned R): δ H( 400 MHz, DMSO-d 6 ) 12.97 (s, 1H), 9.47 (s, 1H), 7.28 (d, J 8.3 Hz, 1H), 6.88 (s, 1H), 5.16 (d, J 7.5 Hz, 1H), 4.53 (q, J 13.2 Hz, 1H), 4.32 (t, J 7.2 Hz, 1H), 4.06 (dq, J 43.3, 14.3 Hz, 2H), 3.59 (q, J 13.6 Hz, 1H), 3.16 - 2.76 (m, 7H), 2.44 - 2.14 (m, 2H), 2.14 - 1.54 (m, 6H), 1.21 (dt, J 29.8, 7.4 Hz, 8H). LCMS (Method 9): [M+H] + m / z 711, RT 2.37 minutes. Chiral LC (Method 18): RT 4.83 minutes, 99.6%.

[0471] Example 33

Chem.

[0472] Examples 34 and 35

Chem.

[0473] Peak 1 (arbitrarily assigned S): δ H( 500 MHz, DMSO-d 6 ) 12.81 (br s, 1H), 9.67 (br s, 1H), 8.87 (t, J 6.3 Hz, 1H), 7.49 - 7.25 (m, 1H), 7.23 - 7.14 (m, 1H), 5.18 (d, J 8.2 Hz, 1H), 4.30 (dd, J 8.3, 5.5 Hz, 1H), 3.94 - 3.84 (m, 2H), 3.22 - 3.08 (m, 1H), 2.76 - 2.57 (m, 1H), 2.48 (s, 3H), 2.35 - 2.25 (m, 1H), 2.12 - 1.92 (m, 3H), 1.90 - 1.70 (m, 2H), 1.60 - 1.51 (m, 1H), 1.46 - 1.35 (m, 1H), 1.35 - 1.23 (m, 1H). LCMS (Method 4): [M+H] + m / z 615, RT 3.51 minutes.

[0474] Peak 2 (arbitrarily assigned R): δ H( 500 MHz, DMSO-d 6 ) 12.81 (br s, 1H), 9.65 (br s, 1H), 8.87 (t, J 6.3 Hz, 1H), 7.48 - 7.26 (m, 1H), 7.23 - 7.15 (m, 1H), 5.18 (d, J 8.2 Hz, 1H), 4.30 (dd, J 8.3, 5.5 Hz, 1H), 3.94 - 3.83 (m, 2H), 3.22 - 3.06 (m, 1H), 2.72 - 2.58 (m, 1H), 2.48 (s, 3H), 2.35 - 2.25 (m, 1H), 2.12 - 1.92 (m, 3H), 1.89 - 1.71 (m, 2H), 1.60 - 1.50 (m, 1H), 1.47 - 1.35 (m, 1H), 1.35 - 1.23 (m, 1H). LCMS (Method 4): [M+H] + m / z 615, RT 3.52 minutes.

[0475] Example 36

Chem.

[0476] Examples 37 and 38

Chem.

[0477] Peak 1 (arbitrarily assigned S): LCMS (Method 9): [M+H] + m / z 597, RT 1.91 minutes. LCMS (Method 24): [M+H] + m / z 597, RT 1.96 minutes.

[0478] Peak 2 (arbitrarily assigned R): LCMS (Method 9): [M+H] + m / z 597, RT 1.89 minutes. LCMS (Method 24): [M+H] + m / z 597, RT 1.94 minutes.

[0479] Example 39

Chemical Structure

[0480] Example 40

Chem.

[0481] Examples 41 and 42

Chem.

[0482] Peak 1 (arbitrarily assigned S): δ H( 300 MHz, DMSO - d 6 )12.80(s,1H),9.64(s,1H),8.74(t,J 6.3 Hz,1H),7.31(d,J 8.4 Hz,1H),7.14(dd,J 8.4,6.5 Hz,1H),5.96(tt,J 56.5,4.4 Hz,1H),5.17(d,J 8.0 Hz,1H),4.35 - 4.03(m,1H),4.05 - 3.67(m,2H),2.65(dtt,J 19.7,9.3,4.5 Hz,1H),2.47(s,3H),2.40 - 2.15(m,2H),2.11 - 1.97(m,3H),1.88 - 1.71(m,2H),1.54(m,1H),1.45 - 1.20(m,2H).LCMS(Method 9):[M + H]+ m / z 597, RT 1.89 minutes. Chiral LC (Method 16): RT 5.37 minutes, 100%.

[0483] Peak 2 (arbitrarily assigned R): δ H( 300 MHz, DMSO-d 6 ) 12.83 (s, 1H), 9.65 (s, 1H), 8.75 (t, J 6.3 Hz, 1H), 7.32 (d, J 8.4 Hz, 1H), 7.15 (dd, J 8.4, 6.5 Hz, 1H), 5.96 (tt, J 56.4, 4.5 Hz, 1H), 5.18 (d, J 8.0 Hz, 1H), 4.36 - 4.02 (m, 1H), 3.88 (dq, J 15.4, 9.3 Hz, 2H), 2.65 (m, 1H), 2.47 (s, 3H), 2.39 - 2.10 (m, 2H), 2.10 - 1.97 (m, 3H), 1.88 - 1.71 (m, 2H), 1.64 - 1.15 (m, 3H). LCMS (Method 9): [M + H] + m / z 597, RT 1.88 minutes. Chiral LC (Method 16): RT 6.46 minutes, 99%.

[0484] Example 43

Chemical Structure

[0485] Examples 44 and 45

Chemical Structure

[0486] Peak 1 (arbitrarily assigned as S): δ H( 400 MHz, DMSO-d 6) 12.83 (br s, 1H), 9.70 (br s, 1H), 8.68 (d, J 8.8 Hz, 1H), 7.64 - 7.22 (m, 1H), 7.19 - 7.09 (m, 1H), 6.15 - 5.80 (m, 1H), 5.19 (d, J 7.2 Hz, 1H), 4.67 - 4.53 (m, 1H), 4.25 - 4.14 (m, 1H), 2.71 - 2.55 (m, 1H), 2.48 (s, 3H), 2.37 - 2.25 (m, 1H), 2.23 - 1.93 (m, 4H), 1.91 - 1.68 (m, 2H), 1.60 - 1.50 (m, 1H), 1.49 - 1.26 (m, 2H), 1.23 (d, J 7.1 Hz, 3H). LCMS (Method 4): [M + H] + m / z 611, RT 3.49 minutes.

[0487] Peak 2 (arbitrarily assigned R): δ H( 400 MHz, DMSO-d 6 ) 12.90 (s, 1H), 9.72 (s, 1H), 8.77 (d, J 8.9 Hz, 1H), 7.67 - 7.26 (m, 1H), 7.20 (dd, J 8.3, 6.6 Hz, 1H), 6.12 - 5.73 (m, 1H), 5.18 (d, J 8.1 Hz, 1H), 4.66 - 4.48 (m, 1H), 4.18 (dd, J 8.4, 6.3 Hz, 1H), 2.71 - 2.55 (m, 1H), 2.48 (s, 3H), 2.35 - 2.14 (m, 2H), 2.12 - 1.92 (m, 3H), 1.91 - 1.68 (m, 2H), 1.60 - 1.51 (m, 1H), 1.47 - 1.20 (m, 2H), 1.12 (d, J 7.1 Hz, 3H). LCMS (Method 4): [M + H] + m / z 611, RT 3.52 minutes.

[0488] Example 46

Chemical Structure

[0489] Examples 47 and 48

Chemical Structure

[0490] Peak 1 (arbitrarily assigned S): δ H( 500 MHz, DMSO-d 6 ) 13.24 (br s, 1H), 9.91 (br s, 1H), 8.70 (d, J 8.8 Hz, 1H), 7.40 - 7.22 (m, 1H), 7.20 - 7.08 (m, 1H), 6.14 - 5.84 (m, 1H), 5.20 (d, J 8.0 Hz, 1H), 4.68 - 4.53 (m, 1H), 4.24 - 4.15 (m, 1H), 2.70 - 2.54 (m, 1H), 2.48 (s, 3H), 2.35 - 2.25 (m, 1H), 2.24 - 2.10 (m, 1H), 2.10 - 1.91 (m, 3H), 1.89 - 1.70 (m, 2H), 1.61 - 1.50 (m, 1H), 1.47 - 1.35 (m, 1H), 1.35 - 1.25 (m, 1H), 1.23 (d, J 7.1 Hz, 3H). LCMS (Method 4): [M+H] + m / z 611, RT 3.48 minutes.

[0491] Peak 2 (arbitrarily assigned R): δ H( 500 MHz, DMSO-d 6 ) 13.18 (br s, 1H), 9.91 (br s, 1H), 8.78 (d, J 8.9 Hz, 1H), 7.56 - 7.25 (m, 1H), 7.23 - 7.16 (m, 1H), 6.09 - 5.80 (m, 1H), 5.19 (d, J 8.0 Hz, 1H), 4.65 - 4.51 (m, 1H), 4.21 - 4.15 (m, 1H), 2.68 - 2.54 (m, 1H), 2.47 (s, 3H), 2.35 - 2.24 (m, 1H), 2.24 - 2.14 (m, 1H), 2.12 - 1.91 (m, 3H), 1.89 - 1.70 (m, 2H), 1.58 - 1.50 (m, 1H), 1.48 - 1.36 (m, 1H), 1.35 - 1.22 (m, 1H), 1.11 (d, J 7.1 Hz, 3H). LCMS (Method 4): [M+H] + m / z 611, RT 3.53 minutes.

[0492] Example 49

Chem.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 in the formula A represents C-R １ or N, and E represents C-R₂, R １ represents fluoro and R ２ represents hydrogen, and R ３ represents -NR ３ａ R ３ｂ or R ３ represents a group of formula (Wa), [Chemical 2] wherein the asterisk (*) represents the point of attachment to the remainder of the molecule, the group of formula (Wa) represents azetidin-1-yl, pyrrolidin-1-yl, or morpholin-4-yl, and any of these rings may be optionally substituted by 1 to 6 substituents independently selected from halogen, R ３ａ represents hydrogen or C １－６ alkyl, and R ３ｂ represents C １－６ alkyl, or C ３－７ cycloalkyl(C １－６ ), and any of these groups may be substituted by one, two or three substituents independently selected from halogen, C1-6 alkyl, trifluoromethyl, C1-6 alkylaminocarbonyl, and di(C1-6)alkylaminocarbonyl. R ４ａ represents C １－６ alkyl, and this group may be substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkoxy, and C1-6 alkylsulfonyl. R ４ｂ represents hydrogen, fluoro or C １－６ alkyl, or R ４ａ and R ４ｂ when taken together with the carbon atom to which they are both attached, represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of these groups being optionally substituted by one or two substituents independently selected from C1-6 alkyl, halogen, trifluoroethyl and C2-6 alkoxycarbonyl, R ６ represents C ３－９ cycloalkyl, aryl, or heteroaryl, and any of these groups may be substituted by 1, 2, or 3 substituents independently selected from halogen, C1-6 alkyl, and cyclopropyl a compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, represented by formula (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, 【Chemical Formula 3】 wherein, R １ , R ２ , R ３ , R ４ａ , R ４ｂ , and R ６ are as defined in claim 1, a compound according to claim 1, represented by formula (I-1) or (I-2), or a pharmaceutically acceptable salt thereof.

3. R ６ The compound according to claim 1 or claim 2, wherein R represents heteroaryl, and this group may be substituted by 1, 2 or 3 substituents independently selected from C1-6 alkyl.

4. A compound according to claim 1, represented by formula (IIA), or a pharmaceutically acceptable salt thereof, wherein 【Chemical Formula 4】 in the formula R １６ represents methyl, ethyl, isopropyl or cyclopropyl, A, E, R ３ , R ４ａ and R ４ｂ are as defined in claim 1 a compound according to claim 1, represented by formula (IIA), or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, represented by formula (IIB), or a pharmaceutically acceptable salt thereof, wherein 【Chemical Formula 5】 in the formula X represents CH or N, A, E, R ３ , R ４ａ and R ４ｂ are as defined in claim 1, R １６ is as defined in claim 4, a compound according to claim 1, represented by formula (IIB), or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1, represented by formula (IIC), or a pharmaceutically acceptable salt thereof, wherein [Chemical Formula 6] in the formula R ２６ represents a halogen, A, E, R ３ , R ４ａ and R ４ｂ are as defined in claim 1, a compound according to claim 1, represented by formula (IIC), or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1, represented by formula (IID), or a pharmaceutically acceptable salt thereof, wherein 【Chemical Formula 7】 in the formula R ３６ represents a halogen, A, E, R ３ , R ４ａ and R ４ｂ are as defined in claim 1 a compound according to claim 1, represented by formula (IID), or a pharmaceutically acceptable salt thereof.

8. R ３ is -NR ３ａ R ３ｂ represents, and R ３ａ is as defined in claim 1, and R ３ｂ is difluoroethyl, trifluoroethyl, difluoropropyl, trifluoropropyl, trifluoroisopropyl, (fluoro)(methyl)propyl, methylaminocarbonyl - 2 - methylpropyl, dimethylaminocarbonyl - 2 - methylpropyl, (cyclopropyl)(trifluoromethyl)-methyl, or difluorocyclopropylmethyl, a compound according to any one of claims 1 to 7.

9. R ３ represents a group of formula (Wa) as defined in claim 1, wherein the group of formula (Wa) represents azetidin-1-yl or pyrrolidin-1-yl, and any of these rings may be substituted by 2 to 4 substituents independently selected from halogen, a compound according to any one of claims 1 to 7.

10. R ４ａ The compound according to any one of claims 1 to 9, wherein R represents methyl, methoxymethyl, difluoroethyl, trifluoroethyl, ethylsulfonylethyl, or difluoropropyl.

11. R ４ａ and R ４ｂ when taken together with the carbon atom to which they are both attached, represent cyclobutyl, cyclohexyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of these groups may be unsubstituted or substituted with one or two substituents independently selected from halogen and C2-6 alkoxycarbonyl, a compound according to any one of claims 1 to 9.

12. Methyl (3S)-3-(2-{[(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-3-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate, Methyl (3R)-3-(2-{[(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-3-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate, N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-{5-[(1S)-1-(3,3-difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-{5-[(1R)-1-(3,3-difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2-methylpyrazole-3-carboxamide, N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2-methylpyrazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1S)-3,3,3-trifluoro-1-{[(1R)-2-methyl-1-(methylcarbamoyl)propyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1R)-3,3,3-trifluoro-1-{[(1R)-2-methyl-1-(methylcarbamoyl)propyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-{[(1R)-1-(dimethylcarbamoyl)-2-methyl-propyl]carbamoyl}-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)-{5-[(1R)-1-{[(1R)-1-(dimethylcarbamoyl)-2-methyl-propyl]carbamoyl}-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[3,3,3-trifluoro-1-(3,3,3-trifluoropropyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(5-{1-[(2,2-difluorocyclopropyl)methylcarbamoyl]-3,3,3-trifluoropropyl}-4-fluoro-1H-benzimidazol-2-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-{(S)-(4,4-Difluorocyclohexyl)[4-fluoro-5-(3,3,3-trifluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl)-1H-benzimidazol-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)piperidin-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, Methyl 4-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{[(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl]-4-fluoro-1H-benzimidazol-5-yl}piperidine-1-carboxylate, N-[(S)-{5-[1-(3,3-Difluoroazetidine-1-carbonyl)-3,3-difluorocyclobutyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2-(trideuteriomethyl)pyrazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)tetrahydropyran-4-yl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-{5-[2-(3,3-Difluoroazetidin-1-yl)-1-methyl-2-oxoethyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2-methylpyrazole-3-carboxamide, N-[(S)-{5-[(1S)-2-(3,3-Difluoroazetidin-1-yl)-1-methyl-2-oxoethyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2-methylpyrazole-3-carboxamide, N-[(S)-{5-[(1R)-2-(3,3-difluoroazetidin-1-yl)-1-methyl-2-oxoethyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2-methylpyrazole-3-carboxamide, N-[(S)-{5-[1-(3,3-difluoroazetidine-1-carbonyl)-4,4-difluorocyclohexyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(5-{4-[(2,2-difluorocyclopropyl)methylcarbamoyl]-tetrahydropyran-4-yl}-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1S)-3,3,3-trifluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1R)-3,3,3-trifluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[3,3,3-trifluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1S)-3,3,3-trifluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1R)-3,3,3-trifluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoroethylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoroethylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoroethylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-cyclohexyl]-1H-imidazo[4,5-b]pyridin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide monohormate salt, N-[(S)-(4,4-difluorocyclohexyl){5-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-{(S)-(4,4-difluorocyclohexyl)[5-(3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]-carbamoyl}propyl)-4-fluoro-1H-benzimidazol-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-{(S)-(4,4-difluorocyclohexyl)[5-(3,3-difluoro-1-{[(1R)-2,2,2-trifluoro-1-methylethyl]-carbamoyl}propyl)-4-fluoro-1H-benzimidazol-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-{[(1R)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-3,3-difluoro-1-{[(1R)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-fluorobenzamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-fluorobenzamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-fluorobenzamide, N-[(S)-(5-{1-[(1-Cyclopropyl-2,2,2-trifluoroethyl)carbamoyl]-3,3-difluoropropyl}-4-fluoro-1H-benzimidazol-2-yl)(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[1-(2,2-Difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-1-(2,2-Difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-1-(2,2-Difluoropropylcarbamoyl)-3,3-difluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(5-{3,3-difluoro-1-[(2-fluoro-2-methylpropyl)-carbamoyl]propyl}-4-fluoro-1H-benzimidazol-2-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(5-{(1R)-3,3-difluoro-1-[(2-fluoro-2-methylpropyl)-carbamoyl]propyl}-4-fluoro-1H-benzimidazol-2-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(5-{(1S)-3,3-difluoro-1-[(2-fluoro-2-methylpropyl)-carbamoyl]propyl}-4-fluoro-1H-benzimidazol-2-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{3,3,3-trifluoro-1-[(2-fluoro-2-methylpropyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]-1,2,5-oxadiazole-3-carboxamide, 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{[(1R)-3,3,3-trifluoro-1-[(2-fluoro-2-methylpropyl)carbamoyl]propyl]-1H-benzimidazol-2-yl)methyl]-1,2,5-oxadiazole-3-carboxamide, 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{[(1S)-3,3,3-trifluoro-1-[(2-fluoro-2-methylpropyl)carbamoyl]propyl]-1H-benzimidazol-2-yl)methyl]-1,2,5-oxadiazole-3-carboxamide, 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{3,3,3-trifluoro-1-[(2-fluoro-2-methyl-propyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{ (1R)-3,3,3-trifluoro-1-[(2-fluoro-2-methyl-propyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{ (1S)-3,3,3-trifluoro-1-[(2-fluoro-2-methyl-propyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[1-(methoxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1S)-1-(methoxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1R)-1-(methoxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-cyclohexyl]-1H-imidazo[4,5-b]pyridin-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, 1-(2-{[(S)-(4,4-difluorocyclohexyl)[(1-fluorocyclopropanecarbonyl)amino]methyl]-1H-imidazo[4,5-b]pyridin-5-yl})-4,4-difluoro-N-(2,2,2-trifluoroethyl)cyclohexanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl)(5-{[(1S)-3,3-difluoro-1-[(2-fluoro-2-methylpropyl)-carbamoyl]butyl}-4-fluoro-1H-benzimidazol-2-yl)methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1-fluorocyclopropanecarboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3-difluorobutyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, N-[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3-difluoro-butyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide, and N-[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3-difluoro-butyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide The compound according to claim 1, selected from

13. A pharmaceutical composition comprising the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

14. A pharmaceutical composition comprising the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of inflammatory or autoimmune disorders.

15. A pharmaceutical composition comprising the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer, pain, pain associated with inflammation.

16. A pharmaceutical composition comprising the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, associated with a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16, further comprising an additional pharmaceutically active ingredient.

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

19. Use of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment and / or prevention of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer, pain, pain associated with inflammation.

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