Imidazopyridazine derivatives as IL-17 modulators

Abstract

Thus, the series of substituted imidazo[1,2-b]pyridazine derivatives defined herein, which are potent modulators of human IL-17 activity, are beneficial in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

Description

[Technical Field]

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

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

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

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

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

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

[0007] WO 2019 / 138017 describes a class of fused bicyclic imidazole derivatives, including benzimidazole derivatives and analogues thereof, which are said to act as modulators of IL-17 activity and therefore be beneficial in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders.

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

[0009] Heterocyclic compounds said to be capable of modulating IL-17 activity are also described in WO 2020 / 127685, WO 2020 / 146194, and WO 2020 / 182666.

[0010] WO 2020 / 120140 and WO 2020 / 120141, and co-pending International Applications PCT / IB2020 / 055970, PCT / EP2020 / 067758, and PCT / EP2020 / 067759 (all published on December 30, 2020 as WO 2020 / 261141, WO 2020 / 260425, and WO 2020 / 260426), describe a distinct class of chemical compounds that are said to act as modulators of IL-17 activity and therefore be beneficial in the treatment of pathological conditions, including deleterious inflammatory and autoimmune disorders.

[0011] However, none of the prior art available to date discloses or suggests the precise structural class of substituted imidazo[1,2-b]pyridazine derivatives provided by the present invention. Summary of the Invention [Means for solving the problem]

[0012] In addition to being potent modulators of human IL-17 activity, the compounds of the present invention have other significant advantages. In particular, the compounds of the present invention exhibit valuable metabolic stability as determined by either microsome or hepatocyte incubation. The compounds of the present invention also exhibit useful permeability as determined by standard assays, such as the Caco-2 permeability assay.

[0013] The present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, E represents a group of formula (Ea), (Eb), (Ec), (Ed), or (Ee): [ka] where the asterisk (*) represents the point of attachment to the rest of the molecule; A represents a group of formula (Aa), (Ab), (Ac), (Ad), or (Ae): [ka] where the asterisk (*) represents the point of attachment to the rest of the molecule; Y is -O-, -N(R 7 )-, -C(R 5a )(R 5b )-, -S-, -S(O)-, -S(O)2-, or -S(O)(NR 8 )-represents; Z represents heteroaryl, which may be optionally substituted by one or more substituents; R 1a represents hydrogen, fluoro, chloro, methyl, difluoromethyl, or trifluoromethyl; R 1b represents hydrogen, fluoro, chloro, methyl, difluoromethyl, or trifluoromethyl; R 2 -OR 2a or R 2 is C 3-9 Cycloalkyl, C 4-12 Bicycloalkyl, C 3-7 Heterocycloalkyl, or C 4-9 represents heterobicycloalkyl, any of which groups may be optionally substituted by one or more substituents; R 2a is C 1-6 represents alkyl; or R 2a is C 3-9 represents cycloalkyl, which may be optionally substituted by one or more substituents; R 3 is -NR 3a R 3b or R 3 represents a group of formula (Wa): [ka] where the asterisk (*) represents the point of attachment to the rest of the molecule; W represents the residue of an optionally substituted saturated monocyclic ring containing 3 to 6 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom; or W represents the residue of an optionally substituted saturated bicyclic ring system containing from 4 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom; or W represents the residue of an optionally substituted saturated spirocyclic ring system containing from 5 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom; R 3a is hydrogen or C 1-6 represents alkyl; R 3b is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl(C 1-6 ) Alkyl, C 4-12 Bicycloalkyl, aryl, aryl(C 1-6 ) Alkyl, C 3-7 Heterocycloalkyl, C 3-7 Heterocycloalkyl(C 1-6 ) alkyl, heteroaryl, or heteroaryl (C 1-6 ) alkyl, any of which groups may be optionally substituted by one or more substituents; R 4a represents hydrogen, fluoro, or hydroxy; or R 4a is C 1-6 represents alkyl, which may be optionally substituted by one or more substituents; R4b represents hydrogen or fluoro; or R 4b is C 1-6 represents alkyl, which may be optionally substituted by one or more substituents; or R 4a and R 4b together with the carbon atom to which they are both attached, C 3-9 Cycloalkyl or C 3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents; R 5a represents hydrogen, fluoro, methyl, difluoromethyl, or trifluoromethyl; R 5b represents hydrogen, fluoro, methyl, or hydroxy; or R 5a and R 5b together with the carbon atom to which they are both attached represent cyclopropyl; R 6 -OR 6a or -NR 6b R 6c or R 6 is C 1-6 Alkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl(C 1-6 ) Alkyl, aryl, aryl (C 1-6 ) Alkyl, C 3-7 Heterocycloalkyl, C 3-7 Heterocycloalkyl-(C 1-6 ) alkyl, heteroaryl, or heteroaryl (C 1-6 ) alkyl, any of which groups may be optionally substituted by one or more substituents; R 6a is C 1-6 represents alkyl; or R 6a is C 3-9 Cycloalkyl or C 3-7heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents; R 6b is hydrogen or C 1-6 represents alkyl; R 6c is hydrogen or C 1-6 represents alkyl; or R 6b and R 6c taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R 7 -COR 7a , -CO2R 7a or -SO2R 7b or R 7 represents hydrogen; or R 7 is C 1-6 Alkyl, C 3-9 Cycloalkyl, or C 3-7 heterocycloalkyl, any of which groups may be optionally substituted with one or more fluorine atoms; R 7a is C optionally substituted by one or more fluorine atoms 1-6 represents alkyl; R 7b is C 1-6 represents alkyl; R 8 is C 1-6 The present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R represents alkyl.

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

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

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

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

[0018] The present invention also provides a method for the treatment and / or prevention of disorders in which the administration of a modulator of IL-17 function is indicated, 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.

[0019] When any of the groups in the compound of formula (I) above is described as being optionally substituted, this group may be unsubstituted or may be substituted with one or more substituents.Generally, such a group is unsubstituted or substituted with 1, 2, 3, or 4 substituents.Typically, such a group is unsubstituted or substituted with 1, 2, or 3 substituents.Preferably, such a group is unsubstituted or substituted with 1 or 2 substituents.

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

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

[0022] Suitable alkyl groups that may be present in the compounds used in the present invention include straight and branched C 1-6 Alkyl groups, such as C 1-4 Examples of alkyl groups include methyl and ethyl groups, as well as straight-chain or branched propyl, butyl, and pentyl groups. Specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl, and 3-methylbutyl. 1-6 Alkoxy," "C 1-6 alkylthio", "C 1-6 alkylsulfonyl", and "C 1-6Derived expressions such as "alkylamino" should be construed accordingly.

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

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

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

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

[0027] As used herein, "C 3-7The term "heterocycloalkyl" refers to a saturated monocyclic ring containing from 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulfur, and nitrogen, and may include benzo-fused analogs thereof. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydro-thiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[1,2,5]thiadiazolo[2,3-a]-pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl, and azocanyl.

[0028] As used herein, "C 4-9 The term "heterobicycloalkyl" refers to a C1-C12 alkyl group in which one or more of the carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. 4-9Exemplary heterobicycloalkyl groups include 6-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-az ... octanyl, 8-oxabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl, and 3,9-diazabicyclo[4.2.1]nonanyl.

[0029] As used herein, the term "heteroaryl" refers to a monovalent aromatic group containing at least five atoms from a single ring or multiple fused rings, in which one or more carbon atoms are replaced by one or more heteroatoms selected from oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b]-[1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl. pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, imidazo-[4 ,5-b]pyridinyl, imidazo[1,2-b]pyridazinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo-[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]-triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro[1,2, 4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl, and chromenyl groups.

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

[0031] If a compound of formula (I) has one or more asymmetric centers, it may exist as an enantiomer accordingly. If a compound according to the present invention has two or more asymmetric centers, it may further exist as a diastereomer. It should be understood that the present invention extends to the use of all such enantiomers and diastereomers, as well as mixtures thereof in any proportion, including racemates. Formula (I) and the formulae set forth below are intended to represent all individual stereoisomers and all possible mixtures thereof, unless otherwise stated or indicated. In addition, compounds of formula (I) may exist as tautomers, such as keto (CHC=O)-enol (CH=CHOH) tautomers or amide (NHC=O)-hydroxyimine (N=COH) tautomers. Formula (I) and the formulae set forth below are intended to represent all individual tautomers and all possible mixtures thereof, unless otherwise stated or indicated.

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

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

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

[0035] In general, the present invention provides compounds of formula (IA-1), (IA-2), (IA-3), (IA-4), or (IA-5) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, A, R 1a , R 1b , and R 6 is as defined above.

[0036] Suitably, the present invention provides a compound of formula (IA-1) or (IA-4) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0037] Generally, A represents a group of formula (Aa), (Ab), (Ac), or (Ad).

[0038] In a first embodiment, A represents a group of formula (Aa). In a second embodiment, A represents a group of formula (Ab). In a third embodiment, A represents a group of formula (Ac). In a fourth embodiment, A represents a group of formula (Ad). In a fifth embodiment, A represents a group of formula (Ae).

[0039] Typically, A represents a group of formula (Aa), (Ac), (Ad), or (Ae).

[0040] Suitably, A represents a group of formula (Ac).

[0041] In general, the present invention provides compounds of formula (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, E, Y, Z, R 1a , R 1b , R 2 , R 3 , R 4a , R 4b , and R 6 is as defined above.

[0042] More particularly, the present invention provides compounds of formula (IB-1), (IB-2), (IB-3), or (IB-4) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0043] Typically, the present invention provides a compound of formula (IB-1), (IB-3), (IB-4), or (IB-5) as defined above, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0044] Suitably, the present invention provides a compound of formula (IB-3) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

[0045] In a first embodiment, Y represents -O-. In a second embodiment, Y represents -N(R 7 In a third embodiment, Y represents -C(R 5a )(R 5b )-. In a fourth embodiment, Y represents -S-. In a fifth embodiment, Y represents -S(O)-. In a sixth embodiment, Y represents -S(O)2-. In a seventh embodiment, Y represents -S(O)(NR 8 )- represents.

[0046] Typically, Y is -O-, -N(R 7 )-, -C(R 5a )(R5b )-, or -S(O)2-, wherein R 5a , R 5b , and R 7 is as defined above.

[0047] Suitably, Y is -N(R 7 )- or -C(R 5a )(R 5b )-, where R 5a , R 5b , and R 7 is as defined above.

[0048] Preferably, Y is -C(R 5a )(R 5b )-, where R 5a and R 5b is as defined above.

[0049] Generally, Z is furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyridinyl, imidazolyl, pyrazolo[1,5-a]pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-b]pyridazinyl Nyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo [1,5-a]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl, or chromenyl, any of which groups may be optionally substituted by one or more substituents.

[0050] Suitably, Z represents pyrazolyl, pyrazolo[1,5-a]pyridinyl, isoxazolyl, isothiazolyl, imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyridinyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, any of which groups may optionally be substituted by one or more substituents.

[0051] Typically, Z represents imidazolyl, triazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, or tetrazolyl, any of which groups may be optionally substituted by one or more substituents.

[0052] More particularly, Z represents [1,2,4]triazolo[4,3-a]pyridinyl or tetrazolyl, either of which groups may be optionally substituted by one or more substituents.

[0053] Suitably, Z represents triazolyl, which may be optionally substituted by one or more substituents.

[0054] Typical examples of optional substituents on Z include halogen, cyano, nitro, C 1-6 Alkyl, difluoromethyl, difluoroethyl, trifluoro(C 1-6 ) alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]-pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxy(C 1-6 ) Alkyl, oxo, C 1-6Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, C 1-6 Alkylamino, di(C 1-6 ) alkyl-amino, amino(C 1-6 ) alkyl, di(C 1-6 ) Alkylamino(C 1-6 ) Alkyl, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkylcarbonyl, carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) alkylaminosulfonyl and di(C 1-6 ) alkyl-sulfoximino; and 1, 2, or (where possible) 3 substituents independently selected from:

[0055] Suitable examples of optional substituents on Z include halogen, cyano, C 1-6 Alkyl, difluoromethyl, difluoroethyl, trifluoro(C 1-6 ) alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, cyanobicyclo[1.1.1]-pentanyl, and C 1-6 The group may have one, two, or (when possible) three substituents independently selected from alkylamino.

[0056] Illustrative examples of optional substituents on Z include halogen and trifluoro (C 1-6) alkyl.

[0057] Suitable examples of optional substituents on Z include trifluoro (C 1-6 ) alkyl.

[0058] Representative examples of specific substituents on Z include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluoro-cyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro-[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, oxo, methoxy, isopropanol, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, oxo, methoxy, hydroxyisopropyl ... and one, two, or (where possible) three substituents independently selected from oxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, aminomethyl, dimethylaminomethyl, acetylamino, methoxycarbonylamino, methyl-sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, amino-carbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylamino-sulfonyl, dimethylaminosulfonyl, and dimethylsulfoximino.

[0059] Suitable examples of particular substituents on Z include one, two, or (where possible) three substituents independently selected from fluoro, cyano, methyl, difluoro-methyl, difluoroethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluoro-cyclopropylmethyl, cyanobicyclo[1.1.1]pentanyl, and methylamino.

[0060] Illustrative examples of particular substituents on Z include 1, 2, or (where possible) 3 substituents independently selected from fluoro and trifluoroethyl.

[0061] Suitable examples of specific substituents on Z include 1, 2, or (where possible) 3 substituents independently selected from trifluoroethyl.

[0062] Typical values ​​for Z include trifluoroethylpyrazolyl, (methyl)(trifluoroethyl)-pyrazolyl, pyrazolo[1,5-a]pyridinyl, methylindazolyl, trifluoroethylisoxazolyl, (methyl)-(trifluoroethyl)isoxazolyl, trifluoroethylisothiazolyl, trifluoroethylimidazolyl, cyclopropylmethylimidazolyl, (methyl)(trifluoroethyl)imidazolyl, imidazo[1,2-a]-pyridinyl, difluoroethyltriazolyl, trifluoroethyltriazolyl, difluorocyclopropyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[1.1.1]pentanyl- triazolyl, (fluoro)(trifluoroethyl)triazolyl, (methyl)(trifluoroethyl)triazolyl, (difluoro-methyl)(trifluoroethyl)triazolyl, (cyclopropylmethyl)(difluoromethyl)triazolyl, (methyl-amino)(trifluoroethyl)triazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, fluoro[1,2,4]triazolo[4,3-a]pyridinyl, cyano[1,2,4]triazolo[4,3-a]pyridinyl, benzotriazolyl, trifluoroethyltetrazolyl, trifluoroethylpyridinyl, trifluoroethylpyridazinyl, trifluoroethylpyrimidinyl, and trifluoroethylpyrazinyl.

[0063] Exemplary values ​​of Z include cyclopropylmethylimidazolyl, difluoroethyl-triazolyl, trifluoroethyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[1.1.1]pentanyltriazolyl, fluoro[1,2,4]triazolo[4,3-a]pyridinyl, cyano[1,2,4]-triazolo[4,3-a]pyridinyl, and trifluoroethyltetrazolyl.

[0064] Suitable values ​​for Z include fluoro[1,2,4]triazolo[4,3-a]pyridinyl and trifluoroethyltetrazolyl.

[0065] Suitable values ​​for Z include trifluoroethyltriazolyl.

[0066] Suitably, Z represents a group of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh), (Zj), (Zk), (Zl), (Zm), (Zn), (Zp), (Zq), (Zr), (Zs), (Zt), (Zu), (Zv), (Zw), (Zx), (Zy), (Zz), (Zaa), or (Zab): [ka] [ka] During the ceremony, The asterisk (*) represents the point of attachment to the rest of the molecule; R 1z is hydrogen, C 1-6 Alkyl, difluoromethyl, difluoroethyl, trifluoro(C 1-6 )-Alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluoro-cyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy(C 2-6 ) Alkyl, C 1-6 Alkyl sulfonyl, amino (C 2-6 ) alkyl, di(C 1-6 ) Alkylamino(C 1-6 ) Alkyl, C 2-6 Alkyl carbonyl, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, or di(C 1-6 ) alkylaminosulfonyl; and R2z is hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, difluoromethyl, trifluoro(C 1-6 ) alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropyl-methyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxy(C 1-6 ) Alkyl, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, C 1-6 Alkylamino, di(C 1-6 ) alkyl-amino, amino(C 1-6 ) alkyl, di(C 1-6 ) Alkylamino(C 1-6 ) Alkyl, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkylcarbonyl, carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) alkylaminosulfonyl, or di(C 1-6 ) alkyl-sulfoximino.

[0067] Particular values ​​of Z include groups of formula (Zk), (Zm), (Zp), (Zq), (Zt), (Zu), (Zv), (Zw), and (Zx) defined above.

[0068] Suitable values ​​of Z include groups of formula (Zu) and (Zw) defined above.

[0069] Suitably, Z represents a group of formula (Zq) as defined above.

[0070] Typically, R 1z is hydrogen, C 1-6 Alkyl, difluoroethyl, trifluoro(C 1-6 ) alkyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, or cyanobicyclo[1.1.1]pentanyl.

[0071] R 1z Suitable values ​​of include hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]pentanyl, cyano-bicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxyethyl, hydroxyisopropyl, methylsulfonyl, aminoethyl, dimethylaminomethyl, acetyl, methoxy-carbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino-carbonyl, aminosulfonyl, methylaminosulfonyl, and dimethylaminosulfonyl.

[0072] R 1z Typical values ​​of include hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoroethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, and cyanobicyclo[1.1.1]pentanyl.

[0073] R 1zExemplary values ​​of include difluoroethyl, trifluoroethyl, difluorocyclobutyl, cyclopropylmethyl, and cyanobicyclo[1.1.1]pentanyl.

[0074] Preferably, R 1z represents trifluoroethyl.

[0075] Typically, R 2z is hydrogen, halogen, cyano, C 1-6 Alkyl, trifluoro(C 1-6 ) alkyl, cyclopropylmethyl, difluorocyclopropylmethyl, or C 1-6 represents alkylamino.

[0076] Preferably, R 2z represents hydrogen, halogen, or cyano. In a first embodiment, R 2z represents hydrogen. In a second embodiment, R 2z represents halogen, in particular fluoro. In a third embodiment, R 2z represents cyano.

[0077] R 2zSuitable values ​​for are hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, trifluoro-ethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[1.1.1]-pentanyl, cyanobicyclo[1.1.1]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl Examples of alkyl, aryl, aryl- ...

[0078] R 2z Typical values ​​of include hydrogen, fluoro, cyano, methyl, difluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropylmethyl, difluorocyclopropylmethyl, and methylamino.

[0079] R 2z Suitable values ​​of include hydrogen, fluoro, and cyano.

[0080] R 2z A specific value for is fluoro.

[0081] In the first embodiment, R 1a represents hydrogen. In a second embodiment, R1a represents fluoro. In a third embodiment, R 1a represents chloro. In a fourth embodiment, R 1a represents methyl. In a fifth embodiment, R 1a represents difluoromethyl. In a sixth embodiment, R 1a represents trifluoromethyl.

[0082] Typically, R 1a represents hydrogen, fluoro, chloro, or methyl.

[0083] In general, R 1a represents hydrogen or fluoro.

[0084] Preferably, R 1a represents hydrogen.

[0085] In the first embodiment, R 1b represents hydrogen. In a second embodiment, R 1b represents fluoro. In a third embodiment, R 1b represents chloro. In a fourth embodiment, R 1b represents methyl. In a fifth embodiment, R 1b represents difluoromethyl. In a sixth embodiment, R 1b represents trifluoromethyl.

[0086] Typically, R 1b represents hydrogen, fluoro, chloro, or methyl.

[0087] In general, R 1b represents hydrogen or fluoro.

[0088] Preferably, R 1b represents hydrogen.

[0089] Preferably, R 2 is C 3-9 Cycloalkyl, C 4-12 Bicycloalkyl, or C 3-7and heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.

[0090] Appropriately, R 2 is C 3-9 Cycloalkyl or C 4-12 represents bicycloalkyl, any of which groups may be optionally substituted by one or more substituents.

[0091] R 2 Typical examples of include cyclobutyl, bicyclo[1.1.1]pentanyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, and morpholinyl, any of which groups may be optionally substituted by one or more substituents.

[0092] R 2 Suitable examples of include bicyclo[1.1.1]pentanyl and pyrrolidinyl, either of which groups may be optionally substituted by one or more substituents.

[0093] R 2 Suitable examples of include bicyclo[1.1.1]pentanyl, which may be optionally substituted by one or more substituents.

[0094] R 2 Typical examples of the above optional substituents include 1, 2, 3, or 4 substituents independently selected from halogen.

[0095] R 2 Typical examples of the above specific substituents include 1, 2, 3, or 4 substituents independently selected from fluoro.

[0096] R 2Typical values ​​of include difluorocyclobutyl, fluorobicyclo[1.1.1]pentanyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, difluorotetrahydropyranyl, and tetrafluoromorpholinyl.

[0097] R 2 Suitable values ​​of include fluorobicyclo[1.1.1]pentanyl and tetrafluoro-pyrrolidinyl.

[0098] R 2 Suitable values ​​of include fluorobicyclo[1.1.1]pentanyl.

[0099] In the first embodiment, R 2a is C 1-6 In a second embodiment, R 2a is an optionally substituted C 3-9 represents cycloalkyl.

[0100] Typically, R 2a is C 1-6 represents alkyl, or R 2a represents cyclobutyl, which may be optionally substituted by one or more substituents.

[0101] R 2a Typical examples of the above optional substituents include halogen, cyano, nitro, C 1-6 Alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 ) Alkyl, oxo, C 1-6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, amino(C 1-6 ) Alkyl, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, C 2-6 Alkylcarbonylamino, C 2-6Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkylcarbonyl, carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 ) alkylaminosulfonyl.

[0102] R 2a Suitable examples of the above optional substituents include 1, 2, or 3 substituents independently selected from halogen.

[0103] R 2a Typical 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, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, and dimethyl-aminosulfonyl.

[0104] R 2a Suitable examples of the above specific substituents include 1, 2, or 3 substituents independently selected from fluoro.

[0105] R 2aIllustrative examples of particular values ​​of include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, and difluorocyclobutyl.

[0106] In the first embodiment, R 3 Ha-NR 3a R 3b In the second embodiment, R 3 represents a group of formula (Wa) as defined above.

[0107] In the first embodiment, R 3a represents hydrogen. In a second embodiment, R 3a is C 1-6 In a first aspect of this embodiment, R 3a represents methyl. In a second aspect of that embodiment, R 3a represents ethyl.

[0108] Typically, R 3b is C 1-6 Alkyl or C 3-7 Cycloalkyl(C 1-6 ) alkyl, any of which groups may be optionally substituted by one or more substituents.

[0109] Preferably, R 3b is C 1-6 represents alkyl, which may be optionally substituted by one or more substituents.

[0110] In the first embodiment, R 3b is an optionally substituted C 1-6 In a second embodiment, R 3b is an optionally substituted C 3-7 In a third embodiment, R 3b is an optionally substituted C 3-7 Cycloalkyl(C 1-6 ) alkyl. In a fourth embodiment, R 3b is an optionally substituted C4-12 In a fifth embodiment, R 3b represents an optionally substituted aryl. In a sixth embodiment, R 3b is an optionally substituted aryl (C 1-6 ) alkyl. In a seventh embodiment, R 3b is an optionally substituted C 3-7 In an eighth embodiment, R represents heterocycloalkyl. 3b is an optionally substituted C 3-7 Heterocycloalkyl(C 1-6 ) alkyl. In a ninth embodiment, R 3b represents an optionally substituted heteroaryl. In a tenth embodiment, R 3b is an optionally substituted heteroaryl (C 1-6 ) represents alkyl.

[0111] R 3b Suitable examples of include ethyl, propyl, isopropyl, 2-methylpropyl, and cyclopropylmethyl, any of which groups may be optionally substituted by one or more substituents.

[0112] R 3b Typical examples of include ethyl, isopropyl, 2-methylpropyl, and cyclopropylmethyl, any of which groups may be optionally substituted by one or more substituents.

[0113] R 3b Suitable examples of include ethyl, which may be optionally substituted by one or more substituents.

[0114] R 3b Typical examples of the above optional substituents include halogen, cyano, nitro, C 1-6 Alkyl, trifluoromethyl, hydroxy, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, C 1-6 Alkyl-amino, di(C 1-6 ) Alkylamino, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkylcarbonyl, carboxy, C 2-6 Alkoxycarbonyl, Amino-carbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) alkylaminosulfonyl, and di(C 1-6 ) alkylsulfoximino; and 1, 2, or 3 substituents independently selected from:

[0115] R 3b Suitable examples of the above optional substituents include halogen, trifluoromethyl, and C 1-6 alkylamino-carbonyl.

[0116] R 3b Suitable examples of the above optional substituents include 1, 2, or 3 substituents independently selected from halogen.

[0117] R 3bTypical examples of the above specific substituents include one, two, or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoximino.

[0118] R 3b Suitable examples of the above particular substituents include 1, 2, or 3 substituents independently selected from fluoro, trifluoromethyl, and methylamino-carbonyl.

[0119] R 3b Suitable examples of the above specific substituents include 1, 2, or 3 substituents independently selected from fluoro.

[0120] R 3b Typical values ​​include difluoroethyl, trifluoroethyl, trifluoroisopropyl, methylaminocarbonyl-2-methylpropyl, (cyclopropyl)(trifluoromethyl)methyl, and difluorocyclopropylmethyl. Further values ​​include difluoropropyl.

[0121] R 3b Representative values ​​of include trifluoroethyl, difluoropropyl, trifluoro-isopropyl, methylaminocarbonyl-2-methylpropyl, and (cyclopropyl)(trifluoromethyl)-methyl.

[0122] R 3bSuitable values ​​of include trifluoroethyl, trifluoroisopropyl, methylaminocarbonyl-2-methylpropyl, and (cyclopropyl)(trifluoromethyl)methyl.

[0123] R 3b Suitable values ​​for include trifluoroethyl.

[0124] In a first embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 3 to 6 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but not more than 1 O or S atom. In a first aspect of that embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but not more than 1 O or S atom.

[0125] In a second embodiment, W represents the residue of an optionally substituted saturated bicyclic ring system containing 4 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but not more than 1 O or S atom. In a first aspect of that embodiment, W represents the residue of an optionally substituted saturated bicyclic ring system containing 5, 6, or 7 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but not more than 1 O or S atom.

[0126] In a third embodiment, W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom. In a first aspect of that embodiment, W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5, 6, or 7 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom.

[0127] Suitably, W represents the residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms, 1 nitrogen atom, and 0 or 1 oxygen atom. In a first embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms and 1 nitrogen atom. In a first aspect of that embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 3 carbon atoms and 1 nitrogen atom. In a second aspect of that embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms and 1 nitrogen atom. In a second embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms, 1 nitrogen atom, and 1 oxygen atom.

[0128] In a first embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and no additional heteroatoms (i.e., an optionally substituted azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or hexahydroazepin-1-yl ring). In a second embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and one additional heteroatom selected from N, O, and S. In a first aspect of that embodiment, the group of formula (Wa) is an optionally substituted morpholin-4-yl moiety. In a third embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and two additional heteroatoms selected from N, O, and S, of which not more than one is O or S. In a fourth embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and three additional heteroatoms selected from N, O, and S, not more than one of which is O or S.

[0129] 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]hexane- 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-aza spiro[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]-decan-2-yl, 2,4,8-triazaspiro[4.5]decan-4-yl, and 2,4,8-triazaspiro[4.5]decan-8-yl, any of which groups may be optionally substituted with one or more substituents.

[0130] In a first embodiment, the group of formula (Wa) is unsubstituted. In a second embodiment, the group of formula (Wa) is substituted with one or more substituents, typically 1 to 6 substituents, and preferably 2 to 4 substituents. In a first aspect of the embodiment, the group of formula (Wa) is substituted with one substituent. In a second aspect of the embodiment, the group of formula (Wa) is substituted with two substituents. In a third aspect of the embodiment, the group of formula (Wa) is substituted with three substituents. In a fourth aspect of the embodiment, the group of formula (Wa) is substituted with four substituents. In a fifth aspect of the embodiment, the group of formula (Wa) is substituted with five substituents. In a sixth aspect of the embodiment, the group of formula (Wa) is substituted with six substituents.

[0131] 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 1-6 Alkyl sulfonyl, 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 ) Alkyl-amino, C2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, amino carbonyl, C 1-6 Alkylaminocarbonyl, and di(C 1-6 ) alkylaminocarbonyl.

[0132] Suitable examples of optional substituents on the group of formula (Wa) include halogen.

[0133] Representative examples of particular substituents on the group of formula (Wa) include fluoro, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulfonyl, cyano, oxo, formyl, acetyl, ethylcarbonyl, tert-butylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy-carbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino, aminomethyl, methyl-amino, ethylamino, dimethylamino, acetylamino, tert-butoxycarbonylamino, methyl-sulfonylamino, aminocarbonyl, methylaminocarbonyl, and dimethylaminocarbonyl.

[0134] Suitable examples of particular substituents on the group of formula (Wa) include fluoro.

[0135] In general, R 4a represents hydrogen or fluoro, or R 4a is C 1-6 represents alkyl, which may be optionally substituted by one or more substituents.

[0136] Typically, R 4a represents hydrogen, or R 4a is C 1-6represents alkyl, which may be optionally substituted by one or more substituents.

[0137] Preferably, R 4a is C 1-6 represents alkyl, which may be optionally substituted by one or more substituents.

[0138] In the first embodiment, R 4a represents hydrogen. In a second embodiment, R 4a represents fluoro. In a third embodiment, R 4a represents hydroxy. In a fourth embodiment, R 4a is C 1-6 In a first aspect of that embodiment, R represents alkyl, in particular methyl or ethyl, which may be optionally substituted by one or more substituents. 4a represents optionally substituted methyl. In a second aspect of that embodiment, R 4a represents optionally substituted ethyl.

[0139] R 4a Typical examples of the above optional substituents include halogen, cyano, nitro, hydroxy, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, C 2-6 Alkyl-carbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkyl-carbonyl, carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di-(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6Alkylaminosulfonyl, di(C 1-6 ) alkylamino-sulfonyl, and di(C 1-6 ) alkylsulfoximino; and 1, 2, or 3 substituents independently selected from:

[0140] R 4a Suitable examples of the above optional substituents include 1, 2, or 3 substituents independently selected from halogen.

[0141] R 4a Typical examples of the above specific substituents include one, two, or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino-sulfonyl, and dimethylsulfoximino.

[0142] R 4a Suitable examples of the above specific substituents include 1, 2, or 3 substituents independently selected from fluoro.

[0143] R 4a Exemplary values ​​of include hydrogen, fluoro, hydroxy, methyl, difluoroethyl, and trifluoroethyl.

[0144] R 4a Typical values ​​of include methyl, difluoroethyl, and trifluoroethyl.

[0145] R 4a Suitable values ​​for include difluoroethyl.

[0146] In general, R 4b is hydrogen, fluoro, or C 1-6 Represents alkyl.

[0147] In the first embodiment, R 4b represents hydrogen. In a second embodiment, R 4b represents fluoro. In a third embodiment, R 4b is C 1-6 In a first aspect of this embodiment, R represents alkyl, in particular methyl or ethyl, which may be unsubstituted or substituted by one or more substituents. 4b represents unsubstituted or substituted methyl. In a second aspect of that embodiment, R 4b represents unsubstituted or substituted ethyl.

[0148] R 4b Typical examples of the above optional substituents include halogen, cyano, nitro, hydroxy, C 1-6 Alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, C 2-6 Alkyl-carbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkyl-carbonyl, carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di-(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) alkylamino-sulfonyl, and di(C 1-6) alkylsulfoximino; and 1, 2, or 3 substituents independently selected from:

[0149] R 4b Typical examples of the above specific substituents include one, two, or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino-sulfonyl, and dimethylsulfoximino.

[0150] R 4b Typical values ​​of include hydrogen and fluoro.

[0151] Alternatively, R 4a and R 4b may be taken together to form an optionally substituted cyclic moiety. Thus, R 4a and R 4b together with the carbon atom to which they are both attached, C 3-7 Cycloalkyl or C 3-7 It may also represent heterocycloalkyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0152] In the first embodiment, R 4a and R 4b together with the carbon atom to which they are both attached, C 3-7Cycloalkyl may suitably be represented, which may be unsubstituted or substituted by one or more substituents, typically one or two. 4a and R 4b together with the carbon atoms to which they are both attached may suitably represent cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. As a particular illustration of this embodiment, R 4a and R 4b , together with the carbon atom to which they are both attached, may suitably represent cyclobutyl or cyclohexyl, either of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a first aspect of that embodiment, R 4a and R 4b may, together with the carbon atoms to which they are both attached, suitably represent a cyclopropyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a second aspect of that embodiment, R 4a and R 4b may, together with the carbon atoms to which they are both attached, suitably represent a cyclobutyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a third aspect of that embodiment, R 4a and R 4b may, together with the carbon atoms to which they are both attached, suitably represent a cyclopentyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a fourth aspect of that embodiment, R 4a and R 4btogether with the carbon atoms to which they are both attached may suitably represent a cyclohexyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0153] In the second embodiment, R 4a and R 4b together with the carbon atom to which they are both attached, C 3-7 Suitable examples of this embodiment include heterocycloalkyl, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. 4a and R 4b together with the carbon atoms to which they are both attached may suitably represent oxetanyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. As a particular illustration of this embodiment, R 4a and R 4b , together with the carbon atoms to which they are both attached, may suitably represent pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a first aspect of that embodiment, R 4a and R 4b may, together with the carbon atoms to which they are both attached, suitably represent an oxetanyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a second aspect of that embodiment, R 4a and R 4bmay, together with the carbon atoms to which they are both attached, suitably represent a pyrrolidinyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a third aspect of that embodiment, R 4a and R 4b may, together with the carbon atoms to which they are both attached, suitably represent a tetrahydropyranyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents. In a fourth aspect of that embodiment, R 4a and R 4b taken together with the carbon atoms to which they are both attached may suitably represent a piperidinyl ring, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0154] Typically, R 4a and R 4b together with the carbon atom to which they are both attached may represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, or piperidinyl, any of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0155] Appropriately, R 4a and R 4b taken together with the carbon atom to which they are both attached may represent cyclohexyl or tetrahydropyranyl, either of which groups may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0156] Preferably, R 4a and R 4btaken together with the carbon atom to which they are both attached may represent cyclohexyl, which may be unsubstituted or substituted by one or more substituents, typically one or two substituents.

[0157] R 4a and R 4b Typical examples of optional substituents on the cyclic moiety formed by 1-6 Alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, hydroxy, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl-sulfinyl, C 1-6 Alkyl sulfonyl, C 2-6 Alkyl carbonyl, C 2-6 Alkoxycarbonyl, Amino, C 1-6 Alkyl-amino, and di(C 1-6 ) alkylamino.

[0158] R 4a and R 4b Suitable examples of optional substituents on the cyclic moiety formed by include 1, 2, or 3 substituents independently selected from halogen.

[0159] R 4a and R 4b Typical examples of particular substituents on the cyclic moiety formed by include one, two, or three substituents independently selected from methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, methoxycarbonyl, ethoxycarbonyl, amino, methylamino, and dimethylamino.

[0160] R 4a and R 4bSuitable examples of specific substituents on the cyclic moiety formed by include 1, 2, or 3 substituents independently selected from fluoro.

[0161] R 4a and R 4b Representative examples of the cyclic moiety formed by include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonyl-pyrrolidinyl, tetrahydropyranyl, piperidinyl, and methoxycarbonylpiperidinyl.

[0162] R 4a and R 4b Representative examples of the cyclic moiety formed by include difluorocyclohexyl and tetrahydropyranyl.

[0163] R 4a and R 4b Suitable examples of the cyclic moiety formed by include difluoro-cyclohexyl.

[0164] In the first embodiment, R 5a represents hydrogen. In a second embodiment, R 5a represents fluoro. In a third embodiment, R 5a represents methyl. In a fourth embodiment, R 5a represents difluoromethyl. In a fifth embodiment, R 5a represents trifluoromethyl.

[0165] Typically, R 5a represents hydrogen, fluoro, or trifluoromethyl.

[0166] Preferably, R 5a represents fluoro or trifluoromethyl.

[0167] Appropriately, R 5a represents fluoro.

[0168] In the first embodiment, R5b represents hydrogen. In a second embodiment, R 5b represents fluoro. In a third embodiment, R 5b represents methyl. In a fourth embodiment, R 5b represents hydroxy.

[0169] Typically, R 5b represents hydrogen, fluoro, or hydroxy.

[0170] Preferably, R 5b represents fluoro or hydroxy.

[0171] Appropriately, R 5b represents fluoro.

[0172] Alternatively, R 5a and R 5b may be taken together to form a spiro bond. 5a and R 5b together with the carbon atom to which they are both attached may represent cyclopropyl.

[0173] Typically, R 6 HA-OR 6a 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, any of which groups may be optionally substituted by one or more substituents.

[0174] Appropriately, R 6 HA-OR 6a or -NR 6b R 6c represents or R 6represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.

[0175] Preferably, R 6 HA-OR 6a represents or R 6 represents heteroaryl, which may be optionally substituted by one or more substituents.

[0176] In the first embodiment, R 6 is an optionally substituted C 1-6 In a second embodiment, R 6 is an optionally substituted C 3-9 In a third embodiment, R 6 is an optionally substituted C 3-9 Cycloalkyl(C 1-6 ) alkyl. In a fourth embodiment, R 6 represents an optionally substituted aryl. In a fifth embodiment, R 6 is an optionally substituted aryl (C 1-6 ) alkyl. In a sixth embodiment, R 6 is an optionally substituted C 3-7 In a seventh embodiment, R represents heterocycloalkyl. 6 is an optionally substituted C 3-7 Heterocycloalkyl(C 1-6 ) alkyl. In an eighth embodiment, R 6 represents an optionally substituted heteroaryl. In a ninth embodiment, R 6 is an optionally substituted heteroaryl (C 1-6 ) alkyl. In a tenth embodiment, R 6 HA-OR 6a In an eleventh embodiment, R 6 Ha-NR 6a R 6b Represents.

[0177] R 6 A typical example of this is -OR 6aor -NR 6a R 6b and methyl, ethyl, propyl, 2-methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, triazolyl, pyridinyl, triazolyl-methyl, benzotriazolylmethyl, or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.

[0178] R 6 A typical example is -OR 6a or -NR 6a R 6b and phenyl, pyrazolyl, isoxazolyl, oxadiazolyl, or triazolyl, any of which groups may be optionally substituted by one or more substituents.

[0179] R 6 Illustrative examples of -OR include 6a and pyrazolyl, isoxazolyl, oxadiazolyl, or triazolyl, any of which groups may be optionally substituted by one or more substituents.

[0180] R 6 Suitable examples of include pyrazolyl, isoxazolyl, oxadiazolyl, and triazolyl, any of which groups may be optionally substituted by one or more substituents.

[0181] R 6 Suitable examples of include pyrazolyl and oxadiazolyl, either of which groups may be optionally substituted by one or more substituents.

[0182] R 6 A particular example of is oxadiazolyl, which may be optionally substituted by one or more substituents.

[0183] R 6 Typical examples of the above optional substituents include halogen, cyano, nitro, C 1-6 Alkyl, trifluoromethyl, cyclopropyl, phenyl, fluorophenyl, hydroxy, hydroxy(C 1-6 ) Alkyl, oxo, C 1-6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, amino(C 1-6 ) Alkyl, C 1-6 Alkylamino, di(C 1-6 ) alkylamino, pyrrolidinyl, tetrahydro-pyranyl, morpholinyl, piperazinyl, C 2-6 Alkylcarbonylamino, C 2-6 Alkylcarbonylamino-(C 1-6 ) Alkyl, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkyl-carbonyl, carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 ) alkylamino-sulfonyl, and di(C 1-6 ) alkylsulfoximinyl.

[0184] R 6 Suitable examples of the above optional substituents include halogen, C 1-6 and 1, 2, or 3 substituents independently selected from alkyl, and cyclopropyl.

[0185] R 6 Suitable examples of the above optional substituents include C 1-6Included are 1, 2, or 3 substituents independently selected from alkyl and cyclopropyl.

[0186] R 6 Typical examples of the above specific substituents include one, two, or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, cyclopropyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl-amino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonyl-amino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, and dimethylsulfoximinyl.

[0187] R 6 Suitable examples of the above particular substituents include 1, 2, or 3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, and cyclopropyl.

[0188] R 6 Suitable examples of the above specific substituents include 1, 2, or 3 substituents independently selected from methyl, ethyl, isopropyl, and cyclopropyl.

[0189] R 6Illustrative examples of the above 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, isopropylpyrazolyl, (methyl)-(tetrahydropyranyl)pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl, isopropyltriazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, pyridinylmethyl, and aminopyridinylmethyl.

[0190] R 6Preferred values ​​of include methylpyrazolyl, ethylpyrazolyl, isopropyl-pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl, and isopropyltriazolyl.

[0191] R 6 Typical values ​​of include isopropylpyrazolyl, ethylisoxazolyl, methyl-oxadiazolyl, ethyloxadiazolyl, cyclopropyloxadiazolyl, and isopropyltriazolyl.

[0192] R 6 Selected values ​​of include methylpyrazolyl, ethylpyrazolyl, methyloxadiazolyl, and ethyloxadiazolyl.

[0193] R 6 Particular examples of selected values ​​of R include methyloxadiazolyl and ethyloxadiazolyl. 6 represents methyloxadiazolyl. In a second embodiment, R 6 represents optionally substituted ethyloxadiazolyl.

[0194] In general, R 6a is C 1-6 represents alkyl, or R 6a is C 3-9 represents a cycloalkyl, which may be optionally substituted by one or more substituents.

[0195] In the first embodiment, R 6a is C 1-6 In a second embodiment, R 6a is an optionally substituted C 3-9 In a third embodiment, R 6a is an optionally substituted C 3-7 represents heterocycloalkyl.

[0196] Appropriately, R 6a is C 1-6 represents alkyl, or R 6a represents cyclobutyl or oxetanyl, either of which groups may be optionally substituted by one or more substituents.

[0197] Typically, R 6a is C 1-6 represents alkyl, or R 6a represents cyclobutyl, which may be optionally substituted by one or more substituents.

[0198] R 6a Typical examples of the above optional substituents include halogen, cyano, nitro, C 1-6 Alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 ) Alkyl, oxo, C 1-6 Alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, amino, amino(C 1-6 ) Alkyl, C 1-6 Alkylamino, di(C 1-6 ) Alkylamino, C 2-6 Alkylcarbonylamino, C 2-6 Alkoxycarbonylamino, C 1-6 Alkyl sulfonyl amino, formyl, C 2-6 Alkylcarbonyl, carboxy, C 2-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 ) Alkylaminocarbonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, and di(C 1-6 ) alkylaminosulfonyl.

[0199] R 6aSuitable examples of the above optional substituents include 1, 2, or 3 substituents independently selected from halogen.

[0200] R 6a Typical 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, methylamino-carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, and dimethyl-aminosulfonyl.

[0201] R 6a Suitable examples of the above specific substituents include 1, 2, or 3 substituents independently selected from fluoro.

[0202] R 6a Representative examples of specific values ​​of include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, difluorocyclobutyl, and oxetanyl.

[0203] R 6a Illustrative examples of particular values ​​of include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, and difluorocyclobutyl.

[0204] Typically, R 6a represents cyclobutyl.

[0205] Typically, R 6brepresents hydrogen or methyl.

[0206] In the first embodiment, R 6b represents hydrogen. In a second embodiment, R 6b is C 1-6 It stands for alkyl, especially methyl.

[0207] Typically, R 6c represents hydrogen or methyl.

[0208] In the first embodiment, R 6c represents hydrogen. In a second embodiment, R 6c is C 1-6 It stands for alkyl, especially methyl.

[0209] Alternatively, partial-NR 6b R 6c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.

[0210] Heterocyclic moiety -NR 6b R 6c Selected examples of the above suitable substituents include C 1-6 Alkyl, C 1-6 Alkyl sulfonyl, hydroxy, hydroxy(C 1-6 ) alkyl, amino (C 1-6 ) Alkyl, cyano, oxo, C 2-6 Alkylcarbonyl, carboxy, C 2-6 Alkoxycarbonyl, Amino, C 2-6 Alkylcarbonyl-amino, C 2-6 Alkylcarbonylamino (C 1-6 ) Alkyl, C 2-6 Alkoxycarbonylamino, C1-6 Alkylsulfonyl-amino, and aminocarbonyl are included.

[0211] Heterocyclic moiety -NR 6b R 6c Selected examples of the above particular substituents include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy-carbonylamino, methylsulfonylamino, and aminocarbonyl.

[0212] In general, R 7 -COR 7a , -CO2R 7a , or -SO2R 7b represents or R 7 represents hydrogen, or R 7 is C 1-6 Alkyl or C 3-9 cycloalkyl, any of which groups may be optionally substituted with one or more fluorine atoms.

[0213] More specifically, R 7 -COR 7a , -CO2R 7a , or -SO2R 7b represents or R 7 represents hydrogen, or R 7 is C 1-6 represents alkyl, which group may be optionally substituted with one or more fluorine atoms, generally 1, 2 or 3 fluorine atoms, typically 2 fluorine atoms.

[0214] Typically, R 7 is C 3-7 represents heterocycloalkyl, which may be optionally substituted with one or more fluorine atoms.

[0215] Preferably, R 7 Ha-CO2R 7a Represents.

[0216] In the first embodiment, R 7 HA-COR 7a In the second embodiment, R 7 Ha-CO2R 7a In the third embodiment, R 7 Ha-CO2R 7a In the fourth embodiment, R 7 represents hydrogen. In a fifth embodiment, R 7 is optionally substituted by one or more fluorine atoms, typically 1, 2, or 3 fluorine atoms; 1-6 In one aspect of this embodiment, R 7 is the unsubstituted C 1-6 In another aspect of this embodiment, R represents alkyl, in particular methyl or ethyl. 7 is a C substituted by one, two, or three fluorine atoms, typically two fluorine atoms 1-6 In a sixth embodiment, R represents alkyl. An example of this embodiment is difluoroethyl. 7 is optionally substituted by one or more fluorine atoms, typically 1, 2, or 3 fluorine atoms; 3-9 In one aspect of this embodiment, R represents cycloalkyl. 7 is the unsubstituted C 3-9 In another aspect of this embodiment, R represents cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 7 is a C substituted by one, two, or three fluorine atoms, typically two fluorine atoms 3-9 In a seventh embodiment, R represents cycloalkyl. An example of this embodiment is difluorocyclobutyl. 7 is optionally substituted by one or more fluorine atoms, typically 1, 2, or 3 fluorine atoms; 3-7 In one aspect of this embodiment, R represents heterocycloalkyl. 7 is the unsubstituted C 3-7 In another aspect of this embodiment, R7 is a C substituted by one, two, or three fluorine atoms, typically two fluorine atoms; 3-7 represents heterocycloalkyl.

[0217] R 7 Particular values ​​of include oxetanyl.

[0218] Typically, R 7a is C optionally substituted by 1, 2, or 3 fluorine atoms; 1-6 Represents alkyl.

[0219] Preferably, R 7a is C 1-6 Alkyl or difluoro(C 1-6 ) represents alkyl.

[0220] In the first embodiment, R 7a is C 1-6 In a first aspect of this embodiment, R 7a represents methyl. In a second aspect of that embodiment, R 7a represents ethyl. In a second embodiment, R 7a is difluoro(C 1-6 )-alkyl, in particular difluoroethyl.

[0221] R 7a Particular values ​​of include methyl and difluoroethyl.

[0222] Preferably, R 7b represents methyl or ethyl. In a first embodiment, R 7b represents methyl. In a second embodiment, R 7b represents ethyl.

[0223] Preferably, R 8 represents methyl or ethyl. In a first embodiment, R 8 represents methyl. In a second embodiment, R 8 represents ethyl.

[0224] Various subclasses of compounds according to the present invention are represented by compounds of formula (IIA-1), (IIA-2), (IIB-1), and (IIB-2) and N-oxides thereof, and pharmaceutically acceptable salts thereof: [ka] [ka] During the ceremony, X represents CH or N; R 16 represents methyl, ethyl, isopropyl, or cyclopropyl; and A is as defined above.

[0225] In a first embodiment, X represents CH. In a second embodiment, X represents N.

[0226] In the first embodiment, R 16 represents methyl. In a second embodiment, R 16 represents ethyl. In a third embodiment, R 16 represents isopropyl. In a fourth embodiment, R 16 represents cyclopropyl.

[0227] Typically, R 16 represents methyl, ethyl, or cyclopropyl.

[0228] Preferably, R 16 represents methyl or ethyl.

[0229] Specific novel compounds according to the present invention include each of the compounds whose preparation is described in the accompanying examples, and pharmaceutically acceptable salts and solvates thereof.

[0230] The compounds according to the invention are useful in the treatment and / or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

[0231] The compounds according to the invention are useful for the treatment and / or prevention of pathological disorders mediated by the pro-inflammatory IL-17 cytokine or associated with increased levels of the pro-inflammatory IL-17 cytokine. In general, pathological conditions include infections (viral, bacterial, fungal, and parasitic), infection-related endotoxic shock, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman's disease, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathy, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, celiac disease, gallbladder disease, folliculitis, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, and autoimmune diabetes. , type 1 diabetes, Lyme arthritis, meningoencephalitis, immune-mediated inflammatory diseases of the central and peripheral nervous system, e.g., multiple sclerosis and Guillain-Barré syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrotic disorders, e.g., pulmonary fibrosis, liver fibrosis, kidney fibrosis, scleroderma, or systemic sclerosis, cancer (both solid tumors such as melanoma, hepatoblastoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer, and hematological malignancies, particularly acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer, and colon cancer), heart disease, including ischemic diseases such as myocardial infarction and atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria, and pain (particularly pain associated with inflammation).

[0232] WO 2009 / 089036 discloses that modulators 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). Consequently, compounds according to the present invention are useful for treating and / or preventing IL-17-mediated ocular inflammatory disorders, particularly IL-17-mediated ocular surface inflammatory disorders, including dry eye syndrome. Ocular surface inflammatory disorders include dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial-thickness grafts, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal and ocular surface inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (atopic) eye disease, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndrome include keratoconjunctivitis sicca (KCS), Sjögren's syndrome, Sjögren's syndrome-associated keratoconjunctivitis sicca, non-Sjögren's syndrome-associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorders, decreased tear volume, aqueous tear dysfunction (ATD), meibomian gland dysfunction, and evaporative loss.

[0233] Illustratively, the compounds of the invention may be useful for the treatment and / or prevention of a pathological disorder 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).

[0234] 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.

[0235] The present invention also provides a pharmaceutical composition comprising the compound according to the invention described above, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers.

[0236] Pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, ocular, or rectal administration, or in a form suitable for administration by inhalation or insufflation.

[0237] For oral administration, the pharmaceutical compositions can take the form of tablets, lozenges, or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or 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 take the form of, for example, solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents, emulsifying agents, non-aqueous vehicles, or preservatives. The preparations can also contain buffer salts, flavoring agents, coloring agents, or sweetening agents, as appropriate.

[0238] Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[0239] For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.

[0240] The compound according to the present invention can be formulated for parenteral administration by injection, for example, by bolus injection or infusion.The injection preparation can be provided in a unit dosage form, for example, in a glass ampoule, or in a multi-dose container, for example, in a glass vial.The injection composition can be in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizers, preservatives, and / or dispersing agents.Alternatively, the active ingredient can be in powder form, which can be reconstituted with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0241] In addition to the formulations described above, the compounds of the present invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation or by intramuscular injection.

[0242] For nasal administration or administration by inhalation, the compounds according to the invention can conveniently be delivered in the form of an aerosol spray for a pressurized pack or a nebulizer using a suitable propellant, for example, dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas or mixture of gases.

[0243] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispenser device may be accompanied by instructions for administration.

[0244] For topical administration, the compound of the present invention can be conveniently formulated into a suitable ointment, which contains the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Specific carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, and water.Alternatively, the compound of the present invention can be formulated into a suitable lotion, which contains 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.

[0245] For ocular administration, the compounds according to the invention can be conveniently formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, with or without preservatives such as bactericides or fungicides, e.g., phenylmercuric nitrate, benzylalkonium chloride, or chlorhexidine acetate. Alternatively, for ocular administration, the compounds according to the invention can be formulated into an ointment such as petrolatum.

[0246] For rectal administration, the compounds according to the present invention can be conveniently formulated as suppositories.These can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient.Such materials include, for example, cocoa butter, beeswax, and polyethylene glycol.

[0247] The amount of the compound according to the present invention required for the prevention or treatment of a particular condition varies depending on the compound selected and the condition of the patient being treated. However, in general, the daily dosage can be in the range of about 10 ng / kg to 1000 mg / kg, typically 100 ng / kg to 100 mg / kg, for example, about 0.01 mg / kg to 40 mg / kg body weight for oral or buccal administration, about 10 ng / kg to 50 mg / kg body weight for parenteral administration, and about 0.05 mg to about 1000 mg, for example, about 0.5 mg to about 1000 mg for nasal administration or administration by inhalation or insufflation.

[0248] If desired, the compounds according to the invention may be co-administered with another pharmaceutically active agent, for example, an anti-inflammatory molecule.

[0249] The compounds of formula (I) above have the formula R 6 can be prepared by a process comprising reacting a carboxylic acid of —COH with a compound of formula (III): [ka] In the formula, A, E, R 1a , R 1b and R 6 is as defined above.

[0250] The reaction is conveniently carried out in the presence of a coupling agent and a base. Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU); and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. Suitable bases include organic amines, such as trialkylamines such as N,N-diisopropylethylamine; or pyridine. The reaction is conveniently carried out in a suitable solvent, such as a cyclic ether such as tetrahydrofuran; or a dipolar aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate, at ambient or elevated temperature.

[0251] Alternatively, the reaction may be conveniently effected in the presence of a coupling agent such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). The reaction is suitably carried out in a suitable solvent, for example an organic nitrile solvent such as acetonitrile, at a suitable temperature, for example a temperature in the region of 0°C.

[0252] R 6 C 1-6 When alkyl, e.g., methyl, is represented, the compound of formula (I) above may be of the formula R 6 It can be prepared by a method comprising reacting a compound of -COCl, such as acetyl chloride, with a compound of formula (III) as defined above. The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, such as trialkylamines, such as N,N-diisopropylethylamine. The reaction is conveniently carried out in a suitable solvent, such as a cyclic ether, such as tetrahydrofuran, at ambient temperature.

[0253] R 6 -OR 6a represents a compound of formula (I) above, the compound of formula (I) may be 6aThe compound of formula (III) can be prepared by a two-step process comprising reacting the -OH compound with N,N'-disuccinimidyl carbonate, ideally in the presence of a base, for example an organic amine such as triethylamine, and (ii) reacting the resulting material with a compound of formula (III) as defined above. Steps (i) and (ii) are conveniently carried out at ambient temperature in a suitable solvent, for example a chlorinated solvent such as dichloromethane or an organic nitrile solvent such as acetonitrile.

[0254] The intermediate of formula (III) above can be prepared by removing the N-protecting group R from the compound of formula (IV) P Can be prepared by removal of: [ka] In the formula, A, E, R 1a , and R 1b is as defined above, and R P represents an N-protecting group.

[0255] N-protecting group R P is suitably tert-butoxycarbonyl (BOC), in which case its removal may conveniently be brought about by treatment with an acid, for example a mineral acid such as hydrochloric acid or an organic acid such as trifluoroacetic acid.

[0256] Alternatively, an N-protecting group R P may be benzyloxycarbonyl, in which case its removal may conveniently be effected by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of a hydrogenation catalyst such as palladium on carbon or palladium hydroxide on carbon. P In a variant where is benzyloxycarbonyl, its removal can be brought about by treatment with boron tribromide.

[0257] In another procedure, compounds of formula (I) above, in which A represents a group of formula (Ac), can be prepared by (i) saponifying a compound of formula (V); [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , and R 6 is as defined above, and Alk 1 is C 1-4 alkyl, for example, methyl, ethyl, or tert-butyl; (ii) Compound (III) and Formula R 6 -COH under conditions similar to those described above for the reaction between a carboxylic acid and the resulting carboxylic acid derivative of formula R 3 The compound can be prepared by a two-step process comprising the reaction of a compound of —H with a compound of —H.

[0258] Similarly, the intermediate of formula (IV) above, in which A represents a group of formula (Ac), (i) saponifying a compound of formula (VI); [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , R P , and Alk 1 is as defined above; (ii) Compound (III) and Formula R 6 -COH under conditions similar to those described above for the reaction between a carboxylic acid and the resulting carboxylic acid derivative of formula R 3 The compound can be prepared by a two-step process comprising the reaction of a compound of —H with a compound of —H.

[0259] Alk 1When represents methyl or ethyl, the saponification reaction in step (i) is generally induced by treatment with a base. Suitable bases include inorganic hydroxides, for example, alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. The reaction is carried out in a solvent such as water and a suitable organic solvent, for example, a cyclic ether such as tetrahydrofuran or a C alkoxy group such as methanol. 1-4 It is conveniently carried out in an alkanol at ambient or elevated temperature.

[0260] Or Alk 1 When represents tert-butyl, the saponification reaction in step (i) can generally be effected by treatment with an acid, for example an organic acid such as trifluoroacetic acid. The reaction is conveniently carried out in a suitable organic solvent, for example a chlorinated solvent such as dichloromethane, at ambient temperature.

[0261] Alternative coupling agents that may be usefully employed in step (ii) include 2-chloro-1-methylpyridinium iodide.

[0262] The intermediate of formula (V) above can be prepared by reacting compound (III) with compound of formula R 6 Under conditions similar to those described above for the reaction between —COH and a carboxylic acid of formula R 6 It can be prepared by reacting a carboxylic acid of —COH with a compound of formula (VII): [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , R 6 and Alk 1 is as defined above.

[0263] The intermediate of formula (VII) above can be prepared by removing the N-protecting group R from the compound of formula (IV) P from the compound of formula (VI) as defined above under conditions similar to those described above for the removal of the N-protecting group R PIt can be prepared by removing

[0264] The intermediate of formula (VI) above can be prepared by reacting a compound of formula (VIII) with a compound of formula (IX): [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , Alk 1 , and R P is as defined above, and L 1 represents a suitable leaving group.

[0265] Leaving group L 1 is typically a halogen atom, for example bromo.

[0266] The reaction is typically carried out in the presence of a base. Suitably, the base may be an inorganic base, for example, a bicarbonate, such as sodium bicarbonate, or an organic base, such as pyridine. The reaction is carried out in a suitable solvent, for example, C 10 0 C 20 0 C 15 0 C 25 0 C 16 0 C 25 0 C 17 0 C 18 0 C 25 0 C 19 0 C 26 1-4 This is conveniently carried out in an alkanol or a cyclic ether such as 1,4-dioxane at elevated temperatures.

[0267] In another procedure, the compound of formula (I) above, in which A represents a group of formula (Aa) or (Ab), can be prepared by reacting a compound (III) with a group of formula R 6 Under conditions similar to those described above for the reaction between -COH and carboxylic acids, formula R 2 can be prepared by a process comprising reacting a carboxylic acid of —COH with a compound of formula (X): [ka] During the ceremony, A 1 represents a group of formula (Aa-1) or (Ab-1): [ka] where the asterisk (*) represents the point of attachment to the rest of the molecule; E, Y, R 1a , R 1b , R 2 , and R 6 is as defined above.

[0268] The intermediate of formula (X) above can be prepared by removing the N-protecting group R from a compound of formula (XI) z Can be prepared by removal of: [ka] During the ceremony, A 2 represents a group of formula (Aa-2) or (Ab-2): [ka] where the asterisk (*) represents the point of attachment to the rest of the molecule; R z represents an N-protecting group; E, Y, R 1a , R 1b , and R 6 is as defined above.

[0269] N-protecting group R z is suitably tert-butoxycarbonyl (BOC), in which case its removal may conveniently be brought about by treatment with an acid, for example a mineral acid such as hydrochloric acid or an organic acid such as trifluoroacetic acid.

[0270] The intermediate of formula (XI) above can be prepared by the following steps: (i) Removal of the N-protecting group R from a compound of formula (XII) under conditions similar to those described above P Removal of: [ka] In the formula, E, A 2 , R 1a , R 1b , and R P is as defined above; (ii) Compound (III) and Formula R 6 under conditions similar to those described above for the reaction between —COH and a carboxylic acid of formula R 6 Reaction of -CO2H with carboxylic acids It can be prepared by a two-step procedure, including:

[0271] The intermediate of formula (XII) above can be reacted with a compound of formula A in the presence of a transition metal catalyst. 2 -COH with a compound of formula (XIII): [ka] In the formula, E, A 2 , R 1a , R 1b , and R P is as defined above, and L 2 represents a suitable leaving group.

[0272] Leaving group L 2 is preferably a halogen atom, for example chloro or bromo.

[0273] Suitable transition metal catalysts for the reaction include [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis-{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C}iridium(III) hexafluorophosphate. The reaction is generally carried out in the presence of nickel(II) chloride ethylene glycol dimethyl ether complex and 4,4'-di-tert-butyl-2,2'-dipyridyl. The reaction is preferably carried out in the presence of a base, for example, an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, or an inorganic base such as cesium carbonate, and the reactants are typically exposed to a bright light source. A suitable bright light source typically includes the "integrated photoreactor" described in ACS Cent. Sci., 2017, 3, 647-653. The reaction is conveniently carried out at ambient temperature in a suitable solvent, for example a dipolar aprotic solvent such as N,N-dimethylformamide.

[0274] The intermediate of formula (XIII) above can be prepared by reacting a compound of formula (IX) as defined above with a compound of formula (XIV) under conditions similar to those described above for the reaction of compound (VIII) with compound (IX): [ka] In the formula, R 1a , R 1b , and L 2 is as defined above.

[0275] Alternatively, the intermediate of formula (XII) above can be prepared by reacting a compound of formula (IX) as defined above with a compound of formula (VIIIA) under conditions similar to those described above for the reaction of compound (VIII) with compound (IX): [ka] In the formula, A 2 , R 1a , and R1b is as defined above.

[0276] The intermediate of formula (VIIIA) can be prepared by reacting compound (XIII) with compound of formula A 2 Under conditions similar to those described above for the reaction with compounds of formula A 2 It can be prepared by reacting a compound of -CO2H with a compound of formula (XIV) as defined above.

[0277] In another procedure, A represents a group of formula (Ad) and Z represents a group of formula (Zt), as defined above, where R 2z represents hydrogen), compounds of formula (I) are compounds of formula R 1z -NH2 compounds and trialkyl orthoformate HC(O-Alk 1 )3 can be prepared by a process comprising the step of reacting a compound of formula (XV): [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , R 6 , R 1z , and Alk 1 is as defined above.

[0278] The reaction is conveniently carried out in the presence of acetic acid at elevated temperature. The reaction can typically be carried out in a suitable solvent, for example a cyclic ether such as 1,4-dioxane.

[0279] The intermediate of formula (XV) above may be prepared by reacting a compound of formula (V) as defined above with hydrazine hydrate.

[0280] The reaction is carried out in a suitable solvent, e.g., C 1-4 It is conveniently carried out in an alkanol at elevated temperature.

[0281] The above intermediate of formula (IV), wherein A represents a group of formula (Ad) and Z represents a group of formula (Zu), as defined above, can be prepared by the following steps: (i) saponification of a compound of formula (VI) as defined above by treatment with a base; (ii) Compound (III) and Formula R 6 Reaction of the resulting carboxylic acid derivative with a compound of formula (XVI) under conditions similar to those described above for the reaction of -COH with a carboxylic acid, [ka] In the formula, R 2z is as defined above, (iii) cyclization of the resulting material by treatment with triphenylphosphine in the presence of a base.

[0282] The saponification reaction in step (i) is generally brought about by treatment with a base. Suitable bases include inorganic hydroxides, for example alkali metal hydroxides such as lithium hydroxide.

[0283] Suitable bases for use in step (iii) include organic amines, for example trialkylamines such as triethylamine. The reaction is conveniently carried out at ambient temperature in the presence of hexachloroethane and a suitable solvent, for example a cyclic ether such as tetrahydrofuran.

[0284] In another procedure, A represents a group of formula (Ad) and Z represents a group of formula (Zw) or (Zx) as defined above, where R 1z is other than hydrogen), compounds of formula (I) can be prepared by the following steps: (i) reacting an alkali metal azide with a compound of formula (XVII); [ka] In the formula, E, R 1a , R1b , R 4a , R 4b , and R 6 is as defined above; (ii) The resulting material is treated with the formula R 1z -L 3 wherein R 1z is as defined above (and is other than hydrogen), and L 3 can be prepared by a two-step procedure, including: where R represents a suitable leaving group.

[0285] In step (i), the alkali metal azide is preferably sodium azide. The reaction is conveniently carried out at elevated temperature in the presence of ammonium chloride and a suitable solvent, for example a dipolar aprotic solvent such as N,N-dimethylformamide.

[0286] Leaving group L 3 may suitably be a sulfonyloxy derivative, for example trifluoro-methanesulfonyloxy.

[0287] Step (ii) is generally accomplished in the presence of a base. Suitable bases include alkali metal carbonates, such as potassium carbonate. The reaction is conveniently carried out at elevated temperatures in a suitable solvent, such as a carbonyl-containing solvent such as acetone.

[0288] The intermediate of formula (XVII) above can be prepared by the following steps: (i) reacting a compound of formula (XIII) as defined above with ammonia; (ii) reacting the resulting material with trifluoroacetic anhydride in the presence of pyridine.

[0289] Step (i) is carried out in a suitable solvent, e.g., C 1-4 It is conveniently carried out in an alkanol at elevated temperature.

[0290] Step (ii) is conveniently carried out in a suitable solvent, for example a cyclic ether such as 1,4-dioxane, at ambient temperature.

[0291] A represents a group of formula (Ad) and Z represents a group of formula (Zq) as defined above, where R 2z is hydrogen), the intermediate of formula (IV) above can be converted to a compound of formula R 1z - can be prepared by reacting an azide derivative of N3 with a compound of formula (XVIII): [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , R 1z , and R P is as defined above.

[0292] Suitable transition metal catalysts for use in the above reaction include chloro-(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II).

[0293] The reaction is conveniently carried out at elevated temperature in a suitable solvent or mixture of solvents. Typical solvents include alkyl ethers, such as tert-butyl methyl ether, or 1,2-dimethoxyethane; and cyclic ethers, such as tetrahydrofuran.

[0294] The intermediate of formula (XVIII) above can be prepared by reacting a compound of formula (XIX) with dimethyl(1-diazo-2-oxopropyl)phosphonate, [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , and R P is as defined above.

[0295] The reaction is generally carried out in the presence of a base. Suitably, the base may be an alkali metal carbonate, for example, potassium carbonate. The reaction is conveniently carried out at ambient temperature in a suitable solvent or mixture of solvents. Typical solvents include C 1-4 Alkanols, such as methanol; and chlorinated solvents, such as dichloromethane.

[0296] The intermediate of formula (XIX) above can be prepared by the following steps: (i) O-protecting group R from compound of formula (XX) s Removal of: [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , and R P is as defined above, and R s represents an O-protecting group; (ii) treatment of the compound thereby obtained with an oxidizing agent.

[0297] O-protecting group R s is preferably acetyl.

[0298] R s When represents acetyl, its removal in step (i) above may conveniently be brought about by treatment with a base. Suitably, the base may be an alkali metal carbonate, for example potassium carbonate. The reaction may be carried out in a suitable solvent, for example C 1 , such as methanol. 1-4 It is conveniently carried out in an alkanol at ambient temperature.

[0299] A suitable oxidizing agent for use in step (ii) above is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane). The reaction is conveniently carried out in a suitable solvent, e.g., a chlorinated solvent such as dichloromethane, at ambient temperature.

[0300] Alternatively, the oxidizing agent used in step (ii) above may comprise sulfur trioxide pyridine complex, in which case the reaction may conveniently be achieved in the presence of a base. Suitably the base may be an organic amine, for example N,N-diisopropylethylamine.

[0301] The intermediate of formula (XX) above can be prepared by reacting a compound of formula (IX) as defined above with a compound of formula (XXI) under conditions similar to those described above for the reaction of compound (VIII) with compound (IX): [ka] In the formula, R 1a , R 1b , R 4a , R 4b and R s is as defined above.

[0302] The intermediate of formula (IV) above, in which A represents a group of formula (Ad) and Z represents a group of formula (Zw) as defined above, can be prepared by reacting azidotrimethylsilane with a compound of formula (XXII): [ka] In the formula, E, R 1a , R 1b , R 4a , R 4b , R 1z , and R P is as defined above.

[0303] The reaction is generally accomplished in the presence of triphenylphosphine and an azodicarboxylate ester, such as diisopropyl azodicarboxylate (DIAD). The reaction is conveniently carried out at ambient temperature in a suitable solvent, such as a cyclic ether, such as tetrahydrofuran.

[0304] The intermediate of formula (XXII) above is (i) saponification of a compound of formula (VI) as defined above by treatment with a base; (ii) Compound (III) and Formula R 6 -COH under conditions similar to those described above for the reaction between a carboxylic acid and the resulting carboxylic acid derivative of formula R 1z Reaction of -NH2 with compounds (iii) treatment of the resulting carboxamide derivative with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide).

[0305] The saponification reaction in step (i) is generally brought about by treatment with a base. Suitable bases include inorganic hydroxides, for example alkali metal hydroxides such as lithium hydroxide.

[0306] Step (iii) is conveniently carried out in a suitable solvent, for example a cyclic ether such as 1,4-dioxane, at elevated temperature.

[0307] In another procedure, A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 Ga-COR 7a The compound of formula (I) can be prepared by reacting a compound (III) with a compound of formula R 6 Under conditions similar to those described above for the reaction between -COH and carboxylic acids, formula R 7a can be prepared by a process comprising reacting a carboxylic acid of —COH with a compound of formula (XXIII): [ka] During the ceremony, A 11 represents a group of formula (Ae-1): [ka] where the asterisk (*) represents the point of attachment to the rest of the molecule; E, R 1a , R 1b , R 2 , and R 6 is as defined above.

[0308] Similarly, A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 Ga-COR 7a The intermediate of the above formula (IV) can be prepared by reacting a compound (III) with a compound of formula R 6 Under conditions similar to those described above for the reaction between —COH and a carboxylic acid of formula R 7a It can be prepared by reacting a carboxylic acid of —COH with a compound of formula (XXIV): [ka] In the formula, E, A 11 , R 1a , R 1b , and R P is as defined above.

[0309] A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 Ga-CO2R 7a The compound of formula (I) above can be prepared by converting the compound of formula (XXIII) defined above into the compound of formula L 4a -CO2R 7a wherein L 4a represents a suitable leaving group, and R 7a is as defined above.

[0310] Similarly, A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 Ga-CO2R 7a and the intermediate of formula (IV) above can be prepared by reacting a compound of formula (XXIV) as defined above with the compound of formula L 4a -CO2R 7a can be prepared by reacting a compound of formula 4a and R 7a is as defined above.

[0311] Leaving group L 4a is preferably a halogen atom, for example chloro. Alternatively, the leaving group L 4a may suitably be 2,5-dioxopyrrolidin-1-yloxy.

[0312] The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, for example, trialkylamines such as N,N-diisopropylethylamine or triethylamine. The reaction is conveniently carried out in a suitable solvent, for example, a chlorinated solvent such as dichloromethane, at ambient temperature.

[0313] A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 Ga-SO2R 7b The compound of formula (I) above can be prepared by converting the compound of formula (XXIII) defined above into the compound of formula L 4b -SO2R 7b wherein L 4b represents a suitable leaving group, and R 7b is as defined above.

[0314] Similarly, A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 Ga-SO2R 7band the intermediate of formula (IV) above can be prepared by reacting a compound of formula (XXIV) as defined above with the compound of formula L 4b -SO2R 7b can be prepared by reacting a compound of formula 4b and R 7b is as defined above.

[0315] Leaving group L 4b is preferably a halogen atom, for example chloro.

[0316] The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, for example, trialkylamines such as N,N-diisopropylethylamine or triethylamine. The reaction is conveniently carried out in a suitable solvent, for example, a chlorinated solvent such as dichloromethane, at ambient temperature.

[0317] A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 optionally substituted by one or more fluorine atoms, 1-6 The compound of formula (I) above can be prepared by reacting a compound of formula (XXIII) defined above with a compound of formula L 5 -R 7c wherein L 5 represents a suitable leaving group, and R 7c is C optionally substituted by one or more fluorine atoms 1-6 Represents alkyl.

[0318] Similarly, A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 optionally substituted by one or more fluorine atoms, 1-6 The intermediate of formula (IV) above can be prepared by reacting a compound of formula (XXIV) as defined above with a compound of formula L 5 -R 7c can be prepared by reacting a compound of formula 5 and R7c is as defined above.

[0319] Leaving group L 5 may suitably be a sulfonyloxy derivative, for example trifluoro-methanesulfonyloxy.

[0320] The reaction is conveniently carried out in the presence of a base. Suitable bases include organic amines, for example trialkylamines such as triethylamine. The reaction is conveniently carried out in a suitable solvent, for example a chlorinated solvent such as dichloromethane, at ambient temperature.

[0321] A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 optionally substituted by one or more fluorine atoms, 3-9 Cycloalkyl or C-bonded C 3-7 Heterocycloalkyl (e.g., 3,3-difluoro-cyclobutyl or oxetan-3-yl)), compounds of formula (I) above can be prepared by a process comprising reacting a compound of formula (XXIII) as defined above with a suitable cycloalkanone or heterocycloalkanone, optionally substituted by one or more fluorine atoms (e.g., 3,3-difluorocyclobutanone or oxetan-3-one), in the presence of a reducing agent.

[0322] Similarly, A represents a group of formula (Ae) where Y is NR 7 represents, and R 7 optionally substituted by one or more fluorine atoms, 3-9 Cycloalkyl or C-bonded C 3-7Intermediates of formula (IV) above, representing heterocycloalkyl (e.g., 3,3-difluoro-cyclobutyl or oxetan-3-yl), can be prepared by reacting a compound of formula (XXIV) as defined above with an appropriate cycloalkanone or heterocycloalkanone, optionally substituted by one or more fluorine atoms (e.g., 3,3-difluorocyclobutanone or oxetan-3-one), in the presence of a reducing agent.

[0323] The reducing agent is preferably sodium triacetoxyborohydride. The reaction is conveniently carried out in the presence of acetic acid.

[0324] As will be appreciated, the compounds of formula (XXIII) above correspond themselves to compounds of formula (I) as defined above, in which A represents a group of formula (Ae) (in which Y is NR 7 represents, and R 7 represents hydrogen).

[0325] The compounds of formula (XXIII) above can be conveniently prepared by reacting the corresponding compound of formula (I) with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid, wherein A represents a group of formula (Ae) and Y is NR 7 (wherein R 7 -CO2R 7a represents, and R 7a represents tert-butyl).

[0326] Similarly, the intermediate of formula (XXIV) above may be conveniently prepared by reacting the corresponding compound of formula (IV) with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid, wherein A represents a group of formula (Ae) and Y is NR 7 (wherein R 7 -CO2R 7a represents, and R 7a represents tert-butyl).

[0327] The intermediate of formula (IV) above, wherein A represents a group of formula (Ae), can be prepared by the following steps: (i) saponifying a compound of formula (XXV): [ka] During the ceremony, A 12 represents a group of formula (Ae-2): [ka] where the asterisk (*) represents the point of attachment to the rest of the molecule; E, Y, R 1a , R 1b , R P , and Alk 1 is as defined above; (ii) Compound (III) and Formula R 6 and the resulting carboxamide derivative with a carboxylic acid of formula R under conditions similar to those described above for the reaction of —COH with a carboxylic acid of formula R. 2 Reaction of -H with compounds (iii) reducing the C=C double bond of the Y-containing ring.

[0328] The saponification reaction in step (i) is generally induced by treatment with a base. Suitable bases include inorganic hydroxides, such as alkali metal hydroxides, such as lithium hydroxide or sodium hydroxide. Step (i) can be carried out in water and / or a suitable organic solvent, such as a cyclic ether, such as tetrahydrofuran, or a C 2 -based solvent, such as methanol or ethanol. 1-4 It is conveniently carried out in an alkanol at ambient or elevated temperature.

[0329] Alternative coupling agents that may be usefully employed in step (ii) include 2-chloro-1-methylpyridinium iodide.

[0330] Reduction of the C=C double bond in step (iii) may conveniently be effected by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of a hydrogenation catalyst such as palladium on carbon or palladium hydroxide on carbon.

[0331] The intermediate of formula (XXV) can be reacted with a compound of formula A in the presence of a transition metal catalyst. 12 -L 6 can be prepared by reacting a compound of formula (XXVI): [ka] In the formula, M 1 represents -B(OH)2 or its cyclic ester formed with an organic diol, e.g., pinacol, 1,3-propanediol, or neopentyl glycol; L 6 represents a suitable leaving group, E, A 12 , R 1a , R 1b , and R P is as defined above.

[0332] Leaving group L 6 is suitably a halogen atom, for example chloro or bromo. Alternatively, the leaving group L 6 may suitably be a sulfonyloxy derivative, for example methanesulfonyloxy or trifluoromethanesulfonyloxy.

[0333] The transition metal catalyst may suitably be tris(dibenzylideneacetone)-palladium(0), which may typically be used in conjunction with 2-dicyclohexyl-phosphino-2',4',6'-triisopropylbiphenyl (XPhos). Typically, the reaction is carried out in the presence of potassium phosphate at elevated temperatures.

[0334] Alternatively, the transition metal catalyst may be [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction may conveniently be carried out in the presence of potassium carbonate at elevated temperatures.

[0335] Alternatively, the intermediate of formula (XXV) can be produced by reacting a compound of formula (XXVI) with a compound of formula A in the presence of a transition metal catalyst. 12 -L 6 under conditions similar to those described above for the reaction between a compound of formula A 12 -M 1 can be prepared by reacting a compound of formula (XIII) as defined above with a compound of formula (XIII).

[0336] For example, M 1 The intermediate of formula (XXVI) above, where represents the cyclic ester of -B(OH) formed with pinacol, can be prepared by reacting bis(pinacolato)diboron with a compound of formula (XIII) defined above in the presence of a transition metal catalyst.

[0337] Similarly, M 1 represents the cyclic ester of -B(OH) formed with pinacol, 12 -M 1 can be prepared by reacting bis(pinacolato)diboron with the compound of formula A defined above in the presence of a transition metal catalyst. 12 -L 6 can be prepared by reacting the compound with

[0338] The transition metal catalyst may suitably be tris(dibenzylideneacetone)-palladium(0), which may typically be used in conjunction with 2-dicyclohexyl-phosphino-2',4',6'-triisopropylbiphenyl (XPhos). Typically, the reaction is carried out in the presence of potassium acetate at elevated temperatures.

[0339] If they are not commercially available, the starting materials of formula (VIII), (IX), (XIV), (XVI), and (XXI) can be prepared by methods similar to those described in the accompanying examples or by standard methods well known in the art.

[0340] It will be appreciated that any compound of formula (I) initially obtained from any of the above processes can, where appropriate, subsequently be elaborated into further compounds of formula (I) by techniques known in the art. By way of example, a compound containing an N-BOC moiety (BOC is an abbreviation for tert-butoxy-carbonyl) can be converted to the corresponding compound containing an NH moiety by treatment with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

[0341] Compounds containing an NH function can be alkylated, e.g., methylated, typically by treatment with a suitable alkyl halide, e.g., iodomethane, in the presence of a base, e.g., an inorganic carbonate such as sodium carbonate.

[0342] Compounds containing an NH function can be acylated, e.g., acetylated, typically by treatment with a suitable acyl halide, e.g., acetyl chloride, in the presence of a base, e.g., an organic base such as N,N-diisopropylethylamine or triethylamine. Similarly, compounds containing an NH function can be acylated, e.g., acetylated, typically by treatment with a suitable acyl anhydride, e.g., acetic anhydride, in the presence of a base, e.g., an organic base such as triethylamine.

[0343] Similarly, compounds containing an NH functional group are typically reacted with an appropriate C 1-4 Treatment with an alkylsulfonyl chloride reagent, e.g., methylsulfonyl chloride, affords NS(O)Alk 1 Functional group (in the formula, Alk 1 can be converted to the corresponding compound containing

[0344] Similarly, compounds containing an NH functional group can be converted to the corresponding compounds containing a carbamate or urea moiety, typically by treatment with a suitable chloroformic acid or carbamoyl chloride reagent in the presence of a base, for example, an organic base such as triethylamine or N,N-diisopropylethylamine. Alternatively, compounds containing an NH functional group can 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, for example, an organic base such as triethylamine. Alternatively, compounds containing an NH functional group can be converted to the corresponding compounds containing a urea moiety by treatment with a suitable isocyanate derivative Alk, typically in the presence of a base, for example, an organic base such as triethylamine. 1 Treatment with -N=C=O gives the urea moiety NC(O)N(H)Alk 1 (In the formula, Alk 1 can be converted to the corresponding compound containing

[0345] Compounds containing an NH functionality can be converted to the corresponding compounds containing an NC(H) functionality by treatment with an appropriate aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride.

[0346] C 1-4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1 is as defined above) can be converted to the corresponding compound containing a carboxylic acid (—COH) moiety by treatment with a base, e.g., an alkali metal hydroxide salt such as lithium hydroxide. Alternatively, a compound containing a tert-butoxy-carbonyl moiety can be converted to the corresponding compound containing a carboxylic acid (—COH) moiety by treatment with trifluoroacetic acid.

[0347] Compounds containing a carboxylic acid (-COH) moiety can be prepared by reacting compound (III) with the compound of formula R 6They can be converted to the corresponding compounds containing an amide moiety by treatment with an appropriate amine under conditions similar to those described above for the reaction of -CO2H with a carboxylic acid.

[0348] C 1-4 Alkoxycarbonyl moiety -CO2Alk 1 (In the formula, Alk 1 is as defined above) can be converted to the corresponding compound containing a hydroxymethyl (—CHOH) moiety by treatment with a reducing agent such as lithium aluminum hydride.

[0349] C 1-4 Alkylcarbonyloxy moiety -OC(O)Alk 1 (In the formula, Alk 1 is as defined above), e.g., acetoxy, can be converted to the corresponding compound containing a hydroxy (—OH) moiety by treatment with a base, e.g., an alkali metal hydroxide salt such as sodium hydroxide.

[0350] Compounds containing halogen atoms, such as bromo, can be converted to the corresponding compounds containing optionally substituted aryl, heterocycloalkenyl, or heteroaryl moieties by treatment with an appropriately substituted aryl, heterocycloalkenyl, or heteroarylboronic acid or its cyclic ester formed with 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 may be [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Alternatively, the transition metal catalyst may be tris(dibenzylideneacetone)dipalladium(0), which may be advantageously used in conjunction with 2-dicyclohexyl-phosphino-2',4',6'-triisopropylbiphenyl (XPhos). Preferably, the base is an inorganic base such as sodium carbonate or potassium carbonate.

[0351] Compounds containing halogen atoms, such as 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 [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and a transition metal catalyst such as 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 such as sodium carbonate or potassium carbonate.

[0352] Compounds containing a cyano (-CN) moiety can be converted to the corresponding compounds containing a 1-aminoethyl moiety by a two-step process involving (i) reaction with methylmagnesium chloride, ideally in the presence of titanium(IV) isopropoxide, and (ii) treatment of the resulting material with a reducing agent such as sodium borohydride. If an excess of methylmagnesium chloride is used in step (i), the corresponding compounds containing a 1-amino-1-methylethyl moiety can be obtained.

[0353] Compounds containing the moiety -S- can be converted to the corresponding compounds containing the moiety -S(O)(NH)- by treatment with (diacetoxyiodo)benzene and ammonium carbamate.

[0354] 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, for example, palladium on carbon.

[0355] 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, for example, 3-chloroperbenzoic acid.

[0356] When a mixture of products is obtained from any of the above-described processes for the preparation of 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 utilizing, for example, silica and / or alumina in combination with a suitable solvent system.

[0357] If the above-described method for preparing the compound according to the present invention results in a mixture of stereoisomers, these isomers can be separated by conventional techniques. In particular, if it is desired to obtain a specific enantiomer of the compound of formula (I), it can be produced from the corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, such as salts, can be produced by reacting a mixture of an enantiomer 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, for example, by crystallization, and the desired enantiomer can be recovered, for example, by treating with an acid if the diastereomer is a salt. In another resolution process, the racemate of formula (I) can be separated using chiral HPLC. Furthermore, if desired, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the above-described methods. Alternatively, a specific enantiomer can be obtained by enantiospecific enzymatic biotransformation, e.g., ester hydrolysis using an esterase, followed by purification of the enantiomerically pure hydrolyzed acid from the unreacted ester antipode. Chromatography, recrystallization, and other conventional separation procedures can also be used with intermediates or final products where it is desired to obtain a specific geometric isomer of the present invention.

[0358] During any of the above synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by conventional protecting groups such as those described in Greene's Protective Groups in Organic Synthesis, ed. P.G.M.Wuts, John Wiley & Sons, 5th ed., 2014. The protecting groups may be removed at any convenient subsequent stage using methods known in the art.

[0359] Compounds according to the invention potently inhibit IL-17-induced IL-6 release from human dermal fibroblasts. Thus, when tested in the HDF cell line assay described below, compounds of the invention have a pIC of 5.0 or greater, generally 6.0 or greater, usually 7.0 or greater, typically 7.2 or greater, suitably 7.5 or greater, ideally 7.8 or greater, and preferably 8.0 or greater. 50 Values ​​are shown (pIC 50 ha-log 10 [I C 50 ], and IC 50 is expressed as a molar concentration, one skilled in the art would recognize a higher pIC 50 It will be appreciated that a higher value indicates a more active compound).

[0360] Inhibition of IL-17A-induced IL-6 release from a dermal fibroblast cell line The purpose of this assay is to test the neutralizing ability of IL-17 protein in a human primary cell line. Although stimulation of normal human dermal fibroblasts (HDFs) with IL-17 alone produces only a very weak signal, in combination with certain other cytokines, such as TNFα, a synergistic effect can be observed in the production of inflammatory cytokines, namely IL-6.

[0361] HDFs were stimulated with IL-17A (50 pM) in combination with TNF-α (25 pM). The resulting IL-6 response was then measured using a homogeneous time-resolved FRET kit from Cisbio. The kit utilizes two monoclonal antibodies, one labeled with Eu cryptate (donor) and the other labeled with d2 or XL665 (acceptor). The intensity of the signal is proportional to the concentration of IL-6 present in the sample (the ratio is calculated as 665 / 620 × 10).

[0362] This assay measures the ability of compounds to inhibit IL-17-induced IL-6 release from human dermal fibroblasts.

[0363] HDF cells (Sigma #106-05n) were cultured in complete medium (DMEM + 10% FCS + 2 mM L-glutamine) and maintained in tissue culture flasks using standard techniques. Cells were harvested from the tissue culture flasks the morning of the assay using TrypLE (Invitrogen #12605036). Complete medium (45 mL) was used to neutralize the TrypLE, and the cells were centrifuged at 300 x g for 3 minutes. Cells were resuspended in complete medium (5 mL) and counted to yield 3.125 x 10 4 After adjusting the concentration to cells / mL, 40 μL / well was added to a 384-well assay plate (Corning #3701). Cells were allowed to adhere to the plate for a minimum of 3 hours at 37°C / 5% CO2.

[0364] After serially diluting the compounds in DMSO, the aqueous dilutions were placed in a 384-well dilution plate (Greiner #781281) and 5 μL from the titration plate was transferred to 45 μL of complete medium and mixed to obtain a solution containing 10% DMSO.

[0365] A mixture of TNFα and IL-17 cytokines was prepared in complete medium to a final concentration of 25 pM TNFα / 50 pM IL-17A, and then 30 μL of the solution was added to a 384-well reagent plate (Greiner #781281).

[0366] Ten µL of the aqueous dilution plate was transferred to a reagent plate containing 30 µL of diluted cytokines to yield a 2.5% DMSO solution. The compounds were incubated with the cytokine mixture at 37 °C for 5 hours. After incubation, 10 µL was transferred to an assay plate to yield a 0.5% DMSO solution, which was then incubated at 37 °C / 5% CO for 18-20 hours.

[0367] Europium cryptate and Alexa 665 from the Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) were diluted in reconstitution buffer and mixed 1:1 according to the kit insert. 10 μL of FRET reagent was added to a white low-volume 384-well plate (Greiner #784075), and then 10 μL of the supernatant was transferred from the assay plate to the Greiner reagent plate. The mixture was incubated at room temperature with gentle shaking (<400 rpm) for 3 hours before being read on a Synergy Neo 2 plate reader (excitation: 330 nm; emission: 615 / 645 nm).

[0368] When tested in the HDF cell line assay described above, the compounds in the attached examples had the following pIC 50 It was found to show value. [Table 1]

[0369] The following examples illustrate the preparation of compounds according to the invention.

[0370] example Abbreviation DCM: dichloromethane THF: tetrahydrofuran MeOH: Methanol EtOH: ethanol DMSO: dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide EtOAc: ethyl acetate TFA: Trifluoroacetic acid IPA: Isopropyl alcohol DMAP: 4-(dimethylamino)pyridine TBME: tert-butyl methyl ether LDA: lithium diisopropylamide NBS: N-bromosuccinimide DIAD: Diisopropyl azodicarboxylate Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene T3P®: Propylphosphonic anhydride solution HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate {Ir[dF(CF3)ppy]2(dtbpy)}PF6: [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis-{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C}iridium(III) hexafluorophosphate Lawesson's Reagent: 2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide h: time rt: room temperature M: mass; moles RT: retention time HPLC: High-Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry SFC: Supercritical Fluid Chromatography FCC: Flash column chromatography

[0371] Analysis and Separation Methods Method 1 X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile phase B: acetonitrile + 5% water + 0.1% ammonia solution Gradient program: Flow rate 1 mL / min 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

[0372] Method 2 Waters UPLC® BEH™ C18, part number 186002352, 2.1 x 100 mm, 1.7 μm column Column temperature: 40℃ Mobile phase A: 2 mM ammonium bicarbonate buffered to pH 10 Mobile phase B: acetonitrile Gradient program flow rate 0.6 mL / min Time A% B% 0.00 95.00 5.00 5.30 0 100 5.80 0 100 5.82 95.00 5.00 7.00 95.00 5.00

[0373] Method 3 Phenomenex, Kinetex-XB C18, 2.1 mm x 100 mm, 1.7 μm column Column temperature: 40℃ Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Gradient program: flow rate 0.6 mL / min; injection volume 1 μL Time A% B% 0.00 95 5 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 UV 215nm, PDA spectrum 200-400nm, step 1nm MSD scan positive 150-850

[0374] Method 4 X-Bridge C18 Waters 2.1 x 20 mm, 2.5 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 Gradient program: Flow rate 1 mL / min 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

[0375] Method 5 X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: Flow rate 1 mL / min 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

[0376] Method 6 X-Bridge C18 Waters 2.1 x 20 mm, 2.5 μm column Column temperature: 40℃ Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: Flow rate 1 mL / min 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

[0377] Method 7 Phenomenex Gemini NX-C18 2 x 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 Gradient program: Flow rate 1 mL / min 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

[0378] Method 8 Waters Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 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 Gradient program: flow rate 1.5 mL / min 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

[0379] Method 9 Waters Sunfire C18 30 x 100 mm, 10 μm column Column temperature: room temperature Mobile phase A: Water + 0.1% formic acid Mobile phase B: acetonitrile + 0.1% formic acid Gradient program: flow rate 40 mL / min Time A% B% 0.00 70 30 0.55 70 30 11.0 5 95 13.1 5 95 13.31 70 30

[0380] Method 10 Waters Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 μm Column Mobile phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile phase B: acetonitrile + 5% water + 0.1% formic acid Gradient program: flow rate 1.5 mL / min 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

[0381] Method 11 Phenomenex Gemini NX-C18 2 x 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 Gradient program: Flow rate 1 mL / min 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

[0382] Intermediate 1 tert-Butyl N-(6-chloro-5-methylpyridazin-3-yl)carbamate To a stirred solution of 6-chloro-5-methylpyridazin-3-amine (4.21 g, 29.3 mmol) and DIPEA (20 mL, 0.117 mol) in DMF (45 mL) were successively added di-tert-butyl dicarbonate (14.55 g, 66.7 mmol) and DMAP (358 mg, 2.93 mmol). The reaction mixture was stirred at rt for 3 h and then concentrated to dryness under high vacuum. The resulting brown solid was dissolved in methanol (45 mL) and dipotassium carbonate (4.05 g, 29.3 mmol) was added. The reaction mixture was stirred at rt for 16 h, then concentrated under vacuum, redissolved in EtOAc (250 mL), and washed with water (200 mL). The resulting suspension was filtered through a pad of Celite®, washing with EtOAc (500 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (40 mL), then dried over sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by silica column chromatography eluting with 0-50% EtOAc in heptane to afford the title compound (6.87 g, 79%) as a white solid.

number

[0383] Intermediate 2 2-[6-(tert-butoxycarbonylamino)-3-chloropyridazin-4-yl]acetic acid To a solution of Intermediate 1 (5.02 g, 20.6 mmol) in THF (60 mL) at −50° C., 2 M LDA in THF / n-heptane / ethylbenzene (31 mL, 61.8 mmol) was added dropwise. The reaction mixture was stirred at −50° C. for 5 minutes, then slowly warmed to −30° C. and stirred for 20 minutes. Gaseous CO was bubbled through the reaction mixture (the internal temperature reached −10° C. upon addition). The reaction mixture was recooled to −50° C. and stirred for an additional 40 minutes, then diluted with saturated aqueous NH4Cl (20 mL) and EtOAc (20 mL). The organic layer was discarded. The pH of the aqueous layer was adjusted to pH 3–4 using 2 M aqueous HCl. The resulting aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound (4.7 g, 62%) as an orange oil.

number

[0384] Intermediate 3 2-[6-(tert-butoxycarbonylamino)-3-chloropyridazin-4-yl]acetic acid methyl ester To a solution of intermediate 2 (79%, 4.70 g, 12.9 mmol) in methanol (40 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 40.0 mmol). The reaction mixture was stirred for 4 h. The pH of the reaction was adjusted to pH 7 using saturated aqueous NaHCO3, and then water (100 mL) was added. The resulting solid precipitate was collected by vacuum filtration, washed with a minimal amount of water, and then dried in a vacuum oven at 40 °C for 16 h to afford the title compound (3.83 g, 93%) as a white solid.

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[0385] Intermediate 4 Methyl 2-[6-(tert-butoxycarbonylamino)-3-chloropyridazin-4-yl]-4,4-difluorobut-2-enoate To a solution of intermediate 3 (1.22 g, 4.04 mmol) in 1,4-dioxane (24 mL) was added triethylamine (1127 μL, 8.09 mmol) and 1-ethoxy-2,2-difluoroethanol (637 mg, 5.05 mmol). The reaction mixture was heated at 102° C. for 3 h. An additional portion of triethylamine (0.56 mL, 4.04 mmol) and 1-ethoxy-2,2-difluoroethanol (0.56 mL, 5.05 mmol) was added. The reaction mixture was heated at 102° C. for an additional 3 h and then concentrated in vacuo. The resulting brown oil was purified by silica column chromatography eluting with 0 to 40% EtOAc in heptane to afford the title compound (965 mg, 66%) as a white solid.

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[0386] Intermediate 5 Methyl 2-(6-amino-3-chloropyridazin-4-yl)-4,4-difluorobut-2-enoate Intermediate 4 (90%, 528 mg, 1.31 mmol) was stirred in DCM (2.5 mL) and TFA (1.5 mL, 19.6 mmol) at rt for 2 h. The reaction mixture was diluted with DCM (30 mL) and washed with saturated aqueous NaHCO (2 × 10 mL) and brine (10 mL), then dried over sodium sulfate and concentrated in vacuo to give the title compound (90% pure) (357 mg, 93%) as a yellow oil.

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[0387] Intermediate 6 Methyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-6-chloro-imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobut-2-enoate Intermediate 5 (90%, 357 mg, 1.22 mmol) and benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (640 mg, 1.58 mmol) were stirred in dry 1,4-dioxane (5 mL) and 2,6-dimethylpyridine (369 μL, 3.17 mmol) was added. The reaction mixture was sealed and heated at 80° C. for 3.5 h. The residue was diluted with ethyl acetate (50 mL) and washed with water (20 mL), saturated aqueous NH4Cl (20 mL), water (20 mL), and brine (20 mL), then dried over sodium sulfate and concentrated in vacuo. The material was purified by silica column chromatography eluting with a gradient of 0-100% ethyl acetate in heptane to afford the title compound (90% pure) (673 mg, 87%) as a yellow / orange foam.

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[0388] Intermediate 7 Methyl 2-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate Intermediate 6 (90%, 600 mg, 0.949 mmol) was dissolved in methanol (20 mL) and 1 M aqueous HCl (5.0 mL, 5.00 mmol) was added, followed by 10% Pd / C (50% wet) (5.0%, 202 mg, 0.0949 mmol). The reaction mixture was stirred under 1 atmosphere of H for 2.5 h, then filtered through Celite® and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO (30 mL). The aqueous layer was further extracted with ethyl acetate (20 mL). The organic extracts were combined, washed with brine (20 mL), then dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with a gradient of 0–90% MeOH in DCM to afford the title compound (95% pure) (260 mg, 65%) as an orange oil.

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[0389] Intermediate 8 Methyl 2-{2-[(S)-(tert-butoxycarbonylamino)(4,4-difluorocyclohexyl)methyl]imidazo-[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate Intermediate 7 (95%, 500 mg, 1.18 mmol) was dissolved in DCM (20 mL) and di-tert-butyl dicarbonate (309 mg, 1.42 mmol) was added. The reaction mixture was stirred at rt for 2.5 h, then diluted with DCM (20 mL), washed with water (2 × 20 mL), dried over sodium sulfate, and concentrated in vacuo to give the title compound (90% pure) (660 mg, 100%) as a brown foam.

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[0390] Intermediate 9 2-{2-[(S)-(tert-butoxycarbonylamino)(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]-pyridazin-7-yl}-4,4-difluorobutanoic acid Intermediate 8 (90%, 660 mg, 1.18 mmol) was dissolved in water (5 mL), methanol (5 mL), and THF (5 mL). Lithium hydroxide hydrate (1:1:1) (198 mg, 4.73 mmol) was added, and the reaction mixture was stirred for 45 minutes and then concentrated in vacuo to remove most of the organic solvent. The remaining mixture was diluted with ethyl acetate (30 mL) and water (30 mL), and the aqueous portion was then adjusted to pH 5 using 1 M aqueous HCl (5 mL). The mixture was separated, and the aqueous layer was further extracted with ethyl acetate (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the title compound (95% pure) (610 mg, 100%) as a yellow foam.

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[0391] Intermediate 10 tert-Butyl N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]carbamate Intermediate 9 (95%, 610 mg, 1.19 mmol) was dissolved in DMF (8 mL). 2,2,2-Trifluoroethanamine (0.10 mL, 1.30 mmol) and DIPEA (0.41 mL, 2.37 mmol) were added, followed by HATU (541 mg, 1.42 mmol). The reaction mixture was stirred at rt for 70 min, and then additional 2,2,2-trifluoroethanamine (0.10 mL, 1.30 mmol) and HATU (150 mg, 0.39 mmol) were added. The reaction mixture was stirred for 20 min, then diluted with water (20 mL) and sonicated. The mixture was filtered, and the sticky solid was washed with a small amount of water. The solid was dissolved in ethyl acetate, dried over sodium sulfate, and concentrated in vacuo to give the title compound (90% pure) (753 mg, 100%) as an orange foam.

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[0392] Intermediate 11 2-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluoro-N-(2,2,2-trifluoroethyl)butanamide Intermediate 10 (90%, 753 mg, 1.19 mmol) was stirred in DCM (7.5 mL) and TFA (2.5 mL) for 45 minutes and then concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with saturated aqueous NaHCO3 (2 x 20 mL) and brine (20 mL), then dried over sodium sulfate and concentrated in vacuo. The material was purified by silica column chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound (364 mg, 65%) as a light brown solid.

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[0393] Intermediate 12 Ethyl 2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}imidazo[1,2-b]pyridazin-7-yl)-4,4-difluorobutanoate HATU (161 mg, 0.423 mmol) was added to a mixture of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (54 mg, 0.423 mmol) and DIPEA (123 μL, 0.705 mmol) in DMF (3 mL) at rt. The reaction mixture was stirred at rt for 5 min, then a solution of Intermediate 21 (128 mg, 0.282 mmol) and DIPEA (123 μL, 0.705 mmol) in DMF (3 mL) was added. The reaction mixture was stirred at rt for 16 h, then diluted with EtOAc (50 mL) and washed with water (3 × 60 mL). The organic phase was dried over sodium sulfate and concentrated to dryness in vacuo. The crude residue was purified by silica column chromatography eluting with 10–60% EtOAc in heptane to afford the title compound (112 mg, 55%) as a tan gum.

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[0394] Intermediate 13 2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}imidazo[1,2-b]pyridazin-7-yl)-4,4-difluorobutanoic acid A mixture of lithium hydroxide monohydrate (20 mg, 0.468 mmol) and Intermediate 12 (112 mg, 0.213 mmol) in THF (2.5 mL), water (0.4 mL), and methanol (1 mL) was stirred at rt for 16 h. The reaction mixture was concentrated to a low volume in vacuo, diluted with EtOAc (50 mL), and then 0.5 M aqueous HCl was added until a pH of 3 was reached. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The organic phase was washed with brine, dried over sodium sulfate, and then concentrated to dryness in vacuo to give the title compound (90 mg, 82%) as a yellow solid.

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[0395] Intermediate 14 tert-Butyl N-[(1R)-2-methyl-1-(methylcarbamoyl)propyl]carbamate To a solution of N-(tert-butoxycarbonyl)-D-valine (1200 mg, 5.52 mmol) in DCM (25 mL) was added DIPEA (2.2 mL, 12.2 mmol) and (1H-benzotriazol-1-yloxy)[tris-(dimethylamino)]phosphonium hexafluorophosphate (2443 mg, 5.52 mmol). Methylamine (2 M, 4.4 mL, 8.84 mmol) was added, and the solution was stirred for 18 h. DCM (25 mL) was added, and the reaction mixture was washed with saturated aqueous NH4Cl (10 mL) and saturated aqueous NaHCO3 (10 mL), then dried over magnesium sulfate. The solvent was removed. The resulting solid was purified by silica column chromatography eluting with 0–50% EtOAc in heptane to give the title compound (1.32 g, 98%) as a white solid.

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[0396] Intermediate 15 (2R)-2-Amino-N,3-dimethylbutanamide trifluoroacetate To a solution of intermediate 14 (300 mg, 1.30 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred for 1 h. The solvent was removed and excess TFA was azeotroped with 1:1 DCM / heptane to give the title compound (containing 50% TFA) (474 ​​mg, 149%) as a pale yellow oil.

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[0397] Intermediate 16 2-[6-(tert-butoxycarbonylamino)-3-chloropyridazin-4-yl]acetic acid ethyl ester HCl in 1,4-dioxane (4 M, 4.6 mL, 18.6 mmol) was added to a solution of intermediate 2 (3.56 g, 12.4 mmol) in ethanol (44.5 mL) at rt. The reaction mixture was stirred at rt for 22 h, then diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (30 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate, then filtered and concentrated to dryness. The residue was purified by silica column chromatography eluting with 10-30% EtOAc in heptane to give the title compound (3.17 g, 81%) as an off-white solid.

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[0398] Intermediate 17 Ethyl 2-[6-(tert-butoxycarbonylamino)-3-chloropyridazin-4-yl]-4,4-difluorobut-2-enoate 1-Ethoxy-2,2-difluoroethanol (90%, 3.0 mL, 24.5 mmol) was added to a solution of intermediate 16 (1.55 g, 4.91 mmol) and triethylamine (2.7 mL, 19.6 mmol) in 1,4-dioxane (10 mL) at rt. The reaction mixture was stirred at 100 °C in a pressure round-bottom flask for 16 h and then concentrated to dryness. The residue was purified by silica column chromatography eluting with 10-20% EtOAc in heptane to give the title compound (1.39 g, 62%) as a yellow gum.

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[0399] Intermediate 18 Ethyl 2-[6-(tert-butoxycarbonylamino)-3-chloropyridazin-4-yl]-4,4-difluorobutanoate Sodium borohydride (27 mg, 0.719 mmol) was added to a solution of Intermediate 17 (255 mg, 0.675 mmol) in DCM (3.5 mL) at −4° C., followed by the addition of ethanol (3.5 mL). The reaction mixture was maintained at −4° C. with stirring for 15 min. Saturated aqueous NH4Cl (30 mL) was added, and the reaction mixture was stirred at −4° C. for 15 min, then diluted with water (30 mL) and DCM (60 mL). The layers were separated, and the aqueous layer was extracted with DCM (2×30 mL). The combined organic phases were filtered through a phase separation filter and then concentrated to dryness under vacuum to give the title compound (261 mg, 83%) as a pale yellow gum.

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[0400] Intermediate 19 Ethyl 2-(6-amino-3-chloropyridazin-4-yl)-4,4-difluorobutanoate TFA (1.1 mL, 14.4 mmol) was added to a solution of Intermediate 18 (281 mg, 0.741 mmol) in DCM (1.1 mL) at rt. The reaction mixture was stirred at rt for 3 h, then diluted with DCM (10 mL) and saturated aqueous NaHCO3 (10 mL) was added. The layers were separated and the aqueous phase was re-extracted with DCM (2 x 10 mL). The organic phase was dried over sodium sulfate and then concentrated to dryness in vacuo to give the title compound (207 mg, 86%) as a tan gum.

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[0401] Intermediate 20 Ethyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-6-chloro-imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate 2,6-Dimethylpyridine (220 μL, 1.89 mmol) was added to a stirred mixture of Intermediate 19 (203 mg, 0.726 mmol) and benzyl N-[(1S)-3-bromo-1-(4,4-difluoro-cyclohexyl)-2-oxopropyl]carbamate (381 mg, 0.944 mmol) in 1,4-dioxane (2.9 mL). The reaction mixture was stirred in a pressure vial at 80 °C for 4 h. The residue was diluted with EtOAc (50 mL), washed with water (20 mL) and brine (10 mL), then dried over sodium sulfate and concentrated to dryness in vacuo. The crude residue was purified by silica column chromatography eluting with 10–100% EtOAc in heptane to afford the title compound (355 mg, 84%) as a tan gum.

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[0402] Intermediate 21 Ethyl 2-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate hydrochloride Intermediate 20 (165 mg, 0.282 mmol) was dissolved in ethanol (7 mL) and 1 M aqueous HCl (1.4 mL, 1.41 mmol). The reaction mixture was cycled between vacuum and nitrogen three times, then 10% Pd / C (50% wet, 120 mg, 0.0564 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere at rt for 3 h and then filtered through a pad of Celite®. The solid was washed with EtOH (50 mL) and EtOAc (50 mL). The combined filtrate was concentrated to dryness and azeotroped in vacuo with toluene (3 × 3 mL) to give the title compound (16 mg, 100%) as a tan solid.

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[0403] Intermediate 22 Ethyl 1-(3,6-dichloropyridazin-4-yl)-4,4-difluorocyclohexanecarboxylate n-Butyllithium in hexane (2.5 M, 7.2 mL, 18.0 mmol) was added dropwise to a stirred solution of dicyclohexylamine (3.6 mL, 18.1 mmol) in anhydrous toluene (24 mL) under nitrogen at 0° C. The resulting white suspension was stirred at 0° C. for 20 minutes, then at 20° C. for 30 minutes, before being cooled to 0° C. Ethyl 4,4-difluorocyclohexane-carboxylate (2.19 mL, 12.53 mmol) was added dropwise. The resulting yellow-orange cloudy suspension was stirred at 0 °C for 15 min, then at 20 °C for 15 min, and then added to a dry flask containing 4-bromo-3,6-dichloropyridazine (95%, 2.50 g, 10.4 mmol) and methanesulfonato(tri-t-butylphosphino)(2'-methylamino-1,1'-biphenyl-2-yl)-palladium(II) [P(t-Bu)3 palladacycle fourth generation] (CAS number 1621274-11-0) (620 mg, 1.06 mmol) under nitrogen. The mixture was stirred at 20 °C under nitrogen for 18 h, then diluted with DCM (50 mL) and quenched with 0.5 M aqueous hydrochloric acid (50 mL). The suspension was filtered through a Celite® pad and washed with DCM (50 mL) and water (30 mL). The organic phase was separated and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic extracts were washed with 0.5 M aqueous hydrochloric acid (50 mL) and brine (50 mL), then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with a gradient of 0 to 30% EtOAc in heptane to afford the title compound (76% pure) (859 mg, 19%) as an orange waxy solid.

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[0404] Intermediate 23 Ethyl 1-[6-(tert-butoxycarbonylamino)-3-chloropyridazin-4-yl]-4,4-difluoro-cyclohexanecarboxylate Intermediate 22 (79%, 900 mg, 2.10 mmol), tert-butyl carbamate (296.5 mg, 2.53 mmol), and cesium carbonate (972 mg, 1.59 mmol) were suspended in anhydrous 1,4-dioxane (10.6 mL) and purged with nitrogen while sonicating for 5 minutes. Tris-(dibenzylideneacetone)dipalladium(0) (77.4 mg, 84.5 μmol) and Xantphos (97.2 mg, 0.17 mmol) were added. The mixture was purged with nitrogen while sonicating for 5 minutes, then sealed under nitrogen, heated at 90 °C for 18 h, and diluted with EtOAc (20 mL). The solids were removed by filtration through Celite® and washing with EtOAc (3 × 30 mL). The filtrate was concentrated in vacuo. The residue was purified by silica column chromatography eluting with a gradient of 0-40% EtOAc in heptane to afford the title compound (91% pure) (597 mg, 62%) as a tan powder.

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[0405] Intermediate 24 Ethyl 1-(6-amino-3-chloropyridazin-4-yl)-4,4-difluorocyclohexanecarboxylate TFA (2 mL, 26.9 mmol) was added to a stirred solution of Intermediate 23 (91%, 615 mg, 1.33 mmol) in DCM (14 mL). The reaction mixture was stirred at 20° C. for 4 h, then quenched with saturated aqueous sodium bicarbonate (30 mL) and diluted with DCM (30 mL). The biphasic mixture was stirred at 20° C. for 5 min, then the organic phase was separated and washed with saturated aqueous sodium bicarbonate (20 mL). The combined aqueous washes were extracted with DCM (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, and then concentrated in vacuo to afford the title compound (90% pure) (474 ​​mg, 100%) as an orange-yellow powder.

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[0406] Intermediate 25 Ethyl 1-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]-6-chloro-imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorocyclohexanecarboxylate A suspension of Intermediate 24 (90%, 474 mg, 1.33 mmol), benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (639 mg, 1.58 mmol), and sodium bicarbonate (247 mg, 2.94 mmol) in IPA (7.3 mL) was sealed under nitrogen and heated at 65 °C for 18 h. After cooling, the mixture was diluted with water (30 mL) and saturated aqueous sodium bicarbonate (10 mL) and then extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with a gradient of 5–60% EtOAc in heptane to afford the title compound (90% pure) (788 mg, 85%) as an orange viscous oil.

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[0407] Intermediate 26 Ethyl 1-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorocyclohexanecarboxylate hydrochloride A suspension of Intermediate 25 (90%, 788 mg, 1.13 mmol) and 10% palladium on carbon (50% water-wet, 188 mg, 0.09 mmol) in 4:1 EtOH / water (17.5 mL) was placed under a hydrogen atmosphere and stirred for 18 h at 20° C. The reaction mixture was filtered through Celite®, washed with EtOH (5×50 mL), and then concentrated in vacuo to afford the title compound (95% pure) (536 mg, 91%) as a tan powder.

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[0408] Intermediate 27 Ethyl 1-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}imidazo[1,2-b]pyridazin-7-yl)-4,4-difluorocyclohexanecarboxylate HATU (400 mg, 1.05 mmol) was added to a stirred solution of Intermediate 26 (95%, 400 mg, 0.77 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (124 mg, 0.97 mmol), and DIPEA (0.35 mL, 2.00 mmol) in anhydrous DMF (4 mL). The reaction mixture was stirred at 20 °C under nitrogen for 18 h, then quenched with saturated aqueous sodium bicarbonate (10 mL) and diluted with water (10 mL). The material was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed successively with 0.5 M aqueous hydrochloric acid / brine (1:1, 20 mL) and water / brine (1:1, 3 × 20 mL). The organic phase was dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with a gradient of 0-60% EtOAc in heptane to afford the title compound (93% pure) (321 mg, 68%) as an off-white powder.

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[0409] Intermediate 28 1-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-methyl}imidazo[1,2-b]pyridazin-7-yl)-4,4-difluorocyclohexanecarboxylic acid Aqueous lithium hydroxide (1 M, 2.8 mL, 2.8 mmol) was added to a stirred solution of Intermediate 27 (93%, 320 mg, 0.53 mmol) in MeOH (11 mL). The mixture was heated at 50° C. for 24 h. After cooling, the volatiles were removed in vacuo and the aqueous residue was diluted with water (30 mL). The pH was adjusted to pH 1 with 1 M aqueous hydrochloric acid and the material was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, then filtered and concentrated in vacuo to afford the title compound (92% pure) (330 mg, quantitative) as an off-white powder.

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[0410] Intermediate 29 Methyl 2-[6-(tert-butoxycarbonylamino)pyridazin-4-yl]-4,4-difluorobutanoate To a solution of intermediate 4 (2.20 g, 6.05 mmol) in ethanol (60 mL) under N was added 10% palladium on carbon (220 mg, 0.207 mmol). The reaction flask was placed under an atmosphere of H and the reaction mixture was stirred at rt for 20 h, then filtered through a pad of Celite® and concentrated in vacuo. The crude material was purified by flash column chromatography eluting with a gradient of 0 to 50% EtOAc in isohexane to afford the title compound (278 mg, 14%) as a colorless amorphous solid.

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[0411] Intermediate 30 Methyl 2-(6-aminopyridazin-4-yl)-4,4-difluorobutanoate To a solution of intermediate 29 (345 mg, 1.04 mmol) in DCM (4.2 mL) was added TFA (4.2 mL). The reaction mixture was heated at 40° C. for 30 minutes and then concentrated in vacuo. The residue was dissolved in DCM (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were passed through a phase separator and then concentrated in vacuo to give the title compound (157 mg, 65%) as an off-white amorphous solid.

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[0412] Intermediate 31 Methyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate To a solution of Intermediate 30 (150 mg, 0.649 mmol) and benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (315 mg, 0.779 mmol) in IPA (3.2 mL) was added sodium bicarbonate (82 mg, 0.98 mmol). The reaction mixture was stirred at 80 °C overnight and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL). The organic layer was washed with water (20 mL) and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0 to 80% EtOAc in isohexane to afford the title compound (151 mg, 43%) as an off-white amorphous solid.

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[0413] Intermediate 32 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]-pyridazin-7-yl}-4,4-difluorobutanoic acid To a solution of intermediate 31 (151 mg, 0.281 mmol) in THF (1.2 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (24 mg, 0.56 mmol). The reaction mixture was stirred at 40° C. for 1 h, then neutralized with 2 M aqueous hydrochloric acid (0.28 mL) and concentrated in vacuo to give the title compound (146 mg, 99%) as a yellow amorphous solid.

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[0414] Intermediate 33 Benzyl N-{(S)-(4,4-difluorocyclohexyl)[7-(3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl)imidazo[1,2-b]pyridazin-2-yl]methyl}carbamate To a solution of Intermediate 32 (146 mg, 0.279 mmol), (S)-2-amino-1,1,1-trifluoropropane hydrochloride (53 mg, 0.34 mmol), and DIPEA (0.15 mL, 0.84 mmol) in DMF (2.8 mL) was added HATU (131 mg, 0.335 mmol). The reaction mixture was stirred at rt for 10 min and then concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (2 × 20 mL), and the combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0–60% EtOAc in isohexane to afford the title compound (176 mg, 98%) as an off-white amorphous solid.

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[0415] Intermediate 34 2-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]butanamide To a solution of intermediate 33 (176 mg, 0.274 mmol) in ethanol (2.7 mL) under N was added 10% palladium on carbon (88 mg, 0.08 mmol). The reaction flask was placed under an atmosphere of H and the reaction mixture was stirred at rt for 3 h, then filtered through a pad of Celite® and concentrated in vacuo to give the title compound (109 mg, 82%) as a green oil.

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[0416] Intermediate 35 5-(Dicyclopropylmethyl)imidazolidine-2,4-dione A stirred mixture of diammonium carbonate (47.10 g, 0.501 mol), 2,2-dicyclopropylacetaldehyde (95%, 26.10 g, 0.200 mol), and potassium cyanide (13.09 g, 0.201 mol) in a mixture of ethanol (140 mL) and water (140 mL) was heated at 60° C. for 18 h. To the cooled reaction mixture, 2 N HCl (200 mL) was added in portions, followed by 6 N HCl (100 mL). Additional 2 N HCl (60 mL) was added, and the mixture was stirred at rt for 1 h. Additional 2 N HCl (50 mL) was added to the mixture, and the solid was filtered off, washed with water (2×200 mL), and dried to give the title compound (95% pure) (32.81 g, 80%) as a white solid.

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[0417] Intermediate 36 2-(benzyloxycarbonylamino)-3,3-dicyclopropylpropanoic acid To a stirred solution of Intermediate 35 (95%, 1.00 g, 4.89 mmol) in 1,4-dioxane (6 mL) was added 5 M aqueous sodium hydroxide (6.0 mL, 30.0 mmol). The mixture was heated at 100° C. for 18 h, then 1,4-dioxane (6 mL) and water (6 mL) were added, and the mixture was heated at 120° C. for 2 days. To the cooled reaction mixture, TBME (10 mL) and water (10 mL) were added. The biphasic mixture was filtered. To the filtrate, 6 N HCl (6 mL) and TBME (10 mL) were added. The undissolved solid was filtered off. To the filtrate, TBME (10 mL) was added. The layers were separated, and the aqueous layer was washed with TBME (3×10 mL). To the aqueous layer, 5 N aqueous NaOH (0.5 mL) was added, and the pH of the solution was adjusted to pH 7 using 6 N HCl / 5 N aqueous NaOH. To the aqueous solution (approximately 40 mL) was added THF (20 mL), followed by NaHCO (1.01 g), followed by disodium carbonate (1.01 g, 9.53 mmol), followed by 1-(benzyloxycarbonyloxy)pyrrolidine-2,5-dione (0.90 g, 3.61 mmol) at rt. The mixture was stirred at rt for 2.5 days, then TBME (20 mL) was added, followed by water (30 mL). The organic layer was separated. Water (10 mL) was added to the aqueous layer. The aqueous layer was washed with TBME (10 mL), then filtered and washed with TBME (10 mL). The pH of the aqueous layer was adjusted to pH 3 using 6 N HCl (approximately 4 mL). Seeded with crystals from the previous batch, the flask was then cooled externally and left for 2 h. The contents were filtered off, then washed with water (2×10 mL) and dried to give the title compound (719 mg, 49%) as a white solid.

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[0418] Intermediate 37 tert-Butyl 4-(benzyloxycarbonylamino)-5,5-dicyclopropyl-3-oxopentanoate Intermediate 36 (1.00 g, 3.30 mmol) was dissolved in anhydrous THF (12 mL) under nitrogen, and DIPEA (650 μL, 3.72 mmol) was added, followed by HATU (1.40 g, 3.68 mmol). The mixture was stirred under nitrogen for 1.5 h. In a separate flask, a solution of LDA in THF / heptane / ethylbenzene (2 M, 7.0 mL, 14.0 mmol) and anhydrous THF (10 mL) was placed under nitrogen and cooled to −78° C. tert-Butyl acetate (1.9 mL, 14.2 mmol) was added dropwise over approximately 5 minutes. The resulting solution was stirred under nitrogen at −78° C. for 1 h, then a separate solution of activated acid was added dropwise, maintaining the internal temperature below −60° C. The resulting mixture was stirred under nitrogen at −78° C. for 1 h, then quenched at −78° C. by the addition of saturated aqueous NH4Cl (50 mL). The mixture was warmed to rt and then extracted with EtOAc (100 mL). The organic layer was washed with brine (50 mL), then dried (NaSO) and concentrated to dryness in vacuo. The residue was purified by flash column chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound (85% pure) (1.15 g, 74%) as a pale yellow oil.

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[0419] Intermediate 38 Benzyl N-[3-bromo-1-(dicyclopropylmethyl)-2-oxopropyl]carbamate Intermediate 37 (85%, 1.15 g, 2.43 mmol) was dissolved in methanol (5 mL) and 2,6-dimethylpyridine (30 μL, 0.258 mmol) was added, followed by NBS (440 mg, 2.47 mmol). The reaction mixture was stirred under nitrogen for 18 h, diluted with EtOAc (50 mL), washed with a 50% mixture of water and brine (2 × 40 mL), washed with brine (20 mL), then dried (NaSO) and concentrated to dryness in vacuo. The residue was dissolved in toluene (11 mL) and TFA (1.4 mL, 18.8 mmol) was added. The reaction mixture was stirred under nitrogen at 80 °C for 2.5 h, then cooled to rt and concentrated to dryness in vacuo. The residue was purified by flash column chromatography eluting with 30-100% DCM in heptane followed by 0-100% EtOAc in DCM to give the title compound (87% pure) (780 mg, 73%) as a colorless solid.

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[0420] Intermediate 39 Ethyl 2-{2-[1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]-6-chloroimidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate Intermediate 19 (365 mg, 1.305 mmol) and Intermediate 38 (90%, 606.6 mg, 1.435 mmol) were dissolved in dry THF (10 mL) and sodium bicarbonate (328.9 mg, 3.915 mmol) was added. The reaction mixture was heated with stirring at 70 °C for 18 h and then cooled to rt. The resulting solid was filtered off and washed with DCM. The filtrate was concentrated in vacuo. The material was purified by silica column chromatography eluting with a gradient of 0 to 40% ethyl acetate in heptane to afford the title compound (566 mg, 77%) as a yellow / orange foam.

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[0421] Intermediate 40 Ethyl 2-{2-[(1S)-1-amino-2,2-dicyclopropylethyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate hydrochloride Intermediate 39 (275 mg, 0.490 mmol) was dissolved in EtOH (15 mL) and 1 M aqueous HCl (2.45 mL, 2.450 mmol) was added, followed by the addition of 10% Pd / C (50% wet) (5.0%, 52.16 mg, 0.0245 mmol). The reaction mixture was stirred under 1 atmosphere of H for 3 h, then filtered through Celite® and concentrated in vacuo to remove the solvent. The residue was azeotroped in vacuo with toluene (3 × 3 mL) to give the title compound (190 mg, 90%) as a yellow solid.

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[0422] Intermediate 41 Ethyl 2-(2-{(1S)-2,2-dicyclopropyl-1-[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]-ethyl}imidazo[1,2-b]pyridazin-7-yl)-4,4-difluorobutanoate Intermediate 40 (190 mg, 0.443 mmol) and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (68 mg, 0.531 mmol) were stirred in anhydrous DMF (3 mL). DIPEA (232 μL, 1.329 mmol) was added, followed by HATU (202 mg, 0.531 mmol). The mixture was stirred at rt for 3 h, then diluted with EtOAc (30 mL) and washed with water (3 × 20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude residue was purified by flash column chromatography eluting with a gradient of 0 to 40% ethyl acetate in heptane to afford the title compound (156 mg, 71%) as a yellow solid.

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[0423] Intermediate 42 2-(2-{(1S)-2,2-dicyclopropyl-1-[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]ethyl}-imidazo[1,2-b]pyridazin-7-yl)-4,4-difluorobutanoic acid A mixture of lithium hydroxide monohydrate (29 mg, 0.679 mmol) and Intermediate 41 (155 mg, 0.308 mmol) in THF (4 mL), water (0.6 mL), and methanol (1.5 mL) was stirred at rt for 16 h. The reaction mixture was concentrated to a low volume in vacuo and then diluted with ethyl acetate (50 mL). Aqueous HCl (0.5 M) was added until a pH of 3 was reached. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The organic phase was washed with brine, dried over sodium sulfate, then filtered and concentrated to dryness in vacuo to give the title compound (142 mg, 97%) as a yellow solid.

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[0424] Intermediate 43 Lithium 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-4,4-difluorobutanoate A mixture of lithium hydroxide monohydrate (56 mg, 1.29 mmol) and Intermediate 58 (324 mg, 0.589 mmol) in THF (7 mL), water (1.5 mL), and methanol (3 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to dryness in vacuo, redissolved in toluene (5 mL), and reconcentrated in vacuo. The residue was redissolved in toluene (5 mL) and reconcentrated to dryness in vacuo twice more to give the title compound (311 mg, 95%) as a yellow solid.

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[0425] Intermediate 44 Benzyl N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]carbamate HATU (671 mg, 1.77 mmol) was added to a mixture of intermediate 43 (311 mg, 0.589 mmol) and DIPEA (308 μL, 1.77 mmol) in anhydrous DMF (8 mL) at rt. The reaction mixture was stirred at rt for 5 min, and then 2,2,2-trifluoroethanamine (139 μL, 1.77 mmol) was added. The reaction mixture was stirred at rt for 16 h, then diluted with EtOAc (50 mL) and washed with water (3 × 60 mL). The organic phase was dried over sodium sulfate, then filtered and concentrated to dryness. The resulting crude material was purified by FCC (Biotage Isolera, SiO, gradient elution 10–60% EtOAc:heptane) to afford the title compound (246 mg, 68%) as a yellow gum.

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[0426] Intermediate 45 Benzyl N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethyl-carbamothioyl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]carbamate Lawesson's reagent (85 mg, 0.210 mmol) was added to a solution of intermediate 44 (211 mg, 0.350 mmol) in anhydrous 1,4-dioxane (2 mL) under nitrogen. The reaction mixture was stirred at 90 °C for 22 h, then diluted with EtOAc (60 mL) and washed with saturated aqueous NaHCO (20 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, then filtered and concentrated to dryness in vacuo. The resulting crude material was purified by FCC (Biotage Isolera, gradient elution 10-60% EtOAc:heptane) to afford the title compound (154 mg, 71%) as a tan gum.

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[0427] Intermediate 46 Benzyl N-[(S)-(4,4-difluorocyclohexyl)(7-{3,3-difluoro-1-[1-(2,2,2-trifluoroethyl)-tetrazol-5-yl]propyl}imidazo[1,2-b]pyridazin-2-yl)methyl]carbamate Triphenylphosphine (98 mg, 0.373 mmol) was added to a solution of Intermediate 45 (154 mg, 0.249 mmol), DIAD (73 μL, 0.373 mmol), and azido(trimethyl)silane (98 μL, 0.746 mmol) in anhydrous THF (0.8 mL) at rt. The reaction mixture was stirred at rt for 3 days, then diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO. The aqueous phase was re-extracted with EtOAc (3 × 30 mL). The organic phase was dried over sodium sulfate, then filtered and concentrated to dryness in vacuo. The resulting crude material was purified by FCC (Biotage Isolera, SiO, gradient elution 10–50% EtOAc:heptane) to afford the title compound (122 mg, 62%) as a tan gum.

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[0428] Intermediate 47 (S)-(4,4-Difluorocyclohexyl)(7-{3,3-difluoro-1-[1-(2,2,2-trifluoroethyl)tetrazol-5-yl]-propyl}imidazo[1,2-b]pyridazin-2-yl)methanamine Intermediate 46 (122 mg, 0.194 mmol) was dissolved in EtOH (14 mL) and water (1.4 mL). The reaction mixture was cycled between vacuum and nitrogen three times, then palladium on carbon (10% loading, 50% water) (5.0%, 83 mg, 0.0388 mmol) was added. The reaction mixture was cycled between vacuum and hydrogen three times, then stirred under a hydrogen atmosphere at rt for 22 h. The reaction vessel was purged of hydrogen by cycling between vacuum and nitrogen three times. The reaction mixture was filtered through a pad of Celite®, and the solid was washed with EtOH (3 × 30 mL). The combined filtrate was concentrated to dryness and then azeotroped with toluene (3 × 3 mL) under vacuum to afford the title compound (96 mg, 100%) as a light tan gum.

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[0429] Intermediate 48 Benzyl N-[(S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl]-carbamate A solution of benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (1.65 g, 4.08 mmol), 5-chloropyridazin-3-amine trifluoroacetate (900 mg, 3.670 mmol), and sodium bicarbonate (650 mg, 7.74 mmol) in 2-propanol (40 mL) was stirred at 80 °C for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 to 35% EtOAc in isohexane and then lyophilized from water / acetonitrile to give the title compound (758 mg, 47%) as a pale powder.

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[0430] Intermediate 49 O 1 -tert-Butyl O 3-Ethyl 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)-methyl]imidazo[1,2-b]pyridazin-7-yl}-2,5-dihydropyrrole-1,3-dicarboxylate Bis(pinacolato)diboron (370 mg, 1.46 mmol), potassium acetate (325 mg, 3.28 mmol), tris(dibenzylideneacteon)dipalladium(0) (120 mg, 0.13 mmol), XPhos (130 mg, 0.26 mmol), and O 1 -tert-Butyl O 3 -ethyl 4-(trifluoromethylsulfonyloxy)-2,5-dihydro-pyrrole-1,3-dicarboxylate (WO 2020 / 261141, Intermediate 4) (513 mg, 1.3 mmol) was placed in a vial, followed by anhydrous 1,4-dioxane (2.6 mL). The reaction mixture was thoroughly degassed and then heated at 100° C. for 2 h. Intermediate 48 (460 mg, 1.06 mmol) was added, followed by a solution of potassium phosphate tribasic (425 mg, 2.00 mmol) in water (1.1 mL). The mixture was again degassed and heated at 90° C. for 1 h, then diluted with EtOAc (50 mL) and washed with water (2×50 mL). The aqueous layer was re-extracted with EtOAc (50 mL). The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0-100% EtOAc in isohexane, then freeze-dried from water / acetonitrile to give the title compound (486 mg, 72%) as a pale yellow solid.

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[0431] Intermediate 50 Lithium 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-1-(tert-butoxycarbonyl)-2,5-dihydropyrrole-3-carboxylate To a stirred solution of intermediate 49 in EtOH (9 mL) was added lithium hydroxide monohydrate (67 mg, 1.60 mmol) in water (3 mL). After 5 h, the reaction mixture was concentrated in vacuo and then lyophilized from water / acetonitrile to give the title compound (489 mg, quantitative) as a yellow solid.

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[0432] Intermediate 51 tert-Butyl 3-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo-[1,2-b]pyridazin-7-yl}-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)-2,5-dihydropyrrole-1-carboxylate To a solution of intermediate 50 (473 mg, 0.77 mmol) in DMF (2.60 mL) and DIPEA (0.53 mL, 3.0 mmol) was added 3,3,4,4-tetrafluoropyrrolidine hydrochloride (167 mg, 0.93 mmol), followed by HATU (328 mg, 0.85 mmol). The mixture was stirred for 2 h and then diluted with saturated aqueous sodium bicarbonate (30 mL) and DCM (30 mL). The organic layer was separated, and the aqueous layer was re-extracted with DCM (3 × 30 mL). The combined organic layers were dried and concentrated. The residue was purified by flash column chromatography eluting with a gradient of 0 to 100% EtOAc in isohexane, followed by lyophilization from water / acetonitrile to give the title compound (475 mg, 84%) as a pale yellow solid.

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[0433] Intermediate 52 tert-Butyl (3RS,4RS)-3-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]-pyridazin-7-yl}-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate To a stirred solution of intermediate 51 (280 mg, 0.38 mmol) in EtOH (4 mL) was added palladium hydroxide on carbon (30 mg, 0.043 mmol) and ammonium formate (481 mg, 7.63 mmol). The reaction mixture was thoroughly degassed and then placed under a hydrogen atmosphere for 18 h. An additional portion of palladium hydroxide on carbon (26 mg) was added. The reaction mixture was degassed and placed under a hydrogen atmosphere for 36 h, then filtered through Celite® and concentrated in vacuo. The residue was dissolved in DCM (10 mL) and washed with 1.5 M aqueous sodium carbonate solution (10 mL). The aqueous layer was re-extracted with DCM (10 mL). The combined organic extracts were passed through a phase separator and then concentrated in vacuo to give the title compound (mixture of pyrrolidine cis isomers) (230 mg, quantitative) as a black foam.

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[0434] Intermediate 53 tert-Butyl (3RS,4RS)-3-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}imidazo[1,2-b]pyridazin-7-yl)-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate To a solution of intermediate 52 (230 mg, 0.38 mmol) in DMF (3.2 mL) and DIPEA (0.20 mL, 1.1 mmol) was added 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (65 mg, 0.48 mmol), followed by HATU (189 mg, 0.48 mmol). The reaction mixture was stirred for 1.5 h, then diluted with water (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0 to 100% EtOAc in isohexane and then lyophilized from water / acetonitrile to give the title compound (mixture of pyrrolidine cis isomers) (171 mg, 44%) as an off-white solid.

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[0435] Intermediate 54 N-[(S)-(4,4-Difluorocyclohexyl){7-[(3RS,4RS)-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidin-3-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 53 (75 mg, 0.10 mmol) in DCM (2 mL) was added 4 M HCl in 1,4-dioxane (2 mL). The reaction mixture was stirred for 1.5 h and then concentrated in vacuo. The residue was partitioned between EtOAc (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the aqueous layer was re-extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried, concentrated in vacuo, and then lyophilized from water / acetonitrile to give the title compound (mixture of pyrrolidine cis isomers) (63.3 mg, 98%) as an off-white solid.

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[0436] Intermediate 55 tert-Butyl 2-(6-aminopyridazin-4-yl)-4,4-difluoropiperidine-1-carboxylate A solution of 5-chloropyridazin-3-amine (300 mg, 2.31 mmol), 1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (920 mg, 3.47 mmol), {Ir[dF(CF3)ppy]2(dtbpy)}PF6 (50.0 mg, 44.6 μmol), nickel(II) chloride ethylene glycol dimethyl ether complex (50.0 mg, 0.228 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (93.0 mg, 0.346 mmol), and cesium carbonate (1.13 g, 3.47 mmol) in DMF (25 mL) was purged with nitrogen gas for 5 min and then irradiated under a 450 nm LED for 72 h. The solvent was removed under reduced pressure. The residue was purified by silica column chromatography eluting with 0-20% MeOH in EtOAc to give the crude title compound (440 mg, 60%) as an orange solid which was used without further purification.

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[0437] Intermediate 56 tert-Butyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo-[1,2-b]pyridazin-7-yl}-4,4-difluoropiperidine-1-carboxylate A solution of intermediate 55 (430 mg, 1.37 mmol), benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (660 mg, 1.63 mmol), and sodium bicarbonate (140 mg, 1.66 mmol) in 2-propanol (15 mL) was stirred overnight at 80° C. The reaction mixture was concentrated and the residue was purified by silica column chromatography eluting with 0 to 40% EtOAc in hexane to give the title compound (86 mg, 7%) as an orange solid.

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[0438] Intermediate 57 tert-Butyl 2-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2-b]pyridazin-7-yl)-4,4-difluoropiperidine-1-carboxylate A mixture of intermediate 56 (87.0 mg, 98 μmol), hydrogen chloride in 1,4-dioxane (4.0 M, 70.0 μL, 0.28 mmol), and palladium on carbon (10% w / w loading, 20.0 mg) in ethanol (5 mL) was stirred at rt for 5 h under a hydrogen atmosphere. The reaction mixture was filtered and washed with ethanol (5 mL). The filtrate was concentrated. The residue was combined with HATU (47.0 mg, 0.12 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (16.0 mg, 0.12 mmol), and DIPEA (0.10 mL, 0.60 mmol) and suspended in DMF (1.0 mL). The mixture was stirred at rt for 2 h, and then the solvent was removed under reduced pressure. The residue was purified by silica column chromatography eluting with 0-40% EtOAc in hexanes to give the title compound (46 mg, 78%) as a yellow oil.

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[0439] Intermediate 58 Ethyl 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]-pyridazin-7-yl}-4,4-difluorobutanoate To a solution of Intermediate 21 (2.80 g, 6.17 mmol) and triethylamine (2.58 mL, 18.5 mmol) in DCM (62 mL) was added N-(benzyloxycarbonyloxy)succinimide (1.90 g, 7.41 mmol). The reaction mixture was stirred at rt for 10 min, then diluted with DCM (40 mL) and washed with water (100 mL). The aqueous layer was diluted with DCM (2 × 50 mL) and the combined organic extracts were washed with brine (100 mL). The organic layer was passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0–60% EtOAc in isohexane to afford the title compound (3.13 g, 92%) as an off-white amorphous solid.

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[0440] Intermediate 59 2-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]-pyridazin-7-yl}-4,4-difluorobutanoic acid To a solution of intermediate 58 (1.20 g, 2.18 mmol) in THF (8.8 mL) and water (2.2 mL) was added lithium hydroxide monohydrate (186 mg, 4.36 mmol). The reaction mixture was warmed to 40° C. and stirred for 3.5 h, then neutralized with aqueous HCl (2 M, 2.2 mL) and concentrated in vacuo to give the title compound (1.32 g, 116%) as a yellow amorphous solid.

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[0441] Intermediate 60 Benzyl N-{(S)-(4,4-difluorocyclohexyl)[7-(3,3-difluoro-1-{[(5-fluoropyridin-2-yl)-amino]carbamoyl}propyl)imidazo[1,2-b]pyridazin-2-yl]methyl}carbamate To a solution of intermediate 59 (1.14 g, 2.18 mmol) in EtOAc (21.8 mL) was added pyridine (0.88 mL, 10.9 mmol), followed by T3P® solution (1.68 mol / L, 5.45 mmol in 3.24 mL of EtOAc). The mixture was stirred for 5 minutes, and then (5-fluoropyridin-2-yl)-hydrazine (339 mg, 2.62 mmol) was added. The reaction mixture was warmed to 40° C., stirred for 5 minutes, and then cooled to rt. A small amount of ice chips was added, and the mixture was stirred for another 5 minutes. EtOAc (50 mL) was added, and the organic layer was washed with water (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0 to 100% EtOAc in isohexane to afford the title compound (755 mg, 55%) as an orange amorphous solid.

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[0442] Intermediate 61 Benzyl N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]carbamate To a solution of intermediate 60 (750 mg, 1.19 mmol) in THF (3 mL) at 0 °C was added triethylamine (0.66 mL, 4.75 mmol), followed by triphenylphosphine (623 mg, 2.38 mmol) and hexachloroethane (568 mg, 2.38 mmol). The reaction mixture was warmed to 40 °C and stirred for 1.5 h, then diluted with EtOAc (40 mL) and washed with water (40 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0 to 100% EtOAc in isohexane to afford the title compound (706 mg, 97%) as an off-white amorphous solid.

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[0443] Intermediate 62 (S)-(4,4-Difluorocyclohexyl){7-[3,3-difluoro-1-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propyl]imidazo[1,2-b]pyridazin-2-yl}methanamine To a solution of intermediate 61 (700 mg, 1.14 mmol) in DCM (11.4 mL) at 0 °C was added boron tribromide solution (1.0 M in DCM) (2.28 mL, 2.28 mmol) dropwise. The reaction mixture was warmed to rt and stirred for 1.5 h, then quenched with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0–20% MeOH in DCM to afford the title compound (361 mg, 66%) as a colorless amorphous solid.

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[0444] Intermediate 63 tert-Butyl N-(5-chloropyridazin-3-yl)carbamate To a nitrogen-degassed mixture of 3,5-dichloropyridazine (60.00 g, 0.403 mol), tert-butyl carbamate (48.63 g, 0.415 mol), cesium carbonate (266 g, 0.819 mol), and Xantphos (23.51 g, 40.6 mmol) in dry 1,4-dioxane (0.6 L) was added palladium(II) acetate (4.60 g, 20.5 mmol). The reaction mixture was further degassed and then heated at 80 °C for 18 h. The cooled reaction mixture was filtered through Celite® and rinsed with 1,4-dioxane (4 × 150 mL). The filtrate was concentrated in vacuo, followed by the addition of DCM (0.25 L), water (0.25 L), and brine (0.25 L). The biphasic system was filtered through glass fiber paper, and the organic layer was retained. The aqueous layer was re-extracted with DCM (100 mL). The organic layers were combined and dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and purified by dry flash chromatography eluting with 0 to 30% EtOAc in heptane to afford the title compound (37.8 g, 41%) as an off-white solid.

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[0445] Intermediate 64 Methyl 4-[6-(tert-butoxycarbonylamino)pyridazin-4-yl]tetrahydropyran-4-carboxylate A solution of methyl tetrahydropyran-4-carboxylate (0.51 mL, 3.8 mmol) and Intermediate 63 (0.44 g, 1.92 mmol) in THF (10 mL) was added dropwise to lithium bis(trimethylsilyl)amide (1.0 M in toluene) (5.8 mL, 5.8 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 3 h and then at rt for an additional 2 h, then quenched by the addition of saturated aqueous NH4Cl (50 mL) and DCM (40 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with a gradient of 0–100% EtOAc in hexanes to afford the title compound (350 mg, 54%) as a white solid.

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[0446] Intermediate 65 Methyl 4-(6-aminopyridazin-4-yl)tetrahydropyran-4-carboxylate To a solution of intermediate 64 (341 mg, 1.01 mmol) in DCM (5 mL) was added TFA (2.5 mL). The reaction mixture was stirred at rt for 1 h, then concentrated in vacuo and diluted with DCM (20 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (20 mL), and the aqueous layer was back-extracted with a mixture of MeOH in DCM (2%, 2 × 20 mL). The combined organic extracts were passed through a phase separator and then concentrated in vacuo to give the title compound (250 mg) as a colorless amorphous solid, which was used without further purification.

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[0447] Intermediate 66 Methyl 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}tetrahydropyran-4-carboxylate To a mixture of Intermediate 65 (240 mg, 1.01 mmol), benzyl N-[(1S)-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]carbamate (613 mg, 1.52 mmol), and sodium bicarbonate (170 mg, 2.02 mmol) was added 2-propanol (5 mL). The reaction mixture was stirred at 80 °C overnight and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (2 × 20 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, 25 g, Isolera) eluting with a gradient of 0 to 80% EtOAc in isohexane to afford the title compound (304 mg, 53%) as an orange solid.

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[0448] Intermediate 67 Lithium 4-{2-[(S)-benzyloxycarbonylamino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}tetrahydropyran-4-carboxylate Intermediate 66 (300 mg, 0.53 mmol) was dissolved in THF (2 mL) and treated with lithium hydroxide monohydrate (53 mg, 1.24 mmol) dissolved in water (1 mL). MeOH (1 mL) was added to aid dissolution. The mixture was stirred overnight and then evaporated in vacuo to give the title compound (304 mg, 92%) as a white solid, which was used without further purification.

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[0449] Intermediate 68 Benzyl N-[(S)-(4,4-difluorocyclohexyl){7-[4-(2,2-difluoropropylcarbamoyl)-tetrahydropyran-4-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]carbamate Intermediate 67 (302 mg, 0.535 mmol) and 2,2-difluoropropylamine hydrochloride (82 mg, 0.59 mmol) were suspended in DCM (10 mL) and treated with DIPEA (3 mL, 17.2 mmol). The mixture was stirred for 1 min, then HATU (218 mg, 0.562 mmol) was added. DMF (1 mL) was added to aid dissolution. The mixture was left stirring overnight, then partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was washed with brine (3 × 20 mL), then passed through a hydrophobic frit and evaporated in vacuo. The brown gum was purified by silica column chromatography eluting with a 0-100% gradient of EtOAc in DCM to give the title compound (250 mg, 73%).

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[0450] Intermediate 69 4-{2-[(S)-amino(4,4-difluorocyclohexyl)methyl]imidazo[1,2-b]pyridazin-7-yl}-N-(2,2-difluoropropyl)tetrahydropyran-4-carboxamide Intermediate 68 (245 mg, 0.397 mmol) was dissolved in ethanol (10 mL) and degassed with nitrogen. Palladium on carbon (50 mg, 0.047 mmol) was added. The reaction mixture was placed under an atmosphere of hydrogen gas and stirred at rt for 24 h, then filtered through Celite®, washed with DCM, and evaporated in vacuo to give the title compound (200 mg, 97%) as a pale gray solid.

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[0451] Example 1 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of 2-chloro-1-methylpyridinium iodide (21 mg, 0.0809 mmol) in DMA (0.2 mL) was added DIPEA (0.055 mL, 0.311 mmol) and 2,2,2-trifluoroethanamine (0.0074 mL, 0.0933 mmol). Intermediate 13 (31 mg, 0.0622 mmol) in DMA was added. The reaction mixture was heated at 50 °C for 18 h, then cooled and diluted with EtOAc (10 mL), water (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The resulting brown oil was purified by silica column chromatography, eluting with 0–50% EtOAc in heptane, to afford the title compound (19 mg, 53%) as a light brown gum.

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[0452] Example 2 [ka] N-{(S)-(4,4-Difluorocyclohexyl)[7-(3,3-difluoro-1-{[(1R)-2-methyl-1-(methylcarbamoyl)-propyl]carbamoyl}propyl)imidazo[1,2-b]pyridazin-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 13 (40 mg, 0.0803 mmol) in DMF (1 mL) was added DIPEA (70 μL, 0.401 mmol), intermediate 15 (89 mg, 0.241 mmol), and HATU (37 mg, 0.0963 mmol). The reaction mixture was stirred for 18 h, then diluted with water (10 mL) and extracted with EtOAc (25 mL). The organic layer was washed with water (3 × 10 mL), dried over magnesium sulfate, and the solvent was removed. The resulting oil was purified by silica column chromatography eluting with 0–70% EtOAc in heptane to afford the title compound (30 mg, 61%) as a white solid.

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[0453] Examples 3A and 3B [ka] N-[(S)-{7-[(1R)-1-{[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3,3-difluoro-propyl]imidazo[1,2-b]pyridazin-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-{7-[(1S)-1-{[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3,3-difluoro-propyl]imidazo[1,2-b]pyridazin-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 13 (94 mg, 0.188 mmol) in DMA (1 mL) was added to a solution of 2-chloro-1-methylpyridinium iodide (63 mg, 0.244 mmol), (1S)-1-cyclopropyl-2,2,2-trifluoroethanamine (31 mg, 0.225 mmol), and DIPEA (164 μL, 0.939 mmol) in DMA (1 mL). The reaction mixture was heated in a sealed tube at 50 °C for 1 h, then diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography eluting with a gradient of 0 to 100% ethyl acetate in heptane, followed by reverse-phase column chromatography eluting with 5 to 100% aqueous acetonitrile containing 0.1% formic acid, followed by preparative HPLC (Method 9). The stereoisomers were separated by chiral HPLC (Chiralcel OD-H, 20 × 250 mm, 5 μm, eluting with 95% heptane and 5% IPA at 18 mL / min) to give the title compounds (peak 1, 13 mg, 11%; and peak 2, 22 mg, 19%) as white solids. Peak 1:

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[0454] General method 1 Intermediate 11 (72 mg, 0.153 mmol) and the specific carboxylic acid derivative (0.169 mmol) were stirred in DMF (1 mL). DIPEA (0.055 mL, 0.307 mmol) was added, followed by HATU (70 mg, 0.184 mmol). The reaction mixture was stirred for 40 min and then diluted with ethyl acetate (3 mL). The resulting material was washed with water (2 mL), saturated aqueous NH4Cl (2 mL), water (2 mL), and brine (2 mL) and then concentrated in vacuo. The residue was purified by reverse-phase column chromatography eluting with a gradient of 5 to 100% aqueous acetonitrile containing 0.1% formic acid, followed by preparative HPLC (Method 9).

[0455] Examples 4A and 4B [ka] 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-(2,2,2-trifluoro-ethylcarbamoyl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1 S )-3,3-Difluoro-1-(2,2,2-trifluoro-ethylcarbamoyl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide Prepared from 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (26 mg, 0.169 mmol) according to general method 1, followed by separation of stereoisomers by chiral SFC (Chiralcel OJ-H, 10 × 250 mm, 5 μm, eluting with 5% MeOH and 95% CO at 15 mL / min) gave the title compounds (peak 1, 10 mg, 11%; and peak 2, 10 mg, 11%) as white solids. Peak 1:

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[0456] Example 5 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide Prepared from 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (24 mg, 0.169 mmol) according to general method 1 to give the title compound (50 mg, 54%) as a white solid.

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[0457] Examples 6A and 6B [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-ethylisoxazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl){7-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-ethylisoxazole-3-carboxamide Prepared from 4-ethylisoxazole-3-carboxylic acid (24 mg, 0.169 mmol) according to general method 1, followed by separation of stereoisomers by chiral SFC (Chiralcel OJ-H, 10 × 250 mm, 5 μm, eluting with 5% IPA and 95% CO at 15 mL / min) gave the title compounds (peak 1, 10 mg, 11%; and peak 2, 8 mg, 9%) as white solids. Peak 1:

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[0458] Example 7 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-2-isopropylpyrazole-3-carboxamide Prepared from 1-isopropyl-1H-pyrazole-5-carboxylic acid (26 mg, 0.169 mmol) according to general method 1 to give the title compound (53 mg, 56%) as a white solid.

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[0459] Example 8 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide Prepared from 2-isopropyl-1,2,4-triazole-3-carboxylic acid (26 mg, 0.169 mmol) according to general method 1 to give the title compound (48 mg, 50%) as a white solid.

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[0460] Example 9 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-cyclohexyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide HATU (131 mg, 0.34 mmol) was added to a stirred solution of Intermediate 28 (92%, 150 mg, 0.26 mmol), 2,2,2-trifluoroethanamine (42 μL, 0.53 mmol), and DIPEA (92 μL, 0.53 mmol) in anhydrous DMF (2.6 mL). The reaction mixture was stirred at 20 °C under nitrogen for 18 h, then quenched with saturated aqueous sodium bicarbonate (10 mL) and diluted with water (10 mL). The resulting material was extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed successively with 0.5 M aqueous hydrochloric acid / brine (1:1, 20 mL) and water / brine (1:1, 3 × 20 mL). The organic phase was dried over magnesium sulfate, then filtered and concentrated in vacuo. The residue was purified by basic preparative HPLC to give the title compound (98% purity) (118 mg, 73%) as a white powder.

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[0461] Examples 10A and 10B [ka] 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1S)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 34 (109 mg, 0.226 mmol), 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (35 mg, 0.23 mmol), and DIPEA (88 mg, 0.68 mmol) in DMF (2.3 mL) was added HATU (106 mg, 0.270 mmol). The reaction mixture was stirred at rt for 5 min, then diluted with DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (2 × 20 mL), and the combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0–80% EtOAc in isohexane. The resulting diastereomeric mixture (1:1) was subjected to chiral SFC purification (Chiralpak IC 250 × 20 mm, 5 μm column, flow rate 100 mL / min, 60 bar, column temperature 40 °C) eluting with 3% MeOH (+0.1% NH OH) in CO to give, after lyophilization, the title compounds (peak 1, 20 mg, 20%; and peak 2, 23 mg, 23%). Peak 1:

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[0462] Example 11 [ka] N-(2,2-Dicyclopropyl-1-{7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)propyl]-imidazo[1,2-b]pyridazin-2-yl}ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 42 (140 mg, 0.295 mmol) in DMA (1 mL) was added to a solution of 2-chloro-1-methylpyridinium iodide (98 mg, 0.383 mmol), 2,2,2-trifluoroethanamine (52.6 mg, 0.531 mmol), and DIPEA (154.6 μL, 0.885 mmol) in DMA (1 mL). The reaction mixture was heated in a sealed tube at 50 °C for 2 h, then diluted with water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0 to 50% ethyl acetate in heptane to afford the title compound (131 mg, 80%) as an off-white solid.

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[0463] Example 12 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[(1S)-3,3-difluoro-1-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(S)-(4,4-Difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 62 (50 mg, 0.10 mmol), 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (17 mg, 0.13 mmol), and DIPEA (0.05 mL, 0.31 mmol) in DMF (0.52 mL) was added HATU (49 mg, 0.13 mmol). The reaction mixture was stirred at rt for 10 min and then diluted with DCM (5 mL) and water (5 mL). The aqueous layer was extracted with DCM (2 × 5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with a gradient of 0–100% EtOAc in isohexane followed by preparative HPLC to give a mixture of two stereoisomers. The desired stereoisomer, the second eluting peak, RT 7.29 min, was isolated by chiral HPLC (Chiralpak IC 250 x 20 mm, 5 μm, eluting with 3-40% MeOH (+0.1% NH4OH) at 100 mL / min) to give the title compound (3.5 mg, 27%) as a colorless amorphous solid. The undesired first eluting peak has a RT 6.91 min. The absolute stereochemistry of the carbon atom adjacent to the difluoroethyl group is unknown.

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[0464] Example 13 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[1-(oxetan-3-yl)-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidin-3-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of intermediate 54 (63 mg, 0.10 mmol) in DCM (3 mL) was added oxetan-3-one (7.3 μL, 0.11 mmol) and acetic acid (6.48 μL, 0.11 mmol). The mixture was stirred for 5 min, then sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added. The mixture was stirred for 18 h, then another portion of oxetan-3-one (7.3 μL, 0.11 mmol) and sodium triacetoxyborohydride (35 mg, 0.16 mmol) was added. The reaction mixture was stirred at rt for 5 h, then partitioned between DCM (20 mL) and brine (20 mL). The layers were separated, and the aqueous layer was re-extracted with DCM (2 × 20 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of 0–40% MeOH in EtOAc. The resulting material (a 1:1 mixture of pyrrolidine cis isomers) was subjected to chiral SFC purification (Chiralpak IC 250 × 20 mm, 5 μm column, flow rate 100 mL / min, column temperature 40 °C, eluting with a 3–40% MeOH (+0.1% NH4OH) method) to give the title compound (9 mg, 13%) as the first eluting peak. The absolute stereochemistry of the pyrrolidine ring is unknown.

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[0465] Example 14 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[4-(2,2-difluoropropylcarbamoyl)tetrahydropyran-4-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Intermediate 69 (50 mg, 0.095 mmol), DIPEA (0.03 mL, 0.2 mmol), and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (15 mg, 0.11 mmol) were dissolved in DCM (5 mL) and then HATU (50 mg, 0.13 mmol) was added. The reaction mixture was stirred overnight, then diluted with DCM (10 mL), washed with water (10 mL), passed through a hydrophobic frit, and evaporated. The residue was dissolved in MeOH and then purified by preparative HPLC to give the title compound (10 mg, 18%) as a white solid.

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[0466] Example 15 [ka] N-[(S)-(4,4-Difluorocyclohexyl)(7-{(1S*)-3,3-difluoro-1-[1-(2,2,2-trifluoroethyl)tetrazol-5-yl]propyl}imidazo[1,2-b]pyridazin-2-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide HATU (111 mg, 0.291 mmol) was added to a mixture of 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (37 mg, 0.291 mmol) and DIPEA (0.081 mL, 0.466 mmol) in anhydrous DMF (3 mL) at rt. The reaction mixture was stirred at rt for 5 min, and then intermediate 47 (96 mg, 0.194 mmol) was added. The reaction mixture was stirred at rt for 16 h, then diluted with EtOAc (50 mL) and washed with water (10 mL). The organic phase was dried over sodium sulfate, then filtered and concentrated to dryness in vacuo. The resulting material was purified by FCC (Biotage Isolera, SiO2, gradient elution with 10-50% EtOAc:heptane) followed by chiral preparative SFC LCMS (Waters Thar 3100 SFC system connected to a Waters 2998 PDA detector, Chiralcel OJ-H, 10 × 250 mm, 5 μm, eluting with 8% acetonitrile:92% CO2 at 15 mL / min) to give the title compound (desired isomer) (5.7 mg). The stereochemistry adjacent to the tetrazole carbon is arbitrarily assigned. A second (undesired) isomer was also isolated.

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[0467] Example 16 [ka] N-[(S)-(4,4-Difluorocyclohexyl){7-[4,4-difluoro-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)piperidin-2-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide A solution of intermediate 57 (46 mg, 76 μmol) and TFA (1.0 mL) in DCM (1.5 mL) was stirred at rt for 2 h, and then the reaction mixture was concentrated. The residue was dissolved in MeOH (0.5 mL). The solution was loaded onto an SCX column and eluted with MeOH, followed by 7N methanolic ammonia. The basic eluent was concentrated. The residue was mixed with 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (32.0 mg, 0.25 mmol), HATU (94.0 mg, 0.25 mmol), DIPEA (60 μL, 0.34 mmol), and DMF (1.0 mL). The mixture was stirred at rt for 1 h, and then concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient of 0 to 50% EtOAc in hexanes. Diastereomeric separation of the resulting yellow solid (30 mg) was performed on an SFC Prep 100 equipped with a Chiralpak IC 150 x 4.6 mm, 3 μm column (flow rate 3 mL / min, run time 7.5 min, elution with 3–40% methanol (+0.1% ammonia solution)) to give the title compound (first eluting peak) (9 mg, 20%) along with the opposite diastereomer. The absolute stereochemistry at the 2-position of the piperidine ring is unknown.

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[0468] Example 17 [ka] 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[4-(2,2-difluoropropylcarbamoyl)-tetrahydropyran-4-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide Intermediate 69 (50 mg, 0.095 mmol), DIPEA (0.03 mL, 0.2 mmol), and 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (20 mg, 0.13 mmol) were dissolved in DCM (5 mL) and then HATU (50 mg, 0.13 mmol) was added. The reaction mixture was stirred overnight, then diluted with DCM (10 mL), washed with water (10 mL), passed through a hydrophobic frit, and evaporated in vacuo. The residue was dissolved in MeOH and then purified by basic C18 preparative HPLC to give the title compound (26 mg, 44%) as a white solid.

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Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, E represents a group of formula (Ea), (Eb), (Ec), (Ed), or (Ee): 【Chemistry 2】 where the asterisk (*) represents the point of attachment to the rest of the molecule; A represents a group of formula (Aa), (Ab), (Ac), (Ad), or (Ae): 【Transformation 3】 where the asterisk (*) represents the point of attachment to the rest of the molecule; Y is -O-, -N(R ７ ) -, -C(R ５ａ ) (R ５ｂ )-, -S-, -S(O)-, -S(O) ２ -, or -S(O)(N-R ８ )- represents; Z represents heteroaryl, which may be optionally substituted by one or more substituents; R １ａ represents hydrogen, fluoro, chloro, methyl, difluoromethyl, or trifluoromethyl; R １ｂ represents hydrogen, fluoro, chloro, methyl, difluoromethyl, or trifluoromethyl; R ２ is -OR ２ａ or R ２ is C ３－９ Cycloalkyl, C ４－１２ Bicycloalkyl, C ３－７ heterocycloalkyl, or C ４－９ heterobicycloalkyl, any of which groups may be optionally substituted by one or more substituents; R ２ａ is C １－６ represents alkyl; or R ２ａ is C ３－９ represents cycloalkyl, which may be optionally substituted by one or more substituents; R ３ is -NR ３ａ R ３ｂ or R ３ represents a group of formula (Wa): 【Chemistry 4】 where the asterisk (*) represents the point of attachment to the rest of the molecule; W represents the residue of an optionally substituted saturated monocyclic ring containing 3 to 6 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom; or W represents the residue of an optionally substituted saturated bicyclic ring system containing 4 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom; or W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5 to 10 carbon atoms, 1 nitrogen atom, and 0, 1, 2, or 3 additional heteroatoms independently selected from N, O, and S, but containing not more than 1 O or S atom; R ３ａ is hydrogen or C １－６ represents alkyl; R ３ｂ is C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl (C １－６ ) alkyl, C ４－１２ Bicycloalkyl, aryl, aryl (C １－６ ) alkyl, C ３－７ Heterocycloalkyl, C ３－７ Heterocycloalkyl (C １－６ ) alkyl, heteroaryl, or heteroaryl (C １－６ ) alkyl, any of which groups may be optionally substituted by one or more substituents; R ４ａ represents hydrogen, fluoro, or hydroxy; or R ４ａ is C １－６ represents alkyl, which may be optionally substituted by one or more substituents; R ４ｂ represents hydrogen or fluoro; or R ４ｂ is C １－６ represents alkyl, which may be optionally substituted by one or more substituents; or R ４ａ and R ４ｂ together with the carbon atom to which they are both attached, ３－９ Cycloalkyl or C ３－７ heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents; R ５ａ represents hydrogen, fluoro, methyl, difluoromethyl, or trifluoromethyl; and R ５ｂ represents hydrogen, fluoro, methyl, or hydroxy; or R ５ａ and R ５ｂ together with the carbon atom to which they are both attached represent cyclopropyl; R ６ is -OR ６ａ Or -NR ６ｂ R ６ｃ or R ６ is C １－６ Alkyl, C ３－９ Cycloalkyl, C ３－９ Cycloalkyl (C １－６ ) alkyl, aryl, aryl (C １－６ ) alkyl, C ３－７ Heterocycloalkyl, C ３－７ Heterocycloalkyl-(C １－６ ) alkyl, heteroaryl, or heteroaryl (C １－６ ) alkyl, any of which groups may be optionally substituted by one or more substituents; R ６ａ is C １－６ represents alkyl; or R ６ａ is C ３－９ Cycloalkyl or C ３－７ heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents; R ６ｂ is hydrogen or C １－６ represents alkyl; and R ６ｃ is hydrogen or C １－６ represents alkyl; or R ６ｂ and R ６ｃ together with the nitrogen atom to which they are both attached represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; R ７ is -COR ７ａ , -CO ２ R ７ａ Or -SO ２ R ７ｂ or R ７ represents hydrogen; or R ７ is C １－６ Alkyl, C ３－９ cycloalkyl, or C ３－７ heterocycloalkyl, any of which groups may be optionally substituted with one or more fluorine atoms; R ７ａ is C optionally substituted by one or more fluorine atoms １－６ represents alkyl; R ７ｂ is C １－６ represents alkyl; and R ８ is C １－６ represents alkyl, A compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. 2. A compound according to claim 1, wherein E represents a group of formula (Ea) or (Ed) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

3. 3. A compound according to claim 1 or 2, wherein A represents a group of formula (Aa), (Ac), (Ad), or (Ae) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

4. R ６ 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: represents heteroaryl, which group may be optionally substituted by one or more substituents.

5. The compound of claim 1 represented by formula (IIA-1), or a pharmaceutically acceptable salt thereof: 【Transformation 5】 During the ceremony, X represents CH or N; R １６ represents methyl, ethyl, isopropyl, or cyclopropyl; and A is as defined in claim 1. The compound according to claim 1, represented by formula (IIA-1), or a pharmaceutically acceptable salt thereof:

6. The compound of claim 1 represented by formula (IIA-2), or a pharmaceutically acceptable salt thereof: 【Transformation 6】 During the ceremony, A is as defined in claim 1; and X and R １６ is as defined in claim 5, The compound according to claim 1, represented by formula (IIA-2), or a pharmaceutically acceptable salt thereof:

7. The compound of claim 1 represented by formula (IIB-1), or a pharmaceutically acceptable salt thereof: 【Transformation 7】 During the ceremony, A is as defined in claim 1; and X and R １６ is as defined in claim 5, The compound according to claim 1, represented by formula (IIB-1), or a pharmaceutically acceptable salt thereof:

8. The compound of claim 1 represented by formula (IIB-2), or a pharmaceutically acceptable salt thereof: 【Transformation 8】 During the ceremony, A is as defined in claim 1; and X and R １６ is as defined in claim 5, The compound according to claim 1, represented by formula (IIB-2), or a pharmaceutically acceptable salt thereof:

9. The compound N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-{(S)-(4,4-difluorocyclohexyl)[7-(3,3-difluoro-1-{[(1R)-2-methyl-1-(methylcarbamoyl)-propyl]carbamoyl}propyl)imidazo[1,2-b]pyridazin-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-{7-[(1R)-1-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3,3-difluoro-propyl]imidazo[1,2-b]pyridazin-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-{7-[(1S)-1-{[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]carbamoyl}-3,3-difluoro-propyl]imidazo[1,2-b]pyridazin-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-(2,2,2-trifluoro-ethylcarbamoyl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide; 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1S)-3,3-difluoro-1-(2,2,2-trifluoro-ethylcarbamoyl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-ethylisoxazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-ethylisoxazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-2-isopropylpyrazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-2-isopropyl-1,2,4-triazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-cyclohexyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1S)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide; 4-cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide; N-(2,2-dicyclopropyl-1-{7-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)propyl]-imidazo[1,2-b]pyridazin-2-yl}ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[(1S)-3,3-difluoro-1-(6-fluoro-[1,2,4]triazolo[4,3-a]-pyridin-3-yl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[(1R)-3,3-difluoro-1-(6-fluoro-[1,2,4]triazolo[4,3-a]-pyridin-3-yl)propyl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[1-(oxetan-3-yl)-4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidin-3-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[4-(2,2-difluoropropylcarbamoyl)tetrahydropyran-4-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl)(7-{(1S*)-3,3-difluoro-1-[1-(2,2,2-trifluoroethyl)tetrazol-5-yl]propyl}imidazo[1,2-b]pyridazin-2-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; N-[(S)-(4,4-difluorocyclohexyl){7-[4,4-difluoro-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)piperidin-2-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide; and 4-Cyclopropyl-N-[(S)-(4,4-difluorocyclohexyl){7-[4-(2,2-difluoropropylcarbamoyl)-tetrahydropyran-4-yl]imidazo[1,2-b]pyridazin-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide 2. The compound of claim 1, which is a compound selected from the group consisting of:

10. 10. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of disorders in which the administration of a modulator of IL-17 function is indicated.

12. 10. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of an inflammatory or autoimmune disorder.

13. 10. A pharmaceutical composition comprising a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

14. 14. The pharmaceutical composition of claim 13, further comprising an additional pharmaceutically active ingredient.

15. Use of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of disorders in which the administration of a modulator of IL-17 function is indicated.

16. 10. Use of a compound of formula (I) as defined in 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.

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