FIELD OF THE INVENTION

This invention relates to novel amino-acid amides and derivatives thereof, to said compounds for use in therapy and to pharmaceutical compositions comprising said compounds.

BACKGROUND OF THE INVENTION

IL-17 (also known as IL-17A or CTLA8) is a pro-inflammatory cytokine involved in antimicrobial defense at epithelial surfaces. IL-17 is comprised of two covalently joined IL-17A subunits (IL-17AA) with an approximate mass of 32 kDa, and signals through a receptor comprising IL17RA and IL17RC subunits. This receptor is predominantly expressed in epithelial and mesenchymal cells. The IL17RA/IL17RC receptor is also used by IL-17 variants IL-17AF and IL-17FF, which both are successively weaker, partial agonists on this receptor (Monin, L., Gaffen, S.L.; 2018, Cold Spring Harb. Perspect. Biol. 10. doi : 10.1101/cshperspect.a028522). Crucial for signaling is the assembly of signaling complexes containing the multifunctional protein ACT1/CIKS, which in turn can recruit TRAF and other proteins.

Via these signaling complexes IL-17 induces cytokines, chemokines, antimicrobial peptides and growth factors via activation of transcription factor NFkB or via MAP kinase-dependent pathways (e.g. IL-6, IL-8, CXCL1, CXCL2, CXCL5, CCL20, G-CSF, BD4) and stabilizes the mRNAs of certain inflammatory cytokines, such as CXCL1. This leads to amplification of their effects. Further, IL-17 acts in concert with IL-lbeta, IL-22 and IFNgamma (Amatya, N. et al., Trends in Immunology, 2017, 38, 310-322. doi: 10.1016/j.it.2017.01.006; Onishi, R.M., Gaffen, S.L. Immunology, 2010, 129, 311-321. doi: 10.1111/j.l365- 2567.2009.03240.x).

IL-17 is secreted by a variety of immune cells, such as Thl7 helper cells, Tcl7 cytotoxic cells, ILC3 innate cells, NKT cells, TCRbeta+ natural T cells and gamma-deltaT-cells (Monin, L., Gaffen, S.L.; 2018, Cold Spring Harb. Perspect. Biol. 10. doi : 10.1101/cshperspect.a028522). Increased, disease-provoking levels of IL-17 are observed in several autoimmune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis and psoriatic arthritis. Other diseases where deregulation of IL-17 is observed are rheumatoid arthritis, systemic lupus erythematosus, asthma, inflammatory bowel disease, autoimmune uveitis, multiple sclerosis and certain cancers (Gaffen, S.L. et al., Nat Rev Immunol., 2014, 14, 585-600. doi: 10.1038/nri3707; Monin, L., Gaffen, S.L.; 2018, Cold Spring Harb. Perspect. Biol. 10. doi : 10.1101/cshperspect.a028522). Hence, IL- 17 is a significant therapeutic target. Therapeutic, neutralizing antibodies against IL-17A (Secukinumab, Ixekizumab) or receptor IL17RA (Brodalumab) have shown high efficacy in the treatment of psoriasis, ankylosing spondylitis and psoriatic arthritis. These antibodies have long half-lives in the body.

Although various antibodies against IL-17A or IL-17RA are approved, there are currently no approved, orally available modulators of IL-17.

The following patent applications describe small molecule modulators:

WO2013116682, WO2014066726, WO2018229079, WO2019223718, W02019138017, W02020011731, W02020120140, W02020120141, WO2020127685, WO2020146194, WO2020163554, WO2020182666, W02020260426, W02020260425, W02020261141, WO2021055376, WO2021098844, W02021204800A, W02021204801A, WO2021170627, W02021170631, WO2021220183, WO2021222404, WO2021239743, WO2021239745, WO2021250194, WO2021255174, WO2021255085, WO2021255086, W02022091056, WO2022096412, WO2022128584, US20220235038, EP3943495, CN112824399A, CN112341429A, CN112341435A, CN112341439A, CN112341440A, CN112341441A, CN112341442A, CN112341446A, CN112341450A, CN112341451A, CN112341519A, CN113683598A, CN113880767, CN113880766, CN113999234, and CN113943278 all disclose Compounds for Modulating IL-17.

Scientific Reports (2016) 6, 30859 discloses Macrocyclic IL-17A Antagonists, Scientific Reports (2022) 12, 14561 discloses Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site and Leslie Dakin, 12 ^th Swiss Course on Medicinal Chemistry, Leysin, October 09-14, 2016 discloses 'Hit Identification, binding site elucidation and structure guided design of novel macrocyclic IL- 17A antagonists'.

Orally available, highly efficacious small molecule IL-17 modulators which bind to IL-17 to decrease its functional ability to activate the IL-17 receptor complex may have a number of advantages compared to monoclonal antibodies. Oral administration and flexible treatment regimen may be two significant aspects in favor of patient convenience and the compounds may exhibit improved safety due to the possibility of faster withdrawal of the drug should adverse events occur.

Therefore, there is a continuous need to develop small molecule modulators of IL-17, particularly small molecules suitable for oral administration. In addition, some patients may be treated by topical application of small molecule modulators of IL-17. This can be particularly suitable for patients with skin lesions that are readily accessible and limited in body surface area. Topical treatment may also be prescribed for certain patients who could benefit from avoiding systemic modulation of the IL-17 pathway, for example when undergoing treatment for infections or gastrointestinal problems. SUMMARY OF THE INVENTION The inventors have surprisingly found that novel compounds of the present invention exhibit modulating effects on the IL-17 signalling pathway. Compounds of the present invention may have advantageous properties such as high metabolic stability and/or membrane permeability properties that make them suitable for oral administration. Other compounds of the present invention may have advantageous properties for local topical therapy, such as high skin permeability and high metabolic instability. Compounds of the present invention may be beneficial in preventing, treating or ameliorating a variety of diseases which involve up-regulation or de-regulation of IL-17, such as for example psoriasis, ankylosing spondylitis and psoriatic arthritis. Accordingly, the present invention relates to a compound according to formula (Ia) or (Ib) (Ia) (Ib) R ¹ is selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₁ -C ₆ )alkoxy, (C3-C7)cycloalkoxy, phenyl, phenyl-(C1-C4)alkyl, 5-or 6-membered heteroaryl, 9- or 10- membered bicyclic heteroaryl, 4-6-membered heterocycloalkyl and -NR ^c R ^d , wherein said (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, phenyl, phenyl-(C1- C4)alkyl, 5-or 6-membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, and 4-6- membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from R ^a ; R ^a is deuterium, halogen, hydroxy, -NR ^c R ^d , (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6- membered heterocycloalkyl, or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, wherein said (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (C1-C4)alkyl, (C3- C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl-S-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2- and - NR ^c R ^d ; R ^c and R ^d each independently are selected from the group consisting of hydrogen and (C1- C6)alkyl, or R ^c and R ^d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (C1- C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; R ² is selected from the group consisting of -CHR ⁴ R ⁵ , (C3-C10)cycloalkyl and G, wherein said (C3-C10)cycloalkyl and G are optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C ₁ -C ₄ )alkyl and halo(C ₁ -C ₄ )alkyl; G is selected from G1, G2 and G2 G2 _G3 R ⁴ and R ⁵ each independently represent hydrogen, phenyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, and (C3-C7)cycloalkyl(C1-C6)alkyl wherein said phenyl, (C1-C6)alkyl, (C3-C7)cycloalkyl and (C3-C7)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C1-C4)alkyl; with the proviso that at least one of R ⁴ and R ⁵ is different from hydrogen; R ³ is selected from hydrogen, (C1-C4)alkyl, and (C1-C4)cycloalkyl, wherein said (C1-C4)cycloalkyl may optionally be substituted with one or more substituents independently selected from deuterium, halogen, cyano and hydroxy, and wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, (C1-C4)cycloalkyl, (C1-C3)alkoxy, (C3- C4)cycloalkoxy, fluoro(C1-C4)cycloalkyl, and fluoro(C1-C3)alkoxy; Q is 5-membered heteroaryl, wherein said 5-membered heteroaryl is optionally substituted with one or more substituents independently selected from R ^e ; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; Z ¹ , Z ² and Z ³ are selected from N or CR ^b and wherein at least two of Z ¹ , Z ² and Z ³ are CR ^b ; Z ⁴ , Z ⁵ and Z ⁶ are CHR ^b ; n is 0 or 1; R ^b is hydrogen, deuterium, halogen, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or (C ₃ - C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen; or pharmaceutically acceptable salts thereof. In one embodiment the present invention relates to compounds of formula (Ic) or (Id) ( ^{Ic) (Id)} wherein R ¹ , R ² , R ³ , Z ¹ , Z ² , Z ³ Z ⁴ , Z ⁵ , Z ⁶ , Q and n are as defined above; or pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to a compound having the formula (Ie) or (If) f) wherein R ¹ , R ² , R ³ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and R ^e are as defined above. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of general formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined herein together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s), optionally together with one or more other therapeutically active compound(s). In yet another aspect, the invention relates to the use of a compound according to formula (Ia), (Ib), (Ic), (Id), (Ie) and (If) as defined herein for use in therapy, for example for use in treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of IL-17, for example for use in treatment of autoimmune diseases. DETAILED DESCRIPTION OF THE INVENTION Definitions The term “compound of formula (I)” means any of the compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie) and (If) described herein. The term “(Ca-Cb)alkyl” is intended to indicate a hydrocarbon radical obtained when one hydrogen atom is removed from a branched or linear hydrocarbon. Said alkyl comprises (a- b) carbon atoms, such as 1-6, such as 1-4, such as 1-3, such as 2-3 or such as 1-2 carbon atoms. The term includes the subclasses normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl and isohexyl. The term “(Ca-Cb)alkoxy” is intended to indicate a radical of the formula –OR’, wherein R’ is (Ca-Cb)alkyl as indicated herein, wherein the (Ca-Cb)alkyl group is appended to the parent molecular moiety through an oxygen atom, e.g. methoxy (-OCH3), ethoxy (-OCH2CH3), n- propoxy, isopropoxy, butoxy, tert-butoxy, and the like. The term “cyano” is intended to indicate a –CN group attached to the parent molecular moiety through the carbon atom. The term “(Ca-Cb)cycloalkyl” is intended to indicate a saturated (Ca-Cb)cycloalkane hydrocarbon radical, including polycyclic radicals such as bicyclic or tricyclic radicals, including spirocyclic radicals, comprising a-b carbon atoms, such as 3-10 carbon atoms, such as 3-8 carbon atoms, such as 3-7 carbon atoms, such as 3-6 carbon atoms, such as 3-5 carbon atoms or such as 3-4 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, adamantyl, spiro[2.5]octanyl, spiro[2.3]hexanyl, bicyclo[3,1,0]hexanyl, bicyclo[4,1,0]heptanyl and bicyclo[2,2,2]octanyl. The term “(Ca-Cb)cycloalkoxy” is intended to indicate a radical of the formula –OR’, wherein R’ is (C _a -C _b )cycloalkyl as indicated herein, wherein the (C _a -C _b )cycloalkyl group is appended to the parent molecular moiety through an oxygen atom, e.g. cyclopentyloxy or cyclobutyloxy. The term “(Ca-Cb)cycloalkyl(Ca-Cb)alkyl” is intended to indicate an (Ca-Cb)alkyl group as defined herein substituted with one or more (Ca-Cb)cycloalkyl as defined herein, suitably the (Ca-Cb)alkyl group is substituted with one (Ca-Cb)cycloalkyl group. The term “halo(Ca-Cb)alkyl” is intended to indicate an (Ca-Cb)alkyl group as defined herein substituted with one or more halogen atoms as defined herein, e.g. fluoro or chloro, such as difluoromethyl or trifluoromethyl. The term “fluoro(C1-C4)alkyl” is for example intended to indicate a (C1-C4)alkyl group substituted with one or more fluoro atoms, e.g. trifluoromethyl, trifluoroethyl, difluoromethyl or difluoroethyl. The term “halo(Ca-Cb)alkoxy” is intended to indicate a (Ca-Cb)alkoxy group as defined herein substituted with one or more halogen atoms as defined herein, e.g. fluoro or chloro, such as difluoromethoxy or trifluoromethyoxy. The term “fluoro(C1-C3)alkoxy” is intended to indicate a (C1-C3)alkylalkoxy group substituted with one or more fluoro atoms, e.g. trifluoromethoxy. The term “halogen” is intended to indicate a substituent from the 7 ^th main group of the periodic table, such as fluoro, chloro and bromo. The term ”5- or 6-membered heteroaryl” is intended to indicate radicals of monocyclic heteroaromatic rings comprising 5- or 6-membered ring which contains from 1-5 carbon atoms and from 1-4 heteroatoms selected from oxygen, sulphur and nitrogen; such as 2-5 carbon atoms and 1-3 heteroatoms, such as 3-5 carbon atoms and 1-2 heteroatoms, such as 4-5 carbon atoms and 1-2 heteroatoms selected from oxygen, sulphur and nitrogen, such as furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl. The term ”5- or 6-membered heteroaryl” includes compounds wherein a ring member is a C(O) or carbonyl group. The term ”5-membered heteroaryl” is intended to indicate radicals of 5-membered monocyclic heteroaromatic ring which contains from 1-4 carbon atoms and from 1-4 heteroatoms selected from oxygen, sulphur and nitrogen; such as 2-4 carbon atoms and 1- 3 heteroatoms, such as 3-4 carbon atoms and 1-2 heteroatoms, such as 4 carbon atoms and 1 heteroatom selected from oxygen, sulphur and nitrogen; such as furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl. The term ”5-membered heteroaryl” includes compounds wherein a ring member is a C(O) or carbonyl group. The term “9- or 10-membered bicyclic heteroaryl” is intended to indicate fused bicyclic heteroaromatic radicals comprising 9- or 10- carbon or heteroatoms, which for example contain from 3-9 carbon atoms and 1-7 heteroatoms selected from oxygen, sulphur and nitrogen, such as 1-5 heteroatoms and 5-9 carbon atoms, such as 1-3 heteroatoms and 7- 9 carbon atoms, such as 1-2 heteroatoms and 8-9 carbon atoms, such as 1 heteroatom and 8 carbon atoms, such as 1 heteroatom and 9 carbon atoms, such as 2 heteroatom and 7 carbon atoms, such as 2 heteroatom and 8 carbon atoms. Said bicyclic heteroaromatic radicals comprise a 5- or 6-membered heteroaromatic ring fused to phenyl and a 5- or 6- membered heteroaromatic ring fused to another 5- or 6-membered heteroaromatic ring, as defined herein. The heteroaryl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heteroaryl group. Representative examples of 9- or 10-membered bicyclic heteroaryl include, but are not limited to azaindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzothienyl, cinnolyl, imidazopyridinyl, imidazopyrimidinyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl, quinolyl, pyrrolopyrimidinyl, thienopyridinyl, pyrrolo[2,3]pyridinyl, pyrrolo[2,3]pyridinyl, pyrazolo[1,5]pyridinyl, pyrazolo[1,5]pyridazinyl, imidazo[1,2]pyrimidinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3- b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, and imidazo[1,2]pyridazinyl. The term (5- or 6-membered heteroaryl)-(Ca-Cb)alkyl is intended to indicate a 5- or 6- membered heteroaryl appended to the parent molecular moiety through a (Ca-Cb)alkyl group, as defined herein. The term ”(a-b) membered heterocycloalkyl” is intended to indicate a cycloalkane radical as described herein, including polycyclic radicals such as bicyclic or tricyclic radicals, including spirocyclic radicals, wherein one or more carbon atoms of said cycloalkane radical are replaced by heteroatoms, i.e. the a-b membered heterocycloalkyl comprise from a to b carbon- or hetero-atoms. Such a-b membered heterocycloalkyl could comprise for example 2-9 carbon atoms and 1-6 heteroatoms selected from O, N, or S, such as 3-8 carbon atoms and 1-4 heteroatoms, such as 3-7 carbon atoms and 1-3 heteroatoms, such as 3-6 carbon atoms and 1-2 heteroatom. The heterocycloalkyl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heterocycloalkyl group. Representative examples of heterocycloalkyl groups include, but are not limited to azepanyl, azetidinyl, aziridinyl, dioxolanyl, dioxolyl, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thietanyl, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-5-aza-[2.2.1]heptanyl, 2-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-8-azaspiro[3.5]nonanyl, 6-oxa-2- azaspiro[3.3]heptanyl, 2-oxa-7-azaspiro[3,4]octanyl, and 1, 3, 3a, 4, 6, 6a- hexahydrofuro[3,4-c]pyrrolyl. The term includes compounds wherein a ring member of said ”(a-b) membered heterocycloalkyl” is a C(O) or carbonyl group and S(O) group. The term “(a-b membered heterocycloalkyl)-(Cc-Cd)alkyl” is intended to indicate a a-b membered heterocycloalkyl radical appended to the parent molecular moiety through an (Cc-Cd)alkyl group, as defined herein. The term “hydrocarbon radical” is intended to indicate a radical containing only hydrogen and carbon atoms, it may contain one or more double and/or triple carbon-carbon bonds, and it may comprise cyclic moieties in combination with branched or linear moieties. Said hydrocarbon comprises 1-6 carbon atoms, e.g. 1-5, e.g. 1-4, e.g. 1-3, e.g. 1-2 carbon atoms. The term includes alkyl and cycloalkyl as indicated herein. The term “hydroxy(Ca-Cb)alkyl” is intended to indicate an (Ca-Cb)alkyl group as defined above substituted with one or more hydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl. The term “oxo” is intended to indicate an oxygen atom which is connected to the parent molecular moiety via a double bond (=O). The term “phenyl-(Ca-Cb)alkyl” is intended to indicate a phenyl group appended to appended to the parent molecular moiety through an (Ca-Cb)alkyl group, as defined herein. When two or more of the above defined or similar terms are used in combination, such as cycloalkylalkyl or phenyl-(Ca-Cb)alkyl and the like, it is to be understood that the first mentioned radical is a substituent on the latter mentioned radical, where the point of attachment to the parent molecular moiety is on the latter radical. The group C(O) is intended to represent a carbonyl group (C=O). If substituents are described as being independently selected from a group, each substituent is selected independent of the other. Each substituent may therefore be identical or different from the other substituent(s). The term “optionally substituted” means “unsubstituted or substituted”, and therefore the general formulas described herein encompasses compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional substituent(s). As used herein whenever a molecular drawing of a substituent contains an arrow – the arrow indicates the bond attaching the substituent to the rest of the molecule. The term ”pharmaceutically acceptable salt” is intended to indicate salts prepared by reacting a compound of formula (I), which comprise a basic moiety, with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroacetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D- glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane- 1,2-disulfonic, 2-hydroxyethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula (I) comprising an acidic moiety may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, barium hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines (such as diethylamine, tetraalkylammonium hydroxide), hydroxy-lower alkylamines (such as diethanolamine, 2-(diethylamino)-ethanol, ethanolamine, triethanolamine, tromethamine, deanol), cycloalkylamines, ethylene diamine, or benzylamines, (such as benethamine and benzathine), betaine, choline hydroxide, N-methyl-glucamine, hydrabamine, 1H-imidazole, 4-(2-hydroxyethyl)-morpholine, piperazine, 1-(2- hydroxyethyl)-pyrrolidine, L-arginine or L-lysine. Further examples of pharmaceutical acceptable salts are listed in Berge, S.M.; J. Pharm. Sci.; (1977), 66(1), 1-19, and Stahl, P.H. and in Wermuth, C.G, Handbook of Pharmaceutical Salts, Properties, Selection and Use, 2 ^nd Edition, Wiley-VCH, 2011 both of which are incorporated herein by reference. For example when R8 is -L-PO(OH)2 the phosphoric acid group may form a salt with a monovalent cation M ⁺ or divalent cation Q ²⁺ to form a group selected from -L-PO(OH)O- .M ⁺ ,-L-PO(OH)O-.½Q ²⁺ -L-PO(O-)2.2M ⁺ , and -L-PO(O-)2.Q ²⁺ . The term ‘monovalent cation’ is intended to indicate monovalent cations such as alkali metal ions, such as for example sodium (Na ⁺ ), potassium (K ⁺ ) or lithium (Li ⁺ ), or ammonium ions, such as for example NH4 ⁺ , dialkylammonium (NH2((C1-C4)alkyl)2) ⁺ , trialkylammonium (NH((C1-C4)alkyl)3) ⁺ , or tetraalkylammonium (N((C1-C4)alkyl)4) ⁺ , alkylammonium (H3N(C1-C4)alkyl) ⁺ or hydroxyalkylammonium (H3N-hydroxy(C1-C4)alkyl) ⁺ , the protonated forms of L-arginine, L-lysine or the protonated forms of any pharmaceutically acceptable bases such as those mentioned above. The term ‘divalent cation’ is intended to indicate divalent cations such as alkaline earth metal ions such as calcium (Ca ²⁺ ), Magnesium (Mg ²⁺ ), barium (Ba ²⁺ ), or Zinc (Zn ²⁺ ). The term “solvate” is intended to indicate a species formed by interaction between a compound, e.g. a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a solvent, e.g. alcohol, glycerol or water, wherein said species are in a crystalline form. When water is the solvent, said species is referred to as a hydrate. The term “treatment” as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the amelioration, alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. The term may also include prevention of the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects. In one embodiment, the invention relates to a compound of formula (I) as described above, wherein R ² is cyclohexyl wherein said cyclohexyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C ₁ -C ₄ )alkyl and halo(C1-C4)alkyl. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ² is trans 4-methylcyclohexyl. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ² is -CHR ⁴ R ⁵ , wherein R ⁴ and R ⁵ each independently represent hydrogen, phenyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, and (C3-C7)cycloalkyl(C1-C6)alkyl wherein said phenyl, (C1-C6)alkyl, (C3-C7)cycloalkyl and (C3-C7)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C1-C4)alkyl; with the proviso that at least one of R ⁴ and R ⁵ is different from hydrogen. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ² is -CHR ⁴ R ⁵ and wherein R ⁴ and R ⁵ are each independently cyclopropyl or cyclobutyl. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ² is -CHR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are both cyclopropyl. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ¹ is selected from pyrazolyl, isoxazolyl and oxadiazolyl, wherein said pyrazolyl, isoxazolyl and oxadiazolyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C4)alkyl, (C3-C4)cycloalkyl, wherein said (C ₁ -C ₃ )alkyl or (C ₃ -C ₄ )cycloalkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ³ is methyl, methoxymethyl or hydroxymethyl. In another embodiment, the invention relates to a compound of formula (I) as described above, wherein R ³ is methoxymethyl. In another embodiment, the invention relates to a compound of formula (Ic) ( ^Ic) wherein Z ¹ is N or CR ^b , and Z ² and Z ³ are CR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3- C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen. In another embodiment, the invention relates to a compound of formula (Ic) c) wherein Z ¹ is N or CR ^b , and Z ² is CR ^b and Z ³ is CH; and R ^b is halogen. In another embodiment, the invention relates to a compound of formula (Id), ( ^Id) wherein n is 1; Z ⁴ , Z ⁵ and Z ⁶ are CHR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3- C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen. In another embodiment, the invention relates to a compound of formula (Id), ⁾ wherein n is 0; Z ⁶ is CHR ^b ; Z ⁵ is CHR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3- C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen. In another embodiment, the invention relates to a compound having the formula (Ie) or (If) ^f) wherein R ¹ , R ² , R ³ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are as defined above and wherein R ^e is hydrogen or fluoro. In another embodiment, the invention relates to a compound of formula (Ie), wherein R ¹ , R ² , R ³ , Z ¹ , Z ² and Z ³ are as defined above and wherein R ^e is fluoro. In one embodiment the invention relates to any compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) as described herein for use in therapy. In one embodiment the invention relates to any compound of (Ia), (Ib), (Ic), (Id), (Ie) or (If) described herein for use in treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of IL-17. In one embodiment the invention relates to any compound of (Ia), (Ib), (Ic), (Id), (Ie) or (If) described herein for use in the treatment of autoimmune diseases. In one embodiment the invention relates to any compound of (Ia), (Ib), (Ic), (Id), (Ie) or (If) described herein for use in the treatment of psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis. In one embodiment the invention relates to a pharmaceutical composition comprising any compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s). In one embodiment the invention relates to a pharmaceutical composition comprising any compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) together with one or more other therapeutically active compound(s). In one or more embodiments of the present invention, the compounds of general formula (I) have an (EC50) value in a HEK BLue ^TM IL-17 assay of less than 1 micromolar, or of less than 100 nanomolar. The compounds of formula (I) may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a co-solvent that may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline forms, such as polymorphs and pseudopolymorphs, and also mixtures thereof. Compounds of formula (I) comprise asymmetrically substituted (chiral) carbon atoms which give rise to the existence of isomeric forms, e.g. enantiomers and possibly diastereomers. The present invention relates to all such isomers, either in optically pure form or as mixtures thereof (e.g. racemic mixtures or partially purified optical mixtures). Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of procedures known in the art. The various isomeric forms may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. high pressure liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts which may be formed with optically active amines, or with optically active acids. Optically purified compounds may subsequently be liberated from said purified diastereomeric salts. Enantiomers may also be resolved by the formation of diastereomeric derivatives. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occur stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chiral pure starting materials. Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. Any geometric isomer, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. n the compounds of general formula (I), the atoms may exhibit their natural isotopic bundances, or one or more of the atoms may be artificially enriched in a particular isotope aving the same atomic number, but an atomic mass or mass number different from the tomic mass or mass number found in nature. The present invention includes all suitable otopic variations of the compounds of general formula (I). For example, different isotopic orms of hydrogen include ¹ H, ² H and ³ H, different isotopic forms of carbon include ¹² C, ¹³ C nd ¹⁴ C and different isotopic forms of nitrogen include ¹⁴ N and ¹⁵ N. Enriching for deuterium H) may for example increase in-vivo half-life or reduce dosage regimens, or may provide compound useful as a standard for characterization of biological samples. Isotopically nriched compounds within general formula (I) can be prepared by conventional techniques ell known to a person skilled in the art or by processes analogous to those described in he general procedures and examples herein using appropriate isotopically enriched eagents and/or intermediates. ome compounds have lower aqueous solubility which may affect the absorption and onsequently the bioavailability of the compounds. Such compounds may advantageously e administered in the form of prodrugs improving the aqueous solubility of the parent ompound. Such prodrugs which, upon administration, are converted to their parent ompounds may be less active in vitro compared to their parent compounds, but because f the improved aqueous solubility, facilitating the absorption and consequently the oavailability of the parent compounds upon administration, such prodrugs have improved vivo activity compared to their parent compounds. olvates and hydrates form part of the invention claimed. he compounds of the present invention may be useful for preventing, treating or meliorating any of the following diseases: psoriasis, ankylosing spondylitis, pondyloarthritis or psoriatic arthritis, lichen planus, lupus nephritis, Sjögren’s syndrome, cne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, steoarthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), discoid lupus rythematosus (DLE), multiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid rthritis, pityriasis rubra pilaris, pyoderma gangrenosum, hidradenitis suppurativa, discoid pus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyosis, bullous emphigoid, scleroderma, tendinopathy, chronic wounds and cancer. In an embodiment the invention relates to the use of a compound of general formula (I) as defined above, in the manufacture of a medicament for the prophylaxis, treatment or amelioration of any of the following diseases: psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, lichen planus, lupus nephritis, Sjogren's syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE, LN and DLE, multiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum, hidradenitis suppurativa, discoid lupus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyosis, bullous pemphigoid, scleroderma, tendinopathy, chronic wounds and cancer.

In an embodiment the invention relates to the use of a compound of general formula (I) as defined above, in the manufacture of a medicament for the prophylaxis, treatment or amelioration of autoimmune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis.

In an embodiment the invention relates to a method of preventing, treating or ameliorating autoimmune diseases, such as psoriatic arthritis, lichen planus, lupus nephritis, Sjogren's syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE, LN and DLE, multiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum, hidradenitis suppurativa, discoid lupus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyosis, bullous pemphigoid, scleroderma, tendinopathy, chronic wounds and cancer, the method comprising administering to a person suffering from at least one of said diseases an effective amount of one or more compounds according to general formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

In an embodiment the invention relates to a method of preventing, treating or ameliorating autoimmune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, the method comprising administering to a person suffering from at least one of said diseases an effective amount of one or more compounds according to general formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

Besides being useful for human treatment, the compounds of the present invention may also be useful for veterinary treatment of animals including mammals such as horses, cattle, sheep, pigs, dogs, and cats. Pharmaceutical Compositions of the Invention For use in therapy, compounds of the present invention are typically in the form of a pharmaceutical composition. The invention therefore relates to a pharmaceutical composition comprising a compound of Formula (I), optionally together with one or more other therapeutically active compound(s), together with a pharmaceutically acceptable excipient, vehicle or carrier(s). The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Conveniently, the active ingredient comprises from 0.0001-99.9% by weight of the formulation. In the form of a dosage unit, the compound may be administered one or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner. Conveniently, a dosage unit of a formulation contain between 0.001 mg and 1000 mg, preferably between 0.01 mg and 300 mg of a compound of Formula (I). A suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician. The compound may be administered either orally, parenterally, topically, transdermally or intradermally and other routes according to different dosing schedules, e.g. daily, weekly or with monthly intervals. In general a single dose will be in the range from 0.001 to 400 mg/kg body weight. If the treatment involves administration of another therapeutically active compound it is recommended to consult Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9 ^th Ed., J.G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, for useful dosages of said compounds. The administration of a compound of the present invention with one or more other active compounds may be either concomitantly or sequentially. The formulations include e.g. those in a form suitable for oral, rectal, parenteral transdermal, intradermal, ophthalmic, topical, nasal, sublingual or buccal administration. The formulations may conveniently be presented in dosage unit form and may be prepared by but not restricted to any of the methods well known in the art of pharmacy, e.g. as disclosed in Remington, The Science and Practice of Pharmacy, 21ed ed., 2005. All methodsnclude the step of bringing the active ingredient into association with the carrier, which onstitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier, emisolid carrier or a finely divided solid carrier or combinations of these, and then, if necessary, shaping the product into the desired formulation. Formulations of the present invention suitable for oral and buccal administration may be in he form of discrete units as capsules, sachets, tablets, chewing gum or lozenges, each ontaining a predetermined amount of the active ingredient. A tablet may be made by compressing, moulding or freeze drying the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by ompressing, in a suitable machine, the active ingredient(s) in a free-flowing form; for example with a lubricant; a disintegrating agent or a dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier. Freeze dried tablets may be formed in a freeze-dryer from a solution of he drug substance. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of he recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. Liposomal ormulations are also suitable for parenteral administration. Transdermal formulations may be in the form of a plaster, patch, microneedles, liposomal or nanoparticulate delivery systems or other cutaneous formulations applied to the skin. Formulations suitable for ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredients. Liposomal formulations or biodegradable polymer ystems may also be used to present the active ingredient for ophthalmic administration. Formulations suitable for topical, such as dermal, intradermal or ophthalmic administrationnclude liquid or semi-solid preparations, solutions or suspensions. Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomisers. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference, egardless of any separately provided incorporation of particular documents made lsewhere herein. METHODS OF PREPARATION he compounds of the present invention can be prepared in a number of ways well known o those skilled in the art of synthesis. The compounds of the invention could for example e prepared using the reactions and techniques outlined below together with methods nown in the art of synthetic organic chemistry, or variations thereof as appreciated by hose skilled in the art. Preferred methods include, but are not limited to, those described elow. The reactions are carried out in solvents appropriate to the reagents and materials mployed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions,ncluding choice of solvent, reaction atmosphere, reaction temperature, duration of xperiment and work-up procedures, are chosen to be conditions of standard for that eaction, which should be readily recognized by one skilled in the art. Not all compounds alling into a given class may be compatible with some of the reaction conditions required in ome of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used. he compounds of the present invention or any intermediate could be purified, if required, sing standard methods well known to a synthetic organist chemist, e.g. methods escribed in “Purification of Laboratory Chemicals”, 6 ^th ed. 2009, W. Amarego and C. Chai, Butterworth-Heinemann. Starting materials are either known or commercially available compounds, or may be repared by routine synthetic methods well known to a person skilled in the art. Unless otherwise noted, reagents and solvents were used as received from commercial uppliers. The organic solvents used were usually anhydrous. The solvent ratios indicated efer to vol:vol unless otherwise noted. Thin layer chromatography was performed using Merck 6OF254 silica-gel TLC plates. Visualisation of TLC plates was performed using UV ght (254 nm) or by an appropriate staining technique. Proton nuclear magnetic resonance spectra were obtained at the stated frequencies in the solvents indicated. Tetramethylsilane was used as an internal standard for proton spectra. The value of a multiplet, either defined doublet (d), triplet (t), quartet (q) or (m) at the approximate midpoint is given unless a range is quoted. (br) indicates a broad peak, whilst (s) indicates a singlet. Mass spectra were obtained using the following methods. LCMS Method 1 was used, unless otherwise stated. LCMS Method 1: Column: Acquity UPLC HSS T3 1.8µm; 2.1 x 50mm Flow: 0.7mL/min Column temp: 30°C Mobile phases: A: 10 mM Ammonium acetate + 0.1% formic acid, B: 100% Acetonitrile + 0.1% formic acid UV: 240-400 nm njection volume: 1 µl Gradient: T 0 0 1 2 3 3 4 UPLC (inlet method): XEV Metode 1 CM MS – method: Pos_50_1000 or Neg_50_1000 nstruments: Waters Acquity UPLC, Waters XEVO G2-XS QTof, Waters PDA (Photodiode Array) LCMS Method 2: Mass spectra were obtained on a Waters Quattro micro API / Waters SQD2 / Waters Quattro Premier Spectrometer using electrospray ionization and atmospheric-pressure chemical ionization with the column and solvents indicated. LCMS Method 3: Column: Waters Acquity UPLC HSS T3 1.8µm, 2.1 x 50 mm. Column temperature: 60 ^o C. UV: PDA 210-400 nm. Injection volume: 2 µl. Eluents: A: 10 mM Ammonium acetate with 0.1% formic acid, B: 100% Acetonitrile with 0.1% formic acid. Gradient: Ti i A% B% Fl L/ i 0 0 0 1 1 1 MS: Electrospray switching between positive and negative ionisation. Instruments: Waters ACQUITY, Waters SQD, Waters PDA (Photodiode array) LCMS Method 4: Column: Waters ACQUITY BEH 1.7µm , 2.1 x 50 mm. Column temperature: 60 ^o C. UV: PDA 210-400 nm. Injection volume: 2 µl. Eluents: A : 10 mM Ammonium Bicarbonate, B : 100% Acetonitrile Gradient: T 0 0 0 1 1 1 .4 95 5 1.2 MS: Electrospray positive or negative ionisation. Instruments:Waters ACQUITY, Waters QDa (MS detector), Waters PDA (Photodiode Array) Basic preparative HPLC conditions: Column: XBridge Prep C18 5μm OBD, 19x150 mm Eluents: Ammonium formate (50 mM)/acetonitrile, 10-100% acetonitrile Flow: 30 mL/min Acidic preparative HPLC conditions: Column: XTerra ^® RP-18 5μm OBD, 19x150 mm Eluents: 0.1% formic acid in water/acetonitrile, 10-100% acetonitrile Flow: 30 mL/min The following abbreviations have been used throughout: ABPR automated back pressure regulator AcOH acetic acid BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl Boc tert-butoxycarbonyl BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CBz benzyloxycarbonyl CDI carbonyldiimidazole CPME cyclopentyl methyl ether DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DAST (diethylamino)sulfur trifluoride DEA diethylamine DEAD diethyl azodicarboxylate DCC dicyclohexylcarbodiimide DCM dichloromethane DIAD diisopropyl azodicarboxylate DIBAL diisobutylaluminium hydride DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide dppf 1,1′-bis(diphenylphosphino)ferrocene EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide FA formic acid EtOAc ethyl acetate EtOH ethanol HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-oxide hexafluorophosphate HBTU N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HPLC high-performance liquid chromatography IPA isopropyl alcohol LCMS liquid chromatography–mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide Me methyl MeCN acetontitrile MeOH methanol MHz megahertz MsCl methanesulfonyl chloride NBS N-bromosuccinimide NCS N-chlorosuccinimide NMR nuclear magnetic resonance ppm parts per million Prep. preparation Prep. HPLC preparative HPLC PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RT retention time SFC supercritical fluid chromatography SM starting material Soln. solution TBAF tetrabutylammonium fluoride TBME tert-butyl methyl ether TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TIPSCl triisopropylsilyl chloride TLC thin layer chromatography TMEDA tetramethylethylenediamine TMSCl trimethylsilyl chloride TMSI trimethylsilyl iodide TsCl tosyl chloride General Methods Compounds of the invention may be prepared according to the following non-limiting general methods and examples: Scheme 1 Synthesis of a compound of general formula (Ia), wherein R ¹ , R ² , R ³ , Q, Z ¹ , Z ² and Z ³ are as previously defined and PG represents a suitable protecting group: de Compounds of general formula (I) can be prepared, as shown in Scheme 1. Compounds of general formula (Int 1), which are either commercially available, or are synthesised in a racemic form or an enantiomerically pure form, are coupled with amines of general formula (Int 2), which are either commercially available or synthesised, in the presence of a coupling reagent such as T3P, CDI, DCC, HATU, HBTU and EDC and in the majority of cases, in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or acetonitrile to form compounds of formula (Int 3). Protecting groups (PG), such as Boc or Cbz, on compounds of general formula (Int 3) can be removed or selectively removed by methods known to those skilled in the art. Compounds of general formula (Int 4) are coupled with compounds of general formula (Int 5), which are either commercially available or synthesised, in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC and in most of the cases in the presence of a base, such as DIPEA or triethylamine, in a suitable solvents, such as DMF or acetonitrile to form compounds of general formula (Ia). Where the compounds of general formula (Ia) contain protecting groups, those protecting groups can be removed by methods known to those skilled in the art. Racemic compounds of general formula (Int 3), (Int 4) or (Ia) can be separated by chiral SFC, to give the S-enantiomers of compounds of general formula (Int 3), (Int 4) or (Ic). Scheme 2 Synthesis of a compound of general formula (Ia), wherein R ¹ , R ² , R ³ , Q, Z ¹ , Z ² and Z ³ are as previously defined and PG represents a suitable protecting group: cou lin rea ent deprotection Compounds of general formula (Ia) can be prepared, as shown in Scheme 2. Compounds of general formula (Int 1), which are either commercially available or are synthesised in a racemic form or an enantiomerically pure form, are coupled with amines of general formula (Int 2), which are either commercially available or synthesised, in the presence of a coupling reagent such as T3P, CDI, DCC, HATU, HBTU and EDC and in the majority of cases, in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or acetonitrile to form compounds of formula (Int 3). Protecting groups (PG), such as Boc, or Cbz, on compounds of general formula (Int 3) can be removed or selectively removed by methods known to those skilled in the art. Compounds of general formula (Int 6) are coupled with compounds of general formula (Int 5), which are either commercially available or synthesised, in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC and in most of the cases in the presence of a base, such as DIPEA or triethylamine, in a suitable solvents, such as DMF or acetonitrile to form compounds of general formula (Int 7). Compounds of general formula (Ia) can be accessed from compounds of general formula (Int 7) on treatment with TMSI or TMSCl and NaI in a suitable solvent such as MeCN at or above room temperature or BBr3 in DCM. Where the compounds of general formula (Ia) contain protecting groups, those protecting groups can be removed by methods known to those skilled in the art. Racemic compounds of general formula (Int 3), (Int 6), (Int 7) or (Ia) can be separated by chiral SFC, to give the S- enantiomers of compounds of general formula (Int 3), (Int 6), (Int 7) or (Ic). Scheme 3 Synthesis of a compound of general formula (Ib), wherein R ¹ , R ² , R ³ , Q, n, Z ⁴ , Z ⁵ and Z ⁶ are as previously defined and PG represents a suitable protecting group: cou lin rea ent de Compounds of general formula (Ib) can be prepared, as shown in Scheme 3. Compounds of general formula (Int 1), which are either commercially available or are synthesised in a racemic form or an enantiomerically pure form, are coupled with amines of general formula (Int 8), which are either commercially available or synthesised, in the presence of a coupling reagent such as T3P, CDI, DCC, HATU, HBTU and EDC and in the majority of cases, in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or acetonitrile to form compounds of formula (Int 9). Protecting groups (PG), such as Boc, or Cbz, on compounds of general formula (Int 9) can be removed or selectively removed by methods known to those skilled in the art. Compounds of general formula (Int 10) are coupled with compounds of general formula (Int 5), which are either commercially available or synthesised, in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC and in most of the cases in the presence of a base, such as DIPEA or triethylamine, in a suitable solvents, such as DMF or acetonitrile to form compounds of general formula (Ib). Where the compounds of general formula (Ib) contain protecting groups, those protecting groups can be removed by methods known to those skilled in the art. Racemic compounds of general formula (Int 9), (Int 10) or (Ib) can be separated by chiral SFC, to give the S-enantiomers of compounds of general formula (Int 9), (Int 10) or (Id). Scheme 4 Synthesis of a compound of general formula (Ia) or (Ib), wherein R ¹ , R ² , R ³ , Q, n, Z ¹ , Z ² , Z ^3, Z ⁴ , Z ⁵ and Z ⁶ are as previously defined, LG represents a suitable leaving group and PG ¹ and PG ² represent suitable orthogonal protecting groups: couplin rea ent deprotection Compounds of general formula (Ia) and (Ib) can be prepared, as shown in Scheme 4. Compounds of general formula (Int 1), which are either commercially available or are synthesised in a racemic form or an enantiomerically pure form, are coupled with amines of general formula (Int 11), which are either commercially available or synthesised, in the presence of a coupling reagent such as T3P, CDI, DCC, HATU, HBTU and EDC and in the majority of cases, in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or acetonitrile to form compounds of formula (Int 12). Protecting group PG ¹ , such as Boc or Cbz, on compounds of general formula (Int 12) can be selectively removed by methods known to those skilled in the art. Compounds of general formula (Int 13) are coupled with compounds of general formula (Int 5), which are either commercially available or synthesised, in the presence of a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC, and in most of the cases in the presence of a base, such as DIPEA or triethylamine, in a suitable solvents, such as DMF or acetonitrile to form compounds of general formula (Int 14). Protecting group PG ² , such as Boc or Cbz, on compounds of general formula (Int 14) can be removed by methods known to those skilled in the art. Alkylation of compounds of general formula (Int 15) with either compounds of formula (Int 16) or (Int 17), where LG represents a suitable leaving group such as Cl, Br, I, OMs or OTs, in a suitable solvent such as DMF, DMSO or MeCN, in the presence of a suitable base such as Cs2CO3, K2CO3 or TEA to form compounds of formula (Ib) or (Int 7). In the latter case the compounds of general formula (Ia) can be accessed from compounds of formula (Int 7) on treatment with TMSI or TMSCl and NaI in a suitable solvent such as MeCN at or above room temperature or BBr3 in DCM. Racemic compounds of general formula (Int 12), (Int 13), (Int 14), (Int 15) or (Ia) or (Ib) can be separated by chiral SFC, to give the S-enantiomers of compounds of general formula (Int 12), (Int 13), (Int 14), (Int 15) or (Ic) or (Id). Scheme 5 Synthesis of a compound of general formula (Ib), wherein R ¹ , R ² , R ³ , Q, Z ¹ , Z ² , Z ^3, Z ⁴ , Z ⁵ and Z ⁶ are as previously defined. Compounds of general formula (Ib) can be prepared, as shown in Scheme 5. Compounds of general formula (Ia) that are synthesised in a racemic form or an enantiomerically pure form, can be treated with a Pd/C catalyst in an atmosphere of hydrogen or with triethylsilane in a suitable solvent such as MeOH, EtOH or EtOAc. Scheme 6 Synthesis of compounds of general formula (Int 22), wherein R ^a is as previously defined. Int 21 Int 22 Compounds of formula (Int 22) can be prepared as shown in Scheme 6. Compounds of formula (Int 18), which are commercial or synthesised by literature methods, can react with aqueous sodium nitrate in a suitable solvent, such as AcOH, between 0°C and ambient temperature, to give compounds of general formula (Int 19). Treatment of compounds of formula (Int 19) with hydroxylamine hydrochloride in a suitable solvent such as EtOH, in the presence of either a suitable base such as sodium acetate or a suitable acid such as HCl in dioxane, between 60°C and 80°C, gives compounds of general formula (Int 20). Cyclisation to compounds of formula (Int 21) can be effected with CDI in THF. Acidic hydrolysis, using HCl in aqueous dioxane at 100°C or basic hydrolysis, using a suitable base such as LiOH or NaOH, in a suitable solvent such as aqueous THF or MeOH, affords compounds of formula (Int 22). Synthesis of compounds of general formula (Int 26), wherein R ^a is as previously defined. Oxime formation Cyclisation I ^{nt 25} _{Int 26} Compounds of general formula (Int 26) can be prepared as shown in Scheme 7. Compounds of formula (Int 23), which are commercial or synthesised by literature methods, can be treated by methods known to those skilled in the art, to give compounds of formula (Int 24). Compounds of formula (Int 24) can be halogenated with either NCS or NBS in DCM, then reacted with ethyl (E)-3-(dimethylamino)prop-2-enoate in a suitable solvent such as chloroform or DCM, in the presence of a suitable base, such as TEA, to give compounds of formula (Int 25). Compounds of formula (Int 26) can be prepared by basic hydrolysis of compounds of formula (Int 25) using LiOH or NaOH in a suitable solvent such as THF. Scheme 8 Preparation of compounds of formula (Int 29) wherein R ^a is as previously defined. I ^{nt 27} _{Int 28} Int 29 Compounds of general formula (Int 29) can be prepared as shown in Scheme 8 (see WO2020127685A for specific examples and preparations). Compound of formula (Int 27) that are commercial or synthesized can be reacted with alcohols, that are commercial or synthesized, under Mitsunobu conditions, namely in the presence of a phosphine such as triphenylphosphine and a diazodicarboxylate such as DEAD or DIAD, in a suitable solvent such as toluene or THF, to give compounds of formula (Int 28). Those skilled in the art will appreciate that some of the embodiments of R ^a will undergo literature precedented transformations or deprotection, before hydrolysis with an appropriate base such as LiOH or NaOH in a suitable solvent such as MeOH or THF, to give compounds of general formula (Int 29). 952-WO 33 Scheme 9 Preparation of compounds of formula (Int 32) wherein R ^a is as previously defined. A ^lkylation _{Carboxylation} I ^{nt 30 Int 31} _{Int 32} 5 Compounds of general formula (Int 32) can be prepared as shown in Scheme 9. To those skilled in the art, the compound of formula (Int 30) can be alkylated to give compounds of formula (Int 31) that are not commercially available. Preferable conditions use an alkyl halide in a suitable solvent such as MeCN or DMF, in the presence of a suitable base such as potassium carbonate. Compounds of formula (Int 31) are treated with n-butyllithium in10 a suitable solvent such as THF at 0°C, in the presence of carbon dioxide, to give compounds of formula (Int 32). Scheme 10 Synthesis of compounds of general formula (Int 34), wherein R ² , R ³ , Q, Z ¹ , Z ² and Z ³ are as15 previously defined. R-OH is a suitable alcohol. ^nt Compounds of general formula (Int 6) can be coupled to alcohols of general formula (Int 33), which are either commercially available or are synthesized, under appropriate conditions to give compounds of general formula (Int 34). For example, alcohols of general20 formula (Int 33) can be reacted with reagents such as phosgene, diphosgene, triphosgene, CDI, 4-nitrophenyl chloroformate or bis(2,5-dioxopyrrolidin-1-yl) carbonate, optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DCM, to form a reactive intermediate that is subsequently reacted with amines of general formula (Int 6), optionally in the presence of a suitable base, such as TEA, in a suitable solvent,25 such as MeCN or DMF, to give compounds of general formula (Int 34). Alternatively, the amines of general formula (Int 6) can be reacted with reagents such as phosgene, diphosgene, triphosgene, CDI, 4-nitrophenyl chloroformate or bis(2,5-dioxopyrrolidin-1-yl) carbonate, optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DCM to form a reactive intermediate that is subsequently reacted with30 alcohols of general formula (Int 33), optionally in the presence of a suitable base, such as 952-WO 34 TEA, in a suitable solvent, such as MeCN or DMF, to give compounds of general formula (Int 34). Scheme 11 5 Synthesis of compounds of general formula (Int 35), wherein R ² , R ³ , Q, Z ⁴ , Z ⁵ and Z ⁶ are as previously defined. R-OH is a suitable alcohol. carbamate Compounds of general formula (Int 10) can be coupled to alcohols of general formula (Int 33), which are either commercially available or are synthesized, under appropriate 10 conditions to give compounds of general formula (Int 35). For example, alcohols of general formula (Int 33) can be reacted with reagents such as phosgene, diphosgene, triphosgene, CDI, 4-nitrophenyl chloroformate or bis(2,5-dioxopyrrolidin-1-yl) carbonate, optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DCM, to form a reactive intermediate that is subsequently reacted with amines of general formula15 (Int 10), optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DMF, to give compounds of general formula (Int 35). Scheme 12 Preparation of a compound of formula (Int 1), wherein R ² is as previously defined and PG20 represents a suitable protecting group: Int 38 Int 1 Compounds of formula (Int 1) can be prepared as shown in Scheme 12. The reaction of an aldehyde of formula (Int 36) with potassium cyanide and ammonium carbonate in water and methanol forms compounds of formula (Int 37) (For Bucherer Bergs reaction, see:25 Chemical Reviews 2017 117 (23), 13757-13809). Compounds of formula (Int 38) can be prepared by treatment of compounds of formula (Int 37) with alkali hydroxides such as sodium hydroxide or potassium hydroxide in water. The amines of formula (Int 38) can be 952-WO 35 protected by methods known to those skilled in the art using, for example, CbzCl or Boc anhydride. Alternatively compounds of the formula (Int 1) may be commercially available. Scheme 13 5 Synthesis of a compound of formula (Int 1), wherein R ² is as previously defined and PG represents a suitable protecting group: Base HCl/H ₂ O I Alternatively, compounds of general formula (Int 1) can be prepared, as shown in Scheme 13. Compounds of formula (Int 39), where X is OTs, OMs, Cl, Br or I, are reacted with a10 commercially available compound (Int 40) in the presence of an alkali carbonate, such as sodium carbonate, potassium carbonate or caesium carbonate in a suitable solvent such as DMSO, DMF or acetonitrile to form compounds of formula (Int 41). Hydrolysis of a compound of formula (Int 41) can be performed by using aqueous HCl in a suitable solvent, such as THF, to give compounds of general formula (Int 42). The amines of formula (Int15 42) can be protected by methods known to those skilled in the art. The esters of formula (Int 43) are readily converted to compounds of formula (Int 1) in the presence of an alkali hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide. Racemic compounds of general formula (Int 43) can be separated by chiral SFC, to give the S- enantiomers of compounds of general formula (Int 43). 20 Scheme 14 Preparation of an enantiomerically pure compound of formula (Int 1’), wherein R ² is as previously defined and PG represents a suitable protecting group: 952-WO 36 H Int 46 Compounds of formula (Int 1’) can be prepared, as shown in Scheme 14. Compounds of formula (Int 44) and a commercially available ligand (Int 45) are mixed in the presence of Ni ²⁺ /K2CO3 in a protic solvent, such as methanol, to form nickel complexes of formula (Int 5 46) (for dynamic kinetic resolution of α-amino acids, see: Angew. Chem.Int. Ed.2015, 54, 12918-12922). Compounds of formula (Int 1’) are prepared by hydrolysis of compounds of formula (Int 46) in the presence of aq. HCl in a suitable protic solvent such as methanol and then protecting the amino group by using, for example, CbzCl or Boc anhydride. 10 Scheme 15 Preparation of a compound of formula (Int 1’), wherein R ² is as previously defined and PG represents a suitable protecting group: I ^{nt 49} Int 38' _{Int 1'} Compounds of formula (Int 1’) can be prepared, as shown in Scheme 15. Compounds of15 formula (Int 36) that are commercially available or synthesised, can react with (S)-4- methylbenzenesulfinamide (other (S)-aromatic sulfinamides may be used), in the presence of a tetraalkoxytitanium species such as Ti(OEt)4 in a suitable solvent such as DCM to form compounds of formula (Int 47). Compounds of formula (Int 48) can be accessed from compounds of formula (Int 47) with TMSCN and CsF in a suitable solvent such as hexane at20 low temperature or preferably with Et2AlCN in a solvent such as THF at low temperature. Cleavage of the sulfinamide to access compounds of formula (Int 49) can be achieved with 952-WO 37 HCl in a suitable solvent such as THF or 1,4.dioxane at reduced temperature. Further hydrolysis to compounds of formula (Int 38’) can be attained on treatment with concentrated acid such as HCl in water at elevated temperature. The amines of formula (Int 38’) can be protected by methods known to those skilled in the art using, for example, 5 CbzCl or Boc anhydride, to access compounds of formula (Int 1’). Scheme 16 Synthesis of a compound of general formula (Int 52), wherein R ³ , Q, Z ¹ , Z ² and Z ³ are as previously defined and LG represents a suitable leaving group: c ^ouple _reduce 10 ^{Int 50} _{Int 17} Int 51 Int 52 Compounds of formula (Int 52) can be prepared, as shown in Scheme 16. Compounds of formula (Int 50) can react with compounds of formula (Int 17) to form compounds of formula (Int 51). For example when LG is a Cl, Br, I, OMs or OTs, compounds of formula (Int 51) can be accessed in the presence of a base such as Cs2CO3 or K2CO3 in a suitable15 solvent such as DMSO, DMF or MeCN. When LG is OH, the compounds can be reacted in the presence of DEAD or DIAD and PPh3 or P ^t Bu3 in a suitable solvent such as toluene or THF to form compounds of formula (Int 51). Reduction to compounds of formula (Int 52) can be achieved by the reaction of compounds of formula (Int 51) under an atmosphere of hydrogen in the presence of a metal catalyst such as Pd/C or Pt/C, in a solvent such as20 MeOH, EtOH or EtOAc. Alternatively they can be reacted in the presence of triethylsilane, and Pd/C with or without a base such as TEA or DIPEA, in a suitable solvent such as MeOH or EtOH. Scheme 17 25 Synthesis of a compound of general formula (Int 52), wherein R ³ , Q, Z ⁴ , Z ⁵ and Z ⁶ are as previously defined and LG represents a suitable leaving group: Int 50 _{Int 16} Int 53 Int 54 Compounds of formula (Int 54) can be prepared, as shown in Scheme 17. Compounds of formula (Int 50) can react with compounds of formula (Int 16) to form compounds of30 formula (Int 51). For example when LG is a Cl, Br, I, OMs or OTs compounds of formula (Int 53) can be accessed in the presence of a base such as Cs2CO3 or K2CO3 in a suitable 952-WO 38 solvent such as DMSO, DMF or MeCN. When LG is OH, the compounds can be reacted in the presence of DEAD or DIAD and PPh3 or P ^t Bu3 in a suitable solvent such as toluene or THF to form compounds of formula (Int 53). Reduction to compounds of formula (Int 54) can be achieved by the reaction of compounds of formula (Int 53) under an atmosphere of 5 hydrogen in the presence of a metal catalyst such as Pd/C or Pt/C, in a solvent such as MeOH, EtOH or EtOAc. Alternatively they can be reacted in the presence of triethylsilane, and Pd/C with or without a base such as TEA or DIPEA, in a suitable solvent such as MeOH or EtOH. 10 Scheme 18 Synthesis of a compound of general formula (Int 17), wherein R ³ , Z ¹ , Z ² and Z ³ are as previously defined and LG represents a suitable leaving group: Int 55 Int 56 Int 57 Int 17 Compounds of formula (Int 17) can be prepared, as shown in Scheme 18. Compounds of15 formula (Int 56) that are commercially available, or synthesised from commercially available compounds of formula (Int 55) via lithiation using n-BuLi in a suitable solvent such as THF at reduced temperature and quenching with DMF, can be reacted with organometallic reagents such as organomagnesium compounds or organosilane compounds in suitable solvents, such as THF or 2-Me-THF at reduced temperature, to give compounds20 of formula (Int 57). Compound of formula (Int 57) can be used as highlighted in Scheme 16 (as Int 17 when LG = OH) or reacted with MsCl or TsCl in the presence of a suitable base such as TEA or pyridine in a solvent such as DCM or THF to give compounds of formula (Int 17). 25 Scheme 19 Synthesis of a compound of general formula (Int 57), wherein R ³ , Z ¹ , Z ² and Z ³ are as previously defined: I ^{nt 58} _{Int 59 Int 60 Int 57} Alternatively compounds of formula (Int 57) can be prepared as shown in Scheme 19.30 Compounds of formula (Int 58) that are commercially available or synthesised, can be 952-WO 39 treated with N-methoxymethanamine hydrochloride in the presence of a coupling reagent such as T3P, CDI, DCC, HATU, HBTU and EDC and in the majority of cases, in the presence of a base, such as DIPEA or TEA, in a suitable solvent, such as DMF or acetonitrile to form compounds of formula (Int 59). Addition of an appropriate organomagnesium reagent at 5 reduced temperature, in a suitable solvent such as THF, furnishes compounds of formula (Int 60). Compounds of formula (Int 57) can be attained on treatment of compounds of formula (Int 60) with NaBH4 or LiBH4 in a suitable solvent such as MeOH, EtOH or MeCN. Scheme 20 10 Synthesis of a compound of general formula (Int 57), wherein R ³ , Z ¹ , Z ² and Z ³ are as previously defined: I ^{nt 61} _{Int 57} Alternatively compounds of formula (Int 57) can be prepared as shown in Scheme 20. Compounds of formula (Int 61) that are commercially available or synthesised, can be15 reacted with a carboxylic acid, such as 2-hydroxyacetic acid or lactic acid, or an alcohol, such as EtOH, in the presence of ammonium peroxodisulfate in a suitable solvent mix such as water/t-butanol at elevated temperatures, with or without the presence of AgNO3, to give compounds of formula (Int 57). 20 PREPARATIONS AND EXAMPLES PREPARATIONS Preparation 1: (1-Cyclopropyl-2-methoxy-vinyl)cyclopropane. Potassium tert-butoxide (53.0 g, 472 mmol) was added slowly to a suspension of 25 methoxymethyl-(triphenyl)phosphonium chloride (160 g, 467 mmol) in dry THF (700 mL) at 5-10°C under argon (a weak exotherm was observed). The resulting deep red solution was stirred for 45 min at 5-10°C. Then dicyclopropylketone (39 mL, 37.6 g, 341 mmol) was added slowly (exothermic) The dark red colour quickly faded to give a yellow/orange solution. The reaction was stirred for 2 hours at room temperature under argon to give a30 red/orange mixture which was diluted with pentane (200 mL) and quenched with brine (50 mL) and water (100 mL) with vigorous stirring for 10 min. The organic layer was separated, dried (Na2SO4) and evaporated to give an orange syrup. Pentane (1000 mL) was added and 952-WO 40 stirred vigorously overnight and the mixture was filtered through a short pad of SiO2 (height: 10 cm; diameter: 6 cm). The filtrate was concentrated in vacuo to give the title compound (44.0 g, 93% yield) as a clear liquid. ¹ H NMR (300 MHz, CDCl3) δ 5.86 (dd, J = 1.6, 0.7 Hz, 1H), 3.57 (s, 3H), 1.87 – 1.74 (m, 1H), 0.89 – 0.78 (m, 1H), 0.76 – 0.67 (m, 5 2H), 0.64 – 0.57 (m, 2H), 0.51 – 0.41 (m, 2H), 0.27 – 0.19 (m, 2H). Preparation 2: 2,2-Dicyclopropylacetaldehyde. The compound of Preparation 1 (44.0 g, 318 mmol) was stirred vigorously in ether (10010 mL) and 5M HCl (30 mL) overnight at room temperature (reaction monitored by GCMS). The ether layer was separated, the aqueous layer was extracted with ether (2 x 50 mL) and the combined ether layers were dried (Na2SO4) and concentrated in vacuo to give 2,2- dicyclopropylacetaldehyde (39.0 g, 98% yield) as a clear liquid which was used without any further purification. ¹ H NMR (400 MHz, CDCl3) δ 9.74 (d, J = 2.9 Hz, 1H), 1.12 – 1.01 (m,15 1H), 0.95 – 0.81 (m, 2H), 0.66 – 0.49 (m, 4H), 0.34 – 0.19 (m, 4H). Preparation 3: 2-(benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoic acid. Ammonium carbonate (100 g, 1.04 mol) was added to a solution of the compound of20 Preparation 2 (22.8 g, 184 mmol) and KCN (17.9 g, 275 mmol) in EtOH:H2O (200 mL:200 mL) and the reaction mixture was stirred at 100°C for 6 hours. The cooled reaction mixture was concentrated in vacuo to low volume. The pH was adjusted to ~5 with 5M HCl (aq.) and the resulting precipitate was filtered and dried to give crude hydantoin (22.16 g, 62% yield) as a colourless solid that was used without further purification. 25 The crude hydantoin (22.16 g, 114 mmol) was heated at reflux in 9M NaOH (200 mL) overnight, then cooled in an ice bath and 8M HCl (100 mL) was added slowly. Benzyl chloroformate (21.4 g, 126 mmol) was then added with vigorous stirring. The mixture was stirred at room temperature for 1 hour then 8M HCl was added carefully until the pH was between 3 and 4. The mixture was extracted with EtOAc (3 x 100 mL) and the combined30 organic extracts were dried (Na2SO4) and evaporated. Purification by column chromatography (silica gel, eluting with EtOAc:heptane) gave the title compound (21.0 g, 61% yield) as a colourless oil. ¹ H NMR (400 MHz, DMSO-d6) δ = 12.5 (br, s, 1H), 7.42- 952-WO 41 7.20 (m, 6H), 5.09-5.01 (q, J=12.4 Hz 2H), 4.19-4.16 (q, J=4.4 Hz 1H), 0.97-0.95 (m, 1H), 0.80-0.78 (m, 1H), 0.58-0.08 (m, 9H); LCMS (METHOD 3) (ES): m/z 304.2 [M+H] ⁺ , RT = 0.72 min. 5 Preparation 4: methyl (2S)-2-(benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoate (4a) and (2R)-2-(benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoate (4b). Thionyl chloride (75.9 g, 643 mmol) was added dropwise over 20 minutes to a solution of the compound of Preparation 3 (65 g, 214 mmol) in MeOH (650 mL) at 0°C. The reaction10 mixture was warmed to room temperature over 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated aq. NaHCO3 (500 mL) and extracted with EtOAc (3 x 500 mL). The combined extracts were washed with H2O (200 mL) , brine solution (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica gel (100-200 mesh) column 15 chromatography (10% EtOAc/n-Hexane as eluent) to afford methyl 2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoate as an off-white solid (50 g, 73% yield). The mixture of isomers were separated by chiral SFC to afford methyl (S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoate, (24 g, 35.8% yield) and methyl (R)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoa te, (23 g, 33%20 yield) as colourless liquids. Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoa te (4a): ¹ H NMR (400 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 5.5 (d, J=6 Hz, 1H), 5.12 (s, 2H), 4.61-4.58 (dd, J=3.2 Hz , J=6 Hz ,1H), 3.7 (s, 3H), 0.73-0.69 (m, 3H ), 0.68-0.49 (m, 4H), 0.38-0.08 (m, 4H). LCMS (METHOD 2) (ESI): m/z: 318 [M+H] ⁺ ; 97%; RT= 2.22min (ACQUITY BEH C1825 (50mm x 2.1mm ) column, 0.1% Formic acid in water, 0.1% Formic acid in MeCN). Chiral purity: 99%; RT: 3.15 min, Column: CHIRALPAK IF (250 x 4.6 mm) 5µm; Co-solvent: Methanol, Total flow: 3 mL/min, % of co solvent: 15%, ABPR: 100 bar, Temperature: 30°C. Methyl (R)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoa te (4b): ¹ H NMR 30 (400 MHz, CDCl3) δ 7.37-7.31 (m , 5H), 5.5 (d, J=6 Hz, 1H), 5.12 (s, 2H), 4.61-4.58 (dd, J=3.2 Hz, J=6 Hz ,1H), 3.7 (s, 3H), 0.73-0.70 (m, 3H), 0.68-0.49 (m, 4H), 0.38-0.17 (m, 4H). LCMS (METHOD 2) (ESI): m/z: 318 [M+H] ⁺ ; 98%; RT = 2.60 min (ACQUITY BEH C18 (50mm x 2.1mm) column, 0.1% Formic acid in water, 0.1% Formic acid in MeCN). Chiral purity: 99%; RT: 4.50 min, Column: CHIRALPAK IF (250 x 4.6 mm) 5µm; Co-solvent: 42 Methanol, Total flow: 3 mL/min, % of co solvent: 15%, ABPR: 100 bar, Temperature: 30°C. Preparation 5: (2S)-2-(benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoic acid. 5 NaOH (4M aq. solution, 31.3 mmol) was added to a solution of the compound of Preparation 4a (4.96 g, 15.6 mmol) in MeOH (20 mL) and DCM (20 mL) and the reaction mixture was stirred at room temperature for 16 hours. H2O (50 mL) was added and the mixture was extracted with TBME (2 x 100 mL). The aqueous phase was acidified to pH 210 with 4M aq. HCl then extracted with EtOAc (3 x 100 mL). The combined EtOAc layers were dried over MgSO4, filtered and concentrated in vacuo to leave the title compound as a colourless solid (4.56 g, 96% yield). ¹ H NMR (600 MHz, CDCl3) δ 7.41 – 7.28 (m, 5H), 5.53 (d, J = 9.2 Hz, 1H), 5.13 (s, 2H), 4.64 (dd, J = 9.2, 2.6 Hz, 1H), 0.84 – 0.67 (m, 3H), 0.62 – 0.33 (m, 4H), 0.33 – 0.05 (m, 4H). 15 Preparation 6: (3-nitrophenyl)methyl (2S)-2-(tert-butoxycarbonylamino)-3,3- di(cyclobutyl)propanoate and (3-nitrophenyl)methyl (2R)-2-(tert-butoxycarbonylamino)- 3,3-di(cyclobutyl)propanoate. 20 A solution of 2-(tert-butoxycarbonylamino)-3,3-di(cyclobutyl)propanoic acid (4.80 g, 16.1 mmol) in DMF (30 mL) was cooled in an ice bath. Caesium carbonate (5.26 g, 16.1 mmol) was added and the mixture was stirred at 0°C for 1 hour before the addition of 1- (bromomethyl)-3-nitro-benzene (3.49 g, 16.1 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 16 hours. The reaction mixture was25 poured into water (300 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, eluting with EtOAc/heptane) to give the title compound (7.07 g, 96% yield) as a yellow oil that crystallised on storage at 4°C. ¹ H NMR (600 MHz, CDCl3) δ 8.27 (t, J = 1.9 Hz, 1H), 8.21 (ddd, J = 8.3, 2.4, 1.1 Hz,30 1H), 7.71 (dt, J = 7.6, 1.2 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 5.24 (d, J = 13.0 Hz, 1H), 5.22 (d, J = 13.0 Hz, 1H), 4.88 (d, J = 9.5 Hz, 1H), 4.31 (dd, J = 9.5, 2.6 Hz, 1H), 2.22 – 952-WO 43 2.09 (m, 2H), 2.07 – 1.99 (m, 1H), 1.99 – 1.53 (m, 12H), 1.44 (s, 9H); LCMS (METHOD 3) (ES): m/z 455.4 [M+Na] ⁺ , RT = 1.04 min. The two enantiomers were separated by preparative chiral SFC giving (3- nitrophenyl)methyl (2R)-2-(tert-butoxycarbonylamino)-3,3-di(cyclobutyl)propanoa te 5 (Preparation 6a) (Column: Lux A2 (4.6mm x 250mm, 5µm), Eluent: 25:75 MeOH:CO2 (0.2% v/v NH3), Temp: 40°C, Flow rate: 4 mL/min, BPR: 125 Bar, retention time: 1.3 min) and (3-nitrophenyl)methyl (2S)-2-(tert-butoxycarbonylamino)-3,3- di(cyclobutyl)propanoate (Preparation 6b) (Column: Lux A2 (4.6mm x 250mm, 5µm), Eluent: 20:80 IPA:CO2 (0.2% v/v NH3), Temp: 40°C, Flow rate: 4 mL/min, BPR: 125 Bar,10 retention time: 2.2 min). Preparation 7: (2S)-2-(tert-butoxycarbonylamino)-3,3-di(cyclobutyl)propanoi c acid. A solution of LiOH (404 mg, 16.9 mmol) in H2O (5 mL) was added to a solution of the15 compound of Preparation 6b (3.65 g, 8.44 mmol) in dioxane (15 mL) to give an emulsion. This was stirred at room temperature for 6 hours to give a clear solution. The reaction mixture was diluted with H2O (30 mL) and washed with Et2O (2 x 15 mL). The aqueous phase pH was adjusted to 2-3 with 5N HCl (aq.) and extracted with Et2O (2 x 30 mL). These ethereal extracts were washed with aqueous brine solution (10 mL), dried over20 MgSO4, filtered and concentrated in vacuo to give the crude title compound as a colourless oil (1.03 g, 41% yield) which was used without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 6.50 (d, J = 9.3 Hz, 1H), 3.93 (dd, J = 9.3, 3.0 Hz, 1H), 2.36 (q, J = 8.1 Hz, 1H), 2.08 (q, J = 8.9, 8.1 Hz, 1H), 1.95 – 1.49 (m, 13H), 1.38 (s, 9H). Rotamers observed at 6.11 + 6.50 and 3.83 + 3.93; LCMS (METHOD 3) (ES): m/z 296.325 [M-H]-, RT = 0.84 min. Preparation 8: ethyl 2-(benzhydrylideneamino)-2-(4 4-difluorocyclohexyl)acetate. 952-WO 44 4,4-Difluorocyclohexanol (300 mg 2.20 mmol) was dissolved in DCM (5 mL) and tosyl chloride (840 mg , 4.41 mmol) and pyridine (0.71 mL, 700 mg, 8.81 mmol) were added. The reaction was stirred at room temperature over the weekend then quenched by the addition of 1M HCl and extracted with DCM (x2). The combined organic phases were 5 washed with water and brine and then dried (Na2SO4), filtered and evaporated on dicalite. Purification by column chromatography (silica gel, eluting with 0-25% EtOAc in heptane) gave the intermediate (4,4-difluorocyclohexyl) 4-methylbenzenesulfonate (508 mg, 79% yield). The (4,4-difluorocyclohexyl) 4-methylbenzenesulfonate (500 mg , 1.72 mmol) and ethyl 2-(benzhydrylideneamino)acetate (460 mg, 1.72 mmol,) were dissolved in toluene (410 mL) and the mixture was degassed with argon for 2 minutes. LiHMDS (2.1 mL 2.1 mmol) was added slowly, the vial was capped and the reaction was stirred at 100°C for 16h. After cooling to room temperature water was added and the mixture was extracted with EtOAc (x2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated onto silica. Purification by column chromatography (silica gel, eluting with 0-15 25% EtOAc in heptane) gave the title compound (528 mg, 80% yield). ¹ H NMR (300 MHz, DMSO-d6) δ 7.63 – 7.31 (m, 8H), 7.22 – 7.03 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.77 (d, J = 6.1 Hz, 1H), 2.22 – 1.62 (m, 6H), 1.62 – 1.32 (m, 2H), 1.26 – 1.16 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H); LCMS (METHOD 3) (ES): m/z 386.5 [M+H] ⁺ , RT = 0.97 min 20 Preparation 9: nickelous (2S)-2-[(E)-[[2-[(2S)-1-benzylpyrrolidine-2- carbonyl]azanidylphenyl]-phenyl-methylene]amino]-2-(4,4-difl uorocyclohexyl)acetate. The compound of Preparation 8 (500 mg , 1.30 mmol) was dissolved in diethyl ether (5 mL) and 1M HCl (5 mL) was added. The reaction mixture was stirred at room temperature25 for 16 hours and then 4M NaOH was added until the pH was 12-13. The reaction mixture was stirred at 50°C for 3h then allowed to cool to room temperature and stirred for 16 hours. 4M HCl was added to the reaction mixture until the pH reached 5-6 and a precipitate started to appear. After 10 minutes the reaction mixture was filtered, washed with water and freeze dried over the weekend to give the amino acid (184 mg) as a solid. 30 The crude amino acid was combined with (2S)-N-(2-benzoylphenyl)-1-benzyl-pyrrolidine-2- carboxamide (537 mg, 1.40 mmol), nickel (II) acetate hydrate (236 mg, 1.21 mmol), K2CO3 (515 mg, 3.73 mmol) and MeOH (6 mL) in a 20 mL microwave vial. The vial was 952-WO 45 capped and the reaction mixture was stirred for 16 hours at 55°C. The reaction mixture was then stirred at 60°C for a further 24 hours. After cooling, water was added to the reaction and the mixture was extracted with DCM (x3). The combined organic phases were evaporated to dryness and taken up in TBME (20 mL). Precipitation of an orange solid was 5 seen. The mixture was stirred for 10 minutes, the precipitate was filtered off, washed with TBME and freeze dried for 16 hours to give the title compound (460 mg, 58% yield) as an orange solid. ¹ H NMR (300 MHz, DMSO-d6) δ 8.43 – 8.30 (m, 2H), 8.10 (dd, J = 8.8, 1.1 Hz, 1H), 7.68 – 7.43 (m, 4H), 7.41 – 7.26 (m, 3H), 7.17 – 7.04 (m, 2H), 6.67 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 6.58 (dd, J = 8.2, 1.7 Hz, 1H), 4.06 (d, J = 12.3 Hz, 1H), 3.76 (br s,10 1H), 3.65 – 3.51 (m, 2H), 3.48 (d, J = 1.7 Hz, 1H), 3.23 – 3.09 (m, 1H), 2.50 - 2.40 (m, 3H, partially obscured by DMSO signal), 2.36 – 1.76 (m, 5H), 1.74 – 1.22 (m, 4H), 0.63 (br d, J = 9.7 Hz, 1H); LCMS (METHOD 3) (ES): m/z 616.6, 618.6 [M+H] ⁺ , RT = 0.80 min. Preparation 10: (2S)-2-(tert-butoxycarbonylamino)-2-(4,4-difluorocyclohexyl) acetic acid. 15 The compound of Preparation 9 (450 mg, 0.730 mmol) was taken up in MeOH (10 mL) and 4M HCl (2 mL). The reaction was stirred at 60°C for 1 hour, during which time the dark red/orange solution became green. After cooling to room temperature the solution was basified to pH 12 with 2M NaOH and extracted with TBME (x3) to remove the 20 benzophenone by-product. To the basic solution of the amino acid was added Boc anhydride (474 mg, 2.17 mmol) dissolved in THF (5 mL). The reaction mixture was stirred at room temperature for 1 hour, carefully acidified with 2M HCl and extracted with DCM (x2). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound (161 mg, 76% yield). LCMS (METHOD 3) (ES-): m/z 292.4 [M-H]-, RT =25 0.65 min. Preparation 11: 4-methylcyclohexanecarbaldehyde 952-WO 46 A solution of DMSO (3.54 mL, 49.8 mmol) in DCM (8.5 mL) was added dropwise to a solution of oxalyl chloride (3.2 mL, 37.4 mmol) in DCM (150 mL) at -70°C under argon. On complete addition the reaction mixture was stirred at -75°C for 10 minutes. A solution of (4-methylcyclohexyl)methanol (3.55 g, 24.9 mmol) in DCM (15 mL) was added dropwise at 5 -70°C and the reaction mixture was stirred at -70°C for 30 minutes. TEA (11.6 mL, 83.0 mmol) was added and the reaction mixture was stirred for a further 30 mins at -70°C, then to room temperature over 1 hour. The reaction mixture was quenched with H2O and partitioned. The aqueous phase was washed with DCM (150 mL). The combined organic phases were washed with saturated brine solution (150 mL), dried over Na2SO4, filtered10 and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with Et2O in pentane, to afford the title compound as a colourless oil. (3.08 g, 83% yield). ¹ H NMR (600 MHz, CDCl3) δ 9.62 (d, J = 1.7 Hz, 1H), 2.15 (ttd, J = 12.2, 3.6, 1.8 Hz, 1H), 2.06 – 1.89 (m, 2H), 1.89 – 1.74 (m, 2H), 1.38 – 1.31 (m, 1H), 1.31 – 1.22 (m, 2H), 1.01 – 0.92 (m, 2H), 0.91 (d, J = 6.6 Hz,15 3H). Preparation 12: (N)-4-methyl-N-[(4-methylcyclohexyl)methylene]benzenesulfina mide. Tetraethoxytitanium (16.3 mL, 62.0 mmol) was added to a mixture of the compound of20 Preparation 11 (3.07 g, 20.7 mmol) and (S)-4-methylbenzenesulfinamide (3.21 g, 20.7 mmol) in DCM (120 mL) at room temperature. The reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature and quenched slowly with H2O (30 mL). The gelatinous reaction mixture was filtered through hyflo, washing the cake with DCM (2 x 30 mL), H2O (2 x 30 mL) then DCM (2 x 30 mL). The filtrate organic layer was collected. The25 aqueous layer was washed with DCM (150 mL). The combined organic phase was washed with saturated brine solution (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230- 400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil. (3.5 g, 64% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.11 (d, J = 4.9 Hz, 1H), 7.59 – 7.48 (m,30 2H), 7.33 – 7.22 (m, 2H), 2.40 (s, 3H), 2.34 (tdt, J = 12.0, 5.0, 3.5 Hz, 1H), 1.93 – 1.83 (m, 2H), 1.77 (ddtt, J = 13.1, 6.7, 3.3, 1.8 Hz, 2H), 1.38 – 1.23 (m, 3H), 0.97 (tdt, J = 13.3, 11.7, 3.6 Hz, 2H), 0.89 (d, J = 6.5 Hz, 3H). Preparation 13: N-[(S)-cyano-(4-methylcyclohexyl)methyl]-4-methyl-benzenesul finamide. 952-WO 47 2-Propanol (1.01 mL, 13.2 mmol) was added to a solution of diethylalumanylformonitrile (1M soln. in toluene, 19.9 mL) in THF (75 mL) at -70°C, and was stirred at this temperature for 45 minutes under argon. In a separate flask a solution of the compound of 5 Preparation 12 (3.49 g, 13.2 mmol) in THF (130 mL) was cooled to -75°C. To this was added the contents of the first flask via cannula. On complete addition the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to -30°C and saturated ammonium chloride solution (55 mL) was added. The resultant suspension was stirred to room temperature over 1 hour. The reaction mixture was filtered through10 hyflo, washing the cake with H2O (50 mL) then EtOAc (3 x 60 mL). The filtrate organic layer was collected. The aqueous layer was washed with EtOAc (200 mL). The combined organic phase was washed with saturated brine solution (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with ⁱ Pr2O in DCM, to afford the title 15 compound as a colourless solid. (2.70 g, 70% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.68 – 7.54 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.54 (d, J = 7.9 Hz, 1H), 3.95 (dd, J = 7.9, 5.9 Hz, 1H), 2.43 (s, 3H), 1.96 – 1.63 (m, 5H), 1.33 (dqd, J = 12.6, 7.2, 6.6, 3.1 Hz, 1H), 1.18 (dqd, J = 32.4, 12.6, 3.4 Hz, 2H), 1.01 – 0.86 (m, 5H). 20 Preparation 14: (2S)-2-amino-2-(4-methylcyclohexyl)acetonitrile hydrochloride. HCl (4M soln. in 1,4-dioxane, 10.0 mL) was added to a solution of the compound of Preparation 13 (2.50 g, 8.61 mmol) in MeOH (10.0 mL) at 0°C. The reaction mixture was stirred to room temperature over 2 hours. The reaction mixture was concentrated in vacuo25 and azeotroped with MeOH (10.0 mL). The solid was slurried in Et2O (25 mL) for 30 minutes, then filtered and dried in vacuo to afford the title compound as a colourless solid (1.59 g, 93% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 3H), 4.51 (d, J = 5.7 Hz, 1H), 1.92 – 1.78 (m, 3H), 1.78 – 1.68 (m, 2H), 1.30 (dddp, J = 16.5, 13.4, 6.6, 3.2 Hz, 1H), 1.10 (dqd, J = 25.0, 12.6, 3.5 Hz, 2H), 0.94 – 0.84 (m, 5H). 30 952-WO 48 Preparation 15: (2S)-2-amino-2-(4-methylcyclohexyl)acetic acid. H A suspension of the compound of Preparation 14 (1.48 g, 7.84 mmol) in concentrated HCl (15.0 mL) was stirred at 80°C for 24 hours. The cooled reaction mixture was concentrated 5 in vacuo and the residue was slurried in Et2O (35 mL) for 1 hour. The product was collected by filtration and dried overnight in vacuo to afford the title compound as a colourless solid (1.58 g, 96% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 13.70 (s, 1H), 8.40 (s, 3H), 3.68 (d, J = 4.4 Hz, 1H), 1.90 – 1.51 (m, 5H), 1.38 – 1.19 (m, 2H), 1.10 (qd, J = 12.5, 3.2 Hz, 1H), 0.96 – 0.73 (m, 5H). 10 Preparation 16: (2S)-2-(tert-butoxycarbonylamino)-2-(4-methylcyclohexyl)acet ic acid. H A solution of Na2CO3 (3.11 g, 29.3 mmol) in H2O (25.0 mL) was added to a suspension of the compound of Preparation 15 (1.05 g, 5.06 mmol) and tert-butoxycarbonyl tert-butyl15 carbonate (2.21 g, 10.1 mmol) in acetone (24.0 mL) and the reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated in vacuo to low volume. The residue was partitioned between H2O (10 mL) and Et2O (20 mL). The organic layer was collected and washed with H2O (10 mL). The combined aqueous layers were acidified to pH 1 with 2N HCl (aq.) and extracted with EtOAc (2 x 50 mL). The combined20 organic phase was washed with saturated brine solution (30 mL), dried over Na2SO4, filtered and dried in vacuo to afford the title compound as a colourless solid (1.01 g, 70 % yield). ¹ H NMR (600 MHz, DMSO-d6) δ 12.40 (s, 1H), 6.90 (d, J = 8.5 Hz, 1H), 3.78 (dd, J = 8.5, 6.0 Hz, 1H), 1.69 – 1.62 (m, 2H), 1.62 – 1.53 (m, 3H), 1.37 (d, J = 5.3 Hz, 9H), 1.29 – 1.19 (m, 1H), 1.08 (dqd, J = 25.5, 13.3, 12.3, 3.7 Hz, 2H), 0.91 – 0.77 (m, 5H). 25 Preparation 17: tert-butyl 4-[[(2S)-2-(benzyloxycarbonylamino)-3,3-dicyclopropyl- propanoyl]amino]pyrazole-1-carboxylate. 952-WO 49 HATU (2.10 g, 5.4 mmol) was added to a solution of the compound of Preparation 5 (1.10 g, 3.60 mmol), tert-butyl 4-aminopyrazole-1-carboxylate (0.65 g, 3.50 mmol) and TEA (1.0 mL) in DMF (15 mL) at room temperature. The reaction mixture was stirred for 4 hours, 5 then quenched with H2O (50 mL). The precipitate was collected and washed with H2O (3 x 20 mL), then dissolved in DCM, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a tan oil (1.54 g, 91% yield). LCMS (METHOD 3) (ES): m/z 469.3 [M+H] ⁺ , RT = 0.83 min. 10 Preparation 18: tert-butyl 4-[[(2S)-2-amino-3,3-dicyclopropyl-propanoyl]amino]pyrazole- 1- carboxylate. Triethylsilane (1.0 mL) was added dropwise to a thoroughly degassed solution of the compound of Preparation 17 (1.50 g, 3.2 mmol) and Pd/C (200 mg, 0.19 mmol) in MeOH15 (20 mL) under balloon pressure of nitrogen. On complete addition the reaction was stirred for 10 minutes, then filtered through Celite. The cake was washed with MeOH (3 x 20 mL). The combined organic phase was concentrated in vacuo to afford the title compound as a thick oil (0.87 g, 81% yield). LCMS (METHOD 3) (ES): m/z 333.2 [M-H]-, RT = 0.55 min. 20 Preparation 19: tert-butyl 4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole-3- carbonyl)amino]propanoyl]amino]pyrazole-1-carboxylate. HATU (1.30 g, 3.42 mmol) was added to a solution of the compound of Preparation 18 (870 mg, 2.60 mmol), 2-isopropylpyrazole-3-carboxylic acid (450 mg, 2.92 mmol) and TEA (125 mL) in DMF (10 mL) and stirred at room temperature for 10 minutes. H2O (30 mL) was 952-WO 50 added and the reaction mixture was stirred for 20 minutes. The solid was collected by filtration and dried in vacuo, to afford the title compound as a light yellow solid (0.82 g, 1.7 mmol). LCMS (METHOD 3) (ES): m/z 471.4 [M+H] ⁺ , RT = 0.79 min. 5 Preparation 20: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-(1H-pyrazol-4-ylamin o)ethyl]-2- isopropyl-pyrazole-3-carboxamide. TFA (2 mL) was added to a solution of the compound of Preparation 19 (0.82 g, 1.7 mmol) in DCM (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was10 concentrated in vacuo. The residue was dissolved in H2O (20 mL) and basified with solid K2CO3, and the reaction mixture was stirred for 30 minutes. The solid was collected by filtration. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc, to afford the title compound as a colourless solid. (401 mg, 62% yield). LCMS (METHOD 3) (ES): m/z 371.3 [M+H] ⁺ , RT = 0.60 min. 15 Preparation 21: (2-oxopyrrolidin-3-yl)methyl methanesulfonate. MsCl (0.082 mL, 1.06 mmol) was added dropwise to a solution of 3-(hydroxymethyl)- pyrrolidin-2-one (102 mg, 0.89 mmol) and TEA (0.185 mL, 1.33 mmol) in DCM (1.0 mL) at20 0°C. The reaction mixture was stirred for 1 hour, then quenched with 1M HCl (aq.) and extracted with DCM (2 x 1 mL). The combined organic phase was washed with saturated brine solution (1 mL), dried over Na2SO4, filtered and dried in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with MeOH in DCM, to afford the title compound as a colourless solid. (50 mg, 28% yield). ¹ H25 NMR (400 MHz, CDCl3) δ 5.69 (s, 1H), 4.46 (qd, J = 10.1, 4.2 Hz, 2H), 3.50 – 3.32 (m, 2H), 3.04 (s, 3H), 2.77 (tdd, J = 9.1, 4.9, 3.5 Hz, 1H), 2.38 (dddd, J = 12.9, 9.2, 7.0, 3.6 Hz, 1H), 2.22 (dq, J = 13.0, 8.9 Hz, 1H). Preparation 22: 5-bromo-3-(chloromethyl)-2-methoxy-pyridine. 952-WO 51 MsCl (0.65 mL, 8.94 mmol) was added dropwise to a solution of (5-bromo-2-methoxy-3- pyridyl)methanol (1.30 g, 5.96 mmol) in DCM (40 mL) at 0°C. The reaction mixture was stirred at 0°C for 5 minutes, warmed to 40°C and stirred for 90 minutes. The reaction 5 mixture was cooled and quenched with saturated NaHCO3 (aq., 10 mL) and extracted with DCM (2 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (5 mL) and diluted with heptane (10 mL). The solution was concentrated in vacuo until precipitation was seen. The solid was collected by filtration and dried in vacuo to afford the title compound as a colourless solid. 10 (1.30 g, 92% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 2.5 Hz, 1H), 4.68 (s, 2H), 3.93 (s, 3H). Preparation 23: N-[(1S)-1-[[1-[(5-bromo-2-methoxy-3-pyridyl)methyl]pyrazol-4 - yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole- 3-carboxamide. 15 Cs2CO3 (100 mg, 0.31 mmol) was added to a solution of the compound of Preparation 20 (58.0 mg, 0.157 mmol) and the compound of Preparation 22 (51.8 mg, 0.219 mmol) in DMSO (5 mL) and the reaction mixture was stirred at 120°C for 2 hours. The cooled reaction mixture was decanted and the solution purified directly by prep. acidic HPLC to20 afford the title compound (45.0 mg, 50% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 2.4 Hz, 1H), 7.96 (t, J = 1.4 Hz, 2H), 7.55 – 7.44 (m, 2H), 7.34 – 7.27 (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 5.46 (hept, J = 6.6 Hz, 1H), 5.19 (s, 2H), 4.79 (dd, J = 8.2, 5.3 Hz, 1H), 3.96 (s, 3H), 1.48 (dd, J = 8.8, 6.6 Hz, 6H), 0.97 – 0.75 (m, 3H), 0.62 (dtd, J = 7.8, 5.5, 4.5, 2.3 Hz, 1H), 0.58 – 0.45 (m, 3H), 0.42 – 0.31 (m, 2H),25 0.31 – 0.17 (m, 2H); LCMS (METHOD 3) (ES): m/z 572.3 [M+H] ⁺ , RT = 0.82 min. Preparation 24: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-methoxy-3- pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 952-WO 52 N,N,N',N'-tetramethylethane-1,2-diamine (18.3 mg, 0.158 mmol), NaBH4 (6.0 mg, 0.158 mmol) and Pd(dppf)Cl2.DCM (6.4 mg, 0.079 mmol) were added sequentially, under nitrogen, to a thoroughly degassed solution of the compound of Preparation 23 (45.0 mg, 5 0.079 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The cooled reaction mixture was filtered through a thin pad of silica gel, washing well with EtOAc. The filtrate was concentrated in vacuo and the residue was purified directly by prep. acidic HPLC to afford the title compound as a colourless solid (30.5 mg, 78% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 5.1, 1.9 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J10 = 0.7 Hz, 1H), 7.55 – 7.41 (m, 2H), 7.24 (dd, J = 7.3, 1.8 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 7.3, 5.0 Hz, 1H), 6.54 (d, J = 2.1 Hz, 1H), 5.45 (hept, J = 6.9 Hz, 1H), 5.22 (s, 2H), 4.79 (dd, J = 8.2, 5.4 Hz, 1H), 3.98 (s, 3H), 1.47 (dd, J = 9.4, 6.6 Hz, 6H), 1.00 – 0.71 (m, 3H), 0.60 (ddd, J = 8.0, 6.4, 4.1 Hz, 1H), 0.56 – 0.45 (m, 3H), 0.40 – 0.29 (m, 2H), 0.29 – 0.17 (m, 2H); LCMS (METHOD 3) (ES): m/z 492.3 [M+H] ⁺ , RT = 0.7315 min. Preparation 25: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[[2-methoxy-6-(trifluo romethyl)-3- pyridyl]methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 20 Cs2CO3 (97.6 mg, 0.30 mmol) was added to a solution of the compound of Preparation 20 (74.0 mg, 0.20 mmol) and 3-(chloromethyl)-2-methoxy-6-(trifluoromethyl)pyridine (48.0 mg, 0.212 mmol) in DMF (4 mL) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the solution was purified directly by prep. acidic HPLC to afford the title compound (100.6 mg, 90% yield). LCMS (METHOD 3) (ES):25 m/z 560.4 [M+H] ⁺ , RT = 0.84 min. Preparation 26: 1-(2-methoxy-3-pyridyl)ethyl 4-methylbenzenesulfonate. 952-WO 53 TsCl (119.5 mg, 0.627 mmol) was added to a solution of 1-(2-methoxy-3-pyridyl)ethanol (80.0 mg, 0.522 mmol), TEA (0.2 mL) and DMAP (20.0 mg, 0.164 mmol) in DCM (5 mL) at room temperature. The reaction mixture was stirred for 2 days then concentrated in vacuo. 5 The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil. (47.0 mg, 52% yield). ¹ H NMR (600 MHz, CDCl3) δ 8.11 (dd, J = 5.0, 1.9 Hz, 1H), 7.80 (ddd, J = 7.3, 1.9, 0.6 Hz, 1H), 6.92 (dd, J = 7.4, 4.9 Hz, 1H), 5.42 (q, J = 6.8 Hz, 1H), 3.99 (s, 3H), 1.79 (d, J = 6.8 Hz, 3H). 10 Preparation 27: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-p yrazole-3-carboxamide. Cs2CO3 (38.2 mg, 0.117 mmol) was added to a solution of the compound of Preparation 2015 (34.7 mg, 0.094 mmol) and the compound of Preparation 26 (24.0 mg, 0.14 mmol) in DMF (4 mL) and the reaction mixture was stirred at 80°C for 2 hours then at room temperature for 2 days. The reaction mixture was filtered and the solution was purified directly by prep. acidic HPLC to afford the title compound (32.0 mg, 81% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.05 (dd, J = 5.0, 1.9 Hz, 1H), 7.93 (d, J = 5.1 Hz, 1H), 7.49 (t, J = 1.8 Hz,20 1H), 7.44 (d, J = 3.5 Hz, 1H), 7.20 (dd, J = 7.4, 1.9 Hz, 1H), 7.15 (dd, J = 8.4, 4.0 Hz, 1H), 6.80 (dd, J = 7.4, 5.0 Hz, 1H), 6.55 (t, J = 2.4 Hz, 1H), 5.71 (q, J = 7.0 Hz, 1H), 5.43 (pd, J = 6.6, 2.5 Hz, 1H), 4.84 (dd, J = 8.3, 5.4 Hz, 1H), 3.96 (s, 3H), 1.79 (d, J = 7.0 Hz, 3H), 1.50 – 1.38 (m, 7H), 0.84 (tdd, J = 12.8, 8.7, 5.8 Hz, 3H), 0.63 – 0.41 (m, 4H), 0.34 (ddt, J = 17.5, 9.1, 4.4 Hz, 2H), 0.28 – 0.15 (m, 2H); LCMS (METHOD 3) (ES): m/z 504.525 [M-H]-, RT = 0.76 min. Preparation 28: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[[2-methoxy-5-(trifluo romethyl)-3- pyridyl]methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 952-WO 54 According to the method of Preparation 27 the compound of Preparation 20 (150 mg, 0.49 mmol) was reacted with 3-(bromomethyl)-2-methoxy-5-(trifluoromethyl)pyridine (40.1 mg, 0.148 mmol) to afford the title compound as a colourless foam (45.4 mg, 60% yield). ¹ H 5 NMR (400 MHz, CDCl3) δ 8.37 (dd, J = 2.4, 1.2 Hz, 1H), 8.11 (s, 1H), 7.98 (d, J = 0.7 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 5.45 (hept, J = 6.6 Hz, 1H), 5.24 (s, 2H), 4.81 (dd, J = 8.2, 5.4 Hz, 1H), 4.04 (s, 3H), 1.47 (dd, J = 9.6, 6.6 Hz, 6H), 1.00 – 0.75 (m, 3H), 0.68 – 0.43 (m, 4H), 0.43 – 0.31 (m, 2H), 0.31 – 0.17 (m, 2H); LCMS (METHOD 3)10 (ES): m/z 560.4 [M+H] ⁺ , RT = 0.83 min. Preparation 29: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(5-fluoro-2-methoxy-3 - pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 15 According to the method of Preparation 27 the compound of Preparation 20 (15 mg, 0.049 mmol) was reacted with 3-(chloromethyl)-5-fluoro-2-methoxy-pyridine (11.4 mg, 0.065 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (13.7 mg, 63% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 3.0 Hz, 1H), 8.02 (s, 1H), 7.57 – 7.45 (m, 2H), 7.11 (dd, J = 8.4, 3.0 Hz, 1H), 6.9320 (d, J = 2.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 5.25 (s, 2H), 4.72 (t, J = 7.9 Hz, 1H), 3.89 (s, 3H), 1.36 (dd, J = 10.3, 6.6 Hz, 6H), 0.84 (d, J = 7.9 Hz, 1H), 0.72 (d, J = 8.4 Hz, 2H), 0.50 – 0.14 (m, 7H), 0.14 – 0.03 (m, 1H); LCMS (METHOD 4) (ES): m/z 508.4 [M-H]-, RT = 0.75 min. 25 Preparation 30: [2-methoxy 4 trifl r m th l 3 rid l m thanol. 952-WO 55 Diborane (2M in THF, 4.0 mL) was added to a solution of 2-methoxy-4-(trifluoromethyl)- pyridine-3-carboxylic acid (500 mg, 2.26 mmol) in THF (10 mL) at room temperature and stirred for 1 hour. A further aliquot of diborane (2M in THF, 4.0 mL) was added and the reaction mixture was stirred at room temperature for a further 1 hour. The reaction mixture 5 was quenched with 1M HCl (aq., 20 mL) and filtered through Celite, washing the cake thoroughly with TBME. The organic phase was collected and the aqueous phase was extracted with TBME (2 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by prep. acidic HPLC to afford the title compound as a colourless solid (10.0 mg, 2% yield). ¹ H NMR10 (400 MHz, CDCl3) δ 8.26 (dd, J = 5.2, 0.9 Hz, 1H), 7.14 (d, J = 5.3 Hz, 1H), 4.79 (d, J = 1.1 Hz, 2H), 4.07 (s, 3H). Preparation 31: [2-methoxy-4-(trifluoromethyl)-3-pyridyl]methyl methanesulfonate. 15 MsCl (0.02 mL, 0.26 mmol) was added slowly to a solution of the compound of Preparation 30 (25.0 mg, 0.12 mmol) and TEA (0.05 mL, 0.4 mmol) in DCM (1.0 mL) at 5°C. The reaction mixture was stirred for 10 minutes then quenched with H2O (10 mL). The mixture was extracted with DCM (3 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo, to afford the crude title compound (34.4 mg, assume20 100% yield), that was used directly in the next reaction. LCMS (METHOD 3) (ES): m/z 286.1 [M+H] ⁺ , RT = 0.66 min. Preparation 32: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[[2-methoxy-4-(trifluo romethyl)-3- pyridyl]methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 25 According to the method of Preparation 25 the compound of Preparation 20 (54.0 mg, 0.146 mmol) was reacted with the compound of Preparation 31 (34.4 mg, 0.12 mmol) to afford the title compound as a colourless oil after prep. acidic HPLC (50.3 mg, 74% yield). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 5.3 Hz, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.49 (d, J30 = 2.0 Hz, 1H), 7.40 (s, 1H), 7.18 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 5.48 – 5.40 (m, 1H), 5.39 (s, 2H), 4.78 (dd, J = 8.3, 5.5 Hz, 1H), 3.97 (s, 952-WO 56 3H), 1.46 (dd, J = 11.2, 6.6 Hz, 6H), 0.99 – 0.70 (m, 4H), 0.69 – 0.42 (m, 4H), 0.33 (tp, J = 9.2, 4.5 Hz, 2H), 0.29 – 0.14 (m, 2H); LCMS (METHOD 3) (ES): m/z 560.5 [M+H] ⁺ , RT = 0.81 min. 5 Preparation 33: (5-chloro-2-methoxy-3-pyridyl)methyl methanesulfonate. According to the method of Preparation 31, (5-chloro-2-methoxy-3-pyridyl)methanol (30.5 mg, 0.176 mmol) was reacted to afford the title compound (44.2 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 252.1 [M+H] ⁺ , RT = 0.64 min. 10 Preparation 34: N-[(1S)-1-[[1-[(5-chloro-2-methoxy-3-pyridyl)methyl]pyrazol- 4- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole- 3-carboxamide. According to the method of Preparation 25 the compound of Preparation 20 (50.0 mg,15 0.135 mmol) was reacted with the compound of Preparation 31 (44.2 mg, 0.176 mmol) to afford the title compound as a colourless oil after prep. acidic HPLC (48.0 mg, 67% yield). LCMS (METHOD 3) (ES): m/z 526.5 [M+H] ⁺ , RT = 0.81 min. Preparation 35: 5-chloro-N,2-dimethoxy-N-methyl-pyridine-3-carboxamide. 20 HATU (1.10 g, 2.90 mmol) was added to a solution of 5-chloro-2-methoxy-pyridine-3- carboxylic acid (500 mg, 2.70 mmol), N-methoxymethanamine hydrochloride (310 mg, 3.20 mmol) and DIPEA (1.4 mL, 8.0 mmol) in DMF (5.0 mL) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with TBME (2025 mL) and H2O (10 mL). The separated organic layer was washed sequentially with saturated NaHCO3 (aq., 5 mL), H2O (5 mL) and saturated aqueous brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (479 mg, 78% yield). ¹ H 952-WO 57 NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 3.97 (s, 3H), 3.55 (s, 3H), 3.33 (s, 3H); LCMS (METHOD 3) (ES): m/z 231.2 [M+H] ⁺ , RT = 0.56 min. Preparation 36: 1-(5-chloro-2-methoxy-3-pyridyl)ethanone. 5 MeMgBr (3M solution, 0.74 mL, 2.22 mmol) was added to a solution of the compound of Preparation 35 (465 mg, 2.02 mmol) in THF (5.0 mL) at 0°C and stirred for 20 minutes. Analysis indicated the reaction was incomplete. A further portion of MeMgBr (3M solution,10 0.2 mL, 0.6 mmol) was added and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and stirred for 5 minutes then the layers were separated. The aqueous layer was extracted with THF (10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as an orange crystalline solid (241 mg, 64% yield) ¹ H NMR 15 (400 MHz, CDCl3) δ 8.24 (d, J = 2.6 Hz, 1H), 8.07 (d, J = 2.7 Hz, 1H), 4.05 (s, 3H), 2.63 (s, 3H). Preparation 37: 1-(5-chloro-2-methoxy-3-pyridyl)ethanol. 20 NaBH4 (29.7 mg, 0.785 mmol) was added to a solution of the compound of Preparation 36 (265 mg, 1.43 mmol) in EtOH (2 mL) and stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (1 mL) and concentrated in vacuo to low volume. H2O (5 mL) was added and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with saturated aqueous brine (2 mL),25 dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a colourless solid (226 mg, 84% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 2.6 Hz, 1H), 7.73 – 7.60 (m, 1H), 4.99 (q, J = 6.5 Hz, 1H), 3.97 (s, 3H), 1.48 (d, J = 6.5 Hz, 3H). Preparation 38: 5-chloro-3-(1-chloroethyl)-2-methoxy-pyridine. 952-WO 58 MsCl (0.04 mL, 0.53 mmol) was added slowly to a solution of the compound of Preparation 37 (32.9 mg, 0.18 mmol) and TEA (0.12 mL, 0.88 mmol) in DCM (1.0 mL) at 0-5°C. The reaction mixture was stirred for 1 hour then quenched with H2O (5 mL). The mixture was 5 extracted with DCM (2 x 10 mL). The combined organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo, to afford the crude title compound (36.1 mg, assume 100% yield), that was used directly in the next reaction. LCMS (METHOD 3) (ES): m/z 286.1 [M+H] ⁺ , RT = 0.60 min. 10 Preparation 39: N-[(1S)-1-[[1-[1-(5-chloro-2-methoxy-3-pyridyl)ethyl]pyrazol -4- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole- 3-carboxamide. According to the method of Preparation 25 the compound of Preparation 20 (50.0 mg, 0.135 mmol) was reacted with the compound of Preparation 38 (36.1 mg, 0.176 mmol) to15 afford the title compound as a colourless solid after prep. acidic HPLC (19.0 mg, 26% yield). LCMS (METHOD 3) (ES): m/z 540.5 [M+H] ⁺ , RT = 0.85 min. Preparation 40: (2-methoxy-5-methyl-3-pyridyl)methanol. 20 Borane dimethyl sulfide (0.284 mL, 2.99 mmol) was added dropwise to a solution of 2- methoxy-5-methyl-pyridine-3-carboxylic acid (200 mg, 1.20 mmol) in THF (4 mL) at room temperature. On cessation of gas evolution the reaction mixture was stirred at 60°C for 2 hours. The cooled reaction mixture was quenched with careful addition of MeOH (2 mL) and stirred for 30 minutes. The mixture was concentrated in vacuo, and the residue was25 dissolved in NaOH (5M aq. solution, 5 mL). The mixture was extracted with Et2O (2 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (107 mg, 58% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.92 – 7.85 (m, 1H), 7.40 (d, J = 2.3 Hz, 1H), 4.62 (s, 2H), 3.96 (s, 3H), 2.39 (d, J = 22.5 Hz, 1H), 952-WO 59 2.25 (s, 3H). Preparation 41: 3-(chloromethyl)-2-methoxy-5-methyl-pyridine. 5 MsCl (0.054 mL, 0.70 mmol) was added slowly to a solution of the compound of Preparation 40 (26.9 mg, 0.18 mmol) and DIPEA (0.092 mL, 0.53 mmol) in DCM (1.0 mL) at 0-5°C. The reaction mixture was stirred for 1 hour then quenched with H2O (5 mL). The mixture was extracted with DCM (2 x 10 mL). The combined organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo, to afford the crude title compound as a yellow10 oil (30.1 mg, assume 100% yield), that was used directly in the next reaction. LCMS (METHOD 3) (ES): m/z 172.1 [M+H] ⁺ , RT = 0.71 min. Preparation 42: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-methoxy-5-methyl-3 - pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 15 According to the method of Preparation 25 the compound of Preparation 20 (50.0 mg, 0.135 mmol) was reacted with the compound of Preparation 41 (30.1 mg, 0.176 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (26.0 mg, 38% yield). LCMS (METHOD 3) (ES): m/z 506.5 [M+H] ⁺ , RT = 0.76 min. 20 Preparation 43: (6-fluoro-2-methoxy-3-pyridyl)methanol. LiAlH4 (1M in THF, 4.6 mL) was added slowly to a stirring mixture of 6-fluoro-2-methoxy- pyridine-3-carboxylic acid (702 mg, 3.08 mmol) in THF (10 mL) at 5°C. The reaction25 mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0°C and quenched with HCl (2.5M aqueous solution, 3 mL) to pH 3, then diluted with H2O (20 mL) and extracted with DCM (2 x 50 mL). The combined organic phase was washed with saturated brine solution (aq., 25 mL), dried over Na2SO4, filtered and concentrated in 952-WO 60 vacuo. The obtained crude compound was purified by silica column chromatography (230- 400 mesh), eluting with DCM in heptane, to afford the title compound as a colourless oil. (160 mg, 33% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.67 (t, J = 7.9 Hz, 1H), 6.47 (dd, J = 7.8, 2.6 Hz, 1H), 4.63 (d, J = 6.2 Hz, 2H), 3.98 (s, 3H), 2.10 (t, J = 6.4 Hz, 1H). 5 Preparation 44: (6-fluoro-2-methoxy-3-pyridyl)methyl methanesulfonate. According to the method of Preparation 31, the compound of Preparation 43 (30 mg, 0.19 mmol) was reacted to afford the title compound (44.9 mg, assume 100%10 yield). ¹ H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 7.9 Hz, 1H), 6.56 – 6.46 (m, 1H), 5.21 (s, 2H), 3.99 (s, 3H), 3.03 (s, 3H). Preparation 45: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(6-fluoro-2-methoxy-3 - pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 15 According to the method of Preparation 25 the compound of Preparation 20 (60.0 mg, 0.162 mmol) was reacted with the compound of Preparation 44 (44.9 mg, 0.19 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (47.0 mg, 48% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.92 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H),20 7.44 (s, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.42 (dd, J = 7.9, 2.7 Hz, 1H), 5.45 (p, J = 6.6 Hz, 1H), 5.19 (s, 2H), 4.78 (dd, J = 8.2, 5.3 Hz, 1H), 3.97 (s, 3H), 1.47 (dd, J = 9.3, 6.6 Hz, 7H), 0.97 – 0.73 (m, 3H), 0.61 (td, J = 8.3, 4.4 Hz, 1H), 0.51 (ddh, J = 12.7, 7.9, 3.9 Hz, 3H), 0.40 – 0.29 (m, 2H), 0.29 – 0.16 (m, 2H); LCMS (METHOD 3) (ES): m/z 510.5 [M+H] ⁺ , RT = 0.77 min. 25 Preparation 46: tert-butyl (5S)-2-oxo-5-(trifluorometh l) rrolidine-1-carboxylate. 952-WO 61 tert-Butoxycarbonyl tert-butyl carbonate (2.80 g, 13.0 mmol) was added to a solution of (5S)-5-(trifluoromethyl)pyrrolidine-2-one (1.5 g, 9.8 mmol), DMAP (0.2 g, 2.0 mmol) and TEA (1.78 mL, 13.0 mmol) in DCM (50 mL) at room temperature and stirred for 30 minutes. 10% Aqueous citric acid (50 mL) was added and the organic layer was collected, 5 washed with H2O (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a reddish solid (2.45 g, 99% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 5.00 – 4.84 (m, 1H), 2.61 – 2.52 (m, 1H), 2.48 – 2.33 (m, 2H), 2.04 (ddt, J = 13.6, 9.4, 1.1 Hz, 1H), 1.46 (s, 9H). 10 Preparation 47: tert-butyl (3Z,5S)-3-(dimethylaminomethylene)-2-oxo-5- (trifluoromethyl)pyrrolidine-1-carboxylate. 1-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine (348.5 mg, 2.0 mmol) was added to15 a solution of the compound of Preparation 46 (140 mg, 0.55 mmol) in toluene (3 mL) and stirred at 100°C for 1 hour. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a yellow solid (125 mg, 73% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.15 (t, J = 1.6 Hz, 1H), 4.69 (dddd, J = 13.6, 8.5, 6.8, 1.7 Hz,20 1H), 3.17 – 3.07 (m, 1H), 3.05 (s, 6H), 3.01 (dt, J = 15.0, 1.6 Hz, 1H). Preparation 48: tert-butyl (5S)-3-methylene-2-oxo-5-(trifluoromethyl)pyrrolidine-1- carboxylate. 25 DIBAL (1M solution in THF, 5.27 mL) was added dropwise to a solution of the compound of Preparation 47 (1.0 g, 3.2 mmol) in THF (20 mL) at -75°C. On complete addition, the reaction mixture was stirred at -70°C for 1 hour, then warmed to room temperature over 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (aq., 20 mL) and slurried for 10 minutes. The mixture was extracted with TBME (3 x 30 mL). The combined 952-WO 62 organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless solid (642 mg, 75% yield). ¹ H NMR (400 MHz, CDCl3) δ 6.26 (dd, J = 3.5, 1.9 Hz, 1H), 5.60 (dd, J = 3.1, 1.7 5 Hz, 1H), 4.79 (dddd, J = 12.9, 8.1, 6.4, 1.6 Hz, 1H), 2.98 (ddt, J = 17.6, 9.2, 3.3 Hz, 1H), 2.88 (dq, J = 17.4, 1.8 Hz, 1H), 1.54 (d, J = 4.5 Hz, 9H). Preparation 49: tert-butyl (3S,5S)-3-[[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazo le- 3-carbonyl)amino]propanoyl]amino]pyrazol-1-yl]methyl]-2-oxo- 5-10 (trifluoromethyl)pyrrolidine-1-carboxylate. K2CO3 (10 mg, 0.072 mmol) was added to a solution of the compound of Preparation 20 (18.0 mg, 0.048 mmol) and the compound of Preparation 48 (12.0 mg, 0.045 mmol) in DMF and stirred at room temperature for 30 minutes. The reaction mixture was purified15 directly by prep. acidic HPLC to afford the title compound as a colourless solid (4.0 mg, 13% yield). ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.88 – 7.74 (m, 2H), 7.59 – 7.46 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 5.47 (hept, J = 6.6 Hz, 1H), 4.77 (dd, J = 8.1, 5.3 Hz, 1H), 4.62 (dq, J = 9.2, 7.1 Hz, 1H), 4.49 (dd, J = 14.3, 4.3 Hz, 1H), 4.31 (dd, J = 14.3, 6.9 Hz, 1H), 3.25 (dtd, J = 12.2, 7.5, 4.3 Hz, 1H), 2.33 (dd, J = 14.0, 8.6 Hz, 1H),20 2.14 (ddd, J = 14.6, 12.5, 9.2 Hz, 1H), 1.52 (s, 9H), 1.49 (dd, J = 11.9, 6.6 Hz, 6H), 0.94 – 0.74 (m, 3H), 0.63 (dtt, J = 11.4, 4.8, 2.6 Hz, 1H), 0.57 – 0.43 (m, 3H), 0.42 – 0.31 (m, 2H), 0.31 – 0.17 (m, 2H); LCMS (METHOD 3) (ES): m/z 636.5 [M+H] ⁺ , RT = 0.82 min. Preparation 50: tert-butyl (5S)-3-[[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole- 3-25 carbonyl)amino]propanoyl]amino]pyrazol-1-yl]methyl]-2-oxo-5- (trifluoromethyl)pyrrolidine-1-carboxylate. Cs2CO3 (10 mg, 0.072 mmol) was added to a solution of the compound of Preparation 20 (100 mg, 0.27 mmol) and the compound of Preparation 48 (71.6 mg, 0.27 mmol) in MeCN30 and stirred at room temperature for 16 hours. The reaction mixture was purified directly by 952-WO 63 prep. acidic HPLC to initially afford the (3R,5S) diastereomer. However on concentration in vacuo from n-butanol, the product was seen to racemise to afford the title compound as a colourless solid (4.0 mg, 2.1% yield). LCMS (METHOD 3) (ES): m/z 636.5 [M+H] ⁺ , RT = 0.81 and 0.83 min. 5 Preparation 51: (1S)-1-(2-methoxy-3-pyridyl)ethanol (51a) and [(1R)-1-(2-methoxy-3- pyridyl)ethyl] acetate (51b). Lipase B Candida antarctica (1.0 g) was added to a mixture of 1-(2-methoxy-3-10 pyridyl)ethanol (1.3 g, 8.5 mmol) and vinyl acetate (50 mL) and stirred gently at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compounds as colourless oils. 15 51a: (1S)-1-(2-methoxy-3-pyridyl)ethanol (617 mg, 47% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 5.0, 1.9 Hz, 1H), 7.62 (dd, J = 7.3, 1.9 Hz, 1H), 6.90 (dd, J = 7.3, 5.0 Hz, 1H), 5.01 (q, J = 6.5 Hz, 1H), 3.99 (s, 3H), 1.50 (d, J = 6.5 Hz, 3H); LCMS (METHOD 3) (ES): m/z 154.1 [M+H] ⁺ , RT = 0.44 min. 51b: [(1R)-1-(2-methoxy-3-pyridyl)ethyl] acetate (782 mg, 47% yield). ¹ H NMR (400 MHz,20 CDCl ₃ ) δ 8.09 (dt, J = 5.1, 1.4 Hz, 1H), 7.60 (ddd, J = 7.4, 2.0, 1.1 Hz, 1H), 6.88 (ddd, J = 7.7, 5.1, 1.1 Hz, 1H), 6.09 (q, J = 6.5 Hz, 1H), 3.97 (t, J = 0.9 Hz, 3H), 2.10 (t, J = 0.9 Hz, 3H), 1.48 (dd, J = 6.5, 1.0 Hz, 3H); LCMS (METHOD 3) (ES): m/z 196.2 [M+H] ⁺ , RT = 0.64 min. 25 Preparation 52: (1R)-1-(2-methoxy-3-pyridyl)ethanol. K2CO3 (50 mg, 0.36 mmol) was added to a solution of the compound of Preparation 51b (782 mg, 4.01 mmol) in MeOH (10 mL) at room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in H2O (20 mL) and30 extracted with DCM (4 x 20 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a colourless oil (575 mg, 93% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 5.0, 1.9 Hz, 1H), 7.77 – 7.53 (m, 952-WO 64 1H), 6.89 (dd, J = 7.3, 5.0 Hz, 1H), 5.01 (q, J = 6.7 Hz, 1H), 3.99 (d, J = 3.0 Hz, 3H), 2.59 (s, 1H), 1.49 (dd, J = 7.0, 2.4 Hz, 3H); LCMS (METHOD 3) (ES): m/z 154.1 [M+H] ⁺ , RT = 0.44 min. 5 Preparation 53: 2-methoxy-3-[(1S)-1-(4-nitropyrazol-1-yl)ethyl]pyridine. DIAD (0.59 mL, 3.0 mmol) was added to a solution of the compound from Preparation 52 (306.4 mg, 2.0 mmol), 4-nitro-1H-pyrazole (271.4 mg, 2.4 mmol) and triphenylphosphine (786.9 mg, 3.0 mmol) in THF (10mL) at room temperature and stirred for 30 minutes.10 Silica gel (5 g) was added to the reaction mixture and stirred, then concentrated in vacuo. The obtained residue was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless solid (325 mg, 65% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.16 (dd, J = 5.0, 1.8 Hz, 1H), 8.08 (s, 1H), 7.50 (dd, J = 7.5, 1.8 Hz, 1H), 6.92 (dd, J = 7.4, 5.0 Hz, 1H), 5.77 (q, J = 7.1 Hz,15 1H), 3.97 (s, 3H), 1.89 (d, J = 7.1 Hz, 3H); LCMS (METHOD 3) (ES): m/z 249.2 [M+H] ⁺ , RT = 0.66 min. Preparation 54: 1-[(1S)-1-(2-methoxy-3-pyridyl)ethyl]pyrazol-4-amine. 20 Triethylsilane (0.8 mL, 5.0 mmol) was added dropwise to a degassed solution of the compound of Preparation 53 (300 mg, 1.21 mmol) and Pd/C (10%, 50 mg, 0.047 mmol) in MeOH (10 mL) at room temperature. The mixture was stirred for 1 hour. The reaction mixture was filtered through Celite, and the cake was washed well with MeOH. The combined filtrate was concentrated in vacuo to afford the title compound (260 mg, assume25 100% yield). LCMS (METHOD 3) (ES): m/z 219.2 [M+H] ⁺ , RT = 0.36 min. Preparation 55: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1S)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. 952-WO 65 HATU (550 mg, 1.40 mmol) was added to a solution of the compound of Preparation 5 (360 mg, 1.20 mmol), the compound of Preparation 54 (260 mg, 1.2 mmol) and TEA (0.3 ml, 2.15 mmol) in DMF (5 mL) and stirred at room temperature for 30 minutes. The reaction 5 mixture was quenched with H2O (25 mL) and extracted with TBME (3 x 25 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by prep. acidic HPLC to afford the title compound as a colourless solid (453 mg, 75% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.09 – 8.02 (m, 2H), 7.99 (s, 1H), 7.44 (s, 1H), 7.33 (d, J = 8.2 Hz, 5H), 7.22 (dd, J = 7.4, 1.9 Hz, 1H), 6.8010 (dd, J = 7.4, 5.0 Hz, 1H), 5.70 (dd, J = 17.9, 10.8 Hz, 2H), 5.13 (s, 2H), 4.46 (dd, J = 8.6, 4.7 Hz, 1H), 3.97 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H), 0.86 (s, 1H), 0.71 (d, J = 11.1 Hz, 2H), 0.63 – 0.32 (m, 4H), 0.32 – 0.12 (m, 4H); LCMS (METHOD 3) (ES): m/z 504.5 [M+H] ⁺ , RT = 0.81 min. 15 Preparation 56: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(1S)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]propanamide. Triethylsilane (0.8 mL, 5.0 mmol) was added dropwise to a degassed solution of the compound of Preparation 55 (57 mg, 0.113 mmol) and Pd/C (10%, 20 mg, 0.019 mmol) in20 MeOH (5 mL) at room temperature. The mixture was stirred for 10 minutes. The reaction mixture was filtered through Celite, and the cake was washed well with MeOH. The combined filtrate was concentrated in vacuo to afford the title compound (41.8 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 370.4 [M+H] ⁺ , RT = 0.54 min. 25 Preparation 57: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1S)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-p yrazole-3-carboxamide. 952-WO 66 HATU (70.0 mg, 0.18 mmol) was added to a solution of the compound of Preparation 56 (41.8 mg, 0.113 mmol), 2-isopropylpyrazole-3-carboxylic acid (26 mg, 0.168 mmol) and TEA (0.1 ml, 0.71 mmol) in MeCN (5 mL) and stirred at room temperature for 30 minutes. 5 The reaction mixture was purified directly by prep. acidic HPLC to afford the title compound (44.0 mg, 76% yield). ¹ H NMR (600 MHz, CDCl3) δ 8.06 (dd, J = 5.0, 1.9 Hz, 1H), 8.01 (s, 1H), 7.99 – 7.95 (m, 1H), 7.51 (t, J = 2.2 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.23 (dd, J = 7.4, 1.9 Hz, 1H), 7.07 (dd, J = 8.3, 4.5 Hz, 1H), 6.81 (dd, J = 7.4, 5.0 Hz, 1H), 6.55 (dd, J = 3.8, 2.0 Hz, 1H), 5.73 (q, J = 7.0 Hz, 1H), 5.45 (pd, J = 6.6, 2.8 Hz, 1H), 4.80 (dd, J =10 8.2, 5.4 Hz, 1H), 3.97 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H), 1.53 – 1.42 (m, 6H), 0.90 – 0.75 (m, 3H), 0.65 – 0.57 (m, 1H), 0.56 – 0.46 (m, 3H), 0.35 (dtq, J = 17.8, 9.3, 4.8 Hz, 2H), 0.27 – 0.17 (m, 2H); LCMS (METHOD 3) (ES): m/z 506.5 [M+H] ⁺ , RT = 0.77 min. Preparation 58: 2,2,2-trifluoro-1-(2-methoxy-3-pyridyl)ethanol. 15 TBAF (1M solution in THF, 18.0 mL) was added slowly to a solution of 2-methoxypyridine-3- carboxaldehyde (1.15 g, 8.39 mmol) and trimethyl(trifluoromethyl)silane (2M solution in THF, 6.29 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with H2O (100 mL) and extracted with Et2O (3 x 30 mL). The20 combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (1.70 g, 98% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.20 (dq, J = 5.0, 1.6 Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 6.97 (dd, J = 7.4, 5.0 Hz, 1H), 5.24 (qd, J = 6.9, 1.7 Hz, 1H), 4.01 (q, J = 1.0 Hz, 3H),25 3.72 (d, J = 75.7 Hz, 1H). Preparation 59: 2-m th 3 2 2 2 trifl r 1 4 nitr r l 1 l th l]pyridine. 952-WO 67 According to the method of Preparation 53 the compound of Preparation 58 (207.1 mg, 1.0 mmol) was reacted with 4-nitro-1H-pyrazole (135.7 mg, 1.2 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (83.2 mg, 27% yield). ¹ H NMR (600 MHz, CDCl3) δ 8.30 (dd, J = 5.0, 1.9 Hz, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 8.09 (d, J = 7.3 5 Hz, 1H), 7.04 (dd, J = 7.6, 5.0 Hz, 1H), 6.33 (q, J = 7.4 Hz, 1H), 3.98 (s, 3H); LCMS (METHOD 3) (ES): m/z 303.3 [M+H] ⁺ , RT = 0.74 min. Preparation 60: 1-[2,2,2-trifluoro-1-(2-methoxy-3-pyridyl)ethyl]pyrazol-4-am ine. 10 According to the method of Preparation 54 the compound of Preparation 59 (82.0 mg, 0.27 mmol) was reacted to afford the crude title compound as a colourless oil (73.9 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 273.2 [M+H] ⁺ , RT = 0.50 min. 15 Preparation 61: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2,2,2-trifluoro -1-(2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 5 (82.3 mg, 0.27 mmol) was reacted with the compound of Preparation 60 (73.9 mg, 0.27 mmol) to afford20 the title compound as a colourless solid after prep. acidic HPLC (121.3 mg, 80% yield). ¹ H NMR (600 MHz, CDCl3) δ 8.21 (dd, J = 5.0, 1.9 Hz, 1H), 8.17 (s, 1H), 8.11 (d, J = 10.8 Hz, 2H), 7.49 (s, 1H), 7.39 – 7.28 (m, 5H), 6.96 (dd, J = 7.6, 5.0 Hz, 1H), 6.29 (q, J = 7.7 Hz, 1H), 5.76 – 5.62 (m, 1H), 5.11 (s, 2H), 4.45 (dd, J = 8.8, 5.0 Hz, 1H), 3.96 (s, 3H), 0.85 (s, 1H), 0.69 (s, 2H), 0.50 (dq, J = 9.3, 4.8, 4.1 Hz, 2H), 0.39 (t, J = 5.1 Hz, 2H), 0.29 –25 0.19 (m, 3H), 0.15 (dd, J = 9.0, 4.6 Hz, 1H); LCMS (METHOD 3) (ES): m/z 558.5 [M+H] ⁺ , RT = 0.86 min. Preparation 62: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[2,2,2-trifluoro-1-(2-me thoxy-3- pyridyl)ethyl]pyrazol-4-yl]propanamide. 952-WO 68 According to the method of Preparation 56 the compound of Preparation 61 (41.0 mg, 0.07 mmol) was reacted to afford the crude title compound as a colourless oil (31.1 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 424.4 [M+H] ⁺ , RT = 0.63 min. 5 Preparation 63: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2,2,2-trifluoro -1-(2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]ethyl]-2-isopropy l-pyrazole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 62 (31.1 mg, 0.0710 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (14.0 mg, 0.09 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (31.0 mg, 75% yield). ¹ H NMR (600 MHz, CDCl3) δ 8.22 (ddd, J = 5.0, 1.9, 1.1 Hz, 1H), 8.11 (dd, J = 7.7, 1.7 Hz, 1H), 8.07 (d, J = 4.7 Hz, 2H), 7.54 – 7.50 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.96 (ddd, J = 7.5, 5.0, 0.9 Hz, 1H), 6.54 (dd, J = 2.1, 0.9 Hz, 1H), 6.30 (qd, J = 7.7, 2.6 Hz,15 1H), 5.44 (pd, J = 6.7, 1.4 Hz, 1H), 4.78 (ddd, J = 8.2, 5.5, 1.3 Hz, 1H), 3.96 (d, J = 0.9 Hz, 3H), 1.47 (ddd, J = 15.0, 6.6, 1.7 Hz, 6H), 0.91 – 0.76 (m, 3H), 0.65 – 0.58 (m, 1H), 0.51 (dddd, J = 12.3, 10.2, 7.8, 5.2 Hz, 3H), 0.39 – 0.30 (m, 2H), 0.27 – 0.17 (m, 2H); LCMS (METHOD 3) (ES): m/z 560.5 [M+H] ⁺ , RT = 0.83 min. 20 Preparation 64: tert-butyl (5R)-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylate. According to the method of Preparation 46, (5R)-5-(trifluoromethyl)pyrrolidine-2-one (1.5 g, 9.8 m l) was reacted to afford the title compound as a colourless solid (2.40 g, 97% yield). ¹ H NMR (600 MHz, CDCl3) δ 4.74 (dtd, J = 9.0, 7.2, 6.1 Hz, 1H), 2.72 (dddd, J = 952-WO 69 18.0, 11.9, 9.4, 1.1 Hz, 1H), 2.50 (ddt, J = 17.9, 9.7, 1.3 Hz, 1H), 2.35 – 2.14 (m, 2H), 1.54 (s, 9H). Preparation 65: tert-butyl (3Z,5R)-3-(dimethylaminomethylene)-2-oxo-5- 5 (trifluoromethyl)pyrrolidine-1-carboxylate. According to the method of Preparation 47, the compound of Preparation 64 (1.7 g, 6.7 mmol) was reacted to afford the title compound as a light yellow solid (1.84 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 1.7 Hz, 1H), 4.69 (dtd, J = 16.0, 6.8, 1.7 Hz, 1H),10 3.12 (dd, J = 14.8, 9.9 Hz, 1H), 3.05 (s, 6H), 3.01 (dt, J = 15.1, 1.7 Hz, 1H), 1.53 (s, 9H). Preparation 66: tert-butyl (5R)-3-methylene-2-oxo-5-(trifluoromethyl)pyrrolidine-1- carboxylate. 15 According to the method of Preparation 48, the compound of Preparation 65 (1.0 g, 3.2 mmol) was reacted to afford the title compound as a colourless solid (623 mg, 72% yield). 1H NMR (400 MHz, CDCl3) δ 6.26 (s, 1H), 5.60 (s, 1H), 4.79 (p, J = 6.9 Hz, 1H), 3.12 – 2.80 (m, 2H), 1.56 (s, 9H). 20 Preparation 67: tert-butyl (3R,5R)-3-[[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazo le- 3-carbonyl)amino]propanoyl]amino]pyrazol-1-yl]methyl]-2-oxo- 5- (trifluoromethyl)pyrrolidine-1-carboxylate (67a) and tert-butyl (3S,5R)-3-[[4-[[(2S)-3,3- dicyclopropyl-2-[(2-isopropylpyrazole-3-carbonyl)amino]propa noyl]amino]pyrazol-1- yl]methyl]-2-oxo-5-(trifluoromethyl)pyrrolidine-1-carboxylat e (67b). 952-WO 70 According to the method of Preparation 50 the compound of Preparation 20 (100 mg, 0.27 mmol) was reacted with the compound of Preparation 66 (78.8 mg, 0.30 mmol) to afford the title compounds as a colourless solids after prep. acidic HPLC. 5 67a: tert-butyl (3R,5R)-3-[[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazo le-3- carbonyl)amino]propanoyl]amino]pyrazol-1-yl]methyl]-2-oxo-5- (trifluoromethyl)pyrrolidine-1-carboxylate (64 mg, 37% yield); LCMS (METHOD 3) (ES): m/z 636.5 [M+H] ⁺ , RT = 0.83 min. 67b: tert-butyl (3S,5R)-3-[[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazo le-3-10 carbonyl)amino]propanoyl]amino]pyrazol-1-yl]methyl]-2-oxo-5- (trifluoromethyl)pyrrolidine-1-carboxylate (4 mg, 2.3% yield); LCMS (METHOD 3) (ES): m/z 636.5 [M+H] ⁺ , RT = 0.81 min. Preparation 68: 2-methoxy-3-[(1R)-1-(4-nitropyrazol-1-yl)ethyl]pyridine. 15 According to the method of Preparation 53 the compound of Preparation 51a (149 mg, 0.97 mmol) was reacted with 4-nitro-1H-pyrazole (132 mg, 1.17 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (183 mg, 75% yield). LCMS (METHOD 3) (ES): m/z 249.220 [M+H] ⁺ , RT = 0.66 min. Preparation 69: 1-[(1R 1 2 h 3 id l h l l 4 ine. 952-WO 71 According to the method of Preparation 54 the compound of Preparation 68 (130 mg, 0.52 mmol) was reacted to afford the crude title compound as a colourless oil (114.3 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 219.3 [M+H] ⁺ , RT = 0.35 min. 5 Preparation 70: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1R)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 5 (158.9 mg, 0.5210 mmol) was reacted with the compound of Preparation 60 (114.3 mg, 0.52 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (183 mg, 69% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 5.0, 1.8 Hz, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 7.33 (d, J = 9.8 Hz, 5H), 7.22 (dd, J = 7.4, 1.9 Hz, 1H), 6.80 (dd, J = 7.4, 5.0 Hz, 1H), 5.73 (q, J = 7.0 Hz, 1H), 5.64 (s, 1H), 5.13 (s, 2H), 4.45 (dd, J = 8.6, 4.7 Hz, 1H),15 3.97 (s, 3H), 1.81 (d, J = 7.0 Hz, 3H), 0.88 (s, 1H), 0.70 (s, 2H), 0.60 – 0.34 (m, 4H), 0.34 – 0.11 (m, 4H); LCMS (METHOD 3) (ES): m/z 504.5 [M+H] ⁺ , RT = 0.81 min. Preparation 71: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(1R)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]propanamide. 20 According to the method of Preparation 56 the compound of Preparation 70 (32.0 mg, 0.064 mmol) was reacted to afford the crude title compound as a colourless oil (23.5 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 370.4 [M+H] ⁺ , RT = 0.54 min. 25 Preparation 72: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1R)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-p yrazole-3-carboxamide. 952-WO 72 According to the method of Preparation 57 the compound of Preparation 71 (23.5 mg, 0.064 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (14.0 mg, 0.09 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (22.0 mg, 68% 5 yield). ¹ H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.49 (dd, J = 6.8, 3.7 Hz, 2H), 7.25 (d, J = 10.0 Hz, 2H), 7.07 – 6.98 (m, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 4.1 Hz, 1H), 5.74 (d, J = 7.8 Hz, 1H), 5.46 (s, 1H), 4.77 (s, 1H), 3.97 (t, J = 2.7 Hz, 3H), 1.82 (dd, J = 6.4, 3.1 Hz, 3H), 1.48 (t, J = 7.3 Hz, 6H), 0.97 (t, J = 8.5 Hz, 1H), 0.85 (s, 2H), 0.72 – 0.46 (m, 4H), 0.36 (s, 2H), 0.23 (s, 2H); LCMS 10 (METHOD 3) (ES): m/z 506.5 [M+H] ⁺ , RT = 0.77 min. Preparation 73: 5-fluoro-2-methoxy-3-vinyl-pyridine. Pd(dppf)Cl2.DCM (390 mg, 0.478 mmol) was added to a degassed mixture of 3-bromo-5-15 fluoro-2-methoxypyridine (2.06 g, 10.0 mmol), potassium vinyltrifluoroborate (1.61 g, 12.0 mmol) and TEA (1.4 mL, 10.0 mmol) in EtOH (50 mL). The reaction mixture was sealed and heated at 120°C for 2 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in H2O (30 mL) and TBME (30 mL), then filtered through Celite, washing the cake with TBME. The phases of the filtrate were separated and the aqueous20 phase was re-extracted with TBME (30 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (712 mg, 46% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.9 Hz, 1H), 7.44 (dd, J = 8.6, 2.9 Hz, 1H), 6.84 (ddd, J = 17.7, 11.1, 1.4 Hz, 1H),25 5.81 (dd, J = 17.7, 1.0 Hz, 1H), 5.40 (dd, J = 11.1, 1.1 Hz, 1H), 3.96 (s, 3H). Preparation 73: 1-(5-fluoro-2-methoxy-3-pyridyl)ethane-1,2-diol. 952-WO 73 OsO4 (100 mg, 0.39 mmol) was added to a solution of the compound of Preparation 72 (700 mg, 4.57 mmol) and NMO (703 mg, 6.00 mmol) in acetone (20 mL) and H2O (10 mL) at room temperature. The reaction mixture was stirred for 1 hour, then quenched with 5 saturated aqueous Na2SO3 solution (5 mL). The resultant slurry was stirred for 30 minutes at room temperature then poured into H2O (25 mL) and extracted with DCM (3 x 50 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with MeOH in DCM, to afford the title compound as an off-white solid (541 mg, 63%10 yield). ¹ H NMR (600 MHz, DMSO-d6) δ 8.02 (d, J = 3.0 Hz, 1H), 7.60 (dd, J = 8.9, 3.0 Hz, 1H), 5.40 (d, J = 4.9 Hz, 1H), 4.74 (t, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.55 (ddd, J = 11.2, 6.1, 3.3 Hz, 1H). Preparation 74: 1-(5-fluoro-2-methoxy-3-pyridyl)-2-triisopropylsilyloxy-etha nol. 15 TIPSCl (0.74 mL, 3.50 mmol) was added to a solution of the compound of Preparation 73 (540 mg, 2.90 mmol) and imidazole (390 mg, 5.80 mmol) in DMF (5 mL) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with H ₂ O (25 mL) and extracted with TBME (3 x 20 mL). The combined organic phase was20 dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (1.07 g, 97% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 3.0 Hz, 1H), 7.59 (dd, J = 8.5, 3.0 Hz, 1H), 4.94 (dt, J = 7.2, 3.5 Hz, 1H), 4.03 (dd, J = 9.8, 3.5 Hz, 1H), 3.92 (s, 3H), 3.54 (dd, J = 9.8, 7.3 Hz, 1H), 3.15 (d, J25 = 3.5 Hz, 1H), 1.09 – 1.02 (m, 21H); LCMS (METHOD 3) (ES): m/z 344.4 [M+H] ⁺ , RT = 1.07 min. Preparation 75: [2-(5-fluoro-2-methoxy-3-pyridyl)-2-(4-nitropyrazol-1-yl)eth oxy]- triisopropyl-silane. 952-WO 74 According to the method of Preparation 53 the compound of Preparation 74 (1.05 g, 3.06 mmol) was reacted with 4-nitro-1H-pyrazole (415 mg, 3.67 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), 5 eluting with EtOAc in heptane, (1.06 g, 79% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.12 (s, 1H), 8.00 (d, J = 2.9 Hz, 1H), 7.42 (dd, J = 8.3, 2.9 Hz, 1H), 5.67 (dd, J = 7.6, 3.9 Hz, 1H), 4.41 (dd, J = 10.7, 7.6 Hz, 1H), 4.23 (dd, J = 10.6, 3.9 Hz, 1H), 3.96 (s, 3H), 1.05 (s, 3H), 0.98 (dd J = 6 7 4.3 Hz, 18H). 10 Preparation 76: 1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-triisopropylsilyloxy-e thyl]pyrazol-4- amine. According to the method of Preparation 54 the compound of Preparation 75 (300 mg, 0.68 mmol) was reacted to afford the crude title compound as a colourless oil (279.5 mg,15 assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 409.5 [M+H] ⁺ , RT = 1.00 min. Preparation 77: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3- pyridyl)-2-triisopropylsilyloxy-ethyl]pyrazol-4-yl]amino]-2- oxo-ethyl]carbamate. 20 According to the method of Preparation 55 the compound of Preparation 5 (104 mg, 0.34 mmol) was reacted with the compound of Preparation 76 (140mg, 0.34 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (183 mg, 77% yield). ¹ H NMR 952-WO 75 (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.91 (d, J = 2.9 Hz, 2H), 7.49 (s, 1H), 7.33 (dt, J = 11.7, 4.0 Hz, 6H), 5.75 – 5.57 (m, 2H), 5.14 (s, 2H), 4.52 – 4.30 (m, 2H), 4.24 (ddd, J = 10.4, 4.6, 1.6 Hz, 1H), 3.94 (s, 3H), 1.08 – 0.92 (m, 21H), 0.84 (d, J = 21.3 Hz, 1H), 0.77 – 0.63 (m, 2H), 0.60 – 0.32 (m, 4H), 0.32 – 0.12 (m, 4H). LCMS (METHOD 3) (ES): m/z 5 694.7 [M+H] ⁺ , RT = 1.14 min. Preparation 78: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[1-(5-fluoro-2-methoxy-3 -pyridyl)-2- triisopropylsilyloxy-ethyl]pyrazol-4-yl]propanamide. 10 According to the method of Preparation 56 the compound of Preparation 77 (180 mg, 0.26 mmol) was reacted to afford the crude title compound as a colourless oil (145.2 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 560.6 [M+H] ⁺ , RT = 1.24 min. Preparation 79: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3-pyridyl)-15 2-triisopropylsilyloxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl ]-2-isopropyl-pyrazole-3- carboxamide. According to the method of Preparation 57 the compound of Preparation 78 (73.0 mg, 0.13 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (20.0 mg, 0.13 mmol) to20 afford the title compound as a colourless solid after prep. acidic HPLC (72.0 mg, 80% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 2.2 Hz, 1H), 7.91 (d, J = 3.0 Hz, 1H), 7.83 (d, J = 3.4 Hz, 1H), 7.56 – 7.46 (m, 2H), 7.31 (td, J = 8.8, 3.0 Hz, 1H), 7.03 (dd, J = 8.2, 5.1 Hz, 1H), 6.55 (dd, J = 3.7, 2.0 Hz, 1H), 5.65 (td, J = 6.9, 4.6 Hz, 1H), 5.46 (pd, J = 6.7, 2.3 Hz, 1H), 4.78 (dd, J = 8.2, 5.2 Hz, 1H), 4.37 (ddd, J = 10.6, 7.5, 4.5 Hz, 1H),25 4.23 (ddd, J = 10.4, 4.4, 3.1 Hz, 1H), 3.94 (s, 3H), 1.48 (ddd, J = 10.3, 6.6, 1.9 Hz, 6H), 1.08 – 0.92 (m, 21H), 0.83 (tdt, J = 12.8, 9.3, 6.6 Hz, 3H), 0.67 – 0.44 (m, 4H), 0.44 – 952-WO 76 0.30 (m, 2H), 0.23 (qt, J = 8.0, 6.0, 4.3 Hz, 2H); LCMS (METHOD 3) (ES): m/z 696.7 [M+H] ⁺ , RT = 1.13 min. Preparation 80: 2-(5-fluoro-2-methoxy-3-pyridyl)-2-(4-nitropyrazol-1-yl)etha nol. 5 TBAF (1M solution in THF, 2 mL) was added to a solution of the compound of Preparation 75 (650 mg, 1.50 mmol) in THF (10 mL) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with TBME (20 mL) and washed with saturated aqueous NH4Cl solution (20 mL). The aqueous phase was collected and re-extracted with TBME (1010 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230- 400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (365 mg, 87% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.17 (s, 1H), 8.00 (d, J = 2.9 Hz, 1H), 7.33 – 7.23 (m, 1H), 5.72 (dd, J = 7.2, 3.5 Hz, 1H), 4.39 (dt, J = 12.5, 6.315 Hz, 1H), 4.29 – 4.18 (m, 1H), 3.98 (s, 3H), 2.76 (t, J = 5.9 Hz, 1H). Preparation 81: 5-fluoro-2-methoxy-3-[2-methoxy-1-(4-nitropyrazol-1-yl)ethyl ]pyridine. NaH (60% mass, 150 mg, 3.75 mmol) was added portion-wise to a solution of the 20 compound of Preparation 80 (350 mg, 1.24 mmol) in DMF (3 mL) at room temperature and stirred for 10 minutes. MeI (0.3 mL, 5.0 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with TBME (3 x 20 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by25 silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a tan oil (191 mg, 52% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.12 (s, 1H), 8.00 (d, J = 2.9 Hz, 1H), 7.39 (dd, J = 8.2, 3.0 Hz, 1H), 5.78 (dd, J = 7.9, 3.9 Hz, 1H), 4.15 (dd, J = 10.3, 7.9 Hz, 1H), 3.97 (s, 3H), 3.92 (dd, J = 10.4, 4.0 Hz, 1H), 3.38 (s, 3H). 952-WO 77 Preparation 82: 1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-methoxy-ethyl]pyrazol- 4-amine. According to the method of Preparation 54 the compound of Preparation 81 (191 mg, 0.64 5 mmol) was reacted to afford the crude title compound as a colourless oil (171.6 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 267.2 [M+H] ⁺ , RT = 0.43 min. Preparation 83: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3-10 pyridyl)-2-methoxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]car bamate. According to the method of Preparation 55 the compound of Preparation 5 (100 mg, 0.33 mmol) was reacted with the compound of Preparation 82 (85.8 mg, 0.32 mmol) to afford the title compound as light purple solid after prep. acidic HPLC (101 mg, 57% yield). ¹ H15 NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.9 Hz, 1H), 7.51 (s, 1H), 7.37 – 7.28 (m, 6H), 7.23 (dd, J = 8.3, 2.9 Hz, 1H), 5.75 (ddd, J = 8.5, 4.3, 1.6 Hz, 1H), 5.68 (s, 1H), 5.13 (s, 2H), 4.46 (dd, J = 8.7, 4.8 Hz, 1H), 4.14 (ddd, J = 10.2, 8.2, 2.0 Hz, 1H), 3.96 (s, 3H), 3.88 (ddd, J = 10.5, 4.2, 1.0 Hz, 1H), 3.35 (d, J = 1.1 Hz, 3H), 0.86 (s, 1H), 0.71 (s, 2H), 0.58 – 0.33 (m, 4H), 0.33 – 0.14 (m, 4H); LCMS (METHOD20 3) (ES): m/z 552.5 [M+H] ⁺ , RT = 0.83 min. Preparation 84: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[1-(5-fluoro-2-methoxy-3 -pyridyl)-2- methoxy-ethyl]pyrazol-4-yl]propanamide 952-WO 78 According to the method of Preparation 56 the compound of Preparation 83 (101 mg, 0.18 mmol) was reacted to afford the crude title compound as a colourless oil (76.4 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 418.4 [M+H] ⁺ , RT = 0.59 min. 5 Preparation 85: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3-pyridyl)- 2-methoxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl -pyrazole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 84 (38.2 mg, 0.09 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (15.0 mg, 0.098 mmol) to10 afford the title compound as an off-white solid after prep. acidic HPLC (41.0 mg, 82% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.9 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.50 (t, J = 2.6 Hz, 1H), 7.22 (td, J = 8.4, 3.0 Hz, 1H), 7.10 (dd, J = 8.3, 1.8 Hz, 1H), 6.55 (dd, J = 3.3, 2.1 Hz, 1H), 5.83 – 5.67 (m, 1H), 5.44 (pd, J = 6.6, 1.7 Hz, 1H), 4.81 (dd, J = 8.3, 5.2 Hz, 1H), 4.14 (ddd, J = 10.4, 8.2, 5.5 Hz,15 1H), 3.96 (s, 3H), 3.93 – 3.81 (m, 1H), 3.35 (d, J = 2.1 Hz, 3H), 1.46 (td, J = 6.9, 2.3 Hz, 6H), 0.92 – 0.73 (m, 3H), 0.68 – 0.45 (m, 4H), 0.35 (qd, J = 8.6, 8.0, 4.4 Hz, 2H), 0.31 – 0.16 (m, 2H); LCMS (METHOD 3) (ES): m/z 554.6 [M+H] ⁺ , RT = 0.79 min. Preparation 86: 3-bromo-2-methoxy-pyridin-4-amine. 20 NBS (2.60 g, 14.6 mmol) was added to a solution of 2-methoxypyridin-4-amine (1.80 g, 14.6 mmol) in MeCN (30 mL) portion-wise over 15 mins at room temperature. On complete addition the reaction mixture was stirred for 30 minutes, then concentrated in vacuo. The residue was partitioned between TBME (30 mL) and H2O (30 mL). The organic phase was25 collected, dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with DCM in EtOAc, to afford the title compound as a yellow oil (2.65 g, 90% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 5.6 Hz, 1H), 6.29 (d, J = 5.6 Hz, 1H), 4.60 (s, 2H), 3.97 (s, 3H). 30 952-WO 79 Preparation 87: 3-bromo-4-fluoro-2-methoxy-pyridine. t-Butyl nitrite (825 mg, 8.0 mmol) was added to a solution of the compound of Preparation 86 (1.0 g, 4.9 mmol) in HF/pyridine solution (60% mass, 17.0 mL) at -35°C. The reaction 5 mixture was stirred to 10°C over 1 hour then poured into ice/H2O (25 mL) and stirred for 10 minutes. The resultant slurry was extracted with TBME (3 x 25 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a tan oil (610 mg, 60% yield). ¹ H10 NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 7.9, 5.6 Hz, 1H), 6.72 (dd, J = 7.3, 5.6 Hz, 1H), 4.03 (s, 3H). Preparation 88: 4-fluoro-2-methoxy-pyridine-3-carbaldehyde. 15 n-BuLi (2.5M solution in hexane, 0.80 mL, 2.0 mmol) was added dropwise to a solution of the compound of Preparation 87 (412 mg, 2.0 mmol) in THF (5 mL) at -75°C. On complete addition the reaction mixture was stirred at -75°C for 10 minutes. DMF (0.47 mL, 6.0 mmol) was added and the reaction mixture was stirred at -75°C for 30 minutes. The reaction was quenched with saturated aqueous NaHCO3 solution (20 mL) and the resultant20 slurry was extracted with TBME (3 x 20 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a tan oil (153 mg, 49% yield). ¹ H NMR (400 MHz, CDCl3) δ 10.43 – 10.29 (m, 1H), 8.30 (dd, J = 8.1, 5.8 Hz, 1H), 6.75 (ddd, J = 9.4, 5.8, 0.5 Hz, 1H), 4.0925 (s, 3H). Preparation 89: (4-fluoro-2-methox -3-p rid l)methanol LiBH ₄ (42.1 mg, 1.93 mmol) was added in portions to a solution of the compound of30 Preparation 88 (150 mg, 0.97 mmol) in MeOH (5 mL) at room temperature. On complete 952-WO 80 addition the reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was partitioned between DCM (15 mL) and saturated aqueous NH4Cl solution (15 mL). The aqueous phase was collected and extracted with DCM (4 x 15 mL). The combined organic phase was dried over MgSO4, filtered and concentrated 5 in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless solid (91 mg, 60% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 8.5, 5.8 Hz, 1H), 6.68 (dd, J = 8.2, 5.8 Hz, 1H), 4.72 (dd, J = 6.8, 1.3 Hz, 2H), 4.02 (s, 3H), 2.40 (t, J = 6.8 Hz, 1H). 10 Preparation 90: (4-fluoro-2-methoxy-3-pyridyl)methyl methanesulfonate. According to the method of Preparation 21 the compound of Preparation 89 (30.0 mg, 0.19 mmol) was reacted to afford the crude title compound as a colourless oil (44.9 mg, assume15 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 236.2 [M+H] ⁺ , RT = 0.54 min. Preparation 91: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(4-fluoro-2-methoxy-3 - pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 20 Cs2CO3 (200 mg, 0.61 mmol) was added to a solution of the compound of Preparation 20 (84.0 mg, 0.227 mmol) and the compound of Preparation 90 (44.9 mg, 0.19 mmol) in DMSO (3 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified directly by prep. acidic HPLC to afford the title compound as a25 colourless solid (69 mg, 71% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 8.5, 5.8 Hz, 1H), 8.02 (s, 1H), 7.92 (d, J = 0.7 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 0.7 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.70 (dd, J = 8.2, 5.8 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 5.43 (h, J = 6.7 Hz, 1H), 5.27 (d, J = 1.1 Hz, 2H), 4.78 (dd, J = 8.3, 5.4 Hz, 1H), 3.99 (s, 3H), 1.46 (dd, J = 10.8, 6.6 Hz, 6H), 0.93 – 0.73 (m, 3H), 0.68 – 0.43 (m, 4H), 0.43 –30 0.30 (m, 2H), 0.21 (qq, J = 7.7, 3.8, 3.2 Hz, 2H); LCMS (METHOD 3) (ES): m/z 510.4 [M+H] ⁺ , RT = 0.70 min. 952-WO 81 Preparation 92: 1-(6-chloro-3-methoxy-pyridazin-4-yl)ethanol. A solution of ammonium peroxodisulfate (9.31 g, 40.8 mmol) in H2O (30 mL) was added 5 dropwise over 10 minutes, to a solution of 3-chloro-6-methoxy-pyridazine (2.04 g, 14.1 mmol) and in EtOH (45 mL) at 75°C. On complete addition the reaction mixture was stirred at 75°C for 2 hours. Solid NaHCO3 was added to the cooled reaction mixture until neutral pH was attained. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained10 crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless solid (942 mg, 33% yield). LCMS (METHOD 3) (ES): m/z 189.1 [M+H] ⁺ , RT = 0.44 min. Preparation 93: 6-chloro-3-methoxy-4-[1-(4-nitropyrazol-1-yl)ethyl]pyridazin e. 15 DEAD (40% solution in toluene, 5.3 mL, 12.0 mmol) was added to a solution of the compound from Preparation 92 (2.0 g, 11.0 mmol), 4-nitro-1H-pyrazole (1.36 g, 12.0 mmol) and triphenylphosphine (3.1 g, 12.0 mmol) in THF (15mL) at room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The obtained residue20 was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as an off-white solid (2.70 g, 90% yield). LCMS (METHOD 3) (ES): m/z 284.2 [M+H] ⁺ , RT = 0.64 min. Preparation 94: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]pyrazol-4-amin e. 25 Pt/C (10% mass, 0.25 g) was added to a degassed solution of the compound of Preparation 93 (2.20 g, 7.76 mmol) in EtOAc (50 mL) at room temperature under a balloon pressure atmosphere of hydrogen. The reaction mixture was stirred for 4 hours then filtered through 952-WO 82 Celite™, washing the cake with EtOAc. The filtrate was concentrated in vacuo to afford the crude title compound as an orange oil, that was used without further purification (1.97 g, assume 100% yield). LCMS (METHOD 3) (ES): m/z 254.2 [M+H] ⁺ , RT = 0.32 min. 5 Preparation 95: benzyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]py razol- 4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 5 (1.03 g, 3.40 mmol) was reacted with the compound of Preparation 94 (989 mg, 3.90 mmol) to afford10 the title compound as a colourless solid after silica column chromatography (1.76 g, 96% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.07 (s, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.35 (d, J = 4.6 Hz, 6H), 6.86 (dd, J = 1.7, 0.8 Hz, 1H), 6.72 (s, 2H), 5.82 – 5.64 (m, 1H), 5.64 – 5.51 (m, 1H), 5.14 (s, 2H), 4.49 (dd, J = 8.6, 4.9 Hz, 1H), 4.17 (s, 3H), 1.83 (d, J = 7.1 Hz, 3H), 1.75 (s, 1H), 0.95 – 0.65 (m, 3H), 0.61 – 0.36 (m, 4H), 0.36 – 0.12 (m,15 4H); LCMS (METHOD 3) (ES): m/z 539.5 [M+H] ⁺ , RT = 0.81 min. Preparation 96: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[1-(3-methoxypyridazin-4 - yl)ethyl]pyrazol-4-yl]propanamide. 20 According to the method of Preparation 56 the compound of Preparation 70 (161 mg, 0.298 mmol) was reacted to afford the crude title compound as a colourless oil (110 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 371.4 [M+H] ⁺ , RT = 0.51 min. Preparation 97 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(3-methoxypyridazin -4-25 yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide. 952-WO 83 According to the method of Preparation 57 the compound of Preparation 96 (55.0 mg, 0.148 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (22.9.0 mg, 0.148 mmol) to afford the title compound as an off-white solid after prep. basic HPLC (26.0 mg, 5 34% yield). LCMS (METHOD 3) (ES): m/z 507.4 [M+H] ⁺ , RT = 0.64 min. Preparation 98: 2-methoxy-3-[(4-nitropyrazol-1-yl)methyl]pyrazine. According to the method of Preparation 53 (3-methoxypyrazin-2-yl)methanol (205 mg,10 1.46 mmol) was reacted with 4-nitro-1H-pyrazole (150 mg, 1.33 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (218 mg, 70% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.12 (t, J = 1.9 Hz, 2H), 8.08 (s, 1H), 5.48 (s, 2H), 4.04 (s, 3H). 15 Preparation 99: 1-[(3-methoxypyrazin-2-yl)methyl]pyrazol-4-amine. According to the method of Preparation 54 the compound of Preparation 98 (216 mg, 0.92 mmol) was reacted to afford the crude title compound as a red oil (202 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 4) (ES): m/z 206.120 [M+H] ⁺ , RT = 0.30 min. Preparation 100: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxypyrazin-2- yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. 952-WO 84 According to the method of Preparation 55 the compound of Preparation 5 (278.6 mg, 0.92 mmol) was reacted with the compound of Preparation 99 (202 mg, 0.92 mmol) to afford the title compound as a colourless solid after silica column chromatography (311 mg, 69% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.18 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 5 2.8 Hz, 1H), 7.96 (s, 1H), 7.41 (s, 1H), 7.40 – 7.20 (m, 6H), 5.39 (s, 2H), 5.05 (d, J = 2.8 Hz, 2H), 4.27 (dd, J = 9.0, 6.4 Hz, 1H), 3.94 (s, 3H), 0.96 – 0.69 (m, 2H), 0.55 (q, J = 9.0 Hz, 1H), 0.43 (dq, J = 8.2, 4.6, 3.4 Hz, 1H), 0.33 (t, J = 8.7 Hz, 1H), 0.28 – 0.03 (m, 6H). Preparation 101: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(3-methoxypyrazin-2-10 yl)methyl]pyrazol-4-yl]propanamide. According to the method of Preparation 56 the compound of Preparation 100 (60 mg, 0.122 mmol) was reacted to afford the crude title compound as a colourless oil (45.7 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 357.4 [M+H] ⁺ , RT = 0.52 min. 15 Preparation 102: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxypyrazin-2- yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyraz ole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 101 (22.8 mg,20 0.06 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (10.3 mg, 0.067 mmol) to afford the title compound as an off-white solid after prep. basic HPLC (25.1 mg, 80% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.15 (dd, J = 18.6, 2.8 Hz, 2H), 7.98 (s, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.43 (s, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.49 – 5.29 (m, 3H), 4.79 – 4.62 (m, 1H), 3.94 (s, 3H), 1.36 (dd, J = 9.9, 6.6 Hz,25 6H), 0.94 – 0.65 (m, 3H), 0.54 – 0.04 (m, 8H); LCMS (METHOD 4) (ES): m/z 493.4 [M+H] ⁺ , RT = 0.66 min. Preparation 103: 2,2-difluoro-1-(5-fluoro-2-methoxy-3-pyridyl)ethanol. 952-WO 85 TBAF (1M solution in THF, 4.0 mL) was added to a solution of 5-fluoro-2-methoxy-pyridine- 3-carbaldehyde (310 mg, 2.0 mmol) and difluoro(trimethyl)silane (0.4 mL, 3.0 mmol) in THF (5 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 days. The 5 reaction mixture was diluted with H2O (100 mL) and extracted with Et2O (3 x 30 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (31.5 mg, 7.6% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 3.0 Hz, 1H), 7.57 (ddd, J = 8.1, 3.0,10 0.7 Hz, 1H), 5.97 (td, J = 55.4, 2.9 Hz, 1H), 5.04 (dtd, J = 15.9, 6.3, 2.8 Hz, 1H), 3.97 (s, 3H), 3.01 (d, J = 5.7 Hz, 1H); LCMS (METHOD 3) (ES): m/z 208.1 [M+H] ⁺ , RT = 0.56 min. Preparation 104: 3-[2,2-difluoro-1-(4-nitropyrazol-1-yl)ethyl]-5-fluoro-2-met hoxy-pyridine. 15 According to the method of Preparation 53 the compound of Preparation 103 (32 mg, 0.169 mmol) was reacted with 4-nitro-1H-pyrazole (23 mg, 0,203 mmol) to afford the title compound as a colourless oil after prep. acidic HPLC (25 mg, 52% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.15 (s, 1H), 8.10 (d, J = 2.9 Hz, 1H), 7.66 (dd, J = 7.9, 2.9 Hz, 1H), 6.51 (td, J = 54.6, 5.0 Hz, 1H), 5.93 (ddd, J = 11.9, 9.4, 5.0 Hz, 1H), 3.99 (s,20 3H). Preparation 105: 1-[2,2-difluoro-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]pyrazo l-4-amine. According to the method of Preparation 54 the compound of Preparation 104 (25 mg, 0.08225 mmol) was reacted to afford the crude title compound as a colourless oil (22.5 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 273.2 [M+H] ⁺ , RT = 0.47 min. 952-WO 86 Preparation 106: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[2,2-difluoro-1-(5-flu oro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carb amate. According to the method of Preparation 55 the compound of Preparation 5 (30 mg, 0.099 5 mmol) was reacted with the compound of Preparation 105 (22.5 mg, 0.082 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (26 mg, 56% yield) ¹ H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.03 – 7.97 (m, 2H), 7.65 (dd, J = 8.2, 3.0 Hz, 1H), 7.51 (s, 1H), 7.34 (s, 5H), 6.47 (td, J = 55.0, 5.1 Hz, 1H), 5.88 (ddd, J = 13.7, 8.7, 5.2 Hz, 1H), 5.58 (d, J = 40.9 Hz, 1H), 5.13 (d, J = 4.1 Hz, 2H), 4.44 (dd, J = 8.5, 4.7 Hz, 1H),10 3.97 (s, 3H), 0.88 (s, 1H), 0.70 (dd, J = 8.1, 4.8 Hz, 2H), 0.61 – 0.33 (m, 4H), 0.24 (tdd, J = 19.0, 11.8, 7.3 Hz, 4H); LCMS (METHOD 3) (ES): m/z 558.5 [M+H] ⁺ , RT = 0.87 min. Preparation 107: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[2,2-difluoro-1-(5-fluor o-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]propanamide. 15 According to the method of Preparation 56 the compound of Preparation 106 (26.0 mg, 0.047 mmol) was reacted to afford the crude title compound as a colourless oil (19.7 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 424.4 [M+H] ⁺ , RT = 0.55 min. 20 Preparation 108: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[2,2-difluoro-1-(5-flu oro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-i sopropyl-pyrazole-3- carboxamide. 952-WO 87 According to the method of Preparation 57 the compound of Preparation 107 (19.7 mg, 0.047 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (9.0 mg, 0.058mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (11.0 mg, 42% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.23 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 5 8.24 (d, J = 3.2 Hz, 1H), 8.16 (d, J = 1.5 Hz, 1H), 8.02 (ddd, J = 9.1, 6.4, 3.0 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.07 – 6.72 (m, 2H), 6.08 (td, J = 10.6, 5.9 Hz, 1H), 5.47 – 5.24 (m, 1H), 4.70 (t, J = 7.8 Hz, 1H), 3.90 (s, 3H), 1.35 (ddd, J = 10.4, 6.6, 1.5 Hz, 6H), 0.93 – 0.65 (m, 3H), 0.58 – 0.04 (m, 8H); LCMS (METHOD 3) (ES): m/z 560.5 [M+H] ⁺ , RT = 0.83 min. 10 Preparation 109: 5-fluoro-N,2-dimethoxy-N-methyl-pyridine-3-carboxamide. According to the method of Preparation 35, 5-fluoro-2-methoxy-pyridine-3-carboxylic acid (1.0 g, 5.84 mmol) was reacted to afford the title compound as a colourless oil (1.07 g, 15 85% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 3.0 Hz, 1H), 7.42 – 7.31 (m, 1H), 3.96 (s, 3H), 3.55 (s, 3H), 3.33 (s, 3H); LCMS (METHOD 3) (ES): m/z 215.2 [M+H] ⁺ , RT = 0.49 min. Preparation 110: 1-(5-fluoro-2-methoxy-3-pyridyl)ethanone. 20 According to the method of Preparation 36 the compound of Preparation 109 (1.06 g, 4.95 mmol) was reacted to afford the title compound as an orange solid (826 mg, 97% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 3.2 Hz, 1H), 7.87 (dd, J = 8.1, 3.1 Hz, 1H), 4.04 (s, 3H), 2.65 (s, 3H); LCMS (METHOD 3) (ES): m/z 170.2 [M+H] ⁺ , RT = 0.61 min. 25 Preparation 111: 1-(5-fluoro-2-methox -3- rid l)ethanol According to the method of Preparation 37 the compound of Preparation 110 (820 mg, 4.85 952-WO 88 mmol) was reacted to afford the title compound as a colourless oil (576 mg, 69% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 3.0 Hz, 1H), 7.45 (dd, J = 8.4, 3.0 Hz, 1H), 4.99 (dt, J = 8.7, 4.0 Hz, 1H), 3.96 (s, 3H), 2.48 – 2.38 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H) ; LCMS (METHOD 3) (ES): m/z 172.1 [M+H] ⁺ , RT = 0.52 min. 5 Preparation 112: (1S)-1-(5-fluoro-2-methoxy-3-pyridyl)ethanol (112a) and [(1R)-1-(5- fluoro-2-methoxy-3-pyridyl)ethyl] acetate (112b). According to the method of Preparation 51 the compound of Preparation 111 (565 mg, 3.3010 mmol) was reacted to afford the title compounds, 112a: (1S)-1-(5-fluoro-2-methoxy-3-pyridyl)ethanol (225 mg, 40% yield); LCMS (METHOD 3) (ES): m/z 172.1 [M+H] ⁺ , RT = 0.52 min. 112b: [(1R)-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl] acetate (265 mg, 38% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 2.9 Hz, 1H), 7.38 (dd, J = 8.3, 3.0 Hz, 1H), 6.03 (q, J =15 6.5 Hz, 1H), 3.94 (d, J = 0.7 Hz, 3H), 2.12 (d, J = 0.7 Hz, 3H), 1.47 (d, J = 6.5 Hz, 3H); LCMS (METHOD 3) (ES): m/z 214.2 [M+H] ⁺ , RT = 0.69 min. Preparation 113: (1R)-1-(5-fluoro-2-methoxy-3-pyridyl)ethanol. 20 According to the method of Preparation 52 the compound of Preparation 112b (250 mg, 1.17 mmol) was reacted to afford the title compound as a colourless oil (184 mg, 91% yield). LCMS (METHOD 3) (ES): m/z 172.1 [M+H] ⁺ , RT = 0.51 min. Preparation 114: 5-fluoro-2-methoxy-3-[(1S)-1-(4-nitropyrazol-1-yl)ethyl]pyri dine. 25 According to the method of Preparation 53 the compound of Preparation 113 (184 mg, 1.08 mmol) was reacted with 4-nitro-1H-pyrazole (145.9 mg, 1.29 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), 952-WO 89 eluting with EtOAc in heptane, (230 mg, 80% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 2.9 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.98 (t, J = 2.9 Hz, 1H), 7.33 – 7.25 (m, 1H), 5.79 – 5.65 (m, 1H), 3.96 (t, J = 2.6 Hz, 3H), 1.95 – 1.83 (m, 3H); LCMS (METHOD 3) (ES): m/z 267.3 [M+H] ⁺ , RT = 0.71 min. 5 Preparation 115: 1-[(1S)-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]pyrazol-4-amin e. According to the method of Preparation 54 the compound of Preparation 114 (230 mg, 0.86 mmol) was reacted to afford the crude title compound as a reddish oil (207 mg, assume 10 100% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 4.8 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.11 (d, J = 2.7 Hz, 1H), 6.92 (dt, J = 7.7, 3.5 Hz, 1H), 5.66 – 5.49 (m, 1H), 3.96 (d, J = 2.9 Hz, 3H), 1.78 (dd, J = 6.5, 3.0 Hz, 3H); LCMS (METHOD 3) (ES): m/z 237.2 [M+H] ⁺ , RT = 0.42 min. 15 Preparation 116: 2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid. A mixture of the compound of Preparation 2 (23.8 g, 192 mmol), KCN (18.7 g, 287 mmol) and ammonium carbonate (100 g, 1040 mmol) in water:EtOH (200 mL:200 mL) was heated at reflux for 6 hours. The resulting pale yellow solution was cooled to room 20 temperature, most of the EtOH was removed in vacuo, the pH was adjusted to between 5 and 6 with 5M HCl and the precipitate was filtered off and dried in vacuo to give 5- (dicyclopropylmethyl)imidazolidine-2,4-dione (26.4 g, 71% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 8.03 (s, 1H), 4.10 – 4.02 (m, 1H), 0.95 – 0.72 (m, 2H), 0.55 – 0.16 (m, 7H), 0.14 – 0.01 (m, 2H). 25 The crude hydantoin was heated at reflux in 6.7M NaOH (250 mL) for 48 hours, then cooled in an ice bath and 5M HCl (150 mL) was added slowly. To the cooled solution was then added over 5 min a solution of Boc anhydride (44.9 g, 206 mmol) in THF (60 mL). The mixture was stirred at room temperature for 2 hours, then 5M HCl was added carefully until the pH was between 3 and 4. The mixture was extracted with EtOAc (3 x 200 mL) and the30 combined organic extracts were dried (Na2SO4) and evaporated. Purification by column chromatography (silica gel, eluting with EtOAc:heptane) gave 2-(tert-butoxycarbonyl- amino)-3,3-dicyclopropyl-propanoic acid (31 g, 56% yield) as a clear oil that solidified on 952-WO 90 standing. ¹ H NMR (300 MHz, CDCl3) Mixture of rotamers δ 7.90 (br s, 1H), 5.78 (br, 0.15H), 5.26 (d, J = 9.2 Hz, 0.85H), 4.55 (d, J = 9.2 Hz, 0.85H), 4.37 (br, 0.15H), 1.46 (s, 9H), 1.33 – 1.21 (m, 1H), 0.85 – 0.64 (m, 2H), 0.61 – 0.36 (m, 4H), 0.32 – 0.13 (m, 4H); LCMS (METHOD 3) (ES): m/z 268.4 [M-H]-, RT = 0.70 min. 5 Preparation 117: (4-methoxyphenyl)methyl (2R)-2-(tert-butoxycarbonylamino)-3,3- dicyclopropyl-propanoate (117a) and (4-methoxyphenyl)methyl (2S)-2-(tert- butoxycarbonylamino)-3,3-dicyclopropyl-propanoate (117b). 10 EDC (7.77 g, 40.5 mmol) was added to a mixture of the acid of Preparation 116 (7.28 g, 27.0 mmol), 4-methoxybenzylalcohol (4.48 g, 32.4 mmol) and DMAP (3.3 g, 27.0 mmol) in DCM (100 mL) and stirred overnight at room temperature. The reaction mixture was washed with 0.25M Hydrogen chloride (15 mL), dried (Na2SO4) and evaporated. Purification by column chromatography (silica, eluting with EtOAc:heptane) gave the racemic title 15 compound (9.30 g, 88% yield) as a white solid. ¹ H NMR (300 MHz, CDCl3) δ 7.38 – 7.18 (m, 2H), 6.98 – 6.79 (m, 2H), 5.24 (d, J = 9.3 Hz, 1H), 5.09 (s, 2H), 4.53 (d, J = 9.3 Hz, 1H), 3.81 (s, 3H), 1.44 (s, 9H), 0.80 – 0.55 (m, 3H), 0.55 – 0.26 (m, 4H), 0.25 – 0.10 (m, 3H), 0.07 – -0.05 (m, 1H); LCMS (METHOD 3) (ES): m/z 390.3 [M+H] ⁺ , RT = 0.95 min. The two enantiomers were separated by preparative chiral SFC giving (4-20 methoxyphenyl)methyl (2R)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoa te (Preparation 117a) (Column: Lux A2 (4.6mm x 250mm, 5µm), Eluent: 20:80 IPA:CO2 (0.2% v/v NH3), Temp: 40°C, Flow rate: 4 mL/min, BPR: 125 Bar, retention time: 1.4 min) and (4-methoxyphenyl)methyl (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl- propanoate (Preparation 117b) (Column: Lux A2 (4.6mm x 250mm, 5µm), Eluent: 20:8025 IPA:CO2 (0.2% v/v NH3), Temp: 40°C, Flow rate: 4 mL/min, BPR: 125 Bar, retention time: 1.9 min). Preparation 118: (2S)-2-(tert-b tox carbon lamino)-3 3-dic clo ro l-propanoic acid. 952-WO 91 A solution of (4-methoxyphenyl)methyl (2S)-2-(tert-butoxycarbonylamino)-3,3- dicyclopropyl-propanoate (Preparation 117b) (5.30 g, 13.6 mmol) in MeOH (25 mL) was hydrogenated over 10% Pd/C (250 mg) using a hydrogen balloon. After 2½ hours the reaction mixture was filtered and evaporated. Purification by column chromatography 5 (silica, eluting with EtOAc:heptane) gave the title compound (3.50 g, 96% yield) as a clear syrup. ¹ H NMR (400 MHz, DMSO-d6) Mixture of rotamers δ 12.41 (s, 1H), 6.81 (d, J = 9.0 Hz, 0.82H), 6.48 (d, J = 8.2 Hz, 0.18H), 4.12 (dd, J = 9.0, 4.4 Hz, 0.82H), 4.05 (s, 0.18H), 1.39 (s, 7.4H), 1.25 (s, 1.6H), 1.02 – 0.88 (m, 1H), 0.83 – 0.72 (m, 1H), 0.56 – 0.42 (m, 2H), 0.41 – 0.20 (m, 4H), 0.19 – 0.01 (m, 3H); LCMS (METHOD 3) (ES): m/z 268.4 [M-H]-10 , RT = 0.71 min. Preparation 119: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1S)-1-(5-fluoro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carb amate. 15 According to the method of Preparation 55 the compound of Preparation 118 (91.2 mg, 0.339 mmol) was reacted with the compound of Preparation 115 (80.0 mg, 0.339 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (106 mg, 64% yield). LCMS (METHOD 3) (ES): m/z 488.5 [M-H]-, RT = 0.84 min. 20 Preparation 120: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(1S)-1-(5-fluoro-2-oxo- 1H-pyridin- 3-yl)ethyl]pyrazol-4-yl]propanamide. HCl (4M solution in 1,4-dioxane, 2.0 mL) was added to a solution of the compound of Preparation 119 (106 mg, 0.217 mmol) in MeOH (0.5 mL) and stirred at room temperature25 for 2 hours. The reaction mixture was concentrated in vacuo to afford the crude title compound that was used without further purification (81.1 mg assume 100% yield). LCMS (METHOD 3) (ES): m/z 374.4 [M-H]-, RT = 0.43 min. Preparation 121: N,2-dimethoxy-N,5-dimethyl-pyridine-3-carboxamide. 952-WO 92 According to the method of Preparation 35, 2-methoxy-5-methyl-pyridine-3-carboxylic acid (230 mg, 1.38 mmol) was reacted to afford the title compound as a colourless solid (249 mg, 86% yield). LCMS (METHOD 3) (ES): m/z 211.2 [M+H] ⁺ , RT = 0.49 min. 5 Preparation 122: 1-(2-methoxy-5-methyl-3-pyridyl)ethanone. According to the method of Preparation 36 the compound of Preparation 121 (249 mg, 1.18 mmol) was reacted to afford the title compound as a colourless oil (144 mg, 73% yield). 10 LCMS (METHOD 3) (ES): m/z 166.2 [M+H] ⁺ , RT = 0.60 min. Preparation 123: 1-(2-methoxy-5-methyl-3-pyridyl)ethanol. According to the method of Preparation 37 the compound of Preparation 122 (144 mg, 0.8715 mmol) was reacted to afford the title compound as a colourless oil (114 mg, 78% yield). LCMS (METHOD 3) (ES): m/z 168.1 [M+H] ⁺ , RT = 0.50 min. Preparation 124: 2-methoxy-5-methyl-3-[1-(4-nitropyrazol-1-yl)ethyl]pyridine. 20 According to the method of Preparation 53 the compound of Preparation 123 (114 mg, 0.68 mmol) was reacted with 4-nitro-1H-pyrazole (92.5 mg, 0.82 mmol) to afford the title compound as a colourless oil after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (102 mg, 57% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.08 (s, 1H), 7.95 (dd, J = 2.3, 0.9 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 5.74 (q, J = 7.1 Hz,25 1H), 3.93 (s, 3H), 2.25 (s, 3H), 1.88 (d, J = 7.1 Hz, 3H); LCMS (METHOD 3) (ES): m/z 952-WO 93 263.3 [M+H] ⁺ , RT = 0.71 min. Preparation 125: 1-[1-(2-methoxy-5-methyl-3-pyridyl)ethyl]pyrazol-4-amine. 5 According to the method of Preparation 54 the compound of Preparation 124 (90 mg, 0.34 mmol) was reacted to afford the crude title compound as a reddish oil (79.7 mg, assume 100% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 2.4, 1.0 Hz, 1H), 7.22 (d, J = 1.0 Hz, 1H), 7.10 (d, J = 0.9 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 5.61 (q, J = 7.0 Hz, 1H), 3.95 (s, 3H), 2.17 (s, 3H), 1.78 (d, J = 7.1 Hz, 3H); LCMS (METHOD 3) (ES): m/z 233.2 10 [M+H] ⁺ , RT = 0.42 min. Preparation 126: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(2-methoxy-5- methyl-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carba mate. 15 According to the method of Preparation 55 the compound of Preparation 118 (91.6 mg, 0.34 mmol) was reacted with the compound of Preparation 125 (79.0 mg, 0.34 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (124 mg, 75% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 – 7.93 (m, 2H), 7.86 (dd, J = 2.3, 1.0 Hz, 1H), 7.48 (d, J = 0.9 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 5.85 – 5.64 (m, 1H), 5.36 (s, 1H), 4.38 (dd, J =20 8.1, 4.4 Hz, 1H), 3.94 (s, 3H), 2.17 (s, 3H), 1.81 (s, 3H), 1.46 (s, 9H), 1.01 – 0.62 (m, 3H), 0.59 – 0.11 (m, 8H); LCMS (METHOD 3) (ES): m/z 484.5 [M-H]-, RT = 0.83 min. Preparation 127: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[1-(5-methyl-2-oxo-1H-py ridin-3- yl)ethyl]pyrazol-4-yl]propanamide. 25 According to the method of Preparation 120 the compound of Preparation 126 (115 mg, 952-WO 94 0.24 mmol) was reacted to afford the title compound as a colourless oil (87.9mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 370.4 [M-H]-, RT = 0.44 min. Preparation 128: 3-methoxy-6-(trifluoromethyl)pyridazine. 5 NaOMe (4.4M solution in MeOH, 2.6 mL) was added to a solution of 3-chloro-6- (trifluoromethyl)pyridazine (460 mg, 2.5 mmol) in MeOH (10 mL) at room temperature. The resultant yellow solution was stirred for 2 hours, then concentrated in vacuo. The residue was slurried in H2O (10 mL) and the precipitate was collected by filtration. The solid10 was dissolved in EtOAc (400 mL) and washed with H2O (50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a colourless solid (380 mg, 85% yield). LCMS (METHOD 4) (ES): m/z 183.4 [M-H]-, RT = 0.51 min. 15 Preparation 129: 1-[3-methoxy-6-(trifluoromethyl)pyridazin-4-yl]ethanol. A solution of ammonium peroxodisulfate (0.97 g, 4.3 mmol) in H2O (5 mL) was added dropwise over 10 minutes, to a solution of the compound of Preparation 128 (0.38 g, 2.1 mmol), (S)-lactic acid (90% purity, 0.43 g, 4.3 mmol) and AgNO3 in H2O (20 mL) and20 tBuOH (10 mL) at 75°C. On complete addition the reaction mixture was stirred at 75°C for 2 hours. Solid NaHCO3 was added to the cooled reaction mixture until neutral pH was attained. The mixture was extracted with EtOAc (2 x 25 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in25 heptane, to afford the title compound as a colourless solid (93 mg, 20% yield). LCMS (METHOD 3) (ES): m/z 221.1 [M-H]-, RT = 0.49 min. Preparation 130: 3-methoxy-4-[1-(4-nitropyrazol-1-yl)ethyl]-6-(trifluoromethy l)pyridazine. 952-WO 95 According to the method of Preparation 53 the compound of Preparation 129 (93 mg, 0.419 mmol) was reacted with 4-nitro-1H-pyrazole (52.1 mg, 0.46 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), 5 eluting with EtOAc in heptane, (117 mg, 88% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.48 (d, J = 0.8 Hz, 1H), 5.75 (q, J = 7.1 Hz, 1H), 4.29 (s, 3H), 1.95 (d, J = 7.0 Hz, 3H); LCMS (METHOD 3) (ES): m/z 318.2 [M-H]-, RT = 0.71 min. Preparation 131: 1-[1-[2-methoxy-5-(trifluoromethyl)-3-pyridyl]ethyl]pyrazol- 4-amine. 10 According to the method of Preparation 94 the compound of Preparation 130 (117 mg, 0.37mmol) was reacted to afford the crude title compound as a yellow oil (106 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 288.2 [M-H]-, RT = 0.42 min. 15 Preparation 132: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-[2-methoxy-5- (trifluoromethyl)-3-pyridyl]ethyl]pyrazol-4-yl]amino]-2-oxo- ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 118 (91.6 mg, 0.34 mmol) was reacted with the compound of Preparation 131 (79.0 mg, 0.34 mmol) to20 afford the title compound as a colourless solid after silica column chromatography (178 mg, 89% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.52 (s, 1H), 7.18 (s, 1H), 5.68 (q, J = 7.0 Hz, 1H), 5.33 (s, 1H), 4.38 (s, 1H), 4.28 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H), 1.47 (s, 9H), 0.72 (dt, J = 8.2, 4.9 Hz, 3H), 0.59 – 0.35 (m, 4H), 0.27 (dd, J = 11.1, 4.8 Hz, 4H); LCMS (METHOD 3) (ES): m/z 539.5 [M-H]-, RT = 0.84 min. 25 952-WO 96 Preparation 133: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[1-(5-methyl-2-oxo-1H-py ridin-3- yl)ethyl]pyrazol-4-yl]propanamide. According to the method of Preparation 120 the compound of Preparation 132 (172 mg, 5 0.319 mmol) was reacted to afford the title compound as a colourless oil (147 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 425.4 [M+H] ⁺ , RT = 0.55 min. Preparation 134: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4- yl)ethyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]car bamate. 10 According to the method of Preparation 55 the compound of Preparation 118 (1.1 g, 4.20 mmol) was reacted with the compound of Preparation 94 (1.16 g, 4.57 mmol) to afford the title compound as a colourless solid after silica column chromatography (2.17 g, 94% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 4.7 Hz, 1H), 8.09 (s, 1H), 7.52 (s, 1H),15 6.86 (d, J = 0.8 Hz, 1H), 6.54 (s, 1H), 5.66 – 5.52 (m, 1H), 5.36 (s, 1H), 4.40 (s, 1H), 4.17 (s, 3H), 1.84 (d, J = 7.1 Hz, 3H), 1.47 (s, 10H), 0.88 (t, J = 6.8 Hz, 1H), 0.81 – 0.65 (m, 2H), 0.64 – 0.37 (m, 4H), 0.37 – 0.15 (m, 4H); LCMS (METHOD 3) (ES): m/z 505.4 [M+H] ⁺ , RT = 0.80 min. 20 Preparation 135: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl ]pyrazol-4- yl]-3,3-dicyclopropyl-propanamide, hydrochloride. HCl According to the method of Preparation 120 the compound of Preparation 134 (2.17 g, 4.30 mmol) was reacted to afford the title compound as a colourless oil (1.84 g, assume 100%25 yield). LCMS (METHOD 4) (ES): m/z 391.4 [M-H]-, RT = 0.51 min. 952-WO 97 Preparation 136: 1-(6-chloro-3-methoxy-pyridazin-4-yl)-2-methoxy-ethanone. n-BuLi (2.6M solution in toluene, 11.0 mL) was added slowly to a solution of 2,2,6,6- tetramethylpiperidine (3.90 g, 28 mmol) in THF (100 mL) at -30°C. On complete addition 5 the reaction mixture was warmed to -5°C and stirred for 30 minutes, then cooled to -75°C. A solution of 3-chloro-6-methoxy-pyridazine (2.0 g, 14 mmol) in THF (12 mL) was then added dropwise, maintaining internal temperature of the reaction mixture below -70°C. The orange solution was stirred for 30 minutes at -75°C then methyl 2-methoxyacetate (4.1 mL, 42.0 mmol) was added and the reaction was stirred to room temperature. The reaction10 mixture was quenched with aqueous citric acid (5% solution, 40 mL) and extracted with Et2O (2 x 50 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230- 400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (1.17 g, 39% yield). LCMS (METHOD 3) (ES): m/z 217.1 [M+H] ⁺ , RT = 0.52 min. 15 Preparation 137: 1-(6-chloro-3-methoxy-pyridazin-4-yl)-2-methoxy-ethanol. NaBH4 (96.0 mg, 2.54 mmol) was added portion-wise to a solution of the compound of Preparation 136 (1.17 g, 5.40 mmol) in EtOH (20 mL) and stirred at 5°C for 1 hour. The20 reaction mixture was quenched by the slow addition of aqueous citric acid (5% solution, 10 mL) and concentrated in vacuo to low volume. H2O (25 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title 25 compound as a pale yellow solid (750 mg, 64% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 1.1 Hz, 1H), 5.10 – 4.89 (m, 1H), 4.14 (s, 3H), 3.74 (dd, J = 9.7, 3.1 Hz, 1H), 3.50 – 3.34 (m, 5H), 3.27 (d, J = 4.0 Hz, 1H); LCMS (METHOD 3) (ES): m/z 219.1 [M+H] ⁺ , RT = 0.41 min. 30 Preparation 138: 6-chloro-3-methoxy-4-[2-methoxy-1-(4-nitropyrazol-1- yl)ethyl]pyridazine. 952-WO 98 According to the method of Preparation 93 the compound of Preparation 137 (740 mg, 3.40 mmol) was reacted with 4-nitro-1H-pyrazole (440 mg, 3.90 mmol) to afford the title compound as a pale yellow oil after silica column chromatography (230-400 mesh), eluting 5 with EtOAc in heptane, (921 mg, 87% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.15 (s, 1H), 7.24 (d, J = 0.8 Hz, 1H), 5.72 (dd, J = 7.3, 3.7 Hz, 1H), 4.20 (s, 3H), 4.15 – 4.09 (m, 1H), 3.97 (dd, J = 10.5, 3.7 Hz, 1H), 3.39 (s, 3H); LCMS (METHOD 3) (ES): m/z 314.2 [M+H] ⁺ , RT = 0.65 min. 10 Preparation 139: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-2-methoxy-ethyl]pyr azol-4- amine. According to the method of Preparation 94 the compound of Preparation 138 (0.91 g, 2.90 mmol) was reacted to afford the crude title compound as an orange oil (820 mg, assume15 100% yield). LCMS (METHOD 3) (ES): m/z 284.2 [M+H] ⁺ , RT = 0.35 min. Preparation 140: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-2- methoxy-ethyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethy l]carbamate. 20 According to the method of Preparation 55 the compound of Preparation 118 (0.52 g, 1.90 mmol) was reacted with the compound of Preparation 139 (0.55 g, 1.90 mmol) to afford the title compound as a pale yellow solid after silica column chromatography (0.52 g, 50% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.46 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 9.1 Hz, 1H), 5.67 (dd, J = 8.2, 4.5 Hz, 1H), 4.11 (dd,25 J = 9.0, 6.3 Hz, 1H), 4.03 – 3.95 (m, 4H), 3.82 (dd, J = 10.6, 4.6 Hz, 1H), 3.15 (d, J = 0.9 952-WO 99 Hz, 3H), 1.27 (s, 9H), 0.80 – 0.51 (m, 2H), 0.51 – 0.18 (m, 3H), 0.18 – -0.10 (m, 6H); LCMS (METHOD 3) (ES): m/z 535.5 [M+H] ⁺ , RT = 0.80 min. Preparation 141: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-me thoxy- 5 ethyl]pyrazol-4-yl]-3,3-dicyclopropyl-propanamide, hydrochloride. According to the method of Preparation 120 the compound of Preparation 134 (61.0 mg, 0.114 mmol) was reacted to afford the title compound as a colourless solid (48 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 421.3 [M+H] ⁺ , RT = 0.51 min. 10 Preparation 142: (6-chloro-3-methoxy-pyridazin-4-yl)methanol and (3-chloro-6-methoxy- pyridazin-4-yl)methanol. According to the method of Preparation 129 3-chloro-6-methoxy-pyridazine (4.08 g, 28.215 mmol) and 2-hydroxyacetic acid (3.86 g, 50.8 mmol) were reacted to afford the title compounds as a colourless solid after silica column chromatography (1.72 g, 35% yield). NMR showed a 2:1 mix of regioisomers which was taken into the next step. LCMS (METHOD 3) (ES): m/z 175.1 [M+H] ⁺ , RT = 0.36 min. 20 Preparation 143: 6-chloro-3-methoxy-4-[(4-nitropyrazol-1-yl)methyl]pyridazine . According to the method of Preparation 93 the compounds of Preparation 142 (1.72 g, 9.85 mmol) were reacted with 4-nitro-1H-pyrazole (1.11 g, 9.85 mmol) to afford the title compound as a pale yellow oil after silica column chromatography (230-400 mesh), eluting 25 with EtOAc in heptane, (1.11 g, 39% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.15 952-WO 100 (s, 1H), 7.07 (s, 1H), 5.30 (s, 2H), 4.21 (s, 3H); LCMS (METHOD 3) (ES): m/z 270.2 [M+H] ⁺ , RT = 0.56 min. Preparation 144: 1-[(6-chloro-3-methoxy-pyridazin-4-yl)methyl]pyrazol-4-amine . 5 According to the method of Preparation 94 the compound of Preparation 138 (1.11 g, 4.11 mmol) was reacted to afford the crude title compound as a yellow oil (985 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 240.1 [M+H] ⁺ , RT = 0.35 min. 10 Preparation 145: tert-butyl N-[(1S)-1-[[1-[(6-chloro-3-methoxy-pyridazin-4- yl)methyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]ca rbamate. According to the method of Preparation 55 the compound of Preparation 118 (1.11 g, 4.11 mmol) was reacted with the compound of Preparation 144 (985 mg, 4.11 mmol) to afford15 the title compound as an off-white solid (1.92 g, 95% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 7.96 (s, 1H), 7.44 (s, 1H), 6.73 (s, 1H), 6.61 (d, J = 9.1 Hz, 1H), 5.20 (s, 2H), 4.11 (dd, J = 9.1, 6.5 Hz, 1H), 3.96 (s, 3H), 1.28 (s, 9H), 0.78 – 0.52 (m, 2H), 0.48 – -0.07 (m, 9H); LCMS (METHOD 3) (ES): m/z 491.5 [M+H] ⁺ , RT = 0.75 min. 20 Preparation 146: (2S)-2-amino-N-[1-[(3-chloro-6-oxo-1H-pyridazin-5-yl)methyl] pyrazol-4- yl]-3,3-dicyclopropyl-propanamide, hydrochloride. HCl According to the method of Preparation 120 the compound of Preparation 145 (155 mg, 0.316 mmol) was reacted to afford the title compound as a colourless solid (119 mg,25 assume 100% yield). Used directly in next step. 952-WO 101 Preparation 147: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3-pyridyl)- 2-triisopropylsilyloxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl ]-4-methyl-1,2,5-oxadiazole-3- carboxamide. N 5 According to the method of Preparation 57 the compound of Preparation 78 (73.0 mg, 0.13 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (20.0 mg, 0.156 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (65.0 mg, 75% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, J = 4.7 Hz, 1H), 7.91 (d, J = 2.9 Hz, 1H), 7.79 (dd, J = 8.4, 4.5 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.30 (ddd, J = 12.6, 8.4, 2.9 Hz,10 1H), 5.65 (td, J = 7.1, 4.4 Hz, 1H), 4.79 (ddd, J = 7.8, 5.5, 1.8 Hz, 1H), 4.37 (ddd, J = 10.6, 7.5, 5.1 Hz, 1H), 4.24 (ddd, J = 10.5, 4.4, 3.1 Hz, 1H), 3.94 (s, 3H), 2.61 (d, J = 2.1 Hz, 3H), 0.97 (dd, J = 7.2, 4.7 Hz, 19H), 0.94 – 0.73 (m, 4H), 0.61 (td, J = 8.3, 7.9, 4.7 Hz, 1H), 0.52 (td, J = 7.5, 4.7 Hz, 3H), 0.35 (p, J = 4.8 Hz, 2H), 0.29 – 0.20 (m, 2H); LCMS (METHOD 3) (ES): m/z 670.6 [M+H] ⁺ , RT = 1.13 min. 15 Preparation 148: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3-pyridyl)- 2-methoxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1, 2,5-oxadiazole-3- carboxamide. 20 According to the method of Preparation 57 the compound of Preparation 84 (38.2 mg, 0.09 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (20.0 mg, 0.156 mmol) to afford the title compound as an off-white solid after prep. acidic HPLC (28.0 mg, 59% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 1.3 Hz, 1H), 7.91 (dd, J = 3.0, 1.4 Hz, 1H), 7.86 – 7.77 (m, 2H), 7.54 (d, J = 2.0 Hz, 1H), 7.23 (td, J = 8.0, 3.0 Hz, 1H), 5.84 –25 5.62 (m, 1H), 4.79 (dd, J = 8.4, 5.4 Hz, 1H), 4.15 (dt, J = 10.3, 8.2 Hz, 1H), 3.97 (s, 3H), 3.88 (dd, J = 10.4, 4.2 Hz, 1H), 3.36 (d, J = 3.3 Hz, 3H), 2.60 (d, J = 2.3 Hz, 3H), 0.99 – 952-WO 102 0.72 (m, 3H), 0.72 – 0.44 (m, 4H), 0.36 (p, J = 4.5 Hz, 2H), 0.25 (tt, J = 5.1, 3.1 Hz, 2H); LCMS (METHOD 3) (ES): m/z 528.5 [M+H] ⁺ , RT = 0.82 min. Preparation 149: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxypyrazin-2- 5 yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-ox adiazole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 101 (22.8 mg, 0.06 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (8.5 mg, 0.067 mmol) to afford the title compound as a yellow solid after prep. basic HPLC (21.8 mg, 73%10 yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.94 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 2.8 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.99 (d, J = 0.6 Hz, 1H), 7.43 (d, J = 0.7 Hz, 1H), 5.40 (s, 2H), 4.78 (dd, J = 8.9, 6.2 Hz, 1H), 3.94 (s, 3H), 2.48 (s, 3H), 0.91 – 0.67 (m, 3H), 0.56 – 0.09 (m, 8H); LCMS (METHOD 4) (ES): m/z 467.4 [M+H] ⁺ , RT = 0.68 min. 15 Preparation 150: 1-(2-methoxy-3-pyridyl)but-3-en-1-ol. Allyl(chloro)magnesium (2M solution in THF, 17.8 mL) was added to solution of 2- methoxypyridine-3-carbaldehyde (4.43 g, 32.3 mmol) in THF (100 mL) and stirred at 5°C for 1 hour. The reaction mixture was quenched with a saturated aqueous NH4Cl (50 mL)20 and extracted with Et2O (2 x 100 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford the crude title compound as a pale orange oil (5.71 g, 98% yield). LCMS (METHOD 3) (ES): m/z 180.2 [M+H] ⁺ , RT = 0.54 min. Preparation 151: 2-methoxy-3-[1-(4-nitropyrazol-1-yl)but-3-enyl]pyridine. 25 According to the method of Preparation 93 the compound of Preparation 150 (5.71 g, 31.9 mmol) was reacted with 4-nitro-1H-pyrazole (3.96 g, 35.0 mmol) to afford the title compound as a pale yellow oil after silica column chromatography (230-400 mesh), eluting 952-WO 103 with EtOAc in heptane, (3.60 g, 41% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.15 (dd, J = 5.0, 1.9 Hz, 1H), 8.07 (s, 1H), 7.66 (dd, J = 7.5, 1.9 Hz, 1H), 6.93 (dd, J = 7.5, 5.0 Hz, 1H), 5.74 – 5.54 (m, 2H), 5.16 – 5.01 (m, 2H), 3.98 (s, 3H), 3.18 (dddt, J = 14.5, 9.5, 7.1, 1.2 Hz, 1H), 2.91 (dddt, J = 14.6, 6.9, 5.7, 1.4 Hz, 1H); LCMS (METHOD 3) (ES): 5 m/z 275.2 [M+H] ⁺ , RT = 0.76 min. Preparation 152: 1-[(6-chloro-3-methoxy-pyridazin-4-yl)methyl]pyrazol-4-amine . OsO4 (2.5% solution in ^t BuOH, 0.11 mL, 0.0088 mmol) was added to a solution of the10 compound of Preparation 151 (240 mg, 0.88 mmol) in THF (20 mL) and H2O (20 mL) at room temperature. Solid NaIO ₄ (468 mg, 2.19 mmol) was added portion-wise and the resultant slurry was stirred at room temperature for 16 hours. The solid was filtered off and the filtrate was diluted with H2O (10 mL) and extracted with Et2O (2 x 40 mL). The combined organic phase was washed with aqueous Na2S2O3 solution (1%, 15 mL), then15 dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as an orange oil (209 mg, 86% yield). ¹ H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.24 (s, 1H), 8.17 (dd, J = 5.0, 1.8 Hz, 1H), 8.06 (s, 1H), 7.46 (dd, J = 7.4, 1.8 Hz, 1H), 6.91 (dd, J = 7.5, 5.0 Hz, 1H), 6.20 (dd, J = 9.9, 4.0 Hz, 1H), 4.01 (s, 3H), 3.86 (ddd, J = 18.5, 9.9, 0.9 Hz, 1H), 3.20 (dd, J = 18.5, 3.9 Hz, 1H); LCMS (METHOD 3) (ES): m/z 277.2 [M+H] ⁺ , RT20 = 0.60 min. Preparation 153: 3-[3,3-difluoro-1-(4-nitropyrazol-1-yl)propyl]-2-methoxy-pyr idine. DAST (0.24 mL, 1.80mmol) was added to a solution of the compound of Preparation 15225 (0.20 g, 0.72 mmol) in DCM (15 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (20 mL), washed with a saturated aqueous NaHCO3 solution (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a yellow oil (19.0 mg, 8.8% yield). 30 ¹ H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.18 (dd, J = 5.0, 1.9 Hz, 1H), 8.11 (s, 1H), 7.59 (dd, J = 7.4, 1.9 Hz, 1H), 6.93 (dd, J = 7.5, 5.0 Hz, 1H), 5.94 – 5.56 (m, 2H), 4.02 (s, 952-WO 104 3H), 3.27 – 3.02 (m, 1H), 2.75 – 2.54 (m, 1H); LCMS (METHOD 3) (ES): m/z 299.2 [M+H] ⁺ , RT = 0.71 min. Preparation 154: 1-[3,3-difluoro-1-(2-methoxy-3-pyridyl)propyl]pyrazol-4-amin e. 5 Triethylsilane (0.04 mL, 0.252 mmol) was added to a solution of the compound of Preparation 153 (18.8 mg, 0.063 mmol), TEA (0.0176 mL, 0.126 mmol) and Pd/C (10% mass, 18 mg) in MeOH (6 mL) in a capped microwave vial. The reaction mixture was stirred at room temperature for 1 hour, then filtered through Celite™. The filtrate was 10 concentrated to afford the crude title compound (12.0 mg, 71% yield). LCMS (METHOD 4) (ES): m/z 269.2 [M+H] ⁺ , RT = 0.47 min. Preparation 155: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[3,3-difluoro-1-(2- methoxy-3-pyridyl)propyl]pyrazol-4-yl]amino]-2-oxo-ethyl]car bamate. 15 According to the method of Preparation 55 the compound of Preparation 118 (12.0 mg, 0.045 mmol) was reacted with the compound of Preparation 154 (12.0 mg, 0.045 mmol) to afford the title compound as an off-white solid (23 mg, 99% yield). LCMS (METHOD 4) (ES): m/z 520.4 [M+H] ⁺ , RT = 0.79 min. 20 Preparation 156: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[3,3-difluoro-1-(2-metho xy-3- pyridyl)propyl]pyrazol-4-yl]propanamide. 952-WO 105 According to the method of Preparation 120 the compound of Preparation 155 (23 mg, 0.044 mmol) was reacted to afford the title compound as a colourless oil (18.7 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 420.4 [M+H] ⁺ , RT = 0.65 min. 5 Preparation 157: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[3,3-difluoro-1-(2-met hoxy-3- pyridyl)propyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 156 (18.1 mg, 0.043 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (13.3 mg, 0.08610 mmol) to afford the title compound as a colourless solid after prep. basic acidic HPLC (14.0 mg, 58% yield). LCMS (METHOD 4) (ES): m/z 556.5 [M+H] ⁺ , RT = 0.75 min. Preparation 158: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxypyridazin-4 - yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. 15 Triethylsilane (0.20 mL, 1.30 mmol) was added to a degassed solution of the compound of Preparation 145 (150 mg, 0.31 mmol) and Pd/C (10% mass, 30 mg) and stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite™ and the filtrate was purified directly by prep. basic HPLC, to afford the title compound as a colourless solid20 (8.5 mg, 6% yield). LCMS (METHOD 4) (ES): m/z 457.5 [M+H] ⁺ , RT = 0.68 min. Preparation 159: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxypyridazin-4 - yl)methyl]pyrazol-4- l]amino]-2-oxo-eth l]-2-isoprop l-p razole-3-carboxamide. 25 HCl (3M solution in CPME, 1 mL) was added to a solution of the compound of Preparation 952-WO 106 158 (8.5 mg, 0.019 mmol) in MeOH (1 mL) and stirred at 50°C for 2 hours. The reaction mixture was concentrated in vacuo then redissolved in MeCN (2 mL). 2-Isopropylpyrazole- 3-carboxylic acid (3.2 mg, 0.02 mmol), DIPEA (0.0097 mL, 0.056 mmol) and HATU (7.8 mg, 0.02 mmol) were added and the reaction mixture was stirred at room temperature for 5 1 hour. The crude reaction mixture was used directly in the next step. Preparation 160: diethyl 2-(2-cyclopropyl-2-oxo-ethyl)propanedioate. NaH (60% mass, 2.3 g, 59 mmol) was added slowly to a solution of diethyl malonate (8.910 mL, 59 mmol) in THF (100 mL) at 10°C. On complete addition the reaction mixture was stirred for 20 minutes. A solution of 2-bromo-1-cyclopropyl-ethanone (8.7 g, 53 mmol) in THF (5 mL) was then added dropwise over 5 minutes and the resulting suspension was stirred for 1 hour. The reaction mixture was quenched with aqueous citric acid solution (5%, 30 mL) and extracted with Et2O (2 x 100 ml). The combined organic phase was dried15 over Na2SO4, filtered and concentrated in vacuo to afford the title compound as an brown oil (12.0 g, 93% yield) that was used without further purification. Preparation 161: ethyl 3-cyclopropyl-6-oxo-4,5-dihydro-1H-pyridazine-5-carboxylate. 20 Hydrazine monohydrate (2.41 mL, 49.5 mmol) was added slowly to a solution of the compound of Preparation 160 (12.0 g, 49.5 mmol) in EtOH (40 mL) and stirred at room temperature for 20 minutes then at 50°C for 20 minutes. The reaction mixture was concentrated in vacuo to leave the crude title compound (10.4g, assume 100% yield) as a thick dark syrup that was used directly in the next step. LCMS (METHOD 3) (ES): m/z25 211.2 [M+H] ⁺ , RT = 0.44 min. Preparation 162: ethyl 3 l l 6 1H id i 5 b xylate. 952-WO 107 Bromine (2.80 mL, 54.4 mmol) was added to a pre-stirred solution of the compound of Preparation 161 (10.4 g, 49.5 mmol) and NaOAc (12.2 g, 148 mmol) in H2O (50 mL) and tBuOH (25 mL) at room temperature. The reaction mixture was stirred for 3 hours, then diluted with H2O (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic 5 phase was treated with activated charcoal, filtered through a short silica pad and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as an off-white solid (3.90 g, 38% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.66 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.01 (tt, J = 8.3, 5.0 Hz, 1H), 1.28 (t, J =10 7.1 Hz, 3H), 1.07 – 0.87 (m, 2H), 0.87 – 0.70 (m, 2H); LCMS (METHOD 4) (ES): m/z 209.2 [M+H] ⁺ , RT = 0.44 min. Preparation 163: methyl 6-cyclopropyl-3-methoxy-pyridazine-4-carboxylate. 15 The compound from Preparation 162 (3.26 g, 15.7 mmol) and POCl3 (14.6 mL, 157 mmol) were stirred together at 90°C for 2 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (200 mL) and washed with a saturated aqueous solution of NaHCO3 (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to leave the crude intermediate ethyl 3-chloro-6-6cyclopropyl-pyridazine-4-carboxylate (2.4 g, 68%20 yield) as a brown oil. NaOMe (4.4M solution on MeOH, 4.8 mL) was added to a solution of the crude ethyl 3-chloro-6-6cyclopropyl-pyridazine-4-carboxylate (2.4 g, 11 mmol) in MeOH (30 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, diluted with H2O (30 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The25 obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a dark oil (1.18 g, 53% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 4.19 (s, 3H), 3.94 (s, 3H), 2.25 – 1.99 (m, 1H), 1.25 – 0.99 (m, 4H). 30 Preparation 164: (6-cyclo r l 3 m th rid in 4 l m th nol. 952-WO 108 LiAlH4 (2M solution in THF, 0.5 mL) was added dropwise to a solution of the compound of Preparation 163 (280 mg, 1.3 mmol) in THF (10 mL) at 5°C. The resulting solution was stirred for 30 minutes. The reaction mixture was quenched by the careful addition of H2O (38 ^L), NaOH (5M aqueous solution, 38 ^L) then H2O (114 ^L). The reaction mixture was 5 filtered and the filtrate was concentrated in vacuo to afford the tile compound as a yellow oil (240 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 181.2 [M+H] ⁺ , RT = 0.34 min. Preparation 165: 6-cyclopropyl-3-methoxy-4-[(4-nitropyrazol-1-yl)methyl]pyrid azine. 10 According to the method of Preparation 93 the compound of Preparation 164 (240 mg, 1.30 mmol) was reacted with 4-nitro-1H-pyrazole (170 mg, 1.5 mmol) to afford the title compound as a colourless solid after prep. Basic HPLC (54 mg, 15% yield). LCMS (METHOD 3) (ES): m/z 276.3 [M+H] ⁺ , RT = 0.58 min. 15 Preparation 166: 1-[(6-cyclopropyl-3-methoxy-pyridazin-4-yl)methyl]pyrazol-4- amine. According to the method of Preparation 94 the compound of Preparation 165 (52.0 mg, 0.189 mmol) was reacted to afford the crude title compound as a coloured oil (46.3 mg,20 assume 100% yield). LCMS (METHOD 3) (ES): m/z 246.2 [M+H] ⁺ , RT = 0.32 min. Preparation 167: tert-butyl N-[(1S)-2,2-dicyclopropyl-1-[[1-[(6-cyclopropyl-3-methoxy- pyridazin-4-yl)methyl]pyrazol-4-yl]carbamoyl]ethyl]carbamate . 25 According to the method of Preparation 55 the compound of Preparation 118 (50.9 mg, 0.189 mmol) was reacted with the compound of Preparation 166 (46.3 mg, 0.189 mmol) to 952-WO 109 afford the title compound, after prep. basic HPLC, as a colourless solid (58.8 mg, 62% yield). LCMS (METHOD 4) (ES): m/z 497.5 [M+H] ⁺ , RT = 0.75 min. Preparation 168: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(6-cyclopropyl-3-methox y- 5 pyridazin-4-yl)methyl]pyrazol-4-yl]propanamide. According to the method of Preparation 120 the compound of Preparation 167 (58.8 mg, 0.118 mmol) was reacted to afford the title compound as a colourless oil (46.9 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 397.5 [M+H] ⁺ , RT = 0.55 min. 10 Preparation 169: N-[(1S)-2,2-dicyclopropyl-1-[[1-[(6-cyclopropyl-3-methoxy-py ridazin-4- yl)methyl]pyrazol-4-yl]carbamoyl]ethyl]-2-isopropyl-pyrazole -3-carboxamide. According to the method of Preparation 57 the compound of Preparation 168 (46.9 mg,15 0.118 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (20.1 mg, 0.13 mmol) to afford the title compound as a colourless solid after prep. basic acidic HPLC (53.0 mg, 84% yield). LCMS (METHOD 4) (ES): m/z 533.5 [M+H] ⁺ , RT = 0.68 min. Preparation 170: (3-methoxy-6-methyl-pyridazin-4-yl)methanol. 20 According to the method of Preparation 129 3-chloro-6-methyl-pyridazine (2.55 g, 20.5 mmol) and 2-hydroxyacetic acid (2.81 g, 37.0 mmol) were reacted to afford the crude title compound as an off-white solid (2.2 g, 69% yield). LCMS (METHOD 4) (ES): m/z 155.1 [M+H] ⁺ , RT = 0.27 min. 25 Preparation 171: 3-methoxy-6-methyl-4-[(4-nitropyrazol-1-yl)methyl]pyridazine . 952-WO 110 According to the method of Preparation 93 the compound of Preparation 170 (2.2 g, 14.3 mmol) was reacted with 4-nitro-1H-pyrazole (1.86 g, 16.4 mmol) to afford the title compound as a pale orange solid after silica column chromatography (2.80 g, 39% yield). 5 LCMS (METHOD 4) (ES): m/z 250.2 [M+H] ⁺ , RT = 0.45 min. Preparation 172: 1-[(3-methoxy-6-methyl-pyridazin-4-yl)methyl]pyrazol-4-amine . According to the method of Preparation 94 the compound of Preparation 171 (160 mg,10 0.642 mmol) was reacted to afford the crude title compound as a coloured oil (140.7 mg, assume 100% yield). The material was used directly in the next step. Preparation 173: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxy-6-methyl- pyridazin-4-yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbam ate. 15 According to the method of Preparation 55 the compound of Preparation 118 (138 mg, 0.514mmol) was reacted with the compound of Preparation 172 (140 mg, 0.638 mmol) to afford the title compound, after prep. basic HPLC, as a colourless solid (75 mg, 25% yield). The material was used directly in the next step. 20 Preparation 174: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(3-methoxy-6-methyl-pyr idazin-4- yl)methyl]pyrazol-4- l]propenamide h drochloride HCl 952-WO 111 According to the method of Preparation 120 the compound of Preparation 173 (75.0 mg, 0.159 mmol) was reacted to afford the title compound as a colourless oil (64.8 mg, assume 100% yield). The material was used directly in the next step. 5 Preparation 175: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxy-6-methyl-p yridazin- 4-yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyr azole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 174 (64.0 mg, 0.157 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (24.2 mg, 0.15710 mmol) to afford the title compound as a colourless solid after prep. acidic acidic HPLC (26.0 mg, 32% yield). LCMS (METHOD 3) (ES): m/z 507.6 [M+H] ⁺ , RT = 0.66 min. Preparation 176: 3-benzyloxy-1-(6-chloro-3-methoxy-pyridazin-4-yl)propan-1-ol . 15 According to the method of Preparation 136 3-chloro-6-methoxy-pyridazine (2.0 g, 14 mmol) was reacted with 3-benzyloxypropanal (3.2 g, 19 mmol) to afford the title compound as a yellow oil (1.69 g, 40% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 1.1 Hz, 1H), 7.45 – 7.28 (m, 5H), 5.06 – 4.89 (m, 1H), 4.63 – 4.43 (m, 2H), 4.11 (s, 3H), 3.83 – 3.60 (m, 2H), 2.19 (ddt, J = 14.8, 6.2, 3.1 Hz, 1H), 1.89 (dtd, J = 14.8, 8.2, 3.6 Hz,20 1H); LCMS (METHOD 3) (ES): m/z 309.2 [M+H] ⁺ , RT = 0.71 min. Preparation 177: 4-[3-benzyloxy-1-(4-nitropyrazol-1-yl)propyl]-6-chloro-3-met hoxy- pyridazine. 25 According to the method of Preparation 93 the compound of Preparation 176 (1.65 g, 5.34 mmol) was reacted with 4-nitro-1H-pyrazole (604 mg, 5.34 mmol) to afford the title compound as a pale orange solid after silica column chromatography (1.83 g, 84% yield). 952-WO 112 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.3 Hz, 2H), 7.42 (d, J = 0.7 Hz, 1H), 7.39 – 7.29 (m, 3H), 7.28 – 7.23 (m, 2H), 5.74 (dd, J = 10.5, 4.4 Hz, 1H), 4.58 – 4.28 (m, 2H), 4.17 (s, 3H), 3.51 (dt, J = 9.9, 4.4 Hz, 1H), 3.11 (td, J = 9.9, 3.3 Hz, 1H), 2.57 (ddt, J = 14.3, 10.5, 3.7 Hz, 1H), 2.42 (ddt, J = 14.4, 9.7, 4.6 Hz, 1H); LCMS (METHOD 3 (ES): m/z 404.3 5 [M+H] ⁺ , RT = 0.83 min. Preparation 178: 1-[3-benzyloxy-1-(6-chloro-3-methoxy-pyridazin-4-yl)propyl]p yrazol-4- amine. 10 According to the method of Preparation 154 the compound of Preparation 177 (260 mg, 0.64 mmol) was reacted to afford the crude title compound as a coloured oil (220 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 340.3 [M+H] ⁺ , RT = 0.51 min. Preparation 179: tert-butyl N-[(1S)-1-[[1-[3-benzyloxy-1-(6-chloro-3-methoxy-pyridazin-1 5 4-yl)propyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl] carbamate. According to the method of Preparation 55 the compound of Preparation 118 (138 mg, 0.514mmol) was reacted with the compound of Preparation 178 (220 mg, 0.64 mmol) to afford the title compound, after silica column chromatography, as a colourless syrup (15320 mg, 40% yield). LCMS (METHOD 4) (ES): m/z 591.5 [M+H] ⁺ , RT = 0.80 min. Preparation 180: (2S)-2-amino-N-[1-[3-benzyloxy-1-(6-chloro-3-methoxy-pyridaz in-4- yl)propyl]pyrazol-4-yl]-3,3-dicyclopropyl-propanamide. 952-WO 113 According to the method of Preparation 120 the compound of Preparation 179 (153 mg, 0.259 mmol) was reacted to afford the title compound as a colourless oil (127 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 491.4 [M+H] ⁺ , RT = 0.67 min. 5 Preparation 181: N-[(1S)-1-[[1-[3-benzyloxy-1-(6-chloro-3-methoxy-pyridazin-4 - yl)propyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2 -isopropyl-pyrazole-3- carboxamide. 10 According to the method of Preparation 57 the compound of Preparation 180 (127 mg, 0.259 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (39.9 mg, 0.259 mmol) to afford the title compound as a colourless solid after silica column chromatography (113 mg, 69% yield). LCMS (METHOD 4) (ES): m/z 627.5 [M+H] ⁺ , RT = 0.76 min. 15 Preparation 182: (3,3-difluorocyclobutyl) (2,5-dioxopyrrolidin-1-yl) carbonate. Bis(2,5-dioxopyrrolidin-1-yl) carbonate (59.2 mg, 0.23 mmol) was added to a mixture of 3,3-difluorocyclobutanol (25.0 mg, 0.23 mmol) and pyridine (0.022 mL, 0.278 mmol) in MeCN (0.4 mL) and stirred at room temperature for 16 hours. The reaction mixture was20 quenched with saturated aqueous NaHCO3 (0.75 mL) and extracted with EtOAc (2 x 1 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo, to give the title compound as a colourless solid (40.6 mg, 67% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 5.23 – 5.10 (m, 1H), 3.25 – 3.10 (m, 2H), 2.94 – 2.82 (m, 2H), 2.82 (s, 4H). 25 Preparation 183: cyclopropyl (2,5-dioxopyrrolidin-1-yl) carbonate. 952-WO 114 Bis(2,5-dioxopyrrolidin-1-yl) carbonate (224 mg, 0.873 mmol)was added to a mixture of cyclopropanol (50.7 mg, 0.873 mmol) and pyridine (0.084 mL, 1.05 mmol) in MeCN (0.85 mL) and stirred at 40°C for 16 hours. The cooled reaction mixture was quenched with 5 saturated aqueous NaHCO3 (1 mL) and saturated brine solution (0.5 mL) and extracted with EtOAc (2 x 2 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo, to give the title compound as a pale yellow oil (142 mg, 77% yield). 1H NMR (400 MHz, DMSO-d6) δ 4.41 (tt, J = 6.0, 3.0 Hz, 1H), 2.81 (s, 4H), 0.90 – 0.74 (m, 4H). 10 Preparation 184: cyclopropyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxypyrazin-2- yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. N A solution of the compound of Preparation 101 (19.5 mg, 0.088 mmol) in MeCN (0.15 mL)15 was added to a solution of the compound of Preparation 183 (29.9 mg, 0.0713 mmol) and TEA (0.021 mL, 0.147 mmol) in MeCN (0.3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 mL) and extracted with EtOAc (2 x 2 mL). The combined organic phase were washed with saturated brine solution (1 mL) dried over Na2SO4, filtered and concentrated in20 vacuo. The obtained crude compound was purified by silica column chromatography (230- 400 mesh), eluting with DCM in EtOAc, to afford the title compound as an off-white solid (27.7 mg, 81% yield). LCMS (METHOD 4) (ES): m/z 441.4 [M+H] ⁺ , RT = 0.63 min. Preparation 185: 3-[(3-nitropyrazol-1-yl)methyl]pyrrolidin-2-one. 25 DEAD (40% solution in toluene, 2.2 mL, 4.9 mmol) was added to a solution of 3- (hydroxymethyl)pyrrolidin-2-one (520 mg, 4.5 mmol), 3-nitro-1H-pyrazole (460 mg, 4.1 mmol) and triphenylphosphine (1.3 g, 4.9 mmol) in THF (20 mL) at room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo. The obtained residue 952-WO 115 was slurried in EtOAc (15 mL) at reflux for 5 minutes. The resultant suspension was cooled on ice and the precipitate was collected by filtration to afford the title compound as an off- white solid (412 mg, 48% yield). LCMS (METHOD 3) (ES): m/z 284.2 [M+H] ⁺ , RT = 0.64 min. ¹ H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 2.6 Hz, 1H), 7.81 (s, 1H), 7.05 (d, J = 5 2.5 Hz, 1H), 4.48 (dd, J = 13.8, 4.7 Hz, 1H), 4.33 (dd, J = 13.8, 8.2 Hz, 1H), 3.18 – 3.06 (m, 2H), 2.87 (dtd, J = 9.7, 8.4, 4.7 Hz, 1H), 2.08 (dddd, J = 12.3, 8.7, 6.7, 3.2 Hz, 1H), 1.78 (ddt, J = 12.6, 10.4, 8.7 Hz, 1H). LCMS (METHOD 3) (ES): m/z 211.1 [M+H] ⁺ , RT = 0.37 min. 10 Preparation 186: 3-[(3-aminopyrazol-1-yl)methyl]pyrrolidin-2-one, hydrochloride. Pd/C (10% mass, 50 mg) was added to a suspension of the compound of Preparation 185 (412 mg, 1.96 mmol) and stirred under balloon pressure atmosphere of hydrogen for 18 hours. The reaction mixture was filtered through Celite™, HCl (3M solution in MeOH, 2 mL)15 was added to the clear filtrate and concentrated in vacuo to leave the title compound as a colourless solid (412 mg, 97% yield). Preparation 187: 2-methoxy-3-[(3-nitropyrazol-1-yl)methyl]pyridine. 20 According to the method of Preparation 93 (2-methoxy-3-pyridyl)methanol (0.65 g, 5.40 mmol) was reacted with 3-nitro-1H-pyrazole (610 mg, 5.40 mmol) to afford the title compound as a colourless solid after silica column chromatography (0.91 g, 72% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 5.0, 1.9 Hz, 1H), 7.57 – 7.46 (m, 2H), 6.96 – 6.83 (m, 2H), 5.34 (s, 2H), 4.00 (s, 3H); LCMS (METHOD 3) (ES): m/z 235.2 [M+H] ⁺ , RT =25 0.59 min. Preparation 188: 1-[(2-methoxy-3-pyridyl)methyl]pyrazol-3-amine According to the method of Preparation 54 the compound of Preparation 187 (0.91 g, 3.930 mmol) was reacted to afford the title compound as a colourless solid (0.82 g, assume 100% yield). LCMS (METHOD 3) (ES): m/z 205.2 [M+H] ⁺ , RT = 0.41 min. 952-WO 116 Preparation 189: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-methoxy-3- pyridyl)methyl]pyrazol-3-yl]amino]-2-oxo-ethyl]carbamate. 5 According to the method of Preparation 55 the compound of Preparation 118 (54 mg, 0.20 mmol) was reacted with the compound of Preparation 188 (48 mg, 0.23 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (66 mg, 61% yield). LCMS (METHOD 3) (ES): m/z 456.4 [M+H] ⁺ , RT = 0.81 min. 10 Preparation 190: 2-methoxy-3-[(4-nitropyrazol-1-yl)methyl]pyridine. According to the method of Preparation 93 (2-methoxy-3-pyridyl)methanol (2.61 g, 18.7 mmol) was reacted with 4-nitro-1H-pyrazole (2.12 g, 18.7 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), 15 eluting with EtOAc in heptane, (4.27 g, 97% yield). ¹ H NMR (600 MHz, CDCl3) δ 8.29 – 8.14 (m, 1H), 8.06 (d, J = 0.7 Hz, 1H), 7.52 (dd, J = 7.3, 1.8 Hz, 1H), 6.92 (dd, J = 7.3, 5.0 Hz, 1H), 5.28 (s, 1H), 4.00 (s, 2H); LCMS (METHOD 3) (ES): m/z 235.2 [M+H] ⁺ , RT = 0.60 min. 20 Preparation 191: 1-[(2-methoxy-3-pyridyl)methyl]pyrazol-4-amine. According to the method of Preparation 118 the compound of Preparation 190 (4.27 g, 18.2 mmol) was reacted to afford the title compound as a reddish oil (3.43 g, 92% yield). LCMS (METHOD 3) (ES): m/z 205.2 [M+H] ⁺ , RT = 0.37 min. 25 Preparation 192: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-methoxy-3- pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. 952-WO 117 According to the method of Preparation 55 the compound of Preparation 118 (730 mg, 2.7 mmol) was reacted with the compound of Preparation 191 (550 mg, 2.7 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 5 mesh), eluting with EtOAc in heptane, (992 mg, 81% yield). LCMS (METHOD 3) (ES): m/z 456.4 [M+H] ⁺ , RT = 0.74 min. Preparation 193: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(2-methoxy-3 - pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. 10 Selectfluor™ (43.5 mg, 0.123 mmol) was added to a solution of the compound of Preparation 192 (40.0 mg, 0.088 mmol) in DMF (0.5 ml) and DCM (0.5 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (20 mL) and washed with H2O (3 x 20 mL). The organic phase was dried over Na2SO4, filtered and15 concentrated in vacuo to afford the crude title compound that was used without further purification (41.6 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 474.4 [M+H] ⁺ , RT = 0.75 min. Preparation 194: N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(2-methoxy-3 -20 pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. HCl (3M solution in MeOH, 1 mL) was added to a solution of the compound of Preparation 193 (41.6 mg, 0.088 mmol) in MeOH (1 mL) and stirred at 50°C for 1 hour. The reaction mixture was concentrated in vacuo then redissolved in MeCN (2 mL). 2-isopropylpyrazole-25 3-carboxylic acid (16.3 mg, 0.105 mmol), DIPEA (0.061 mL, 0.351 mmol) and HATU (40.1 mg, 0.105 mmol) were added and the reaction mixture was stirred at room temperature for 952-WO 118 3 hours. The reaction mixture was purified directly by prep. basic HPLC to afford the title compound as a colourless solid (12 mg, 26% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 5.0, 1.8 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.32 – 7.21 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 7.3, 5.0 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 5.46 (p, 5 J = 6.6 Hz, 1H), 5.16 (s, 2H), 4.81 (dd, J = 8.2, 4.8 Hz, 1H), 3.98 (s, 3H), 1.48 (dd, J = 10.4, 6.6 Hz, 6H), 0.94 – 0.72 (m, 3H), 0.64 (dt, J = 7.7, 4.2 Hz, 1H), 0.61 – 0.46 (m, 3H), 0.37 (qt, J = 8.9, 4.6 Hz, 2H), 0.32 – 0.20 (m, 2H); LCMS (METHOD 3) (ES): m/z 510.4 [M+H] ⁺ , RT = 0.72 min. 10 Preparation 195: tert-butyl N-[1-[(1S)-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]pyrazol-4- yl]carbamate. tert-Butoxycarbonyl tert-butyl carbonate (1.5 g, 6.9 mmol) was added to a solution of the compound of Preparation 115 (1.22 g, 4.15 mmol) and Na2CO3 (2.0 g, 23.8 mmol) in15 acetone (20 mL) and H2O (10 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated to low volume in vacuo. The residue was diluted with H2O (20 mL) and extracted with TBME (2 x 30 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the 20 title compound as a colourless oil (1.37 g, 78% yield). H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.09 (d, J = 3.0 Hz, 1H), 7.74 (s, 1H), 7.35 (s, 1H), 7.21 (dd, J = 8.8, 3.0 Hz, 1H), 5.66 (q, J = 7.0 Hz, 1H), 3.90 (s, 3H), 1.71 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H). Preparation 196: tert-butyl N-[5-fluoro-1-[(1S)-1-(5-fluoro-2-methoxy-3-25 pyridyl)ethyl]pyrazol-4-yl]carbamate Selectfluor™ (1.7 g, 4.8 mmol) was added to a solution of the compound of Preparation 195 (1.35 g, 4.01 mmol) in MeCN (20 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with TBME (2 x 25 mL). 30 The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), 952-WO 119 eluting with EtOAc in heptane, to give a still impure compound. This was purified by prep. acidic HPLC to afford the title compound (16 mg, 11% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.9 Hz, 1H), 7.58 (s, 1H), 7.23 (s, 1H), 5.83 (s, 1H), 5.69 (q, J = 7.0 Hz, 1H), 3.95 (s, 3H), 1.79 (d, J = 7.0 Hz, 3H), 1.48 (s, 9H); LCMS (METHOD 4) (ES): m/z 353.3 5 [M-H]-, RT = 0.75 min. Preparation 197: 5-fluoro-1-[(1S)-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]pyraz ol-4-amine; hydrochloride. 10 HCl (3M solution in 2-Me-THF, 3 mL) was added to a solution of the compound of Preparation 196 (176 mg, 0.49 mmol) in MeOH (5 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to afford the crude title compound that was used directly in the next step (160 mg, assume 100% yield). 15 Preparation 198: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro- 2-methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]ca rbamate. According to the method of Preparation 55 the compound of Preparation 5 (165.7 mg, 0.546 mmol) was reacted with the compound of Preparation 197 (160 mg, 0.49 mmol) to20 afford the title compound as a colourless solid (222 mg, 82% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.13 (d, J = 3.0 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.51 – 7.23 (m, 7H), 5.69 (q, J = 6.9 Hz, 1H), 5.15 – 4.97 (m, 2H), 4.33 (dd, J = 9.1, 6.5 Hz, 1H), 3.87 (s, 3H), 1.73 (d, J = 7.0 Hz, 3H), 0.85 (dt, J = 13.6, 6.4 Hz, 1H), 0.74 (d, J = 8.9 Hz, 1H), 0.57 – 0.48 (m, 1H), 0.45 (tt, J = 8.9, 4.5 Hz, 1H), 0.34 (tt, J = 8.8, 4.3 Hz, 1H),25 0.25 (dt, J = 7.9, 3.7 Hz, 2H), 0.21 – 0.07 (m, 4H); LCMS (METHOD 4) (ES): m/z 540.4 [M+H] ⁺ , RT = 0.82 min. Preparation 199: (2S)-2-amino-3,3-dicyclopropyl-N-[5-fluoro-1-[(1S)-1-(5-fluo ro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]propanamide. 952-WO 120 According to the method of Preparation 56 the compound of Preparation 198 (120 mg, 0.22 mmol) was reacted to afford the crude title compound as a colourless oil (90.1 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 406.4 [M+H] ⁺ , RT = 0.69 min. 5 Preparation 200: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1R)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-p yrazole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 199 (36 mg, 0.08810 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (30 mg, 0.19 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (34.0 mg, 71% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.33 (d, J = 8.9 Hz, 1H), 8.13 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 2.6 Hz, 1H), 7.54 – 7.38 (m, 2H), 6.92 (d, J = 2.0 Hz, 1H), 5.70 (q, J = 7.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4.78 (dd, J = 9.0, 7.5 Hz, 1H), 3.87 (s, 3H),15 1.73 (d, J = 7.0 Hz, 3H), 1.36 (dd, J = 13.6, 6.6 Hz, 6H), 0.92 – 0.63 (m, 3H), 0.57 – 0.06 (m, 8H); LCMS (METHOD 3) (ES): m/z 542.6 [M+H] ⁺ , RT = 0.84 min. Preparation 201: N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-3-( trifluoromethyl)isoxazole-4-20 carboxamide. According to the method of Preparation 57 the compound of Preparation 199 (18 mg, 0.044 mmol) was reacted with 3-(trifluoromethyl)isoxazole-4-carboxylic acid (15 mg, 0.83 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (16.0 mg, 64%25 yield). LCMS (METHOD 3) (ES): m/z 567.3 [M-H]-, RT = 0.85 min. 952-WO 121 Preparation 202: N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-3-i sopropyl-isoxazole-4- carboxamide. 5 According to the method of Preparation 57 the compound of Preparation 199 (18 mg, 0.044 mmol) was reacted with 3-isopropylisoxazole-4-carboxylic acid (10 mg, 0.64 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (20.0 mg, 84% yield). LCMS (METHOD 3) (ES): m/z 541.4 [M-H]-, RT = 0.85 min. 10 Preparation 203: N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-e thyl-1,2,5-oxadiazole-3- carboxamide. 15 According to the method of Preparation 57 the compound of Preparation 199 (18 mg, 0.044 mmol) was reacted with 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (10 mg, 0.70 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (16.2 mg, 70% yield). LCMS (METHOD 3) (ES): m/z 528.4 [M-H]-, RT = 0.90 min. 20 Preparation 204: cyclopropyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5- fluoro-2-methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-e thyl]carbamate. According to the method of Preparation 184 the compound of Preparation 199 (12 mg, 0.029 mmol) was reacted with the compound of Preparation 183 (17 mg, 0.085 mmol) to 952-WO 122 afford the title compound as a colourless solid after prep. acidic HPLC (11 mg, 76% yield). LCMS (METHOD 3) (ES): m/z 490.5 [M+H] ⁺ , RT = 0.80 min. Preparation 205: [(1R)-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl] methanesulfonate. 5 DABCO (2.40 g, 21 mmol) was added to a solution of the compound of Preparation 113 (1.2 g, 7.0 mmol) and methylsulfonyl methanesulfonate (2.40g, 14 mmol) in DCM (20 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (20 mL) and washed with H2O (20 mL) then saturated aqueous NaHCO3 solution (20 mL). 10 The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford the crude title compound that was used without further purification (1.74 g, assume 100% yield). ¹ H MR (600 MHz, CDCl3) δ 7.98 (d, J = 3.0 Hz, 1H), 7.50 (dd, J = 8.1, 2.9 Hz, 1H), 5.98 – 5.87 (m, 1H), 3.97 (d, J = 0.7 Hz, 3H), 2.99 (s, 3H), 1.66 (dd, J = 6.4, 0.7 Hz, 3H). 15 Preparation 206: 5-fluoro-3-[(1S)-1-(3-fluoropyrazol-1-yl)ethyl]-2-methoxy-py ridine. Cs2CO3 (4.6 g, 14 mmol) was added to a solution of the compound of Preparation 205 (1.74 g, 7.0 mmol) and 3-fluoro-1H-pyrazole (720 mg, 8.4 mmol) in DMF (10 mL) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was20 diluted with H2O (30 mL) and extracted with TBME (2 x 25 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (328 mg, 20% yield). ¹ H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 2.9 Hz, 1H), 7.32 (t, J = 2.4 Hz, 1H), 7.17 – 7.04 (m,25 1H), 5.79 (dd, J = 6.0, 2.4 Hz, 1H), 5.60 – 5.50 (m, 1H), 3.95 (s, 3H), 1.78 (d, J = 7.0 Hz, 3H); LCMS (METHOD 3) (ES): m/z 240.2 [M+H] ⁺ , RT = 0.74 min. Preparation 207: 3-[(1S)-1-(4-bromo-3-fluoro-pyrazol-1-yl)ethyl]-5-fluoro-2-m ethoxy- pyridine. 952-WO 123 NBS (268.4 mg, 1.51 mmol) was added to a solution of the compound of Preparation 206 (328 mg, 1.37 mmol) in DMF (5 mL) and stirred at room temperature for 3 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with TBME (2 x 20 mL). The 5 combined organic phase was washed with a solution of saturated Na2SO3 (5 mL) in H2O (10 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a colourless oil (430 mg, 97% yield). ¹ H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 2.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.2, 2.9 Hz, 1H), 5.58 – 5.46 (m, 1H), 3.95 (s, 3H), 1.77 (d, J = 7.0 Hz, 3H); LCMS (METHOD 3) (ES): m/z 318.1 [M+H] ⁺ , RT = 0.86 min. 10 Preparation 208: N-[3-fluoro-1-[(1S)-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]py razol-4-yl]- 1,1-diphenyl-methanimine. Diphenylmethanimine (94 mg, 0.52 mmol) was added to a degassed mixture of the 15 compound of Preparation 207 (110 mg, 0.346 mmol), BINAP (43 mg, 0.069 mmol), Pd(OAc)2 (7.8 mg, 0.034 mmol) and Cs2CO3 (225.3 mg, 0.69 mmol) in 1,4-dioxane (5 mL). The resultant mix was stirred at 110°C for 2 days. The cooled reaction mixture was diluted with H2O (5 mL) and extracted with TBME (3 x 10 mL). The combined organic phase was washed with a solution of saturated aqueous brine (20 mL), dried over MgSO4, filtered and20 concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound (14 mg, 9.7% yield). LCMS (METHOD 3) (ES): m/z 419.4 [M+H] ⁺ , RT = 0.99 min. 25 Preparation 209: 3-fluoro-1-[(1S)-1-(5-fluoro-2-methox -3- rid l)ethyl]pyrazol-4-amine. 952-WO 124 HCl (4M aq. solution, 0.2 mL) was added to a solution of the compound of Preparation 208 (14 mg, 0.033 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature for 10 min, then diluted with H2O (10 mL) and TBME (15 mL). The aqueous phase was collected and basified to pH 10 with KOH, and extracted with TBME (2 x 15 mL). 5 The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (8.5 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 255.2 [M+H] ⁺ , RT = 0.54 min. Preparation 210: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1S)-1-(5-fl uoro-10 2-methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]ca rbamate. According to the method of Preparation 55 the compound of Preparation 5 (12.2 mg, 0.04 mmol) was reacted with the compound of Preparation 209 (8.5 mg, 0.033 mmol) to afford the title compound as a colourless oil (9 mg, 50% yield). ¹ H NMR (600 MHz, CDCl3) δ 7.9715 (s, 1H), 7.90 (d, J = 2.9 Hz, 1H), 7.74 (s, 1H), 7.43 – 7.31 (m, 5H), 7.12 (dd, J = 8.3, 3.0 Hz, 1H), 5.62 (s, 1H), 5.53 (q, J = 7.0 Hz, 1H), 5.14 (s, 2H), 4.48 (s, 1H), 3.95 (s, 3H), 1.76 (d, J = 7.1 Hz, 3H), 0.86 (td, J = 9.3, 4.8 Hz, 1H), 0.78 – 0.64 (m, 2H), 0.63 – 0.38 (m, 4H), 0.33 – 0.11 (m, 4H); LCMS (METHOD 4) (ES): m/z 540.4 [M+H] ⁺ , RT = 0.85 min. 20 Preparation 211: (2S)-2-amino-3,3-dicyclopropyl-N-[3-fluoro-1-[(1S)-1-(5-fluo ro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]propanamide. According to the method of Preparation 56 the compound of Preparation 210 (9.0 mg, 0.0167 mmol) was reacted to afford the crude title compound as a colourless oil (6.8 mg,25 assume 100% yield). LCMS (METHOD 3) (ES): m/z 406.4 [M+H] ⁺ , RT = 0.58 min. 952-WO 125 Preparation 212: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1S)-1-(5-fl uoro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-e thyl-1,2,5-oxadiazole-3- carboxamide. 5 According to the method of Preparation 57 the compound of Preparation 211 (6.8 mg, 0.016 mmol) was reacted with 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (4.0 mg, 0.028 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (8.8 mg, 100% yield). LCMS (METHOD 3) (ES): m/z 530.5 [M+H] ⁺ , RT = 0.91 min. 10 Preparation 213: N,2-dimethoxy-N-methyl-acetamide. TEA (20 mL, 143 mmol) was added dropwise to a solution of 2-methoxyacetyl chloride (5.0 g, 46.1 mmol) and N-methoxymethanamine hydrochloride (4.95 g, 50.7 mmol) in DCM (50 mL) at 5°C. On complete addition the reaction mixture was stirred at room temperature for15 16 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 40 mL). The combined organic phase was washed with aqueous HCl solution (1M, 30 mL) then with saturated NaHCO3 aqueous solution (20 mL), dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a yellow oil (4.35 g, 64% yield). 1H NMR (400 MHz, CDCl3) δ 4.22 (s, 2H), 3.69 (d, J = 1.7 Hz, 3H), 3.57 – 3.36 (m, 3H),20 3.19 (d, J = 2.1 Hz, 3H). Preparation 214: 1-(5-fluoro-2-methoxy-3-pyridyl)-2-methoxy-ethanone. Isopropylmagnesium chloride lithium chloride complex (1.3M soln. in THF, 0.41 mL, 0.5325 mmol) was added to a solution of 3-bromo-5-fluoro-2-methoxy-pyridine (1.03 g, 5.0 mmol) in THF (20 mL) at -78°C. On complete addition the reaction mixture was warmed to -10°C and stirred for 45 minutes. The reaction mixture was cooled to -78°C and the compound of Preparation 213 (799 mg, 6.0 mmol) was added. The reaction mixture was stirred at -5°C 952-WO 126 for 3 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with TBME (2 x 25 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title 5 compound as a colourless solid (73 mg, 7.3% yield). LCMS (METHOD 3) (ES): m/z 200.1 [M+H] ⁺ , RT = 0.74 min. Preparation 215: 1-(5-fluoro-2-methoxy-3-pyridyl)-2-methoxy-ethanol. 10 NaBH4 (10 mg, 0.26 mmol) was added to a solution of the compound of Preparation 214 (56 mg, 0.28 mmol) in MeOH (3 mL) and stirred at room temperature for 1 hour. The reaction mixture was purified directly by prep. acidic HPLC to afford the title compound (23 mg, 40% yield). LCMS (METHOD 3) (ES): m/z 202.1 [M+H] ⁺ , RT = 0.50 min. 15 Preparation 216: 5-fluoro-3-[1-(3-fluoro-4-nitro-pyrazol-1-yl)-2-methoxy-ethy l]-2- methoxy-pyridine. According to the method of Preparation 53 the compound of Preparation 215 (21 mg, 0.10 mmol) was reacted with 3-fluoro-4-nitro-1H-pyrazole (16.4 mg, 0.125 mmol) to afford the20 title compound as a colourless oil after prep. acidic HPLC (13 mg, 39% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 2.9 Hz, 1H), 7.45 (dd, J = 8.1, 2.9 Hz, 1H), 5.61 (dd, J = 8.2, 3.9 Hz, 1H), 4.09 (dd, J = 10.4, 8.2 Hz, 1H), 3.97 (s, 3H), 3.86 (dd, J = 10.3, 3.9 Hz, 1H), 3.38 (s, 3H); LCMS (METHOD 3) (ES): m/z 315.1 [M+H] ⁺ , RT = 0.77 min. 25 Preparation 217: 3-fluoro-1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-methoxy-ethyl ]pyrazol-4- amine. 952-WO 127 According to the method of Preparation 54 the compound of Preparation 216 (13 mg, 0.041 mmol) was reacted to afford the crude title compound as a colourless oil (11.7 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 5 285.2 [M+H] ⁺ , RT = 0.55 min. Preparation 218: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[1-(5-fluoro- 2- methoxy-3-pyridyl)-2-methoxy-ethyl]pyrazol-4-yl]amino]-2-oxo -ethyl]carbamate. 10 According to the method of Preparation 55 the compound of Preparation 5 (15 mg, 0.049 mmol) was reacted with the compound of Preparation 217 (11.7 mg, 0.033 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (11 mg, 46% yield . ¹ H NMR (400 MHz, CDCl3) δ 8.01 (t, J = 1.5 Hz, 1H), 7.93 (d, J = 2.9 Hz, 1H), 7.77 (s, 1H), 7.44 – 7.28 (m, 6H), 5.59 (dd, J = 8.4, 4.2 Hz, 2H), 5.14 (d, J = 2.0 Hz, 2H), 4.47 (d, J = 7.9 Hz,15 1H), 4.06 (dd, J = 10.4, 8.4 Hz, 1H), 3.96 (s, 3H), 3.82 (dd, J = 10.4, 4.3 Hz, 1H), 3.36 (s, 3H), 0.86 (td, J = 9.0, 4.6 Hz, 1H), 0.70 (tp, J = 8.4, 5.0, 4.3 Hz, 2H), 0.63 – 0.34 (m, 4H), 0.34 – 0.11 (m, 4H). LCMS (METHOD 3) (ES): m/z 570.5 [M+H] ⁺ , RT = 0.89 min. Preparation 219: (2S)-2-amino-3,3-dicyclopropyl-N-[3-fluoro-1-[1-(5-fluoro-2- methoxy-3-20 pyridyl)-2-methoxy-ethyl]pyrazol-4-yl]propanamide. According to the method of Preparation 56 the compound of Preparation 218 (11.0 mg, 0.019mmol) was reacted to afford the crude title compound as a colourless oil (8.4 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 436.4 [M+H] ⁺ , RT = 0.65 min. 952-WO 128 Preparation 220: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[1-(5-fluoro- 2-methoxy- 3-pyridyl)-2-methoxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]- 4-methyl-1,2,5-oxadiazole-3- carboxamide. 5 According to the method of Preparation 57 the compound of Preparation 219 (8.4 mg, 0.019 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (5.0 mg, 0.039 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (5.0 mg, 47% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.02 (t, J = 1.7 Hz, 1H), 7.93 (dd, J = 2.9, 1.9 Hz,10 1H), 7.78 (dd, J = 7.9, 3.5 Hz, 1H), 7.55 (s, 1H), 7.31 (ddd, J = 12.5, 8.3, 3.0 Hz, 1H), 5.67 – 5.51 (m, 1H), 4.81 (dd, J = 8.2, 5.1 Hz, 1H), 4.07 (td, J = 10.1, 8.4 Hz, 1H), 3.96 (d, J = 1.3 Hz, 3H), 3.82 (dd, J = 10.4, 4.2 Hz, 1H), 3.36 (d, J = 4.8 Hz, 3H), 2.61 (d, J = 3.8 Hz, 3H), 0.85 (ddddd, J = 32.8, 17.2, 12.8, 8.8, 3.1 Hz, 4H), 0.73 – 0.61 (m, 1H), 0.61 – 0.46 (m, 3H), 0.36 (dt, J = 4.2, 2.0 Hz, 2H), 0.24 (q, J = 5.2 Hz, 2H); LCMS (METHOD 3)15 (ES): m/z 546.4 [M+H] ⁺ , RT = 0.86 min. Preparation 221: 6-chloro-4-[1-(3-fluoro-4-nitro-pyrazol-1-yl)-2-methoxy-ethy l]-3- methoxy-pyridazine. 20 According to the method of Preparation 53 the compound of Preparation 137 (369 mg, 1.69 mmol) was reacted with 3-fluoro-4-nitro-1H-pyrazole (265.4 mg, 2.03 mmol) to afford the title compound as a colourless oil after prep. acidic HPLC (13 mg, 39% yield). ¹ H NMR (600 MHz, CDCl3) δ 8.26 (d, J = 1.1 Hz, 1H), 7.32 (d, J = 0.8 Hz, 1H), 5.55 (ddt, J = 7.4, 3.6, 1.0 Hz, 1H), 4.20 (s, 3H), 4.05 (dd, J = 10.5, 7.6 Hz, 1H), 3.91 (dd, J = 10.5, 3.7 Hz, 1H),25 3.39 (s, 3H); LCMS (METHOD 3) (ES): m/z 332.2 [M+H] ⁺ , RT = 0.69 min. Preparation 222: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-2-methoxy-ethyl]-3- fluoro- pyrazol-4-amine. 952-WO 129 According to the method of Preparation 94 the compound of Preparation 221 (369 mg, 1.11 mmol) was reacted to afford the crude title compound as a colourless oil (335 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 5 302.1 [M+H] ⁺ , RT = 0.49 min. Preparation 223: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-2- methoxy-ethyl]-3-fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclop ropyl-ethyl]carbamate. 10 According to the method of Preparation 55 the compound of Preparation 118 (300 mg, 1.11 mmol) was reacted with the compound of Preparation 222 (11.7 mg, 1.11 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (427 mg, 69% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.09 (t, J = 1.7 Hz, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.23 (dd, J = 4.3, 0.8 Hz, 1H), 5.50 (dt, J = 5.2, 2.7 Hz, 1H), 5.35 (s, 1H), 4.41 (dd, J = 8.3, 4.2 Hz,15 1H), 4.18 (s, 3H), 4.03 (ddd, J = 10.2, 7.6, 2.4 Hz, 1H), 3.88 (dd, J = 10.4, 4.2 Hz, 1H), 3.36 (s, 3H), 1.47 (s, 9H), 0.92 (tt, J = 8.7, 4.3 Hz, 1H), 0.82 – 0.66 (m, 2H), 0.66 – 0.36 (m, 4H), 0.36 – 0.15 (m, 4H); LCMS (METHOD 3) (ES): m/z 553.4 [M+H] ⁺ , RT = 0.83 min. Preparation 224: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-me thoxy-20 ethyl]-3-fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide hydrochloride. HCl (3M solution in 2-Me-THF, 3 mL) was added to a solution of the compound of Preparation 223 (52.0 mg, 0.094 mmol) in MeOH (6 mL) and DCM (3 mL) and stirred at 50°C for 2 hours. The reaction mixture was concentrated in vacuo to afford the crude title 952-WO 130 compound that was used directly in the next step (44.7 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 439.3 [M+H] ⁺ , RT = 0.57 min. Preparation 225: tert-butyl N-[(1S)-1-[di(cyclobutyl)methyl]-2-[[1-[(2-methoxy-3- 5 pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 7 (100 mg, 0.34 mmol) was reacted with the compound of Preparation 191 (68.7 mg, 0.34 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (104 mg, 64% yield). LCMS10 (METHOD 3) (ES): m/z 484.5 [M+H] ⁺ , RT = 0.88 min. Preparation 226: (2S)-2-amino-3,3-di(cyclobutyl)-N-[1-[(2-oxo-1H-pyridin-3- yl)methyl]pyrazol-4-yl]propanamide. 15 According to the method of Preparation 120 the compound of Preparation 225 (104 mg, 0.215 mmol) was reacted to afford the title compound as a colourless oil (79.5 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 370.4 [M-H]-, RT = 0.45 min. Preparation 227: 3-[(4-nitropyrazol-1-yl)methyl]pyrrolidin-2-one. 20 According to the method of Preparation 93 3-(hydroxymethyl)pyrrolidin-2-one (130 mg, 1.13 mmol) was reacted with 4-nitro-1H-pyrazole (116 mg, 1.03 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (164 mg, 76% yield). LCMS (METHOD 3) (ES): m/z 370.425 [M+H] ⁺ , RT = 0.37 min. 952-WO 131 Preparation 228: 3-[(4-aminopyrazol-1-yl)methyl]pyrrolidin-2-one; hydrochloride. Pd/C (10% mass, 50 mg) was added to a suspension of the compound of Preparation 227 (1.35 g, 6.42 mmol) in EtOAc (40 mL) and MeOH (10 mL) and stirred at room temperature 5 under balloon pressure of hydrogen for 16 hours. The reaction mixture was filtered. To the filtrate was added HCl (3M solution in CPME, 3 mL) and the mixture was concentrated in vacuo. The residue was triturated with Et2O, and the formed solid was collected by filtration and dried in vacuo to afford the title compound as a colourless solid (1.25 g, 90% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 3H), 7.92 (s, 1H), 7.55 (s, 1H), 4.62 – 4.07 (m,10 2H), 3.30 – 2.94 (m, 2H), 2.78 (qd, J = 8.7, 4.4 Hz, 1H), 2.02 (qd, J = 8.7, 8.1, 4.0 Hz, 1H), 1.72 (dq, J = 12.5, 8.9 Hz, 1H). Preparation 229: (2S)-2-amino-2-(4,4-difluorocyclohexyl)-N-[1-[(2-oxopyrrolid in-3- yl)methyl]pyrazol-4-yl]acetamide, hydrochloride. 15 According to the method of Preparation 120 the compound of Example 64 (58.1 mg, 0.128 mmol) was reacted to afford the title compound as a colourless oil (59mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 356.3 [M+H] ⁺ , RT = 0.35 min. 20 Preparation 230: tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[1-[(2-methoxy-3- pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 10 (178 mg, 0.436 mmol) was reacted with the compound of Preparation 191 (128.3 mg, 0.436 mmol) to25 afford the title compound as a pinkish solid after silica column chromatography (192 mg, 39% yield). LCMS (METHOD 4) (ES): m/z 480.4 [M+H] ⁺ , RT = 0.70 min. 952-WO 132 Preparation 231: (2S)-2-amino-2-(4,4-difluorocyclohexyl)-N-[1-[(2-methoxy-3- pyridyl)methyl]pyrazol-4-yl]acetamide, hydrochloride. 5 According to the method of Preparation 120 the compound of Preparation 230 (74.9 mg, 0.125 mmol) was reacted to afford the title compound as a colourless solid (80.3 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 380.3 [M+H] ⁺ , RT = 0.54 min. Preparation 232: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[1-[(2-methoxy-3-10 pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 231 (17.3 mg, 0.042 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (7.1 mg, 0.046 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (15.7 mg, 69%15 yield). LCMS (METHOD 4) (ES): m/z 516.4 [M+H] ⁺ , RT = 0.66 min. Preparation 233: 2-cyclopropyl-N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[1-[(2-m ethoxy-3- pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]pyrazole-3-ca rboxamide. H Cl 20 According to the method of Preparation 57 the compound of Preparation 231 (17.3 mg, 0.042 mmol) was reacted with 2-cyclopropylpyrazole-3-carboxylic acid (7.0 mg, 0.046 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (15.4 mg, 68% yield). LCMS (METHOD 4) (ES): m/z 514.4 [M+H] ⁺ , RT = 0.64 min. 952-WO 133 Preparation 234: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[1-[(2-methoxy-3- pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-ethyl-1,2, 5-oxadiazole-3-carboxamide. 5 According to the method of Preparation 57 the compound of Preparation 231 (17.3 mg, 0.042 mmol) was reacted with 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (6.5 mg, 0.046 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (14.5 mg, 65% yield). LCMS (METHOD 4) (ES): m/z 504.4 [M+H] ⁺ , RT = 0.71 min. 10 Preparation 235: tert-butyl N-[(1S)-2-[[1-[(2-methoxy-3-pyridyl)methyl]pyrazol-4- yl]amino]-1-(4-methylcyclohexyl)-2-oxo-ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 16 (100 mg, 0.369 mmol) was reacted with the compound of Preparation 191 (75.3 mg, 0.369 mmol) to afford15 the title compound as a colourless solid after prep. acidic HPLC (134 mg, 79% yield). LCMS (METHOD 3) (ES): m/z 458.4 [M+H] ⁺ , RT = 0.82 min. Preparation 236: (2S)-2-amino-2-(4-methylcyclohexyl)-N-[1-[(2-oxo-1H-pyridin- 3- yl)methyl]pyrazol-4-yl]acetamide, hydrochloride. HCl 20 According to the method of Preparation 224 the compound of Preparation 235 (134 mg, 0.29 mmol) was reacted to afford the title compound as a colourless solid (100 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 344.3 [M+H] ⁺ , RT = 0.42 min. 952-WO 134 Preparation 237: tert-butyl N-[(1S)-2-[[1-[(2-methoxy-3-pyridyl)methyl]pyrazol-4- yl]amino]-1-(4-methylcyclohexyl)-2-oxo-ethyl]carbamate. 5 According to the method of Preparation 55 the compound of Preparation 16 (91.9 mg, 0.339 mmol) was reacted with the compound of Preparation 115 (80.0 mg, 0.339 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (112 mg, 67% yield). LCMS (METHOD 3) (ES): m/z 490.5 [M+H] ⁺ , RT = 0.89 min. 10 Preparation 238: (2S)-2-amino-N-[1-[(1S)-1-(5-fluoro-2-oxo-1H-pyridin-3-yl)et hyl]pyrazol- 4-yl]-2-(4-methylcyclohexyl)acetamide, hydrochloride. According to the method of Preparation 224 the compound of Preparation 237 (112 mg, 0.29 mmol) was reacted to afford the title compound as a colourless solid (85.9 mg,15 assume 100% yield). LCMS (METHOD 3) (ES): m/z 376.4 [M+H] ⁺ , RT = 0.48 min. Preparation 239: tert-butyl N-[(1S)-2-[[1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2- triisopropylsilyloxy-ethyl]pyrazol-4-yl]amino]-1-(4-methylcy clohexyl)-2-oxo- ethyl]carbamate. 20 According to the method of Preparation 55 the compound of Preparation 16 (93 mg, 0.34 mmol) was reacted with the compound of Preparation 76 (140 mg, 0.34 mmol) to afford 952-WO 135 the title compound as a colourless solid after silica column chromatography (174 mg, 76% yield). LCMS (METHOD 3) (ES): m/z 694.7 [M+H] ⁺ , RT = 1.14 min. Preparation 240: (2S)-2-amino-N-[1-[1-(5-fluoro-2-oxo-1H-pyridin-3-yl)-2-hydr oxy- 5 ethyl]pyrazol-4-yl]-2-(4-methylcyclohexyl)acetamide. TMSI (1M soln. in DCM, 2.0 mL) was added to a solution of the compound of Preparation 239 (178 mg, 0.269 mmol) in MeCN (4 mL). The reaction mixture was stirred at room temperature for 2 hours. MeOH (0.5 mL) was added and the reaction mixture was stirred10 for a further 10 minutes, then purified directly by prep. basic HPLC to afford the title compound (73.0 mg, 69% yield). LCMS (METHOD 3) (ES): m/z 392.4 [M+H] ⁺ , RT = 0.41 min. Preparation 241: tert-butyl N-[(1S)-2-[[1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-methoxy-15 ethyl]pyrazol-4-yl]amino]-1-(4-methylcyclohexyl)-2-oxo-ethyl ]carbamate. According to the method of Preparation 55 the compound of Preparation 16 (87 mg, 0.342 mmol) was reacted with the compound of Preparation 82 (85 mg, 0.32 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (110 mg, 66% yield). LCMS20 (METHOD 3) (ES): m/z 520.5 [M+H] ⁺ , RT = 0.88 min. Preparation 242: (2S)-2-amino-N-[1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-methox y- ethyl]pyrazol-4-yl]-2-(4-methylcyclohexyl)acetamide, hydrochloride. 952-WO 136 HCl (3M solution in 2-Me-THF, 1 mL) was added to a solution of the compound of Preparation 241 (55 mg, 0.106 mmol) in CDCl3 (2 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to afford the crude title compound 5 that was used directly in the next step (55 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 420.5 [M+H] ⁺ , RT = 0.65 min. P ^{reparation 243} : ^{N-[(1S)-2-[[1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-metho xy-} ethyl]pyrazol-4-yl]amino]-1-(4-methylcyclohexyl)-2-oxo-ethyl ]-2-isopropyl-pyrazole-3-10 carboxamide. H According to the method of Preparation 57 the compound of Preparation 242 (26.4 mg, 0.05 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (15 mg, 0.117 mmol) to afford the title compound as an off-white solid after prep. acidic HPLC (16.5 mg,15 62% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 2.9, 1.5 Hz, 1H), 7.71 (s, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.23 (td, J = 8.5, 3.0 Hz, 1H), 5.76 (dd, J = 8.3, 4.2 Hz, 1H), 4.41 (t, J = 8.1 Hz, 1H), 4.15 (dt, J = 10.4, 7.9 Hz, 1H), 3.97 (d, J = 1.2 Hz, 3H), 3.87 (dd, J = 10.4, 4.1 Hz, 1H), 3.36 (d, J = 4.0 Hz, 3H), 2.59 (d, J = 3.0 Hz, 3H), 1.97 – 1.69 (m, 5H), 1.29 (d, J = 25.8 Hz, 1H), 1.22 – 1.0520 (m, 2H), 1.05 – 0.84 (m, 5H); LCMS (METHOD 3) (ES): m/z 530.5 [M+H] ⁺ , RT = 0.86 min. Preparation 244: N-[(1S)-2-[[1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-methoxy- ethyl]pyrazol-4-yl]amino]-1-(4-methylcyclohexyl)-2-oxo-ethyl ]-2-isopropyl-pyrazole-3- carboxamide. 952-WO 137 H According to the method of Preparation 57 the compound of Preparation 242 (26.4 mg, 0.05 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (20 mg, 0.13 mmol) to afford the title compound as an off-white solid after prep. acidic HPLC (24 mg, 84% yield). 5 ¹ H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.91 (dd, J = 3.0, 1.3 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 4.0, 2.0 Hz, 1H), 7.23 (ddd, J = 10.6, 8.5, 3.0 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.55 (dd, J = 4.4, 2.0 Hz, 1H), 5.75 (dd, J = 8.3, 4.2 Hz, 1H), 5.40 (pd, J = 6.6, 2.0 Hz, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.14 (ddd, J = 10.3, 8.2, 5.2 Hz, 1H), 3.96 (s, 3H), 3.86 (dd, J = 10.3, 4.1 Hz, 1H), 3.35 (d, J = 3.0 Hz, 3H), 1.8110 (dd, J = 42.4, 12.9 Hz, 4H), 1.46 (td, J = 7.1, 2.7 Hz, 6H), 1.28 (d, J = 21.9 Hz, 1H), 1.11 (dt, J = 14.0, 10.6 Hz, 2H), 1.05 – 0.83 (m, 6H); LCMS (METHOD 3) (ES): m/z 556.6 [M+H] ⁺ , RT = 0.85 min. Preparation 245: tert-butyl N-[(1S)-2-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-15 yl)ethyl]pyrazol-4-yl]amino]-1-(4-methylcyclohexyl)-2-oxo-et hyl]carbamate. According to the method of Preparation 55 the compound of Preparation 16 (923mg, 3.40 mmol) was reacted with the compound of Preparation 94 (989 mg, 3.89 mmol) to afford the crude title compound as a pale pink solid (1.60 g, 92% yield). LCMS (METHOD 3) (ES):20 m/z 507.5 [M+H] ⁺ , RT = 0.79 min. Preparation 246: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl ]pyrazol-4- yl]-2-(4-methylcyclohexyl)acetamide, hydrochloride. 952-WO 138 According to the method of Preparation 224 the compound of Preparation 245 (104 mg, 0.205 mmol) was reacted to afford the title compound as a colourless solid (80.6 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 393.3 [M+H] ⁺ , RT = 0.79 min. 5 Preparation 247: 2-methoxy-3-[(4-nitroimidazol-1-yl)methyl]pyridine. K2CO3 (1.50 g, 10.9 mmol) was added to a solution of 4-nitro-1H-imidazole (281 mg, 2.49 mmol) and 3-(bromomethyl)-2-methoxy-pyridine (402 mg, 1.99 mmol) in MeCN (5 mL)10 and the reaction mixture was stirred at 70°C for 16 hours. The cooled reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was rewashed with H2O (20 mL) and saturated brine solution (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in pet. ether, to afford the15 title compound as a colourless oil (210 mg, 45% yield). LCMS (METHOD 2) (ES): m/z 235.2 [M+H] ⁺ , RT = 1.71 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). Preparation 248: 1-[(2-methoxy-3-pyridyl)methyl]imidazol-4-amine. 20 According to the method of Preparation 186 the compound of Preparation 247 (251 mg, 1.07 mmol) was reacted to afford the title compound as a colourless solid (0.82 g, assume 100% yield). LCMS (METHOD 2) (ES): m/z 205.3 [M+H] ⁺ , RT = 2.76 min. (Xbridge C18 column, 5 mM ammonium bicarbonate in water with MeCN) 25 Preparation 249: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-methoxy-3- pyridyl)methyl]imidazol-4-yl]amino]-2-oxo-ethyl]carbamate. 952-WO 139 According to the method of Preparation 55 the compound of Preparation 5 (90.0 mg, 0.297 mmol) was reacted with the compound of Preparation 248 (90.9 mg, 0.445 mmol) to afford the title compound as a tan solid (75 mg, 51% yield). LCMS (METHOD 2) (ES): m/z 490.0 5 [M+H] ⁺ , RT = 1.93 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). Preparation 250: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(2-methoxy-3- pyridyl)methyl]imidazol-4-yl]propanamide. 10 Pd/C (10% mass, 50 mg) was added to a thoroughly degassed solution of the compound of Preparation 249 (550 mg, 1.12 mmol) in MeOH (20 mL) and THF (5 mL) under balloon pressure atmosphere of hydrogen. The reaction mixture was stirred for 16 hours, then filtered through Celite™. The cake was washed with MeOH (3 x 20 mL). The combined15 organic phase was concentrated in vacuo to afford the title compound (250 mg, 62% yield). LCMS (METHOD 2) (ES): m/z 356.3 [M+H] ⁺ , RT = 1.59 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). Preparation 251: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-methoxy-3-20 pyridyl)methyl]imidazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl -pyrazole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 250 (550 mg, 0.89 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (152 mg, 0.99 mmol) to afford the title compound as a colourless solid after silica column chromatography (300 mg, 952-WO 140 26% yield). LCMS (METHOD 2) (ES): m/z 492.4 [M+H] ⁺ , RT = 1.97 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). Preparation 252: 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-meth oxy-3- 5 pyridyl)methyl]imidazol-4-yl]amino]-2-oxo-ethyl]-1,2,5-oxadi azole-3-carboxamide. According to the method of Preparation 57 the compound of Preparation 250 (397 mg, 0.65 mmol) was reacted with 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (50 mg, 0.32 mmol, synthesis described in WO2020146194A1) to afford the title compound as a 10 colourless solid after silica column chromatography (35 mg, 22% yield). LCMS (METHOD 2) (ES): m/z 492.4 [M+H] ⁺ , RT = 2.15 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). Preparation 253: 2-methoxy-3-[2,2,2-trifluoro-1-(4-nitroimidazol-1-yl)ethyl]p yridine. 15 According to the method of Preparation 93 the compound of Preparation 58 (1.05 g, 5.07 mmol) was reacted with 4-nitro-1H-imidazole (860 mg, 7.60 mmol) to afford the title compound as a yellow solid after silica column chromatography (850 mg, 48% yield). LCMS (METHOD 2) (ES): m/z 303.2 [M+H] ⁺ , RT = 1.72 min. (ACQUITY UPLC BEH C18 column,20 0.05% FA in water with 0.05% FA in MeCN). Preparation 254: 1-[2,2,2-trifluoro-1-(2-methoxy-3-pyridyl)ethyl]imidazol-4-a mine. According to the method of Preparation 54 the compound of Preparation 253 (175 mg, 0.5825 mmol) was reacted to afford the title compound as a tan gummy solid (120 mg, assume 100% yield). LCMS (METHOD 2) (ES): m/z 273.2 [M+H] ⁺ , RT = 1.48 min. (ACQUITY UPLC BEH C18 coluM-Hmn, 0.05% FA in water with 0.05% FA in MeCN). 952-WO 141 Preparation 255: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2,2,2-trifluoro -1-(2- methoxy-3-pyridyl)ethyl]imidazol-4-yl]amino]ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 5 (22.3 mg, 0.073 5 mmol) was reacted with the compound of Preparation 254 (50.0 mg, 0.073 mmol) to afford the title compound as a tan liquid (75 mg, assume 100% yield). LCMS (METHOD 2) (ES): m/z 558.3 [M+H] ⁺ , RT = 2.31 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). 10 Preparation 256: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[2,2,2-trifluoro-1-(2-me thoxy-3- pyridyl)ethyl]imidazol-4-yl]propanamide. According to the method of Preparation 250 the compound of Preparation 255 (75 mg, 0.11 mmol) was reacted to afford the title compound as a tan gummy oil (60 mg, assume 100%15 yield). LCMS (METHOD 2) (ES): m/z 424.3 [M+H] ⁺ , RT = 1.46 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). Preparation 257: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2,2,2-trifluoro -1-(2- methoxy-3-pyridyl)ethyl]imidazol-4-yl]amino]ethyl]-2-isoprop yl-pyrazole-3-carboxamide. 20 According to the method of Preparation 57 the compound of Preparation 256 (60 mg, 0.11 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (18.1 mg, 0.11 mmol) to afford the title compound as a yellow solid after silica column chromatography (49 mg, 952-WO 142 55% yield). LCMS (METHOD 2) (ES): m/z 560.4 [M+H] ⁺ , RT = 2.21min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). Preparation 258: 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2 ,2,2- 5 trifluoro-1-(2-methoxy-3-pyridyl)ethyl]imidazol-4-yl]amino]e thyl]-1,2,5-oxadiazole-3- carboxamide. According to the method of Preparation 57 the compound of Preparation 256 (200 mg, 0.36 mmol) was reacted with 4-cyclopropyl-1,2,5-oxadiazole-3-carboxylic acid (57.5 mg, 0.3610 mmol, synthesis described in WO2020146194A1) to afford the title compound as a yellow solid after silica column chromatography (105 mg, 44% yield). LCMS (METHOD 2) (ES): m/z 560.4 [M+H] ⁺ , RT = 2.45 min. (ACQUITY UPLC BEH C18 column, 0.05% FA in water with 0.05% FA in MeCN). 15 NEW PREPS Preparation 259: (1S)-1-(6-chloro-3-methoxy-pyridazin-4-yl)ethanol and [(1R)-1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl] acetate. 20 According to the method of Preparation 51 the compound of Preparation 92 (2.02 g, 10.7 mmol) was reacted to afford the title compounds. 259a: (1S)-1-(6-chloro-3-methoxy-pyridazin-4-yl)ethanol (970 mg, 48% yield); LCMS (METHOD 3) (ES): m/z 189.3 [M+H] ⁺ , RT = 0.47 min. 259b: [(1R)-1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl] acetate (1.18 g, 48% yield). ¹ H25 NMR (600 MHz, DMSO-d6) δ 7.71 (d, J = 0.8 Hz, 1H), 5.75 (qd, J = 6.6, 0.9 Hz, 1H), 4.09 (s, 3H), 2.12 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H); LCMS (METHOD 3) (ES): m/z 231.3 [M+H] ⁺ , RT = 0.62 min. Preparation 260: (1R)-1-(6-chloro-3-methoxy-pyridazin-4-yl)ethanol. 952-WO 143 According to the method of Preparation 52 the compound of Preparation 259b (1.18 g, 5.12 mmol) was reacted to afford the title compound as a colourless solid (930 mg, 96% yield). LCMS (METHOD 3) (ES): m/z 189.2 [M+H] ⁺ , RT = 0.47 min. 5 Preparation 261: 6-chloro-4-[(1S)-1-(3-fluoro-4-nitro-pyrazol-1-yl)ethyl]-3-m ethoxy- pyridazine. According to the method of Preparation 53 the compound of Preparation 260 (923 mg, 4.8910 mmol) was reacted with 3-fluoro-4-nitro-1H-pyrazole (583 mg, 4.45 mmol) to afford the title compound as a yellow solid after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (902 mg, 63% yield). ¹ H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 1.1 Hz, 1H), 7.25 (s, 1H), 5.53 (q, J = 7.0 Hz, 1H), 4.19 (s, 3H), 1.87 (d, J = 7.0 Hz, 3H); LCMS (METHOD 3) (ES): m/z 302.3 [M+H] ⁺ , RT = 0.71 min. 15 Preparation 262: 1-[(1S)-1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]-3-fluoro -pyrazol-4- amine. According to the method of Preparation 94 the compound of Preparation 261 (354 mg, 1.1720 mmol) was reacted to afford the crude title compound as a reddish solid that was used directly in the next step (325 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 272.3 [M+H] ⁺ , RT = 0.52 min. Preparation 263: tert-butyl N-[(1S)-1-[[1-[(1S)-1-(6-chloro-3-methoxy-pyridazin-4-25 yl)ethyl]-3-fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl -ethyl]carbamate. 952-WO 144 According to the method of Preparation 55 the compound of Preparation 118 (316 mg, 1.17 mmol) was reacted with the compound of Preparation 262 (325 mg, 1.17 mmol) to afford the title compound as an off-white solid after silica column chromatography (480 mg, 74% 5 yield). LCMS (METHOD 3) (ES): m/z 521.6 [M-H]-, RT = 0.87 min. Preparation 264: (2S)-2-amino-N-[1-[(1S)-1-(3-chloro-6-oxo-1H-pyridazin-5-yl) ethyl]-3- fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide;hydrochlo ride. 10 According to the method of Preparation 120 the compound of Preparation 263 (478 mg, 0.91 mmol) was reacted to afford the title compound as an off-white foam (424 mg, 98% yield). LCMS (METHOD 3) (ES): m/z 409.5 [M+H] ⁺ , RT = 0.49 min. Preparation 265: 3-chloro-5-[1-(4-nitropyrazol-1-yl)ethyl]-1H-pyridazin-6-one . 15 According to the method of Preparation 120 the compound of Preparation 94 (430 mg, 1.51 mmol) was reacted to afford the title compound as a pinkish solid that was used without further purification (390 mg, 95% yield). LCMS (METHOD 4) (ES): m/z 268.0 [M-H]-, RT = 0.46 min. 20 Preparation 266: 6-chloro-3-[(4-methoxyphenyl)methoxy]-4-[1-(4-nitropyrazol-1 - yl)ethyl]pyridazine and 6-chloro-2-[(4-methoxyphenyl)methyl]-4-[1-(4-nitropyrazol-1- yl)ethyl]pyridazin-3-one. 952-WO 145 DEAD (40% soln. in toluene, 0.72 mL, 1.60 mmol) was added dropwise to a solution of the compound of Preparation 265 (0.39 g, 1.40 mmol), (4-methoxyphenyl)methanol (0.22 g, 1.60 mmol) and triphenylphosphine (0.42 g, 1.60 mmol) in THF (20 mL) at room 5 temperature. On complete addition the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compounds as a colourless oil (0.5 g, 89% yield). NMR confirmed product as a mixture of regioisomers. Inseparable at this stage so taken on as a10 mixture. LCMS (METHOD 3) (ES): m/z 391.2 [M+H] ⁺ , RT = 0.80 min. Preparation 267: 6-methoxy-3-[(4-methoxyphenyl)methoxy]-4-[1-(4-nitropyrazol- 1- yl)ethyl]pyridazine and 6-methoxy-2-[(4-methoxyphenyl)methyl]-4-[1-(4-nitropyrazol-1 - yl)ethyl]pyridazin-3-one. 15 tBuBrettPhos G3 Pd (20.4 mg, 0.024 mmol) was added to a thoroughly degassed solution of the compounds of Preparation 266 (465 mg, 1.19 mmol), sodium methoxide (90.2 mg, 1.67 mmol) and MeOH (0.24 mL, 5.86 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 65°C for18 hours. The reaction mixture was concentrated in vacuo to low20 volume then diluted with H2O (20 mL) and extracted with Et2O (2 x 40 mL). The combined organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compounds as a colourless oil. (246 mg, 53% yield). LCMS (METHOD 3) (ES): m/z 386.3 [M+H] ⁺ , RT = 0.77 min. NMR confirmed product25 as a mixture of regioisomers. Inseparable at this stage so taken on as a mixture. Preparation 268: 4-[1-(4-aminopyrazol-1-yl)ethyl]-6-methoxy-2-[(4- methoxyphenyl)methyl]pyridazin-3-one and 4-[1-(4-aminopyrazol-1-yl)ethyl]-6-methoxy- 2-[(4-methoxyphenyl)methyl]pyridazin-3-one. 952-WO 146 According to the method of Preparation 54 the compound of Preparation 267 (244 mg, 0.63 mmol) was reacted to afford the crude title compound as a colourless oil (225 mg, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 5 356.3 [M+H] ⁺ , RT = 0.54 and 0.56 min. Inseparable at this stage so taken on as a mixture. Preparation 269: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-[6-methoxy-3-[(4- methoxyphenyl)methoxy]pyridazin-4-yl]ethyl]pyrazol-4-yl]amin o]-2-oxo-ethyl]carbamate10 and benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-[6-methoxy-2-[(4- methoxyphenyl)methyl]-3-oxo-pyridazin-4-yl]ethyl]pyrazol-4-y l]amino]-2-oxo- ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 5 (192 mg, 0.6315 mmol) was reacted with the compounds of Preparation 268 (225 mg, 0.63 mmol) to afford the crude title compounds as an orange oil (406 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 641.5 [M+H] ⁺ , RT = 0.88 min. Inseparable at this stage so taken on as a mixture. 20 Preparation 270: 6 hl 4 1 3 fl 4 i l 1 l h l 3 ethoxy-pyridazine. 952-WO 147 According to the method of Preparation 53 the compound of Preparation 92 (204 mg, 1.08 mmol) was reacted with 3-fluoro-4-nitro-1H-pyrazole (168 mg, 1.28 mmol) to afford the title compound as a yellow solid after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (229 mg, 70% yield). LCMS (METHOD 3) (ES): m/z 302.3 5 [M+H] ⁺ , RT = 0.69 min. Preparation 271: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]-3-fluoro-pyra zol-4-amine. According to the method of Preparation 94 the compound of Preparation 270 (229 mg, 0.7610 mmol) was reacted to afford the crude title compound that was used directly in the next step (206 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 272.1 [M+H] ⁺ , RT = 0.47 min. Preparation 272: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]-3 -15 fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carba mate. According to the method of Preparation 55 the compound of Preparation 118 (204 mg, 0.76 mmol) was reacted with the compound of Preparation 271 (206 mg, 0.76 mmol) to afford the title compound as an off-white solid after prep. acidic HPLC (258 mg, 65% yield). LCMS20 (METHOD 3) (ES): m/z 521.5 [M-H]-, RT = 0.84 min. Preparation 273: (2S)-2-amino-N-[1-[(1S)-1-(3-chloro-6-oxo-1H-pyridazin-5-yl) ethyl]-3- fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide;hydrochlo ride. 25 According to the method of Preparation 120 the compound of Preparation 272 (115 mg, 0.22 mmol) was reacted to afford the title compound as an off-white foam (98 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 409.3 [M+H] ⁺ , RT = 0.57 min. 952-WO 148 Preparation 274: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1SR)-2- methoxy-1-(3-methoxypyridazin-4-yl)ethyl]pyrazol-4-yl]amino] -2-oxo-ethyl]carbamate. 5 Pd/C (10%, 100 mg, 0.094 mmol) was added to a solution of the compound of Preparation 223 (100 mg, 0.18 mmol) and 4-methylmorpholine (0.1 mL, 0.9 mmol) in EtOH (2 mL) under nitrogen and stirred at room temperature under an atmosphere of hydrogen for 2 hours. The reaction mixture was filtered through a PTFE filter and washed with EtOH. The combined filtrate was concentrated in vacuo and purified by prep. acidic HPLC to afford the10 title compound mixture as a white solid (74 mg, 79% yield). LCMS (METHOD 3) (ES): m/z 519.4 [M+H] ⁺ , RT = 0.76 min. Preparation 275: (2S)-2-amino-3,3-dicyclopropyl-N-[3-fluoro-1-[(1SR)-2-methox y-1-(6- oxo-1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]propenamide. 15 HCl (3M solution in 2-Me-THF, 1 mL) was added to a solution of the compound of Preparation 274 (35.0 mg, 0.067 mmol) in MeOH (1 mL) and stirred at 90°C for 2 hours. The reaction mixture was concentrated in vacuo to afford the crude title compound that was used directly in the next step (30.0 mg, assume 100% yield). LCMS (METHOD 3) (ES):20 m/z 405.4 [M+H] ⁺ , RT = 0.50 min. Preparation 276: 3-(difluorometh l)-6-methox -p ridazine DAST (2.30 mL, 17.4 mmol) was added to a solution of 6-methoxypyridazine-3-25 carbaldehyde (1.20 g, 8.69 mmol) in DCM at room temperature and stirred for 18 hours. The reaction mixture was diluted with DCM (80 mL) and washed with sat. aqueous NaHCO3 952-WO 149 (25 mL). The organic layer was filtered through a short silica pad, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as an off-white solid (1.04 g, 74% yield). ¹ H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 9.2 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 6.84 (t, J = 54.7 Hz, 1H), 4.19 (s, 3H); LCMS (METHOD 3) (ES): m/z 161.1 [M+H] ⁺ , 5 RT = 0.45 min. Preparation 277: 1-[6-(difluoromethyl)-3-methoxy-pyridazin-4-yl]ethanol. According to the method of Preparation 129 the compound of Preparation 276 (250 mg,10 1.60 mmol) was reacted to afford the title compound after silica gel chromatography, eluting with EtOAc in heptane, that was used directly in the next step (64.4 mg, 20% yield). LCMS (METHOD 3) (ES): m/z 205.1 [M+H] ⁺ , RT = 0.45 min. Preparation 278: 6-(difluoromethyl)-3-methoxy-4-[1-(4-nitropyrazol-1-yl)ethyl ]pyridazine. 15 According to the method of Preparation 93 the compound of Preparation 277 (64.4 mg, 0.32 mmol) was reacted with 4-nitro-1H-pyrazole (39.2 mg, 0.35 mmol) to afford the title compound as a colourless oil after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (89 mg, 94% yield). LCMS (METHOD 3) (ES): m/z 298.2 [M-H]-, RT20 = 0.65 min. Preparation 279: 1-[1-[6-(difluoromethyl)-3-methoxy-pyridazin-4-yl]ethyl]pyra zol-4- amine. 25 According to the method of Preparation 94 the compound of Preparation 278 (89.0 mg, 0.30 mmol) was reacted to afford the crude title compound as an orange oil (80.0 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 270.2 [M+H] ⁺ , RT = 0.38 min. 952-WO 150 Preparation 280: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-[6-(difluoromethyl) - 3-methoxy-pyridazin-4-yl]ethyl]pyrazol-4-yl]amino]-2-oxo-eth yl]carbamate. According to the method of Preparation 55 the compound of Preparation 118 (80.0 mg, 5 0.30 mmol) was reacted with the compound of Preparation 279 (80.0 mg, 0.30 mmol) to afford the title compound as a pale yellow oil (132 mg, 85% yield). LCMS (METHOD 3) (ES): m/z 521.5 [M+H] ⁺ , RT = 0.79 min. Preparation 281: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[1-[3-(difluoromethyl)-6 -oxo-1H-10 pyridazin-5-yl]ethyl]pyrazol-4-yl]propanamide;hydrochloride. HCl (3M solution in CPME, 2.0 mL) was added to a solution of the compound of Preparation 280 (132 mg, 0.254 mmol) in MeOH (2 mL) and stirred at 50°C for 1 hour. The reaction mixture was concentrated in vacuo to afford the crude title compound that was used15 without further purification as an off-white solid (112 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 407.4 [M+H] ⁺ , RT = 0.52 min. Preparation 282: 6-chloro-4-(3,3-difluoropropyl)-3-methoxy-pyridazine. 20 According to the method of Preparation 129, 3-chloro-6-methoxy-pyridazine (0.87 g, 6.0 mmol) was reacted with 4,4-difluorobutanoic acid (1.05 g, 8.46 mmol) to afford the title compound after silica gel chromatography, eluting with EtOAc in heptane, that was used directly in the next step, as a colourless oil (0.4 g, 28% yield). LCMS (METHOD 3) (ES): m/z 223.1 [M+H] ⁺ , RT = 0.64 min. 25 Preparation 283: 4-(1-bromo-3,3-difluoro-propyl)-6-chloro-3-methoxy-pyridazin e. 952-WO 151 NBS (0.28 g, 1.6 mmol) was added to a solution of the compound of Preparation 282 (0.4 g, 1.8 mmol) and benzoyl peroxide (50 mg) in CCl4 (20 mL) and stirred at 80°C for 2 hours. The cooled reaction mixture was diluted with DCM (20 mL) washed with sat. 5 aqueous NaHCO3 (20 mL) then H2O (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford the crude title compound as an orange oil (0.48 g, assume 100% yield). The material was used directly in the next step. LCMS (METHOD 3) (ES): m/z 303.0 [M+H] ⁺ , RT = 0.72 min. 10 Preparation 284: 6-chloro-4-[3,3-difluoro-1-(4-nitropyrazol-1-yl)propyl]-3-me thoxy- pyridazine. The compound of Preparation 283 (0.48 g, 1.6 mmol) in MeCN (5 mL) was added to a solution of 4-nitro-1H-pyrazole (0.27 g, 2.4 mmol) and Cs2CO3 (1.3 g, 4.0 mmol) in DMF15 (15 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (70 mL) and extracted with Et2O (2 x 40 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a pale yellow oil (274 mg, 52% yield). LCMS (METHOD 4)20 (ES): m/z 332.2 [M-H]-, RT = 0.68 min. Preparation 285: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3-difluoro-propyl ]pyrazol-4- amine. 25 According to the method of Preparation 94 the compound of Preparation 284 (270 mg, 0.81 mmol) was reacted to afford the crude title compound as a yellow oil (250 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 304.2 [M+H] ⁺ , RT = 0.44 min. 952-WO 152 Preparation 286: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3- difluoro-propyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-et hyl]carbamate. 5 According to the method of Preparation 55 the compound of Preparation 118 (220 mg, 0.82 mmol) was reacted with the compound of Preparation 285 (250 mg, 0.82 mmol) to afford the title compound after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, as a colourless solid (367 mg, 80% yield). LCMS (METHOD 3) (ES): m/z 553.4 [M-H]-, RT = 0.83 min. 10 Preparation 287: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-3,3- difluoro- propyl]pyrazol-4-yl]-3,3-dicyclopropyl-propanamide; hydrochloride. According to the method of Preparation 281 the compound of Preparation 286 (367 mg,15 0.66 mmol) was reacted to afford the crude title compound as a pale yellow solid (317 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 441.3 [M+H] ⁺ , RT = 0.55 min. Preparation 288: 6-chloro-4-[3,3-difluoro-1-(3-fluoro-4-nitro-pyrazol-1-yl)pr opyl]-3- methoxy-pyridazine 20 According to the method of Preparation 284 the compound of Preparation 283 (0.5 g, 1.7 mmol) was reacted with 3-fluoro-4-nitro-1H-pyrazole (0.33 g, 2.5 mmol) to afford the title compound after silica column chromatography (230-400 mesh), eluting with EtOAc in 952-WO 153 heptane, as a colourless solid (495 mg, 85% yield). LCMS (METHOD 3) (ES): m/z 352.3 [M+H] ⁺ , RT = 0.74 min. Preparation 289: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3-difluoro-propyl ]-3-fluoro- 5 pyrazol-4-amine. According to the method of Preparation 94 the compound of Preparation 285 (495 mg, 1.41 mmol) was reacted to afford the crude title compound as a yellow oil (453 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 322.3 [M+H] ⁺ , RT = 0.60 min. 10 Preparation 290: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3- difluoro-propyl]-3-fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicycl opropyl-ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 118 (379 mg, 1.4115 mmol) was reacted with the compound of Preparation 289 (453 mg, 1.41 mmol) to afford the title compound after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, as a colourless solid (614 mg, 76% yield). LCMS (METHOD 3) (ES): m/z 571.6 [M-H]-, RT = 0.88 min. 20 Preparation 291: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-3,3- difluoro- propyl]-3-fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide ; hydrochloride. 952-WO 154 According to the method of Preparation 281 the compound of Preparation 290 (614 mg, 1.41 mmol) was reacted to afford the crude title compound as a colourless solid (531 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 459.6 [M+H] ⁺ , RT = 0.53 min. 5 Preparation 292: 6-chloro-4-[3,3-difluoro-1-(3-fluoro-4-nitro-pyrazol-1-yl)pr opyl]-3- methoxy-pyridazine Enantiomer 1 and Enantiomer 2. E ^{nantiomer 1} _{Enantiomer 2} The compound of Preparation 288 (1.4 g, 3.98 mmol) was separated by chiral SFC (Lux C1 (21.2 mm x 250 mm, 5um), 40°C, 50 mL/min, MeCN/CO215:85) to afford the title10 compounds as individual unknown enantiomers. Preparation 292a (Enantiomer 1): 515 mg, 36.7% yield, Chiral analysis: RT = 1.85 min (Lux C1 (4.6 mm x 250 mm, 5um), 40°C, 4 mL/min, MeCN/CO2) Preparation 292b (Enantiomer 2): 520 mg, 37% yield, Chiral analysis: RT = 2.18 min (Lux C1 (4.6 mm x 250 mm, 5um), 40°C, 4 mL/min, MeCN/CO ₂ ) 15 Preparation 293: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3-difluoro-propyl ]-3-fluoro- pyrazol-4-amine, Enantiomer 2. According to the method of Preparation 94 the compound of Preparation 292b (191 mg,20 0.54 mmol) was reacted to afford the crude title compound as a yellow oil (175 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 322.3 [M+H] ⁺ , RT = 0.66 min. Preparation 294: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3- difluoro-propyl]-3-fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicycl opropyl-ethyl]carbamate,25 Diastereomer 2. 952-WO 155 According to the method of Preparation 55 the compound of Preparation 118 (146 mg, 0.54 mmol) was reacted with the compound of Preparation 293 (175 mg, 0.54 mmol) to afford the title compound after silica column chromatography (230-400 mesh), eluting with EtOAc 5 in heptane, as a colourless solid (232 mg, 74% yield). LCMS (METHOD 3) (ES): m/z 571.6 [M-H]-, RT = 0.94 min. Preparation 295: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-3,3- difluoro- propyl]-3-fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide ; hydrochloride, Diastereomer10 2. According to the method of Preparation 281 the compound of Preparation 294 (232 mg, 0.41 mmol) was reacted to afford the crude title compound as a colourless solid (200 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 459.4 [M+H] ⁺ , RT = 0.60 min. 15 Preparation 296: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3-difluoro-propyl ]-3-fluoro- pyrazol-4-amine, Enantiomer 1. According to the method of Preparation 94 the compound of Preparation 292a (522 mg,20 1.48 mmol) was reacted to afford the crude title compound as a yellow oil (477 mg, assume 100% yield). LCMS (METHOD 3) (ES): m/z 322.3 [M+H] ⁺ , RT = 0.65 min. 952-WO 156 Preparation 297: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3- difluoro-propyl]-3-fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicycl opropyl-ethyl]carbamate, Diastereomer 1. 5 According to the method of Preparation 55 the compound of Preparation 118 (197 mg, 0.73 mmol) was reacted with the compound of Preparation 296 (235 mg, 0.73 mmol) to afford the title compound after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, as a colourless solid (400 mg, 96% yield). LCMS (METHOD 3) (ES): m/z 571.5 [M-H]-, RT = 0.94 min. 10 Preparation 298: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-3,3- difluoro- propyl]-3-fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide ; hydrochloride, Diastereomer 1. 15 According to the method of Preparation 281 the compound of Preparation 297 (400 mg, 0.70 mmol) was reacted to afford the crude title compound as a colourless solid (350 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 459.2 [M+H] ⁺ , RT = 0.61 min. Preparation 299: 1-(6-chloro-3-methoxy-pyridazin-4-yl)propan-1-ol. 20 According to the method of Preparation 129, 3-chloro-6-methoxy-pyridazine (2.17 g, 15.0 mmol) was reacted with 2-hydroxybutanoic acid (2.89 g, 27.8 mmol) to afford the title compound after silica gel chromatography, eluting with EtOAc in heptane, that was used directly in the next step, as a pale yellow oil (0.53 g, 17% yield). LCMS (METHOD 3) (ES):25 m/z 203.3 [M+H] ⁺ , RT = 0.55 min. 952-WO 157 Preparation 300: 6-chloro-4-[1-(3-fluoro-4-nitro-pyrazol-1-yl)propyl]-3-metho xy- pyridazine. According to the method of Preparation 93 the compound of Preparation 299 (94.0 mg, 5 0.46mmol) was reacted with 3-fluoro-4-nitro-1H-pyrazole (66.0 mg, 0.50 mmol) to afford the title compound as a colourless solid after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, (63.0 mg, 43% yield). LCMS (METHOD 3) (ES): m/z 316.3 [M+H] ⁺ , RT = 0.75 min. 10 Preparation 301: 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)propyl]-3-fluoro-pyr azol-4- amine. According to the method of Preparation 94 the compound of Preparation 300 (56.0 mg, 0.18 mmol) was reacted to afford the crude title compound as a yellow oil (50.0 mg,15 assume 100% yield). LCMS (METHOD 3) (ES): m/z 286.4 [M+H] ⁺ , RT = 0.58 min. Preparation 302: tert-butyl N-[(1S)-1-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)propyl]- 3-fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]car bamate. 20 According to the method of Preparation 55 the compound of Preparation 118 (47.1 mg, 0.18 mmol) was reacted with the compound of Preparation 301 (50.0 mg, 0.18 mmol) to afford the title compound after silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, as a colourless solid (38.0 mg, 40% yield). LCMS (METHOD 3) (ES): m/z 535.6 [M-H]-, RT = 0.91 min. 25 Preparation 303: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)propy l]-3- fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide. 952-WO 158 According to the method of Preparation 281 the compound of Preparation 302 (38.0 mg, 0.07 mmol) was reacted to afford the crude title compound as a colourless solid (32.5 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 423.2 [M+H] ⁺ , RT = 0.62 min. 5 Preparation 304: tert-butyl N-[(1S)-2-[[1-[(1S)-1-(6-chloro-3-methoxy-pyridazin-4- yl)ethyl]-3-fluoro-pyrazol-4-yl]amino]-1-(4-methylcyclohexyl )-2-oxo-ethyl]carbamate. l N N According to the method of Preparation 55 the compound of Preparation 16 (111 mg,10 0.41mmol) was reacted with the compound of Preparation 262 (111 mg, 0.41 mmol) to afford the title compound as an off-white solid after silica column chromatography (115 mg, 56% yield). LCMS (METHOD 3) (ES): m/z 523.6 [M-H]-, RT = 0.91 min. Preparation 305: (2S)-2-amino-N-[1-[(1S)-1-(3-chloro-6-oxo-1H-pyridazin-5-yl) ethyl]-3-15 fluoro-pyrazol-4-yl]-3,3-dicyclopropyl-propanamide;hydrochlo ride. According to the method of Preparation 120 the compound of Preparation 304 (114 mg, 0.22 mmol) was reacted to afford the title compound as a colourless foam (115 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 411.2 [M+H] ⁺ , RT = 0.62 min. 20 Preparation 306: tert-butyl N-[(1S)-2-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3- difluoro-propyl]-3-fluoro-pyrazol-4-yl]amino]-1-(4,4-difluor ocyclohexyl)-2-oxo- ethyl]carbamate, Diastereomer 1. 952-WO 159 According to the method of Preparation 55 the compound of Preparation 10 (214 mg, 0.73 mmol) was reacted with the compound of Preparation 296 (235 mg, 0.73 mmol) to afford the title compound after silica column chromatography (230-400 mesh), eluting with EtOAc 5 in heptane, as a colourless solid (370 mg, 85% yield). LCMS (METHOD 3) (ES): m/z 595.5 [M-H]-, RT = 0.89 min. Preparation 307: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-3,3- difluoro- propyl]-3-fluoro-pyrazol-4-yl]-2-(4,4-difluorocyclohexyl)ace tamide; hydrochloride, 10 Diastereomer 1. According to the method of Preparation 281 the compound of Preparation 306 (370 mg, 0.62 mmol) was reacted to afford the crude title compound as a colourless solid (320 mg, assume 100% yield). LCMS (METHOD 4) (ES): m/z 483.2 [M+H] ⁺ , RT = 0.56 min. 15 Preparation 308: 3-fluoro-1-[1-(3-methoxypyridazin-4-yl)ethyl]pyrazol-4-amine . N N O O Pd/C (10%, 180 mg) was added to a solution of the compound of Preparation 270 (350 mg, 0.78 mmol) in MeOH (7 mL) and stirred at room temperature for 2 hours under balloon20 pressure hydrogen atmosphere. The reaction mixture was filtered through Celite washing with MeOH, then concentrated in vacuo to give the crude title compound as a gummy solid (300 mg, 65% yield). The compound was used directly in the next step. LCMS (METHOD 2) (ESI): m/z: 328.3 [M+H] ⁺ , RT = 1.44 min (Acquity BEH C18 (50mmx2.1mm), MeCN, H2O). 952-WO 160 Preparation 309: benzyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[3-fluoro-1-[1-(3- methoxypyridazin-4-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl] carbamate. 5 According to the method of Preparation 55, (2S)-2-(benzyloxycarbonylamino)-2-(4,4- difluorocyclohexyl)acetic acid (386 mg, 1.18 mmol) was reacted with the compound of Preparation 308 (350 mg, 0.73 mmol) to afford the title compound as a colourless solid (324 mg, 40% yield). LCMS (METHOD 2) (ESI): m/z: 547.5 [M+H] ⁺ , RT = 2.13 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in10 H2O). Preparation 310: (2S)-2-amino-2-(4,4-difluorocyclohexyl)-N-[3-fluoro-1-[1-(3- methoxypyridazin-4-yl)ethyl]pyrazol-4-yl]acetamide. 15 According to the method of Preparation 250 the compound of Preparation 309 (324 mg, 0.62 mmol) was reacted to afford the crude title compound as a colourless solid (250 mg, assume 100% yield). LCMS (METHOD 2) (ESI): m/z: 413.5 [M+H] ⁺ , RT = 1.28 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). 20 Preparation 311: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[3-fluoro-1-[1-(3- methoxypyridazin-4-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl] -2-isopropyl-pyrazole-3- carboxamide. 952-WO 161 According to the method of Preparation 57 the compound of Preparation 310 (150 mg, 0.36 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (44.9 mg, 0.29 mmol) to afford the crude title compound as a colourless solid (61.7 mg, 31% yield). LCMS (METHOD 5 2) (ESI): m/z: 549.5 [M+H] ⁺ , RT = 2.05 min. (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). Preparation 312: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[3-fluoro-1-[1-(3- methoxypyridazin-4-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl] -4-methyl-1,2,5-oxadiazole-10 3-carboxamide. According to the method of Preparation 57 the compound of Preparation 310 (250 mg, 0.61 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (77.7 mg, 0.61 mmol) to afford the crude title compound as a colourless solid (65.0 mg, 20% yield). LCMS15 (METHOD 2) (ESI): m/z: 523.2[M+H] ⁺ , RT = 1.85 min. (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). Preparation 313: benzyl N-[(1S)-2-[[1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]-3 - fluoro-pyrazol-4-yl]amino]-1-(4,4-difluorocyclohexyl)-2-oxo- ethyl]carbamate. 20 According to the method of Preparation 55, (2S)-2-(benzyloxycarbonylamino)-2-(4,4- difluorocyclohexyl)acetic acid (289 mg, 0.88 mmol) was reacted with the compound of 952-WO 162 Preparation 271 (300 mg, 1.10 mmol) to afford the title compound as an off-white solid (237 mg, 37% yield). LCMS (METHOD 2) (ESI): m/z: 581.3 [M+H] ⁺ , RT = 2.22 min. (Acquity BEH C18 (50mmx2.1mm), MeCN, H2O). 5 Preparation 314: (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl ]-3-fluoro- pyrazol-4-yl]-2-(4,4-difluorocyclohexyl)acetamide; hydrobromide. HBr (47% aqueous solution, 2.5 mL) was added to a solution of the compound of Preparation 313 (250 mg, 0.43 mmol) in DCM (10 mL) and stirred at 50°C for 2 hours. The10 reaction mixture was concentrated in vacuo to afford the title compound as a gummy solid that was used directly in the next step (150 mg, 68% yield). LCMS (METHOD 2) (ESI): m/z: 433.1 [M+H] ⁺ , RT = 1.34 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). 15 Preparation 315: 3-(1-azidoethyl)-5-fluoro-2-methoxy-pyridine. A solution of the compound of Preparation 111 (461 mg, 2.69 mmol) in THF (8 mL) in a 50 mL 2-necked round bottomed flask was cooled to 2°C. DPPA (1.16 mL, 1482 mg, 5.39 mmol) was added, followed by DBU (820 mg, 5.39 mmol) dropwise over 30 min at 2°C and20 the mixture was then allowed to warm to room temperature over 30 minutes. After stirring at room temperature for 1 hour brine (20 mL) was added slowly. The mixture was extracted with EtOAc (2 x 25 mL) and the combined organic extract was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was taken up in DCM (4 mL), filtered and purified by column chromatography (EtOAc, heptane) to give 1-25 (5-fluoro-2-methoxy-3-pyridyl)ethyl diphenyl phosphate (811 mg, 75%) as a colourless oil. LCMS (METHOD 3) (ES): m/z 404.2 [M+H] ⁺ , RT = 0.90 min. Sodium azide (437 mg, 6.73 mmol) was added to a solution of 1-(5-fluoro-2-methoxy-3- pyridyl)ethyl diphenyl phosphate (811 mg, 2.01 mmol) in DMF (6.0 mL) in a microwave vial. The vial was capped and heated at 80°C for 2 hours, then cooled to room temperature 952-WO 163 and poured into water (60 mL) and sat. aq. NaHCO3 (6 mL). The mixture was extracted with EtOAc (2 x 25 mL) and the organic layers were washed with brine (30 mL), combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was taken up in DCM (2.5 mL) and purified by column chromatography (EtOAc, heptane) to give the title compound 5 (259 mg, 47%) as a colourless oil. ¹ H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 3.0 Hz, 1H), 7.41 (dd, J = 8.4, 3.0 Hz, 1H), 4.90 (q, J = 6.8 Hz, 1H), 3.96 (s, 3H), 1.49 (d, J = 6.8 Hz, 3H). Preparation 316: methyl 1-[1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]triazole-4-carboxyl ate. 10 Methyl prop-2-ynoate (218 mg, 2.59 mmol) was added to a solution of the azide of Preparation 315 (254 mg, 1.29 mmol) in MeOH (2.5 mL) followed by a solution of sodium ascorbate (51 mg, 0.26) in water (0.25 mL) and CuSO4 (21 mg, 0.13 mmol) in water (0.25 mL). After stirring at room temperature overnight the MeOH was removed in vacuo and the15 residue was diluted with sat. aq. NaHCO3 (20 mL) and extracted with EtOAc (2 x 20 mL). The organic extracts were washed with brine (20 mL), combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was taken up in DCM (3 mL) and purified by column chromatography (EtOAc, heptane) to give the title compound (310 mg, 81%) as a colourless solid. ¹ H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.17 (d, J = 2.9 Hz, 1H), 7.7120 (dd, J = 8.8, 3.0 Hz, 1H), 6.12 (q, J = 7.0 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H); LCMS (ES): m/z 281.2 [M+H] ⁺ , RT = 0.60 min. Preparation 317: 1-[1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]triazole-4-carboxyl ic acid. 25 1M aq. NaOH (2.64 mL, 2.64 mmol) was added to a suspension of the ester of Preparation 316 (308 mg, 1.10 mmol) in MeOH (3.2 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to remove MeOH, the residue was cooled in an ice bath and 2.5M aq. HCl (1.1 mL) was added. Brine (10 mL) was added to the resulting suspension and the mixture was extracted with DCM/MeOH (9:1, 2 x30 15 mL). The combined organic phases were dried (Na2SO4), filtered and dried in vacuo to give the title compound (292 mg, 95%) as a colourless solid. ¹ H NMR (400 MHz, DMSO) δ 952-WO 164 13.07 (s, 1H), 8.81 (s, 1H), 8.17 (d, J = 2.9 Hz, 1H), 7.69 (dd, J = 8.7, 3.0 Hz, 1H), 6.10 (q, J = 7.1 Hz, 1H), 3.85 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H); LCMS (METHOD 3) (ES): m/z 265.2 [M-H]-, RT = 0.47 min. 5 Preparation 318: tert-butyl N-[1-[1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]triazol-4- yl]carbamate. To a mixture of the acid of Preparation 317 (290 mg, 1.09 mmol), tert-butanol (5 mL) and triethylamine (0.228 mL, 165 mg, 1.63 mmol) in a 20 ml microwave vial, under nitrogen,10 was added DPPA (0.247 mL, 315 mg, 1.14 mmol) and the white suspension was heated to 80°C to give a colourless solution that was stirred overnight. The resulting yellow solution was cooled to room temperature and concentrated in vacuo. Sat. aq. NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The organic extracts were washed with brine (20 mL), combined, dried (Na2SO4), filtered and concentrated in vacuo. 15 The residue was taken up in DCM (5 mL) and purified by column chromatography (EtOAc, heptane) to give the title compound (239 mg, 62%) as a colourless foam. ¹ H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 8.16 (d, J = 2.9 Hz, 1H), 7.96 (s, 1H), 7.64 (dd, J = 8.8, 3.0 Hz, 1H), 6.00 (q, J = 7.1 Hz, 1H), 3.87 (s, 3H), 1.83 (d, J = 7.1 Hz, 3H), 1.44 (s, 9H); LCMS (METHOD 3) (ES): m/z 336.2 [M-H]-, RT = 0.74 min. 20 Preparation 319: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3- pyridyl)ethyl]triazol-4-yl]amino]-2-oxo-ethyl]carbamate. N B H MeOH (2 mL) and 4M HCl in dioxane (2 mL) were added to the compound of Preparation25 318 (237 mg, 0.702 mg) and the resulting solution was stirred at room temperature for 4 hours. Further 4M HCl in dioxane (1 mL) was added an after a further 2.5 hours the solvent was removed in vacuo. DCM (10 mL) was added and the solvent was removed in vacuo to give 1-[1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]triazol-4-amine hydrochloride salt as a white foam that was used without further purification. 30 The crude 1-[1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]triazol-4-amine was taken up in DMF (2.5 mL) and DIPEA (0.60 mL, 454 mg, 3.51 mmol), the acid of Preparation 5 (234 mg, 952-WO 165 0.773) and HATU (320 mg, 0.843 mmol) were added. The resulting mixture was stirred for 14 hours at room temperature then poured into a mixture of water (22.5 mL) and sat. aq. NaHCO3 (2.5 mL). The mixture was extracted with EtOAc (2 x 25 mL) and the organic extracts were washed with brine (20 mL), combined, dried (Na2SO4), filtered and 5 concentrated in vacuo. The residue was taken up in DCM (4 mL) and purified by column chromatography (EtOAc, heptane) to give the title compound (283 mg, 73%) as a colourless foam. ¹ H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.23 – 8.13 (m, 2H), 7.70 – 7.58 (m, 1H), 7.46 – 7.27 (m, 5H), 7.27 – 7.11 (m, 1H), 6.03 (q, J = 7.0 Hz, 1H), 5.04 (s, 2H), 4.41 (dd, J = 9.0, 6.2 Hz, 1H), 3.93 – 3.79 (m, 3H), 1.85 (m, 3H), 1.00 – 0.82 (m,10 1H), 0.82 – 0.69 (m, 1H), 0.63 – 0.49 (m, 1H), 0.49 – 0.39 (m, 1H), 0.38 – 0.28 (m, 1H), 0.26 – 0.08 (m, 5H), 0.09 – 0.01 (m, 1H); LCMS (METHOD 3) (ES): m/z 523.4 [M+H] ⁺ , RT = 0.84 min. Preparation 320: (2S)-2-amino-3,3-dicyclopropyl-N-[1-[1-(5-fluoro-2-methoxy-3 -15 pyridyl)ethyl]triazol-4-yl]propanamide. N C 10% Pd/C (9.0 mg, 0.0085 mmol) and triethylsilane (0.086 mL, 62 mg, 0.54 mmol) were added to a solution of the compound of Preparation 319 (70 mg, 0.134 mmol) in MeOH (4 mL) in a 25 mL round bottomed flask fitted with an empty balloon. After stirring at room20 temperature for 1 hour the flask was flushed with nitrogen, the reaction mixture was filtered through a hyflo pad, washing with MeOH (5 x 8 mL), and concentrated in vacuo to give the title compound (54 mg, 98%) as a colourless glass. LCMS (METHOD 3) (ES): m/z 389.4 [M+H] ⁺ , RT = 0.65 min. 25 Preparation 321: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3- pyridyl)ethyl]triazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-p yrazole-3-carboxamide. A solution of the amine of Preparation 320 (26 mg, 0.066 mmol) in DMF (0.6 mL) was placed in an 8 mL vial and 2-isopropylpyrazole-3-carboxylic acid (11 mg, 0.073 mmol),30 DIPEA (0.034 mL, 26 mg, 0.20 mmol) and HATU (30 mg, 0.079 mmol) were added. The 952-WO 166 solution was stirred at room temperature for 45 minutes then left to stand at 4°C overnight. DMF (0.35 mL) was added and the mixture was purified by basic prep. HPLC to give the title compound (28 mg, 76%) as a colourless solid. ¹ H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.19 (2 x s, 1H), 8.16 (d, J = 2.9 Hz, 1H), 7.63 5 (m, 1H), 7.50 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.04 (q, J = 7.0 Hz, 1H), 5.38 (hept, J = 6.5 Hz, 1H), 4.83 (dd, J = 8.7, 7.2 Hz, 1H), 3.86 (2 x s, 3H), 1.85 (d, J = 7.1 Hz, 3H), 1.37 (d, J = 6.6 Hz, 3H), 1.34 (2 x d, J = 6.6 Hz, 3H), 0.96 – 0.84 (m, 1H), 0.84 – 0.67 (m, 2H), 0.50 – 0.41 (m, 1H), 0.41 – 0.32 (m, 1H), 0.31 – 0.13 (m, 5H), 0.13 – 0.04 (m, 1H); LCMS (METHOD 3) (ES): m/z 525.4 [M+H] ⁺ , RT = 0.75 min. 10 Preparation 322: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-methoxy -3- pyridyl)ethyl]triazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2, 5-oxadiazole-3-carboxamide. According to the method of Preparation 321 the amine of Preparation 320 (26 mg, 0.06615 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid to give the title compound (23 mg, 68%) as a colourless solid. ¹ H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 8.98 (d, J = 8.8 Hz, 1H), 8.21 (2 x s, 1H), 8.16 (d, J = 2.9 Hz, 1H), 7.71 – 7.57 (m, 1H), 6.04 (q, J = 7.0 Hz, 1H), 4.90 (dd, J = 8.8, 5.9 Hz, 1H), 3.86 (2 x s, 3H), 2.48 (s, 3H), 1.86 (d, J = 7.0 Hz, 3H), 0.94 – 0.70 (m, 3H), 0.53 – 0.43 (m, 1H), 0.43 – 0.34 (m, 1H),20 0.32 – 0.09 (m, 6H); LCMS (METHOD 3) (ES): m/z 499.4 [M+H] ⁺ , RT = 0.77 min. Preparation 323: tert-butyl N-[2-[(5-fluoro-2-methoxy-3-pyridyl)-hydroxy-methyl]thiazol- 5-yl]carbamate. 25 ⁿ BuLi (1.6M in THF, 1.5 mL, 2.4 mmol) was added dropwise over 8 minutes to a solution of tert-butyl N-(2-bromothiazol-5-yl)carbamate (300 mg, 1.07 mmol) in THF (3 mL) at -70°C. The mixture was then stirred at -70°C for 2 hours before a solution of 5-fluoro-2-methoxy- pyridine-3-carbaldehyde (208 mg, 1.34 mmol) in THF (1.5 mL) was added dropwise. The resulting mixture was stirred at -70°C for 15 minutes then allowed to warm to 0°C over 830 minutes and stirred at this temperature for 1 hour. Sat. aq. ammonium chloride solution (5 952-WO 167 mL followed by 10 mL) was added with vigorous stirring and the mixture was extracted with EtOAc (2 x 15 mL). The organic extracts were washed with brine (15 mL), combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was taken up in DCM (4 mL) and purified by column chromatography (EtOAc, heptane) to give the title compound 5 (271 mg, 64%) as a yellow resin. ¹ H NMR (400 MHz, DMSO) δ 9.92 (s, 1H), 8.41 (s, 1H), 8.00 (d, J = 3.0 Hz, 1H), 7.76 (dd, J = 8.9, 3.2 Hz, 1H), 6.13 (s, 1H), 5.87 (br s, 1H), 3.73 (s, 3H), 1.50 (s, 9H); LCMS (METHOD 3) (ES): m/z 354.2 [M-H]-, RT = 0.69 min. Preparation 324: 2,2,2-trifluoro-N-[2-[(5-fluoro-2-methoxy-3-pyridyl)methyl]t hiazol-5-10 yl]acetamide. TFA (1.0 g, 0.673 mL) was added to a solution of the alcohol of Preparation 323 (267 mg, 0.676 mmol) in dichloroethane (2 mL) in a microwave vial followed by triethylsilane (0.864 mL, 629 mg, 5.41 mmol). The vial was sealed and the mixture was heated at 60°C for 1815 hours. After cooling to room temperature the mixture was poured into toluene (20 mL) and concentrated in vacuo. Sat. aq. NaHCO3 (20 mL) was added and the mixture was extracted with DCM (2 x 20 mL). The organic extracts were washed with brine (15 mL), combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was freeze dried to give the title compound (186 mg, 82%) as a yellow solid. ¹ H NMR (600 MHz, DMSO) δ 11.78 (s,20 1H), 8.89 (s, 1H), 8.01 (d, J = 3.0 Hz, 1H), 7.33 (dd, J = 8.7, 3.0 Hz, 1H), 4.03 (s, 2H), 3.81 (s, 3H); LCMS (METHOD 3) (ES): m/z 336.1 [M+H] ⁺ , RT = 0.69 min. Preparation 325: 2-[(5-fluoro-2-methoxy-3-pyridyl)methyl]thiazol-5-amine. 25 5M aq. NaOH (161 µL, 0.805 mmol) in water (0.75 ml) was added to a solution of the compound of Preparation 324 (90 mg, 0.268 mmol) in MeOH (0.9 mL) in a microwave vial. The vial was sealed and the mixture was heated at 65°C for 14.5 hours, then cooled to 4°C and left at that temperature overnight. The solvent was removed in vacuo, the residue was partitioned between brine (1 mL) and DCM (2 mL) and the aqueous layer was extracted30 with DCM (3 x 2 mL). The organic extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (34.5 mg, 51%) as a yellow brown resin. 952-WO 168 1H NMR (400 MHz, DMSO) δ 8.07 (s, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.08 (dd, J = 8.9, 3.0 Hz, 1H), 5.40 (s, 2H), 3.89 (s, 3H), 3.81 (s, 2H); LCMS (METHOD 3) (ES): m/z 240.1 [M+H] ⁺ , RT = 0.51 min. 5 Preparation 326: benzyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[2-[(5-fluoro-2-methoxy-3 - pyridyl)methyl]thiazol-5-yl]amino]-2-oxo-ethyl]carbamate. DIPEA (0.071 mL, 54 mg, 0.41 mmol) was added to a solution of the compound of Preparation 325 (33 mg, 0.14 mmol) in DMF (0.45 mL) in a screw cap vial followed by the10 acid of Preparation 5 (42 mg, 0.14 mmol) and HATU (58 mg, 0.15 mmol). The mixture was stirred at room temperature for 4 hours then left at 4°C for 65 hours. Further DIPEA (0.028 mL, 21 mg, 0.17 mmol), the acid of Preparation 5 (17 mg, 0.055 mmol) and HATU (23 mg, 0.061 mmol) were added and the mixture was stirred a further 5 hours at room temperature. The reaction mixture was diluted with DMF (1.5 mL) and purified directly by15 acidic prep. HPLC followed by basic prep. HPLC to give the title compound (26 mg, 36%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 8.60 (s, 1H), 8.00 (d, J = 3.0 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.43 – 7.18 (m, 5H), 7.11 (dd, J = 8.7, 3.0 Hz, 1H), 5.06 (s, 2H), 4.57 (t, J = 8.1 Hz, 1H), 4.19 – 3.99 (m, 2H), 3.84 (s, 3H), 0.95 – 0.80 (m, 1H), 0.80 – 0.67 (m, 1H), 0.61 – 0.48 (m, 1H), 0.48 – 0.36 (m, 1H), 0.36 – 0.28 (m, 1H),20 0.27 – 0.08 (m, 5H), 0.07 – 0.00 (m, 1H); LCMS (METHOD 3) (ES): m/z 525.4 [M+H] ⁺ , RT = 0.81 min. Preparation 327: N-[(1S)-1-(dicyclopropylmethyl)-2-[[2-[(5-fluoro-2-methoxy-3 - pyridyl)methyl]thiazol-5-yl]amino]-2-oxo-ethyl]-2-isopropyl- pyrazole-3-carboxamide. 25 1M TMSI in DCM (0.18 mL, 0.18 mmol) was added to a solution of the compound of Preparation 326 (24 mg, 0.045 mmol) in MeCN (1 mL) and the mixture was stirred at 2°C for 90 minutes. MeOH (0.5 mL) was added and the mixture was concentrated in vacuo. MeCN (1.5 mL) was added and removed in vacuo to give crude (2S)-2-amino-3,3- 952-WO 169 dicyclopropyl-N-[2-[(5-fluoro-2-methoxy-3-pyridyl)methyl]thi azol-5-yl]propenamide (46 mg) that was used without further purification. Crude (2S)-2-amino-3,3-dicyclopropyl-N-[2-[(5-fluoro-2-methoxy-3-p yridyl)methyl]thiazol- 5-yl]propenamide (0.45 mmol) was dissolved in DMF (0.35 mL) and DIPEA (0.077 mL, 58 5 mg, 0.45 mmol), 2-isopropylpyrazole-3-carboxylic acid (8.3 mg, 0.054 mmol) and HATU (22 mg, 0.059 mmol) were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DMF (0.60 mL) and purified by prep. acidic HPLC to give the title compound (9.3 mg, 37%) as a pale yellow solid. LCMS (METHOD 3) (ES): m/z 527.4 [M+H] ⁺ , RT = 0.81 min. 10 Preparation 328: methyl 2-(6-chloro-3-hydroxy-pyridazin-4-yl)propanoate. According to the method of Preparation 1296-chloropyridazin-3-ol (500 mg, 3.83 mmol) and 3-methoxy-2-methyl-3-oxo-propanoic acid (1.01 g, 7.66 mmol) were reacted to afford the15 crude title compound as an off-white solid after silica column chromatography, EtOAc in heptane, (150 mg, 18% yield). LCMS (METHOD 2) (ESI): m/z: 217.0 [M+H] ⁺ , RT = 1.34 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). Preparation 329: methyl 2-(6-chloro-3-methoxy-pyridazin-4-yl)propanoate. 20 MeI (2.93 g, 20.8 mmol) was added to a solution of the compound of Preparation 328 (3.0 g, 13.8 mmol) and Ag2CO3 (7.62 g, 27.7 mmol) in CHCl3 (30 mL) at room temperature and stirred for 16 hours. The reaction mixture was filtered through Celite, washing with EtOAc. The organic layer was washed with H ₂ O (2 x 50 mL), then saturated brine solution (10 mL),25 dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in heptane, to afford the title compound as a colourless oil (650 mg, 15% yield). LCMS (METHOD 2) (ESI): m/z: 231.2 [M+H] ⁺ , RT = 1.59 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). 30 Preparation 330: 4-(6-chloro-3-methoxy-pyridazin-4-yl)-3-oxo-pentanenitrile. 952-WO 170 O O Cl C N N Sodium hexamethyldisilazide (2.0 M soln. in THF, 0.43 mL, 0.86 mmol) was added dropwise to a solution of MeCN (0.5 mL) in THF (5 mL) at -70°C. The reaction mixture was stirred at -70°C for 1 hour. A solution of the compound of Preparation 329 (100 mg, 0.43 5 mmol) in THF (2 mL) was added dropwise and the reaction mixture was stirred for a further 3 hours at -70°C. The reaction mixture was warmed and quenched with aq. NH4Cl and extracted with EtOAc (30 mL). The separated organic layer was washed with H2O (2 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in10 hexane, to afford the title compound (40 mg, 30% yield). LCMS (METHOD 2) (ESI): m/z: 240.2 [M+H] ⁺ , RT = 1.49 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). Preparation 331: 3-[1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]isoxazol-5-ami ne. 15 Hydroxylamine hydrochloride (80.6 mg, 1.17 mmol) was added to a solution of the compound of Preparation 330 (70.0 mg, 0.29 mmol) in 1,4-dioxane (5 mL) at 0°C. NaOAc (71.8 mg, 0.88 mmol) was added and the reaction mixture was stirred to room temperature over 16 hours. The reaction mixture was diluted with EtOAc (30 mL) and20 washed with H2O (2 x 20 mL), then saturated brine solution (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with EtOAc in hexane, to afford the title compound as a colourless oil (30 mg, 35% yield). LCMS (METHOD 2) (ESI): m/z: 255.2 [M+H] ⁺ , RT = 1.43 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN,25 0.05 % formic acid in H2O). Preparation 332: (2,3,4,5,6-pentafluorophenyl) (2S)-2-(benzyloxycarbonylamino)-3,3- dicyclopropyl-propanoate. . 952-WO 171 (2,3,4,5,6-pentafluorophenyl) 2,2,2-trifluoroacetate (4.15 g, 14.8 mmol) was added to a solution of the compound of Preparation 5 (3.0 g, 9.89 mmol) and pyridine (2.4 mL, 29.7 mmol) in DCM (30 mL) at room temperature and the reaction mixture was stirred for 16 5 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 30 mL). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230- 400 mesh), eluting with EtOAc in hexane, to afford the title compound (3.50 g, 57% yield). LCMS (METHOD 2) (ESI): m/z: 470.3 [M+H] ⁺ , RT = 2.30 min (Acquity BEH C18 10 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). Preparation 333: benzyl N-[(1S)-1-[[3-[1-(6-chloro-3-methoxy-pyridazin-4- yl)ethyl]isoxazol-5-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]ca rbamate. 15 Tert-butylmagnesium chloride (1.0 M in THF, 2.76 mL) was added to a solution of the compound of Preparation 331 (10 mg, 0.04 mmol) in THF (2 mL) at 0°C. The reaction mixture was stirred for 10 minutes. The compound of Preparation 332 (23.0 mg, 0.05 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature.20 The reaction mixture was quenched with saturated aq. NH4Cl (2 mL) and extracted with EtOAc (2 x 5 mL). The combined organic phase was washed with brine solution (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a gummy solid that was used as is in the next step (10 mg, 47% yield). LCMS (METHOD 2) (ESI): m/z: 540.2 [M+H] ⁺ , RT = 2.31 min (Acquity BEH C18 (50mmx2.1mm), 0.05%25 formic acid in MeCN, 0.05 % formic acid in H2O). 952-WO 172 Preparation 334: (2S)-2-amino-N-[3-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl ]isoxazol- 5-yl]-3,3-dicyclopropyl-propanamide; hydrobromide. 5 According to the method of Preparation 314 the compound of Preparation 333 (35.0 mg, 0.06 mmol) was reacted to afford the crude title compound as a coloured solid (12.0 mg, 48% yield). LCMS (METHOD 2) (ESI): m/z: 392.2 [M+H] ⁺ , RT = 1.64 min (Acquity BEH C18 (50mmx2.1mm), 0.05% formic acid in MeCN, 0.05 % formic acid in H2O). 10 EXAMPLES Example 1: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxopyrrolidi n-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide. The compound of Preparation 21 (9.39 mg, 0.049 mmol) was added to a solution of the15 compound of Preparation 20 (12.0 mg, 0.032 mmol) and cesium carbonate (12.7 mg, 0.039 mmol) in DMSO (0.2 mL) and the suspension was stirred at room temperature for 17 hours. Cesium carbonate (25.4 mg, 0.078 mmol) and the compound of Preparation 21 (18.78 mg, 0.098 mmol) were added and the reaction mixture was stirred at 60°C for 17 hours. The cooled reaction mixture was quenched with H2O (2 mL) and extracted with DCM20 (3 x 1 mL). The combined organic phase was washed with saturated brine solution (1 mL), dried over Na2SO4, filtered and dried in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with MeOH in DCM, to afford the title compound as a colourless solid. (3.7 mg, 2% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J = 7.5 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 12.2 Hz, 1H), 7.70 (s,25 1H), 7.57 – 7.40 (m, 2H), 6.93 (dd, J = 3.5, 2.0 Hz, 1H), 5.40 (ddq, J = 9.9, 6.7, 3.3 Hz, 1H), 4.71 (ddd, J = 8.9, 7.2, 3.4 Hz, 1H), 4.36 – 4.07 (m, 2H), 3.15 – 2.96 (m, 2H), 2.78 – 2.62 (m, 1H), 2.06 – 1.92 (m, 1H), 1.76 – 1.61 (m, 1H), 1.43 – 1.30 (m, 6H), 0.91 – 0.65 (m, 3H), 0.50 – 0.02 (m, 8H); LCMS (ES): m/z 468.273 [M+H] ⁺ , RT = 2.05 min. 952-WO 173 Example 2: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyrid in-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide. TMSI (1M soln. in DCM, 0.2 mL) was added to a solution of the compound of Preparation 24 5 (8.0 mg, 0.016 mmol) in CDCl3 (1.0 mL) at room temperature and stirred for 2 hours. The reaction mixture was quenched with MeOH (0.2 mL) and concentrated in vacuo. The residue was dissolved in MeCN and purified directly by prep. acidic HPLC to afford the title compound as a colourless solid (4.0 mg, 51% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 0.6 Hz, 1H), 7.49 (dd, J = 2.3, 1.3 Hz, 2H),10 7.34 (dd, J = 6.5, 2.1 Hz, 1H), 7.10 – 7.00 (m, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.14 (t, J = 6.6 Hz, 1H), 5.97 (s, 1H), 5.40 (h, J = 6.6 Hz, 1H), 5.02 (s, 2H), 4.71 (dd, J = 8.8, 7.1 Hz, 1H), 1.36 (dd, J = 9.2, 6.6 Hz, 6H), 0.92 – 0.65 (m, 3H), 0.52 – 0.04 (m, 8H) ; LCMS (ES): m/z 478.256 [M+H] ⁺ , RT = 2.05 min. 15 Example 3: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-3- piperidyl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyraz ole-3-carboxamide. Triethylsilane (1.0 mL) was added dropwise to a thoroughly degassed solution of the compound of Example 2 (18.0 mg, 0.038 mmol) and Pd/C (20 mg, 0.019 mmol) in MeOH20 (3 mL) under balloon pressure of nitrogen. On complete addition the reaction was stirred for 5 days, then filtered through Celite. The cake was washed with MeOH (3 x 2 mL). The combined organic phase was concentrated in vacuo. The obtained crude compound was purified by silica column chromatography (230-400 mesh), eluting with MeOH in DCM, to afford the title compound as a colourless solid. (2.0 mg, 11% yield). ¹ H NMR (600 MHz,25 DMSO-d6) δ 10.14 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 14.5 Hz, 1H), 7.56 (s, 1H), 7.52 – 7.41 (m, 2H), 6.93 (dd, J = 5.7, 2.0 Hz, 1H), 5.41 (pd, J = 6.7, 5.0 Hz, 1H), 4.71 (ddd, J = 8.8, 7.3, 3.9 Hz, 1H), 4.36 (dt, J = 13.7, 4.5 Hz, 1H), 4.26 (ddd, J = 13.5, 7.9, 4.9 Hz, 1H), 3.14 – 2.95 (m, 2H), 2.69 – 2.56 (m, 1H), 1.69 – 1.46 (m, 3H), 1.44 – 1.32 (m, 6H), 1.32 – 1.17 (m, 1H), 0.89 – 0.80 (m, 1H), 0.80 – 0.65 (m, 2H), 0.5230 – 0.05 (m, 8H); LCMS (ES): m/z 482.288 [M+H] ⁺ , RT = 2.08 min. 952-WO 174 Example 4: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[2-oxo-6-(trifl uoromethyl)-1H- pyridin-3-yl]methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-py razole-3-carboxamide. 5 TMSI (1M soln. in DCM, 1.0 mL) was added dropwise to a solution of the compound of Preparation 25 (84.0 mg, 0.15 mmol) in MeCN (5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was purified directly by prep. basic HPLC to afford the title compound (5.0 mg, 6.1% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.21 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H), 7.63 – 7.37 (m, 2H),10 7.27 (s, 2H), 6.93 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.5 Hz, 1H), 5.25 (s, 2H), 4.87 – 4.66 (m, 1H), 1.35 (td, J = 11.3, 10.4, 7.1 Hz, 6H), 0.93 – 0.78 (m, 1H), 0.74 (d, J = 5.9 Hz, 2H), 0.50 – 0.04 (m, 8H); LCMS (ES): m/z 546.244 [M+H] ⁺ , RT = 2.26 min. The examples listed in the table below were all accessed using the method as described for15 Example 4. E S yl]methyl]pyrazol-4-yl]amino]- 952-WO 175 ethyl]-2-isopropyl-pyrazole-3- (2-oxo-1H-pyridin-3-yl)ethyl]- 952-WO 176 pyrazol-4-yl]amino]ethyl]-2-iso- pyrazole-3-carboxamide 952-WO 177 N-[(1S)-1- The examples listed in the table below were all accessed using the method as described for Example 4. 5 E S oxadiazole-3-carboxamide 952-WO 178 N-[(1S)-1-(dicyclopropyl- The examples listed in the table below were all accessed using the method as described for Example 4. E S (5-fluoro-2-oxo-1H-pyridin-3- 952-WO 179 yl)ethyl]pyrazol-4-yl]amino]-2- Example 13: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(3S,5S)-2-oxo- 5- (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]e thyl]-2-isopropyl-pyrazole-3- carboxamide. 5 TFA (0.2 mL) was added to a solution of the compound of Preparation 49 (4.0 mg, 0.006 mmol) in DCM (1.0 mL) and stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo, dissolved in MeCN, and purified directly by prep. acidic HPLC to afford the title compound as a colourless solid (3.0 mg, 89% yield). ¹ H NMR (400 10 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.71 (s, 1H), 8.41 – 8.30 (m, 1H), 7.89 (s, 1H), 7.55 – 7.42 (m, 2H), 6.93 (d, J = 2.0 Hz, 1H), 5.40 (h, J = 6.6 Hz, 1H), 4.81 – 4.64 (m, 1H), 4.28 (qd, J = 14.0, 5.7 Hz, 2H), 4.20 – 4.06 (m, 1H), 2.90 (td, J = 9.7, 8.1, 4.6 Hz, 1H), 2.17 – 1.99 (m, 2H), 1.36 (dd, J = 8.2, 6.6 Hz, 6H), 0.93 – 0.66 (m, 3H), 0.54 – 0.14 (m, 7H), 0.08 (dd, J = 9.3, 4.3 Hz, 1H); LCMS (ES): m/z 536.260 [M+H] ⁺ , RT = 2.20 min. 15 Example 14: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(5S)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]e thyl]-2-isopropyl-pyrazole-3- carboxamide. 952-WO 180 According to the method of Example 13 the compound of Preparation 50 (10.0 mg, 0.015 mmol) was reacted to afford the title compound as a colourless solid after prep. acidic HPLC (6.6 mg, 71% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.20 (d, J = 15.2 Hz, 1H), 8.69 (d, J = 19.3 Hz, 1H), 8.37 (dd, J = 8.9, 6.0 Hz, 1H), 7.88 (d, J = 9.9 Hz, 1H), 7.48 (dd, J = 6.6, 5 2.1 Hz, 2H), 6.93 (dd, J = 3.9, 2.0 Hz, 1H), 5.41 (pd, J = 6.6, 2.5 Hz, 1H), 4.71 (t, J = 7.9 Hz, 1H), 4.38 – 4.03 (m, 3H), 3.02 – 2.82 (m, 1H), 2.40 – 2.22 (m, 0.5H), 2.07 (t, J = 8.9 Hz, 1H), 1.68 (dt, J = 13.4, 8.1 Hz, 0.5H), 1.45 – 1.29 (m, 6H), 0.78 (d, J = 42.1 Hz, 3H), 0.49 – 0.12 (m, 7H), 0.06 (q, J = 4.8 Hz, 1H); LCMS (ES): m/z 536.260 [M+H] ⁺ , RT = 2.18 min. 10 Example 17: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(3R,5R)-2-oxo- 5- (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]e thyl]-2-isopropyl-pyrazole-3- carboxamide. 15 According to the method of Example 13 the compound of Preparation 67a (60.0 mg, 0.094 mmol) was reacted to afford the title compound as a colourless solid after prep. acidic HPLC (45 mg, 89% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.72 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.58 – 7.43 (m, 2H), 6.93 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.77 – 4.64 (m, 1H), 4.35 – 4.19 (m, 2H), 4.19 – 4.10 (m, 1H), 3.03 – 2.8020 (m, 1H), 2.07 (td, J = 10.7, 9.6, 3.7 Hz, 2H), 1.36 (dd, J = 9.5, 6.6 Hz, 6H), 0.90 – 0.78 (m, 1H), 0.73 (t, J = 5.9 Hz, 2H), 0.49 – 0.12 (m, 7H), 0.12 – 0.05 (m, 1H). LCMS (ES): m/z 536.260 [M+H] ⁺ , RT = 2.20 min. Example 18: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(3S,5R)-2-oxo- 5-25 (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]e thyl]-2-isopropyl-pyrazole-3- carboxamide. According to the method of Example 13 the compound of Preparation 67b (4.0 mg, 0.006 mmol) was reacted to afford the title compound as a colourless solid after prep. acidic HPLC30 (2.6 mg, 77% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.65 (s, 1H), 8.35 (d, J 952-WO 181 = 8.9 Hz, 1H), 7.86 (s, 1H), 7.49 (d, J = 2.7 Hz, 2H), 6.93 (d, J = 2.0 Hz, 1H), 5.41 (p, J = 6.6 Hz, 1H), 4.72 (t, J = 7.9 Hz, 1H), 4.39 – 4.12 (m, 3H), 3.07 – 2.86 (m, 1H), 2.28 (dt, J = 13.3, 9.3 Hz, 1H), 1.71 (dt, J = 13.3, 8.2 Hz, 1H), 1.36 (dd, J = 9.3, 6.6 Hz, 6H), 0.83 (d, J = 6.8 Hz, 1H), 0.71 (d, J = 8.5 Hz, 2H), 0.51 – 0.05 (m, 8H); LCMS (ES): m/z 5 536.260 [M+H] ⁺ , RT = 2.18 min. Example 26: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1S)-1-(5-fluoro-2-ox o-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide. 10 HATU (39.9 mg, 0.105 mmol) was added to a solution of the compound of Preparation 120 (39.2 mg, 0.105 mmol), 2-isopropylpyrazole-3-carboxylic acid (16.2 mg, 0.105 mmol) and DIPEA (0.073 mL, 0.42 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 30 minutes, then purified directly by prep. basic HPLC to afford the title compound as a colourless solid (27.3 mg, 51% yield). ¹ H NMR (400 MHz, DMSO-d6) δ15 11.57 (s, 1H), 10.20 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.55 (d, J = 2.6 Hz, 2H), 7.50 (d, J = 1.9 Hz, 1H), 7.09 (dd, J = 8.4, 3.3 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.57 (q, J = 6.9 Hz, 1H), 5.41 (hept, J = 6.7 Hz, 1H), 4.78 – 4.66 (m, 1H), 1.68 (d, J = 7.0 Hz, 3H), 1.38 (d, J = 6.6 Hz, 3H), 1.35 (d, J = 6.6 Hz, 3H), 0.90 – 0.67 (m, 3H), 0.49 – 0.04 (m, 8H); LCMS (ES): m/z 510.263 [M+H] ⁺ , RT = 2.13 min. 20 The examples listed in the table below were all accessed using the method as described for Example 26, and the relevant carboxylic acid. E S 1H-pyridin-3-yl)- 952-WO 182 ethyl]pyrazol-4-yl]- 8 0 3 1 dicyclopropyl-ethyl]- 952-WO 183 2-isopropyl-pyrazole- carboxamide 952-WO 184 N-[(1S)-1-(dicyclo- Example 42: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[3,3-difluoro-1-(2-oxo -1H-pyridin-3- yl)propyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyraz ole-3-carboxamide. 5 TMSCl (0.0128 mL, 0.101 mmol) was added to a mixture of the compound of Preparation 157 (14.0 mg, 0.0252 mmol) and NaI (15.1 mg, 0.101 mmol) in MeCN (2 mL) and stirred at 60°C for 1 hour. The reaction mixture was purified directly by prep. basic HPLC to afford 952-WO 185 the title compound as a colourless solid (6.9 mg, 51% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.18 (s, 1H), 8.32 (dd, J = 8.9, 2.4 Hz, 1H), 7.97 (d, J = 3.5 Hz, 1H), 7.59 (d, J = 3.5 Hz, 1H), 7.49 (t, J = 1.9 Hz, 1H), 7.35 (dt, J = 6.5, 1.9 Hz, 1H), 7.17 (td, J = 6.4, 1.9 Hz, 1H), 6.92 (dd, J = 3.0, 2.0 Hz, 1H), 6.16 (t, J = 6.7 Hz, 1H), 5.89 (tq, J = 5 56.5, 4.3 Hz, 1H), 5.67 (dt, J = 10.0, 3.9 Hz, 1H), 5.40 (heptd, J = 6.6, 2.8 Hz, 1H), 4.71 (dd, J = 8.8, 7.1 Hz, 1H), 3.04 – 2.80 (m, 1H), 2.75 – 2.57 (m, 1H), 1.44 – 1.28 (m, 6H), 0.91 – 0.79 (m, 1H), 0.73 (dd, J = 7.2, 4.7 Hz, 2H), 0.51 – 0.05 (m, 8H); LCMS (METHOD 4) (ES): m/z 542.4 [M+H] ⁺ , RT = 0.63 min. 10 The examples listed in the table below were all accessed using the method as described for Example 42. 15 E S pyrazol-4-yl]amino]-2-oxo- 952-WO 186 ethyl]-2-isopropyl-pyrazole-3- Example 47: (3,3-difluorocyclobutyl) N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-methyl- 2-oxo-1H-pyridin-3-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl] carbamate. 5 DIPEA (0.028 mL, 0.16 mmol) was added to a solution of the compound of Preparation 127 (29.0 mg, 0.079 mmol) and the compound of Preparation 182 (20.0 mg, 0.079 mmol) in MeCN (1 mL). The reaction mixture was stirred at room temperature for 3 days, then purified directly by prep. acidic HPLC to afford the title compound as a colourless solid (40 mg, 100% yield). ¹ NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 9.95 (d, J = 4.7 Hz, 1H),10 7.88 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 3.8 Hz, 1H), 7.47 – 7.39 (m, 1H), 7.10 (dd, J = 2.6, 1.2 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 5.61 – 5.46 (m, 1H), 4.81 (q, J = 7.4, 6.5 Hz, 1H), 4.22 (dd, J = 8.9, 6.3 Hz, 1H), 3.10 – 2.95 (m, 2H), 2.71 – 2.54 (m, 2H), 1.94 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H), 0.89 – 0.78 (m, 1H), 0.77 – 0.65 (m, 1H), 0.60 – 0.49 (m, 1H), 0.48 – 0.03 (m, 8H); LCMS (ES): m/z 504.242 [M+H] ⁺ , RT = 2.16 min. 15 Example 48: cyclopropyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyraz in- 3-yl)methyl]pyrazol-4-yl]amino]ethyl]carbamate. TMSI (1M soln. in DCM, 0.725 mL) was added to a solution of the compound of Preparation20 184 (22.9 mg, 0.052 mmol) in MeCN (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. MeOH (1.0 mL) was added and the reaction mixture was 952-WO 187 concentrated in vacuo. The residue was dissolved in DMF (0.9 mL) and purified directly by prep. acidic HPLC to afford the title compound as an off-white solid (14.2 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.93 (s, 1H), 7.50 – 7.30 (m, 2H), 7.23 (d, J = 4.1 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 5.26 (s, 2H), 4.24 (dd, J = 9.0, 6.3 Hz, 1H), 3.96 5 (tt, J = 6.3, 3.3 Hz, 2H), 0.81 (dq, J = 8.4, 4.1, 3.4 Hz, 1H), 0.76 – 0.66 (m, 1H), 0.66 – 0.48 (m, 5H), 0.48 – 0.38 (m, 1H), 0.33 (td, J = 8.3, 2.7 Hz, 1H), 0.28 – 0.04 (m, 6H); LCMS (ES): m/z 427.210 [M+H] ⁺ , RT = 1.96 min. Example 49: tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxopyrrolidi n-3-10 yl)methyl]pyrazol-3-yl]amino]ethyl]carbamate. According to the method of Preparation 55 the compound of Preparation 118 (54 mg, 0.20 mmol) was reacted with the compound of Preparation 186 (48 mg, 0.22 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (33.6 mg, 35% yield). LCMS15 (METHOD 4) (ES): m/z 432.4 [M+H] ⁺ , RT = 0.62 min. Example 50: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxopyrrolidi n-3- yl)methyl]pyrazol-3-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide. 20 HCl (3M solution in CPME, 1 mL) was added to a solution of the compound of Example 49 (33 mg, 0.076 mmol) in MeOH and stirred at 50°C for 1 hour. The cooled reaction mixture was concentrated in vacuo and the residue was re-dissolved in MeCN (1 mL). 2- isopropylpyrazole-3-carboxylic acid (14.1 mg, 0.09 mmol) and DIPEA (0.053 mL, 0.31 mmol) were added followed by HATU (34.9 mg, 0,092 mmol) and the reaction mixture was25 stirred at room temperature for 1 hour. The reaction mixture was purified directly by prep. acidic HPLC to afford the title compound as a colourless solid (5.2 mg, 15% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.56 (d, J = 9.4 Hz, 1H), 8.28 (dd, J = 8.9, 2.5 Hz, 1H), 7.72 (d, J = 4.1 Hz, 1H), 7.55 (dd, J = 6.3, 2.3 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4.89 – 4.70 (m, 1H), 4.1730 (dddd, J = 62.7, 13.8, 7.2, 4.2 Hz, 2H), 3.24 – 3.02 (m, 2H), 2.72 (ddt, J = 12.5, 8.6, 4.0 952-WO 188 Hz, 1H), 2.00 (ddd, J = 12.5, 9.3, 7.3 Hz, 1H), 1.74 (ddt, J = 12.6, 8.5, 4.3 Hz, 1H), 1.36 (dd, J = 11.5, 6.6 Hz, 6H), 1.01 – 0.60 (m, 3H), 0.54 – 0.04 (m, 8H); LCMS (ES): m/z 468.272 [M+H] ⁺ , RT = 2.08 min. 5 Example 51: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyrid in-3- yl)methyl]pyrazol-3-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide. According to the method of Example 50 the compound of Preparation 189 (66.0 mg, 0.145 mmol) was reacted to afford the title compound as a colourless solid after prep. acidic HPLC10 (19 mg, 27% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 6.5, 2.1 Hz, 1H), 7.09 – 7.01 (m, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 2.2 Hz, 1H), 6.15 (t, J = 6.6 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 5.04 – 4.89 (m, 2H), 4.87 – 4.69 (m, 1H), 1.36 (dd, J = 18.2, 6.6 Hz, 7H), 0.96 – 0.64 (m, 3H), 0.52 – 0.32 (m, 2H), 0.31 – 0.08 (m, 6H); LCMS15 (ES): m/z 478.257 [M+H] ⁺ , RT = 2.08 min. Example 52: N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(2-oxo-1H-py ridin-3- yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyraz ole-3-carboxamide. 20 TMSCl (0.012 mL, 0.094 mmol) was added to a mixture of the compound of Preparation 194 (12.0 mg, 0.024 mmol) and NaI (14.1 mg, 0.094 mmol) in MeCN (3 mL) and stirred at 60°C for 1 hour. The reaction mixture was purified directly by prep. basic HPLC to afford the title compound as a colourless solid (4.0 mg, 34% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.83 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.49 (d, J25 = 2.0 Hz, 1H), 7.36 (dd, J = 6.6, 2.1 Hz, 1H), 7.14 (dd, J = 6.8, 2.0 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.17 (t, J = 6.6 Hz, 1H), 5.41 (p, J = 6.6 Hz, 1H), 4.95 (s, 2H), 4.79 (dd, J = 8.9, 7.3 Hz, 1H), 1.37 (dd, J = 8.4, 6.6 Hz, 6H), 1.00 – 0.63 (m, 3H), 0.59 – 0.08 (m, 8H). LCMS (ES): m/z 496.247 [M+H] ⁺ , RT = 2.07 min. 952-WO 189 Example 58: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1S)-1-(5-fl uoro-2-oxo-1H- pyridin-3-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-ethyl- 1,2,5-oxadiazole-3- carboxamide. 5 According to the method of Example 4 the compound of Preparation 212 (8.8 mg, 0.016 mmol) was reacted to afford the title compound as a colourless solid after prep. acidic HPLC (2.0 mg, 23% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.99 (d, J = 5.2 Hz, 1H), 8.99 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.27 (dd, J = 8.4, 3.2 Hz, 1H), 5.46 (q, J = 7.0 Hz, 1H), 4.87 (dd, J = 9.0, 6.3 Hz, 1H), 2.99 – 2.80 (m, 2H), 1.64 (d, J = 7.0 Hz,10 3H), 1.25 (td, J = 7.5, 1.2 Hz, 3H), 0.94 – 0.61 (m, 3H), 0.53 – 0.10 (m, 8H); LCMS (ES): m/z 516.218 [M+H] ⁺ , RT = 2.34 min. Example 59: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[1-(5-fluoro- 2-oxo-1H- pyridin-3-yl)-2-methoxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethy l]-4-methyl-1,2,5-15 oxadiazole-3-carboxamide. According to the method of Example 4 the compound of Preparation 220 (5.0 mg, 0.009 mmol) was reacted to afford the title compound as a colourless solid after prep. acidic HPLC (1.5 mg, 31% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 9.79 (s, 1H), 8.75 (d, J20 = 9.0 Hz, 1H), 7.84 (t, J = 1.7 Hz, 1H), 7.40 (s, 1H), 7.16 (td, J = 9.1, 3.3 Hz, 1H), 5.42 – 5.23 (m, 1H), 4.66 (dd, J = 9.0, 6.3 Hz, 1H), 3.94 – 3.65 (m, 1H), 3.55 (ddd, J = 10.5, 4.5, 2.6 Hz, 1H), 3.04 (s, 3H), 2.27 (d, J = 1.5 Hz, 3H), 0.71 – 0.43 (m, 3H), 0.33 – -0.13 (m, 8H); LCMS (ES): m/z 532.212 [M+H] ⁺ , RT = 2.26 min. 25 Example 60: N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methox y-ethyl]-3- fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-is opropyl-pyrazole-3- carboxamide. 952-WO 190 According to the method of Example 26 the compound of Preparation 224 (22 mg, 0.046 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (8.0 mg, 0.052 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (15 mg, 56% yield). 5 ¹ H NMR (600 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.82 (d, J = 4.4 Hz, 1H), 8.16 (dd, J = 8.8, 1.3 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.30 (t, J = 1.9 Hz, 1H), 7.00 (dd, J = 19.6, 0.9 Hz, 1H), 6.71 (dd, J = 3.2, 2.0 Hz, 1H), 5.40 (dd, J = 8.7, 4.2 Hz, 1H), 5.20 (pd, J = 6.6, 3.4 Hz, 1H), 4.62 (dd, J = 8.8, 7.5 Hz, 1H), 3.79 (ddd, J = 10.6, 8.6, 7.0 Hz, 1H), 3.63 (dt, J = 10.6, 4.1 Hz, 1H), 3.06 (d, J = 1.3 Hz, 4H), 1.30 – 1.02 (m, 7H), 0.83 – 0.40 (m, 4H),10 0.40 – -0.18 (m, 10H); LCMS (METHOD 4) (ES): m/z 573.3 [M-H]-, RT = 0.68 min. Example 61: N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methox y-ethyl]-3- fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-4-me thyl-1,2,5-oxadiazole-3- carboxamide. 15 According to the method of Example 26 the compound of Preparation 224 (22 mg, 0.046 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (3.6 mg, 0.028 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (12 mg, 47% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.78 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H),20 6.93 (d, J = 17.5 Hz, 1H), 5.37 (dd, J = 8.9, 4.2 Hz, 1H), 4.67 (d, J = 6.5 Hz, 1H), 3.77 (ddd, J = 10.7, 8.7, 6.1 Hz, 1H), 3.61 (dt, J = 10.6, 4.0 Hz, 1H), 3.05 (s, 3H), 2.27 (d, J = 2.1 Hz, 3H), 0.81 – 0.40 (m, 3H), 0.40 – -0.22 (m, 8H); LCMS (METHOD 4) (ES): m/z 547.2 [M-H]-, RT = 0.69 min. 25 Example 62: N-[(1S)-1-[di(cyclobutyl)methyl]-2-oxo-2-[[1-[(2-oxo-1H-pyri din-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-4-ethyl-1,2,5-oxadiazole -3-carboxamide. 952-WO 191 According to the method of Example 26 the compound of Preparation 226 (37.0 mg, 0.10 mmol) was reacted with 4-ethyl-1,2,5-oxadiazole-3-carboxylic acid (14.0 mg, 0.10 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (30.9 mg, 63% 5 yield). ¹ H NMR (600 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.06 (s, 1H), 8.72 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.49 (d, J = 0.7 Hz, 1H), 7.35 (dd, J = 6.5, 2.1 Hz, 1H), 7.07 (dd, J = 6.8, 2.1 Hz, 1H), 6.15 (t, J = 6.6 Hz, 1H), 5.06 – 5.00 (m, 2H), 4.55 (dd, J = 9.0, 4.0 Hz, 1H), 2.90 (qd, J = 7.6, 4.2 Hz, 2H), 2.46 – 2.35 (m, 1H), 2.18 (qd, J = 9.7, 4.6 Hz, 1H), 2.08 (td, J = 10.2, 4.0 Hz, 1H), 1.96 – 1.48 (m, 12H), 1.25 (t, J = 7.5 Hz, 3H); LCMS (ES):10 m/z 494.252 [M+H] ⁺ , RT = 2.40 min. Example 63: N-[(1S)-1-[di(cyclobutyl)methyl]-2-oxo-2-[[1-[(2-oxo-1H-pyri din-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide. 15 According to the method of Example 26 the compound of Preparation 226 (37.0 mg, 0.10 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (15.0 mg, 0.10 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (33.6 mg, 66% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 9.99 (s, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.93 (s, 1H), 7.55 – 7.46 (m, 2H), 7.34 (dd, J = 6.5, 2.1 Hz, 1H), 7.06 (dd, J = 6.8,20 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.14 (t, J = 6.6 Hz, 1H), 5.33 (p, J = 6.6 Hz, 1H), 5.02 (s, 2H), 4.51 (dd, J = 8.9, 4.8 Hz, 1H), 2.45 (q, J = 8.8 Hz, 1H), 2.19 (p, J = 8.9 Hz, 1H), 2.05 (td, J = 10.1, 4.8 Hz, 1H), 1.97 – 1.49 (m, 12H), 1.36 (dd, J = 9.5, 6.6 Hz, 6H); LCMS (ES): m/z 506.288 [M+H] ⁺ , RT = 2.25 min. 25 Example 64: tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxopyrrol idin-3- yl)methyl]pyrazol-4-yl]amino]ethyl]carbamate. 952-WO 192 F F _F ^F H According to the method of Preparation 55 the compound of Preparation 10 (49.9 mg, 0.17 mmol) was reacted with the compound of Preparation 228 (44.2 mg, 0.204 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (64.9 mg, 79% yield). ¹ H 5 NMR (400 MHz, DMSO-d6) δ 10.09 (d, J = 4.1 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.46 (d, J = 9.9 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.27 (ddd, J = 13.9, 4.4, 1.3 Hz, 1H), 4.16 (ddd, J = 13.9, 7.4, 2.0 Hz, 1H), 3.94 (td, J = 8.3, 3.2 Hz, 1H), 3.17 – 3.00 (m, 2H), 2.73 (qd, J = 8.9, 4.3 Hz, 1H), 2.07 – 1.93 (m, 3H), 1.88 – 1.63 (m, 4H), 1.56 (d, J = 13.3 Hz, 1H), 1.38 (s, 9H), 1.35 – 1.15 (m, 3H); LCMS (ES): m/z 456.242 [M+H] ⁺ , RT =10 2.07 min. Example 65: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxopyrrol idin-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide. H 15 According to the method of Example 26 the compound of Preparation 229 (16.7 mg, 0.043 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (7.24 mg, 0.047 mmol) to afford the title compound as an off-white solid after prep. basic HPLC (18.1 mg, 81% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 10.29 (d, J = 4.1 Hz, 1H), 8.57 (dd, J = 8.3, 1.7 Hz, 1H), 7.89 (d, J = 11.0 Hz, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.56 – 7.41 (m, 2H), 6.95 (dd, J20 = 3.3, 2.0 Hz, 1H), 5.39 (hd, J = 6.6, 3.1 Hz, 1H), 4.40 (td, J = 8.6, 3.6 Hz, 1H), 4.28 (ddd, J = 13.9, 4.4, 1.7 Hz, 1H), 4.17 (ddd, J = 13.9, 7.5, 2.8 Hz, 1H), 3.17 – 2.98 (m, 2H), 2.73 (qt, J = 7.4, 4.4 Hz, 1H), 2.15 – 1.94 (m, 4H), 1.94 – 1.55 (m, 5H), 1.45 – 1.23 (m, 8H); LCMS (ES): m/z 492.253 [M+H] ⁺ , RT = 2.02 min. 25 The examples listed in the table below were all accessed using the method as described for Example 26. 952-WO 193 Precursor E S The examples listed in the table below were all accessed using the method as described for Example 4. 5 E S pyrazole-3-carboxamide 952-WO 194 2-cyclopropyl-N-[(1S)-1-(4,4- The examples listed in the table below were all accessed using the method as described for Example 26. 5 E S 3-carboxamide The examples listed in the table below were all accessed using the method as described for10 Example 26. 952-WO 195 Precursor E S The examples listed in the table below were all accessed using the method as described for Example 26. 5 E S carboxamide 952-WO 196 N-[(1S)-2-[[1-[1-(5-fluoro-2- The examples listed in the table below were all accessed using the method as described for Example 4. E S 5 The examples listed in the table below were all accessed using the method as described for Example 26. 952-WO 197 Precursor E S Example 81: 2-isopropyl-N-[(1S)-1-(4-methylcyclohexyl)-2-oxo-2-[[1-[1-(6 -oxo-1H- pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]ethyl]pyrazole-3-car boxamide. 5 Triethylsilane (0.012 mL, 0.076 mmol) was added to a solution of the compound of Example 79 (20.0 mg, 0.038 mmol) and TEA (0.011 mL, 0.076 mmol) in MeOH (3 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in MeCN and purified directly by10 pr . basic HPLC to afford the title compound as a colourless solid (12.0 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 10.28 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 1.4 Hz, 1H), 7.81 (d, J = 4.1 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J = 1.9 Hz, 1H), 6.95 (t, J = 2.3 Hz, 1H), 6.81 (td, J = 3.9, 0.9 Hz, 1H), 5.70 – 5.50 (m, 1H), 5.39 (pd, J = 6.6, 2.1 Hz, 1H), 4.28 (t, J = 8.4 Hz, 1H), 1.90 – 1.62 (m, 7H), 1.59 – 1.49 (m, 1H), 1.40 – 952-WO 198 1.21 (m, 7H), 1.06 (dqd, J = 40.8, 12.2, 11.7, 3.2 Hz, 2H), 0.93 – 0.79 (m, 5H); LCMS (ES): m/z 495.283 [M+H] ⁺ , RT = 2.18 min. Example 82: 4-ethyl-N-[(1S)-1-(4-methylcyclohexyl)-2-oxo-2-[[1-[1-(6-oxo -1H-pyridazin- 5 5-yl)ethyl]pyrazol-4-yl]amino]ethyl]-1,2,5-oxadiazole-3-carb oxamide. Triethylsilane (0.016 mL, 0.101 mmol) was added to a solution of the compound of Example 80 (26.0 mg, 0.050 mmol) and TEA (0.014 mL, 0.101 mmol) in MeOH (3 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate10 was concentrated in vacuo. The residue was dissolved in MeCN and purified directly by prep. basic HPLC to afford the title compound as a colourless solid (13.0 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.13 (s, 1H), 8.02 (t, J = 0.9 Hz, 1H), 7.81 (d, J = 4.1 Hz, 1H), 7.56 (s, 1H), 6.82 (td, J = 4.1, 1.0 Hz, 1H), 5.61 (q, J = 6.9 Hz, 1H), 4.36 (d, J = 8.1 Hz, 1H), 2.89 (qd, J = 7.5, 1.6 Hz, 2H), 1.86 – 1.72 (m, 2H), 1.69 (d, J =15 7.0 Hz, 4H), 1.56 (d, J = 12.9 Hz, 1H), 1.24 (td, J = 7.5, 2.0 Hz, 4H), 1.21 – 0.97 (m, 2H), 0.90 (t, J = 8.0 Hz, 2H), 0.85 (d, J = 6.5 Hz, 4H), 0.45 (q, J = 8.0 Hz, 1H); LCMS (ES): m/z 483.246 [M+H] ⁺ , RT = 2.31 min. The examples listed in the table below were all accessed using the method as described for20 Example 42. E S yl)methyl]imidazol-4- 952-WO 199 yl]amino]ethyl]-2-isopropyl- The examples listed in the table below were all accessed using the method as described for Example 42. E S oxad azo e-3-carboxam de 5 Examples 87:4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1 -[2,2,2-trifluoro-1- (2-oxo-1H-pyridin-3-yl)ethyl]imidazol-4-yl]amino]ethyl]-1,2, 5-oxadiazole-3-carboxamide, diastereomer 1, and Example 88: 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2 ,2,2-trifluoro-1-10 (2-oxo-1H-pyridin-3-yl)ethyl]imidazol-4-yl]amino]ethyl]-1,2, 5-oxadiazole-3-carboxamide, 952-WO 200 diastereomer 2. The compound of Example 86 (25.0 mg, 0.004 mmol) was subjected to prep SFC to afford the 2 products as single diastereomers. 5 Preparative SFC Conditions Column/Dimensions: (R,R)Whelk -01 (250 x 10 x 5µ) % CO2: 60% % Co-solvent: 40% (MeOH) Total Flow: 20 g/min 10 Back Pressure: 100.0 bar Temperature: 30°C UV: 234 nm Stack time: 2.44 min Load/Inj: 6.1 mg/injection 15 Example 87: Peak 1: (5.7 mg, 38% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 12.14 (br s, 1H), 10.63 (s, 1H), 8.95 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.56 (dd, J = 1.9, 6.5 Hz, 1H), 7.34 (s, 1H), 6.55 - 6.48 (m, 1H), 6.34 (t, J = 6.8 Hz, 1H), 4.87 (dd, J = 6.0, 8.9 Hz, 1H), 2.32 - 2.30 (m, 1H), 1.19 - 1.08 (m, 2H), 1.05 - 0.93 (m, 2H), 0.87 - 0.69 (m, 3H), 0.47 - 0.32 (m, 2H), 0.29 - 0.11 (m, 6H); LCMS (ES): m/z20 546.208 [M+H] ⁺ , RT = 2.32 min. Example 88: Peak 2: (10.8 mg, 72% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 10.65 (s, 1H), 8.94 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 7.1 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.55 (dd, J = 1.9, 6.5 Hz, 1H), 7.34 (s, 1H), 6.53 - 6.50 (m, 1H), 6.34 (t, J = 6.8 Hz, 1H), 4.88 (dd, J = 6.1, 8.9 Hz, 1H), 2.32 - 2.25 (m, 1H), 1.19 - 1.06 (m, 2H), 1.04 - 0.9325 (m, 2H), 0.89 - 0.68 (m, 3H), 0.49 - 0.34 (m, 2H), 0.31 - 0.12 (m, 6H); LCMS (ES): m/z 546.208 [M+H] ⁺ , RT = 2.34 min. The examples listed in the table below were all accessed using the method as described for Example 26. 952-WO 201 Precursor E S carboxamide 952-WO 202 N-[(1S)-1-[[1-[(1S)-1-(3- ethyl)pyrazole-3-carboxamide 952-WO 203 N-[(1S)-1-[[1-[(1S)-1-(3- The examples listed in the table below were all accessed using the method as described for Example 26. E S number 952-WO 204 N-[(1S)-1-[[1-[(1RS)-1-(3- Examples 104 and 105: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo- 1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-i sopropyl-pyrazole-3- carboxamide and N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo-3- 5 triethylsilyl-1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2- oxo-ethyl]-2-isopropyl-pyrazole- 3-carboxamide. Triethylsilane (0.1 mL, 0.6 mmol) was added to a degassed solution of the compound of Example 102 (38.0 mg, 0.07 mmol) and Pd/C (10%, 20 mg, 0.019 mmol) in MeOH (3 mL)10 and stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in MeCN and purified directly by prep. acidic HPLC to afford the title compounds thus: Example 104: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo-1H- pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isop ropyl-pyrazole-3-carboxamide: 15 31 mg, 87% yield of a colourless solid; ¹ H NMR (600 MHz, DMSO-d6) δ 13.18 (s, 1H), 10.01 (d, J = 8.3 Hz, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.05 (dd, J = 4.8, 1.9 Hz, 1H), 7.84 (t, J = 3.7 Hz, 1H), 7.49 (t, J = 2.3 Hz, 1H), 7.02 – 6.83 (m, 2H), 5.64 – 5.48 (m, 1H), 5.39 (hd, J = 6.6, 3.8 Hz, 1H), 4.82 (dd, J = 8.9, 7.6 Hz, 1H), 1.65 (dd, J = 7.0, 1.5 Hz, 3H), 1.37 (ddd, J = 14.7, 6.6, 3.0 Hz, 6H), 0.96 – 0.65 (m, 3H), 0.59 – 0.03 (m, 8H); LCMS20 (ES): m/z 511.258 [M+H] ⁺ , RT = 2.18 min. Example 105: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo-3- triethylsilyl-1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2- oxo-ethyl]-2-isopropyl-pyrazole- 952-WO 205 3-carboxamide :1.0 mg, 2.3% yield of a colourless solid; ¹ H NMR (600 MHz, DMSO-d6) δ 13.45 (s, 1H), 10.01 (d, J = 3.3 Hz, 1H), 8.36 (dd, J = 9.0, 3.7 Hz, 1H), 8.07 (dd, J = 4.1, 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 2.7 Hz, 1H), 5.52 (p, J = 7.2 Hz, 1H), 5.47 – 5.30 (m, 1H), 4.82 (t, J = 8.2 Hz, 1H), 1.67 (dd, J = 7.0, 5 1.6 Hz, 3H), 1.36 (ddd, J = 18.0, 6.6, 1.8 Hz, 6H), 0.87 (t, J = 7.9 Hz, 9H), 0.77 (tq, J = 8.4, 2.8 Hz, 1H), 0.74 – 0.64 (m, 8H), 0.45 (dp, J = 13.9, 4.3 Hz, 1H), 0.40 – 0.14 (m, 6H), 0.10 (ddt, J = 14.9, 9.9, 5.0 Hz, 1H) ); LCMS (ES): m/z 625.345 [M+H] ⁺ , RT = 2.68 min. 10 Examples 106 and 107: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo- 1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-m ethyl-1,2,5-oxadiazole-3- carboxamide and N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo-3- triethylsilyl-1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2- oxo-ethyl]-4-methyl-1,2,5- oxadiazole-3-carboxamide. 15 According to the method of Examples 104 and 105 the compound of Example 103 (14.0 mg, 0.027 mmol) was reacted to afford the title compounds thus: Example 106 : N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo-1H- pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-meth yl-1,2,5-oxadiazole-3- 20 carboxamide : 11 mg, 84% yield as a colourless solid. ¹ H NMR (600 MHz, DMSO-d6) δ 13.18 (s, 1H), 10.05 (d, J = 8.2 Hz, 1H), 8.98 (d, J = 8.9 Hz, 1H), 8.06 (dd, J = 4.2, 1.8 Hz, 1H), 7.85 (dd, J = 4.1, 2.5 Hz, 1H), 6.93 (ddd, J = 9.5, 4.1, 0.9 Hz, 1H), 5.60 – 5.45 (m, 1H), 4.88 (dd, J = 8.8, 6.5 Hz, 1H), 3.29 (s, 1H), 2.48 (d, J = 2.7 Hz, 3H), 1.66 (d, J = 7.0 Hz, 3H), 0.85 (dtd, J = 13.3, 6.2, 2.8 Hz, 1H), 0.81 – 0.70 (m, 2H), 0.47 (dtd, J =25 11.6, 8.0, 4.1 Hz, 1H), 0.38 (dq, J = 8.5, 4.3 Hz, 1H), 0.34 – 0.11 (m, 6H); LCMS (ES): m/z 485.206 [M+H] ⁺ , RT = 2.23 min. Example 107: N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-o xo-3- triethylsilyl-1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2- oxo-ethyl]-4-methyl-1,2,5- oxadiazole-3-carboxamide : 1.0 mg, 6% yield as a colourless solid. ¹ H NMR (600 MHz,30 DMSO-d6) δ 13.45 (s, 1H), 10.06 (d, J = 2.3 Hz, 1H), 8.99 (dd, J = 9.0, 3.3 Hz, 1H), 8.08 (dd, J = 5.5, 1.9 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.52 (p, J = 7.3 Hz, 1H), 4.89 (dd, J = 9.0, 6.8 Hz, 1H), 2.48 (s, 3H), 1.68 (dd, J = 6.9, 1.6 Hz, 3H), 0.87 (t, J = 7.9 Hz, 9H), 0.81 – 0.66 (m, 9H), 0.47 (dq, J = 9.3, 4.9 Hz, 1H), 0.38 (dq, J = 9.0, 4.8 Hz, 1H), 0.33 – 0.09 (m, 6H). 952-WO 206 Example 108: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(3-methoxy-6-oxo-1H -pyridazin-5- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide. 5 Triethylsilane (0.30 mL, 1.90 mmol) was added dropwise to a degassed solution of the compounds of Preparation 269 (406 mg, 0.63 mmol) and Pd/C (10%, 80 mg, 0.07 mmol) in MeOH (10 mL) at room temperature and stirred for 18 hours. The reaction mixture was filtered through Celite, and the cake was washed well with MeOH. The combined filtrate was concentrated in vacuo. The residue was dissolved in MeCN (6 mL) and 2-10 isopropylpyrazole-3-carboxylic acid (97.8 mg, 0.63 mmol) and DIPEA (0.22 mL, 1.27 mmol) were added. HATU (265 mg, 0.70 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified directly by prep. basic HPLC to afford the title compound as a colourless solid (19 mg, 5.7% yield . ¹ H NMR (600 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.21 (d, J = 7.5 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H),15 8.01 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 5.3 Hz, 1H), 7.49 (t, J = 2.0 Hz, 1H), 6.93 (dd, J = 2.8, 2.0 Hz, 1H), 6.45 (dd, J = 10.6, 1.0 Hz, 1H), 5.59 (q, J = 7.0 Hz, 1H), 5.41 (pd, J = 6.6, 1.6 Hz, 1H), 4.73 (t, J = 7.7 Hz, 1H), 3.70 (d, J = 1.3 Hz, 3H), 1.70 (dd, J = 7.1, 2.4 Hz, 3H), 1.36 (ddd, J = 13.7, 6.6, 2.0 Hz, 6H), 0.84 (tq, J = 8.4, 4.2 Hz, 1H), 0.79 – 0.71 (m, 2H), 0.44 (t, J = 6.7 Hz, 1H), 0.41 – 0.14 (m, 6H), 0.09 (tq, J = 6.0, 3.5 Hz, 1H).20 LCMS (ES): m/z 523.278 [M+H] ⁺ , RT = 2.17 min. The examples listed in the table below were all accessed using the method as described for Example 26. E S n number 952-WO 207 N-[(1S)-1-(dicyclopropyl- Example 111: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-[3-(difluoromethyl) -6-oxo-1H- pyridazin-5-yl]ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isop ropyl-pyrazole-3-carboxamide. 5 According to the method of Example 26 the compound of Preparation 281 (65 mg, 0.15 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (22.6 mg, 0.15 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (18.1 mg, 22% yield). 1H NMR (600 MHz, DMSO-d6) δ 10.23 (d, J = 3.5 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.05 (d, J = 4.8 Hz, 1H), 7.60 (d, J = 3.3 Hz, 1H), 7.49 (t, J = 1.7 Hz, 1H), 6.93 (t, J = 1.8 Hz,10 1H), 6.88 (dd, J = 4.9, 1.0 Hz, 1H), 6.81 (t, J = 53.9 Hz, 1H), 5.65 (q, J = 7.0 Hz, 1H), 5.41 (pd, J = 6.6, 1.6 Hz, 1H), 4.79 – 4.64 (m, 1H), 1.73 (d, J = 7.1 Hz, 3H), 1.36 (ddd, J = 15.5, 6.6, 1.9 Hz, 6H), 0.84 (dp, J = 8.5, 3.1 Hz, 1H), 0.74 (td, J = 7.5, 2.9 Hz, 2H), 0.47 – 0.40 (m, 1H), 0.40 – 0.13 (m, 6H), 0.08 (tt, J = 8.6, 3.8 Hz, 1H); LCMS (ES): m/z 543.265 [M+H] ⁺ , RT = 2.23 min. 15 Example 112: N-[(1S)-1-[[1-[(1SR)-1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-3, 3-difluoro- propyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-is opropyl-pyrazole-3- carboxamide. 952-WO 208 H According to the method of Example 26 the compound of Preparation 287 (52 mg, 0.11 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (17.0 mg, 0.11 mmol) to afford the title compound as a colourless solid after prep. basic HPLC (30.0 mg, 48% yield). 5 ¹ H NMR (600 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.25 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.65 (d, J = 4.1 Hz, 1H), 7.01 (dd, J = 21.8, 1.0 Hz, 1H), 6.92 (t, J = 2.1 Hz, 1H), 6.14 – 5.84 (m, 1H), 5.76 (dd, J = 10.0, 4.3 Hz, 1H), 5.40 (pd, J = 6.6, 1.6 Hz, 1H), 4.72 (dd, J = 8.7, 7.2 Hz, 1H), 3.09 – 2.84 (m, 1H), 2.84 – 2.67 (m, 1H), 1.49 – 1.24 (m, 6H), 0.88 – 0.80 (m, 1H), 0.78 – 0.70 (m, 2H), 0.47 – 0.40 (m, 1H), 0.40 – 0.24 (m, 3H), 0.1810 (ddd, J = 18.8, 8.0, 4.7 Hz, 3H), 0.08 (p, J = 4.8 Hz, 1H); LCMS (ES): m/z 577.225 [M+H] ⁺ , RT = 2.30 min. Example 113: N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1SR)-3,3-difluoro-1- (6-oxo-1H- pyridazin-5-yl)propyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-iso propyl-pyrazole-3-15 carboxamide. H F F According to the method of Example 81 the compound of Example 112 (20 mg, 0.035 mmol) was reacted to afford the title compound as a colourless solid after prep. basic HPLC (17.0 mg, 90% yield). ¹ H NMR (600 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.24 (s, 1H), 8.3520 (dd, J = 8.8, 1.5 Hz, 1H), 8.06 (t, J = 0.9 Hz, 1H), 7.85 (dd, J = 4.1, 0.8 Hz, 1H), 7.65 (d, J = 5.8 Hz, 1H), 7.49 (t, J = 2.1 Hz, 1H), 7.01 – 6.80 (m, 2H), 5.96 (ttd, J = 56.2, 5.3, 3.7 Hz, 1H), 5.77 (dd, J = 10.1, 4.2 Hz, 1H), 5.41 (heptd, J = 6.6, 3.1 Hz, 1H), 4.79 – 4.58 (m, 1H), 3.03 – 2.85 (m, 1H), 2.73 (qdt, J = 14.9, 9.7, 4.3 Hz, 1H), 1.47 – 1.27 (m, 6H), 0.84 (qd, J = 5.3, 2.8 Hz, 1H), 0.75 (tq, J = 7.5, 4.6 Hz, 2H), 0.54 – 0.05 (m, 8H); LCMS25 (ES): m/z 543.264 [M+H] ⁺ , RT = 2.19 min. The examples listed in the table below were all accessed using the method as described for Example 26. 952-WO 209 Precursor E S carboxamide 952-WO 210 N-[(1S)-1-[[1-[(1SR)-1-(3- carboxamide, Diastereomer 1 952-WO 211 N-[(1S)-1-[[1-[(1SR)-1-(3- The examples listed in the table below were all accessed using the method as described for Example 26. E S isoxazole-4-carboxamide 952-WO 212 The examples listed in the table below were all accessed using the method as described for Example 26. Prec rsor E S carboxamide 5 The examples listed in the table below were all accessed using the method as described for Example 26. 952-WO 213 Precursor E S ethyl]-2-[(3,3-difluorocyclo- 952-WO 214 butyl)methyl]pyrazole-3- Example 134: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[3-fluoro-1-[1-(6-oxo- 1H-pyridazin-5- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide, diastereomer 1 and 5 Example 135: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[3-fluoro-1-[1-(6-oxo- 1H-pyridazin-5- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide, diastereomer 2. According to the method of Example 42 the compound of Preparation 311 (75.0 mg, 0.1410 mmol) was reacted to afford the title compound as a racemic mixture after prep. acidic HPLC (25 mg, 34% yield). The single diastereomers were isolated by prep. SFC. Preparative SFC Conditions Column/Dimensions: Chiralcel OX-H (250 x 10 x 5µ) 15 % CO2: 80% % Co-solvent: 20% (MeOH) Total Flow: 20 g/min Back Pressure: 100.0 bar Temperature: 30°C 20 UV: 228 nm Stack time: 3.20 min Load/Inj: 0.43 mg/injection Example 134: Peak 1: (5.0 mg, 20% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 13.25 - 13.12 (m, 1H), 10.17 - 10.12 (m, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H),25 7.85 (d, J = 4.1 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 6.98 (dd, J = 0.8, 4.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.55 - 5.47 (m, 1H), 5.43 - 5.33 (m, 1H), 4.55 - 4.47 (m, 1H), 2.15 - 1.93 (m, 3H), 1.92 - 1.69 (m, 4H), 1.64 (d, J = 7.0 Hz, 3H), 1.49 - 1.12 (m, 8H); LCMS (ESI): m/z: 535.53 [M+H ⁺ ]; 99.96% RT = 1.94 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; Chiral HPLC: 99.53% (RT: 4.12 min), Column: Lux 30 Cellulose-4 (4.6*250mm)5μm, Co-Solvent: Methanol, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. 952-WO 215 Example 135: Peak 2: (6.0 mg, 24% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 13.18 (s, 1H), 10.15 (s, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 4.1 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 6.97 - 6.94 (m, 1H), 6.93 (d, J = 1.9 Hz, 1H), 5.51 (q, J = 6.7 Hz, 1H), 5.38 (td, J = 6.6, 13.2 Hz, 1H), 4.52 (t, J = 8.5 Hz, 1H), 2.16 - 1.93 (m, 3H), 1.92 - 1.69 (m, 4H), 5 1.64 (d, J = 7.0 Hz, 3H), 1.53 - 1.09 (m, 8H); LCMS (ESI): m/z: 535.53 [M+H ⁺ ]; 99.77% RT = 1.95 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; Chiral HPLC: 97.59% (RT: 5.26 min), Column: Lux Cellulose-4 (4.6*250mm)5μm, Co-Solvent: Methanol, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. 10 Example 136: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[3-fluoro-1-[1-(6-oxo- 1H-pyridazin-5- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxa diazole-3-carboxamide, diastereomer 1, and Example 137: N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[3-fluoro-1-[1-(6-oxo- 1H-pyridazin-5- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxa diazole-3-carboxamide, 15 diastereomer 2. According to the method of Example 42 the compound of Preparation 312 (75.0 mg, 0.14 mmol) was reacted to afford the title compound as a racemic mixture after prep. acidic 20 HPLC (30 mg, 41% yield). The single diastereomers were isolated by prep SFC. Preparative SFC Conditions Column/Dimensions: Chiralcel OX-H (250 x 10 x 5µ) % CO2: 80% 25 % Co-solvent: 20% (MeOH) Total Flow: 20 g/min Back Pressure: 100.0 bar Temperature: 30°C UV: 224 nm 30 Stack time: 4.85 min Load/Inj: 0.81 mg/injection 952-WO 216 Example 136: Peak 1: (7.0 mg, 23% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 13.18 (s, 1H), 10.20 (s, 1H), 9.22 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.85 (d, J = 4.1 Hz, 1H), 6.98 (dd, J = 0.8, 4.1 Hz, 1H), 5.56 - 5.46 (m, 1H), 4.59 (t, J = 8.3 Hz, 1H), 2.47 (s, 3H), 2.13 - 1.92 (m, 3H), 1.92 - 1.67 (m, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.51 - 1.18 (m, 2H); LCMS (ESI): m/z: 5 509.29 [M+H ⁺ ]; 95.25% RT = 3.40 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% TFA in water with MeCN; Chiral HPLC: 99.80% (RT: 3.02 min), Column: Lux Cellulose-4 (4.6*250mm)5μm, Co-Solvent: 0.5% Isopropyl Amine in IPA, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. Example 137: Peak 2: (7.0 mg, 23% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 13.18 (br s,10 1H), 10.21 (s, 1H), 9.22 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 6.96 (dd, J = 0.8, 4.1 Hz, 1H), 5.51 (d, J = 6.8 Hz, 1H), 4.59 (s, 1H), 2.47 (s, 3H), 2.14 - 1.92 (m, 3H), 1.92 - 1.68 (m, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.50 - 1.12 (m, 2H); LCMS (ESI): m/z: 509.45 [M+H ⁺ ]; 99.92% RT = 1.97 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; Chiral HPLC: 98.51% (RT: 3.60 min), Column: Lux Cellulose-4 15 (4.6*250mm)5μm, Co-Solvent: 0.5% Isopropyl Amine in IPA, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. Example 138: N-[(1S)-2-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]-3- fluoro-pyrazol- 4-yl]amino]-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]-2-isopro pyl-pyrazole-3-carboxamide,20 diastereomer 1 and Example 139: N-[(1S)-2-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]-3- fluoro-pyrazol- 4-yl]amino]-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]-2-isopro pyl-pyrazole-3-carboxamide, diastereomer 2. H 25 According to the method of Example 26 the compound of Preparation 314 (52.0 mg, 0.12 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (13.1 mg, 0.09 mmol) to afford the title compound as a racemic mixture after prep. acidic HPLC (30 mg, 43% yield). The single diastereomers were isolated by prep SFC. 30 Preparative SFC Conditions Column/Dimensions: Chiralpak-IF (250 x 4.6 x 5µ) % CO2: 75% % Co-solvent: 25% (iPrOH) 952-WO 217 Total Flow: 3 g/min Back Pressure: 100.0 bar Temperature: 30°C UV: 230 nm 5 Stack time: 3.5 min Load/Inj: 0.77 mg/injection Example 138: Peak 1: (3.0 mg, 10% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 13.44 - 13.20 (m, 1H), 10.14 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.11 (d, J = 0.8 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.54 - 5.46 (m, 1H), 5.42 - 5.33 (m,10 1H), 4.55 - 4.48 (m, 1H), 2.15 - 1.92 (m, 3H), 1.92 - 1.68 (m, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.49 - 1.12 (m, 8H); LCMS (ESI): m/z: 569.47 [M+H ⁺ ]; 98.46% RT = 2.05 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; Chiral HPLC: 99.09% (RT: 2.79 min), Column: CHIRALPAK IF-3 (4.6*150mm)3μm, Co-Solvent: IPA, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. 15 Example 139: Peak 2: (9.0 mg, 30% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 13.33 (s, 1H), 10.15 (s, 1H), 8.57 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.13 (d, J = 0.8 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.54 - 5.45 (m, 1H), 5.43 - 5.33 (m, 1H), 4.52 (t, J = 8.6 Hz, 1H), 2.15 - 1.92 (m, 3H), 1.92 - 1.67 (m, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.48 - 1.16 (m, 8H); LCMS (ESI): m/z: 569.47 [M+H ⁺ ]; 99.47% RT = 2.05 min; Column: Acquity BEH C1820 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; Chiral HPLC: 98.78% (RT: 1.79 min), Column: CHIRALPAK IF-3 (4.6*150mm)3μm, Co-Solvent: IPA, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. Example 140: N-[(1S)-2-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]-3- fluoro-pyrazol-25 4-yl]amino]-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]-4-methyl -1,2,5-oxadiazole-3- carboxamide, diastereomer 1, and Example 141: N-[(1S)-2-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]-3- fluoro-pyrazol- 4-yl]amino]-1-(4,4-difluorocyclohexyl)-2-oxo-ethyl]-4-methyl -1,2,5-oxadiazole-3- carboxamide, diastereomer 2. HB 30 According to the method of Example 26 the compound of Preparation 314 (75.0 mg, 0.17 mmol) was reacted with 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (22.7 mg, 0.17 mmol) 952-WO 218 to afford the title compound as a racemic mixture after prep. acidic HPLC (25 mg, 26% yield). The single diastereomers were isolated by prep SFC. Preparative SFC Conditions 5 Column/Dimensions: Chiralcel OJ-H (250 x 10 x 5µ) % CO2: 80% % Co-solvent: 20% (MeOH) Total Flow: 20 g/min Back Pressure: 100.0 bar 10 Temperature: 30°C UV: 229 nm Stack time: 5.0 min Load/Inj: 1.42 mg/injection Example 140: Peak 1: (5.0 mg, 20% recovery). ¹ H NMR (400 MHz, DMSO-d6) δ = 13.41 - 13.2515 (m, 1H), 10.20 (s, 1H), 9.22 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 0.9 Hz, 1H), 5.54 - 5.46 (m, 1H), 4.63 - 4.54 (m, 1H), 2.47 (s, 3H), 2.13 - 1.93 (m, 3H), 1.91 - 1.67 (m, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.49 - 1.10 (m, 2H); LCMS (ESI): m/z: 543.45 [M+H ⁺ ]; 92.39% RT = 2.08 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; Chiral HPLC: 99.56% (RT: 3.36 min), Column: CHIRALCEL OJ-H (4.6*250mm)5μm,20 Co-Solvent: Methanol, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. Example 141: Peak 2: (4.0 mg, 16% recovery). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.42 - 13.22 (m, 1H), 10.21 (s, 1H), 9.22 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 0.9 Hz, 1H), 5.54 - 5.45 (m, 1H), 4.63 - 4.55 (m, 1H), 2.47 (s, 3H), 2.14 - 1.93 (m, 3H), 1.92 - 1.67 (m, 4H), 1.65 (d, J = 7.0 Hz, 3H), 1.51 - 1.12 (m, 2H); LCMS (ESI): m/z: 543.43 [M+H ⁺ ];25 92.39% RT = 2.08 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; Chiral HPLC: 98.43% (RT: 5.86 min), Column: CHIRALCEL OJ-H (4.6*250mm)5μm, Co-Solvent: Methanol, Column Temperature: 30°C, Flow: 3 g/min, ABPR: 1500 psi. The examples listed in the table below were all accessed using the method as described for30 Example 26. 952-WO 219 Precursor E l M L MS The examples listed in the table below were all synthesised from the indicated starting material using the method as described for Example 4. E S carboxamide 952-WO 220 N-[(1S)-1-(dicyclopropyl- Example 146: N-[(1S)-1-(dicyclopropylmethyl)-2-[[2-[(5-fluoro-2-oxo-1H-py ridin-3- yl)methyl]thiazol-5-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyraz ole-3-carboxamide. 5 A 1M solution of TMSI in DCM (0.20 mL, 0.20 mmol) was added to a solution of the compound of Preparation 327 (9.3 mg, 0.017 mmol) in MeCN (1 mL) in a 8 mL screw cap vial and the mixture was stirred at room temperature for 4 hours. MeOH (0.40 mL) was added and the mixture was concentrated in vacuo. Further MeOH (1.5 mL) was added and removed in vacuo. The residue was dissolved in DMF (1 mL) and purified by acidic prep. 10 HPLC to give the title compound (7.6 mg, 84%) as a yellow solid. ¹ H NMR (400 MHz, DMSO) δ 11.47 (s, 1H), 8.64 (s, 1H), 8.52 (d, J = 8.6 Hz, 1H), 7.53 (t, J = 3.3 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.2, 3.3 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 5.38 (hept, J = 6.6 Hz, 1H), 4.92 (dd, J = 8.5, 6.7 Hz, 1H), 3.97 – 3.89 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H), 1.35 (d, J = 6.6 Hz, 3H), 0.98 – 0.87 (m, 1H), 0.87 – 0.73 (m, 2H), 0.50 –15 0.32 (m, 2H), 0.30 – 0.12 (m, 5H), 0.08 – 0.01 (m, 1H); LCMS (ES): m/z 513.208 [M+H] ⁺ , RT = 2.26 min. Example 147: N-[(1S)-1-[[3-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]iso xazol-5- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-N-methyl- pyrazole-3-carboxamide. HBr 20 According to the method of Example 26 the compound of Preparation 334 (17 mg, 0.04 mmol) was reacted with 2-isopropylpyrazole-3-carboxylic acid (6.7 mg, 0.04 mmol) to afford the title compound as a colourless solid after prep. acidic HPLC (3.4 mg, 14% yield). ¹ H NMR (400 MHz, 952-WO 221 DMSO-d6) δ = 13.40 - 13.01 (m, 1H), 11.98 - 11.70 (m, 1H), 8.51 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 10.9 Hz, 1H), 6.91 (t, J = 2.0 Hz, 1H), 6.25 (d, J = 9.4 Hz, 1H), 5.36 (td, J = 6.7, 13.1 Hz, 1H), 4.76 (t, J = 7.8 Hz, 1H), 4.29 (q, J = 7.0 Hz, 1H), 1.50 (d, J = 7.1 Hz, 3H), 1.39 - 1.32 (m, 6H), 1.09 - 0.88 (m, 1H), 0.87 - 0.69 (m, 2H), 0.55 - 0.42 (m, 1H), 5 0.42 - 0.33 (m, 1H), 0.33 - 0.15 (m, 5H), 0.11 - 0.02 (m, 1H); LCMS (ESI): m/z: 528.26 [M+H ⁺ ]; 80.75% RT = 5.67 min; Column: Acquity BEH C18 (50mmx2.1mm, 1.7um); 0.05% FA in water with MeCN; HPLC Purity: 82.81% RT = 7.67 min; Column: XBridge BEH C18 (150mmX4.6mm,2.5μm) 10 mM Ammonium Bicarbonate in Water with MeCN; Chiral HPLC: 45.59% RT: 1.78 min & 48.87% RT: 2.10 min, Column: LUX CELLULOSE-2 (4.6*150mm)3μm,10 Co-Solvent: 0.5% DEA in Methanol, Column Temperature: 30°C, Flow: 3 mL/min, ABPR: 1500 psi. Example 148: Inhibition of human IL-17-induced SEAP reporter gene activity in HEK-Blue ^TM IL-17 cells 15 50 nL test compounds in 100% DMSO were added into each well reserved for test compounds in a 384-well ViewPlates (Perkin Elmer), by the use of acoustic pipetting. The remaining wells received an equal volume of DMSO, as vehicle control, or VETRANAL® (Merck) in DMSO, as a positive control for cytotoxicity. Subsequently, 5 µl of an anti-IL-17A monoclonal antibody (final concentration 150 ng/ml) was added to the positive control 20 wells. All wells containing test compounds and wells prepared to yield maximum stimulation received 5 µL of human TH-17 supernatant corresponding to 2 ng/mL IL-17A final concentration (measured by IL-17A AlphaLisa® SureFire®, Perkin Elmer). Finally, 45 µl HEK-Blue ^TM IL-17 cells (Invivogen) were added to all the wells resulting in a density of 12500 cells/well and incubated in a humid incubator at 37°C, 5% CO2, overnight. The HEK-25 Blue ^TM IL-17 cells, anti-IL-17A antibody and TH-17 supernatant were all diluted in DMEM with high glucose (Sigma) supplemented with 10% FBS, 1% P/S (Life technologies) and HEK-Blue ^TM selection (Invivogen). After incubation, 5 µl of the supernatant was transferred from the cell plate to a new Viewplate and 45 µl Quanti-Blue ^TM solution, a SEAP detection reagent, was added and the30 Quanti-Blue ^TM /cell supernatant was incubated at 37°C. The plate was inspected for colour development (5 to 60 minutes) and read using Envision, Perkin Elmer, plate reader (absorbance at 620nm). The SEAP levels were calculated as percent of controls. Reduction of the amount of SEAP indicates decreased IL-17 signalling. Concentration response curves were fitted using a four-parameter logistic equation. Relative IC ₅₀ and Emax were reported35 from curves showing acceptable fit (r2>0.9). Cytotoxicity was measured in the cell- containing Viewplate following addition of 7 µL PrestoBlue (Thermo Fisher) and incubation for 2.5-3 hours at room temperature, by measuring fluorescence at 615 nm (excitation at 952-WO 222 535 nm). Fluorescence was directly proportional to the amount of metabolic activity. Reduction of fluorescence signal indicated cytotoxicity. Compounds of the present invention were tested in the assay of Example 148. The results5 are summarized in Table 1. Table 1 Example No HEK Blue ^TM assa 35 73 952-WO 223 36 18 80 41 952-WO 224 81 100 125 45 952-WO 225 126 39 Embodiments: Embodiment 1. A compound according to formula (Ia) or (Ib) 5 (Ia) (Ib) R ¹ is selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₁ -C ₆ )alkoxy, (C3-C7)cycloalkoxy, phenyl, phenyl-(C1-C4)alkyl, 5-or 6-membered heteroaryl, 9- or 10-10 membered bicyclic heteroaryl, 4-6-membered heterocycloalkyl and -NR ^c R ^d , wherein said (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, phenyl, phenyl-(C1- C4)alkyl, 5-or 6-membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, and 4-6- 952-WO 226 membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from R ^a ; R ^a is deuterium, halogen, hydroxy, -NR ^c R ^d , (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3- 5 C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6- membered heterocycloalkyl, or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, wherein said (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, is optionally substituted with one or more substituents10 independently selected from deuterium, halogen, hydroxy, cyano, (C1-C4)alkyl, (C3- C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl-S-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2- and - NR ^c R ^d ; R ^c and R ^d each independently are selected from the group consisting of hydrogen and (C1-15 C6)alkyl, or R ^c and R ^d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (C1- C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; R ² is selected from the group consisting of -CHR ⁴ R ⁵ , (C3-C10)cycloalkyl and G, wherein said20 (C3-C10)cycloalkyl and G are optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C ₁ -C ₄ )alkyl and halo(C ₁ -C ₄ )alkyl; G is selected from G1, G2 and G2 G2 _G3 25 R ⁴ and R ⁵ each independently represent hydrogen, phenyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, and (C3-C7)cycloalkyl(C1-C6)alkyl wherein said phenyl, (C1-C6)alkyl, (C3-C7)cycloalkyl and (C3-C7)cycloalkyl(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C1-C4)alkyl; with the proviso that at least30 one of R ⁴ and R ⁵ is different from hydrogen; R ³ is selected from hydrogen, (C1-C4)alkyl and (C1-C4)cycloalkyl, wherein said 952-WO 227 (C1-C4)cycloalkyl may optionally be substituted with one or more substituents independently selected from deuterium, halogen, cyano and hydroxy, and wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently 5 selected from deuterium, halogen, cyano, hydroxy, (C1-C4)cycloalkyl, (C1-C3)alkoxy, (C3- C4)cycloalkoxy, fluoro(C1-C4)cycloalkyl and fluoro(C1-C3)alkoxy; Q is 5-membered heteroaryl, wherein said 5-membered heteroaryl is optionally substituted with one or more substituents independently selected from R ^e ; 10 R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; 15 Z ¹ , Z ² and Z ³ are selected from N or CR ^b and wherein at least two of Z ¹ , Z ² and Z ³ are CR ^b ; Z ⁴ , Z ⁵ and Z ⁶ are CHR ^b ; n is 0 or 1; 20 R ^b is hydrogen, deuterium, halogen, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, or (C ₃ - C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen; 25 or pharmaceutically acceptable salts thereof. Embodiment 2. The compound according to embodiment 1 having the formula (Ic) or (Id) ₃₀ ^{(Ic) (Id)} 952-WO 228 wherein R ¹ , R ² , R ³ , Z ¹ , Z ² , Z ³ Z ⁴ , Z ⁵ , Z ⁶ , Q and n are as defined above; or pharmaceutically acceptable salts thereof. 5 Embodiment 3. The compound according to any one of embodiments 1-2, wherein R ¹ is selected from pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl, wherein the pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl is optionally substituted with one or more substituents independently selected from R ^a . 10 R ^a is deuterium, halogen, hydroxy, -NR ^c R ^d , (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6- membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, wherein said (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl,15 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (C1-C4)alkyl, (C3- C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl-S-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2- and - NR ^c R ^d ; 20 R ^c and R ^d each independently are selected from the group consisting of hydrogen and (C ₁ - C6)alkyl, or R ^c and R ^d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (C1- C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; 25 R ² is selected from -CHR ⁴ R ⁵ , and (C5-C7)cycloalkyl wherein said (C5-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C1-C4)alkyl and halo(C1-C4)alkyl; and wherein R ⁴ and R ⁵ each independently represent hydrogen, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,30 cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, wherein said phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C1-C4)alkyl; with the proviso that at least one of R ⁴ and R ⁵ is different from hydrogen; 35 R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; 952-WO 229 Q is pyrazolyl wherein said pyrazolyl is optionally substituted with one or more subsitutents selected from R ^e ; 5 R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; or phamaceutically acceptable salts thereof. 10 Embodiment 4. The compound according to any one of embodiments 1-2, wherein R ¹ is selected from pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl, wherein the pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl is15 optionally substituted with one or more substituents independently selected from R ^a . R ^a is deuterium, halogen, hydroxy, -NR ^c R ^d , (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6- membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, wherein said20 (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (C1-C4)alkyl, (C3- C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl-S-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2- and -25 NR ^c R ^d ; R ^c and R ^d each independently are selected from the group consisting of hydrogen and (C1- C6)alkyl, or R ^c and R ^d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (C1- C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more30 substituents independently selected from halogen, cyano and hydroxy; R ² is selected from -CHR ⁴ R ⁵ , wherein R ⁴ and R ⁵ each independently represent hydrogen, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, wherein said phenyl, cyclopropyl, cyclobutyl, cyclopentyl,35 cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C1- C4)alkyl; with the proviso that at least one of R ⁴ and R ⁵ is different from hydrogen; 952-WO 230 R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; 5 Q is pyrazolyl wherein said pyrazolyl is optionally substituted with one or more subsitutents selected from R ^e ; R ^e is deuterium, halogen, (C ₁ -C ₃ )alkyl, wherein said (C ₁ -C ₃ )alkyl may optionally be substituted with one or more substituents independently selected from deuterium and10 halogen; or phamaceutically acceptable salts thereof. Embodiment 5. The compound according to any one of embodiments 1-4, wherein 15 R ² is dicyclopropylmethyl or dicyclobutylmethyl. Embodiment 6. The compound according to any one of embodiments 1-4, wherein R ² is dicyclopropylmethyl. 20 Embodiment 7. The compound according to any one of embodiments 1-2, wherein R ¹ is selected from pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl, wherein the pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl is optionally substituted with one or more substituents independently selected from R ^a . 25 R ^a is deuterium, halogen, hydroxy, -NR ^c R ^d , (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6- membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, wherein said (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl,30 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (C1-C4)alkyl, (C3- C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl-S-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2- and - NR ^c R ^d ; 35 R ^c and R ^d each independently are selected from the group consisting of hydrogen and (C1- C6)alkyl, or R ^c and R ^d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (C1- 952-WO 231 C6)alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; R ² is (C5-C7)cycloalkyl wherein said (C5-C7)cycloalkyl is optionally substituted with one or 5 more substituents independently selected from deuterium, halogen, cyano, (C1-C4)alkyl and halo(C1-C4)alkyl; R ³ is (C ₁ -C ₄ )alkyl, wherein said (C ₁ -C ₄ )alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; 10 Q is pyrazolyl wherein said pyrazolyl is optionally substituted with one or more subsitutents selected from R ^e ; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be 15 substituted with one or more substituents independently selected from deuterium and halogen; or phamaceutically acceptable salts thereof. 20 Embodiment 8. The compound according to any one of embodiments 1-3 and 7 wherein R ² is cyclohexyl wherein said cyclohexyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C1-C4)alkyl and halo(C1-C4)alkyl. Embodiment 9. The compound according to any one of embodiments 1-3, 7 and 8 wherein25 R ² is trans methylcyclohexyl. Embodiment 10. The compound according to any one of embodiments 1-2, wherein R ¹ is selected from pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl,30 wherein said pyrazolyl, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl and triazolyl is optionally substituted with one or more substituents independently selected from R ^a . R ^a is deuterium, halogen, hydroxy, -NR ^c R ^d , (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3- C ₇ )cycloalkyl, (C ₃ -C ₇ )cycloalkyl-(C ₁ -C ₆ )alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6-35 membered heterocycloalkyl or 4-6-membered heterocycloalkyl-(C1-C6)alkyl, wherein said (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl, phenyl, 5- or 6-membered heteroaryl, 4-6-membered heterocycloalkyl or 4-6-membered 952-WO 232 heterocycloalkyl-(C1-C6)alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (C1-C4)alkyl, (C3- C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkyl-S-, (C1-C4)alkyl-SO-, (C1-C4)alkyl-SO2- and - NR ^c R ^d ; 5 R ^c and R ^d each independently are selected from the group consisting of hydrogen and (C1- C6)alkyl, or R ^c and R ^d together form azetidinyl, pyrrolidinyl or piperidinyl, wherein said (C1- C ₆ )alkyl, azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; 10 R ² is selected from G wherein G is wherein said G is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C1-C4)alkyl and halo(C1-C4)alkyl; 15 R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; Q is pyrazolyl wherein said pyrazolyl is optionally substituted with one or more subsitutents20 selected from R ^e ; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; 25 or phamaceutically acceptable salts thereof. Embodiment 11. The compound according to any one of embodiments 1-10, wherein R ¹ is selected from pyrazolyl, isoxazolyl and oxadiazolyl, wherein said pyrazolyl, isoxazolyl30 and oxadiazolyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen. 952-WO 233 Embodiment 12. The compound according to any one of embodiments 1-11 wherein R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 5 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen. 10 Embodiment 13. The compound according to any one of embodiments 1-12, wherein the compound has the formula (Ic) 2 H (Ic) wherein R ¹ , R ² and R ³ are as defined in any one of embodiments 1-12 and wherein 15 Z ¹ is N or CR ^b , and Z ² and Z ³ are CR ^b ; wherein R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3- C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally20 substituted with one or more substituents independently selected from deuterium and halogen. Embodiment 14. The compound according to any one of embodiments 1-12, wherein the compound has the formula (Ic) 25 952-WO 234 R ² O ) 1 ^{2 3} wherein R , R and R are as defined in any one of embodiments 1-12 and wherein Z ¹ is N or CR ^b , and Z ² and Z ³ are CR ^b ; wherein 5 R ^b is halogen. Embodiment 15. The compound according to any one of embodiments 1-12, wherein the compound has the formula formula (Id) 10 (Id) wherein R ¹ , R ² and R ³ are as defined in any one of the embodiments 1-12 above and wherein 15 n is 1; Z ⁴ , Z ⁵ and Z ⁶ are CHR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3-20 C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen. 952-WO 235 Embodiment 16. The compound according to any one of embodiments 1-12, wherein the compound has the formula formula (Id) ) 5 wherein R ¹ , R ² and R ³ are as defined in any one of embodiments 1-12 above and wherein n is 0; Z ⁶ is CHR ^b ; 10 Z ⁵ is CHR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3- C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally15 substituted with one or more substituents independently selected from deuterium and halogen. Embodiment 17. The compound according to any one of embodiments 1-12, wherein the compound has the formula (Ie) or (If) 20 (Ie) (If) wherein R ¹ , R ² , R ³ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and R ^e are as defined in any one of embodiments 1-12. 952-WO 236 Embodiment 18. The compound according to embodiment 2, wherein the compound has the formula (Ie) 5 wherein R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently10 selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; R ² is dicyclopropylmethyl; 15 R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be 20 substituted with one or more substituents independently selected from deuterium and halogen; Z ¹ is N or CR ^b , and Z ² is CR ^b and Z ³ is CH; and 25 R ^b is halogen. Embodiment 19. The compound according to embodiment 2, wherein the compound has the formula (Ie) 952-WO 237 wherein 5 R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; 10 R ² is trans 4-methylcyclohexyl; R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; 15 R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; 20 Z ¹ is N or CR ^b , and Z ² is CR ^b and Z ³ is CH; and R ^b is halogen. Embodiment 20. The compound according to embodiment 2, wherein the compound has25 the formula (If) (If) 952-WO 238 wherein R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently 5 selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; R ² is dicyclopropylmethyl; 10 R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be 15 substituted with one or more substituents independently selected from deuterium and halogen; n is 1; 20 Z ⁴ , Z ⁵ and Z ⁶ are CHR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3- C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and25 halogen. Embodiment 21. The compound according to embodiment 2 , wherein the compound has the formula (If) 30 ^(If) wherein 952-WO 239 R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and 5 halogen; R ² is trans 4-methylcyclohexyl; R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more10 substituents independently selected from hydroxy and (C1-C3)alkoxy; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen; 15 n is 1; Z ⁴ , Z ⁵ and Z ⁶ are CHR ^b ; and 20 R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3- C ₆ )cycloalkyl, wherein said (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy or (C ₃ -C ₆ )cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen. 25 Embodiment 22. The compound according to embodiment 2, wherein the compound has the formula (If) (If) wherein 30 R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be 952-WO 240 substituted with one or more substituents independently selected from deuterium and halogen; R ² is dicyclopropylmethyl; 5 R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be 10 substituted with one or more substituents independently selected from deuterium and halogen; n is 0; 15 Z ⁶ is CHR ^b ; Z ⁵ is CHR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3-20 C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen. Embodiment 23. The compound according to embodiment 2, wherein the compound has25 the formula (If) (If) wherein 30 R ¹ is selected from pyrazol-3-yl and 1,2,5-oxadiazol-4-yl wherein said pyrazol-3-yl and 1,2,5-oxadiazol-4-yl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be 952-WO 241 substituted with one or more substituents independently selected from deuterium and halogen; R ² is trans 4-methylcyclohexyl; 5 R ³ is (C1-C4)alkyl, wherein said (C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3)alkoxy; R ^e is deuterium, halogen, (C1-C3)alkyl, wherein said (C1-C3)alkyl may optionally be10 substituted with one or more substituents independently selected from deuterium and halogen; n is 0; 15 Z ⁶ is CHR ^b ; Z ⁵ is CHR ^b ; and R ^b is hydrogen, deuterium, halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, or (C3-20 C6)cycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C6)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium and halogen. Embodiment 24. The compound according to any one of embodiments 17-23 wherein R ^e is25 hydrogen or fluoro. Embodiment 25. The compound according to any one of embodiments 17-23 wherein R ^e is fluoro. 30 Embodiment 26. The compound according to any one of embodiments 18-23 wherein R ^b and R ^e are both fluoro. Embodiment 27. The compound according to any one of the embodiments above wherein R ³ is methyl, methoxymethyl or hydroxymethyl. 35 Embodiment 28. The compound according to any one of the embodiments above wherein R ³ is methoxymethyl. 952-WO 242 Embodiment 29: N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxopyrrolidi n-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt 5 thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyrid in-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or phamaceutically acceptable salts thereof; 10 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-3-piperi dyl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 15 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[2-oxo-6-(trifl uoromethyl)-1H-pyridin-3- yl]methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[1-(2-oxo-1H-pyr idin-3-yl)ethyl]pyrazol-4-20 yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[2-oxo-5-(trifl uoromethyl)-1H-pyridin-3- yl]methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide or a 25 phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(5-fluoro-2-oxo-1H-py ridin-3-yl)methyl]pyrazol-4- yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 30 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[2-oxo-4-(trifl uoromethyl)-1H-pyridin-3- yl]methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide or a phamaceutically acceptable salt thereof; 35 N-[(1S)-1-[[1-[(5-chloro-2-oxo-1H-pyridin-3-yl)methyl]pyrazo l-4-yl]carbamoyl]-2,2- dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 952-WO 243 N-[(1S)-1-[[1-[1-(5-chloro-2-oxo-1H-pyridin-3-yl)ethyl]pyraz ol-4-yl]carbamoyl]-2,2- dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 5 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(5-methyl-2-oxo-1H-py ridin-3-yl)methyl]pyrazol-4- yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 10 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(6-fluoro-2-oxo-1H-py ridin-3-yl)methyl]pyrazol-4- yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(3S,5S)-2-oxo- 5-15 (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]e thyl]-2-isopropyl-pyrazole-3- carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(5S)-2-oxo-5-( trifluoromethyl)pyrrolidin-3- yl]methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide or a 20 phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(1S)-1-(2-oxo-1 H-pyridin-3-yl)ethyl]pyrazol- 4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2,2,2-trifluoro -1-(2-oxo-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-ca rboxamide or a phamaceutically acceptable salt thereof; 30 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(3R,5R)-2-oxo- 5- (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]e thyl]-2-isopropyl-pyrazole-3- carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(3S,5R)-2-oxo- 5-35 (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]e thyl]-2-isopropyl-pyrazole-3- carboxamide or a phamaceutically acceptable salt thereof; 952-WO 244 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(1R)-1-(2-oxo-1 H-pyridin-3-yl)ethyl]pyrazol- 4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 5 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-oxo-1H- pyridin-3-yl)-2-hydroxy- ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole- 3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-oxo-1H- pyridin-3-yl)-2-methoxy-10 ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole- 3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(4-fluoro-2-oxo-1H-py ridin-3-yl)methyl]pyrazol-4- yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically 15 acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[1-(6-oxo-1H-pyr idazin-5-yl)ethyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 20 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyraz in-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2,2-difluoro-1-(5-fl uoro-2-oxo-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1S)-1-(5-fluoro-2-ox o-1H-pyridin-3-30 yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-methyl-2-oxo-1H- pyridin-3-yl)ethyl]pyrazol- 4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically 35 acceptable salt thereof; 952-WO 245 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1S)-1-(5-fluoro-2-ox o-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxa diazole-3-carboxamide or a phamaceutically acceptable salt thereof; 5 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[1-[6-oxo-3-(tri fluoromethyl)-1H-pyridazin-5- yl]ethyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-ca rboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[1-[6-oxo-3-(tri fluoromethyl)-1H-pyridazin-5-10 yl]ethyl]pyrazol-4-yl]amino]ethyl]-4-ethyl-1,2,5-oxadiazole- 3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]pyr azol-4-yl]carbamoyl]-2,2- dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable15 salt thereof; N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]pyr azol-4-yl]carbamoyl]-2,2- dicyclopropyl-ethyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide or a phamaceutically acceptable salt thereof; 20 N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methox y-ethyl]pyrazol-4- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole- 3-carboxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-1-[[1-[(3-chloro-6-oxo-1H-pyridazin-5-yl)methyl]pyra zol-4-yl]carbamoyl]-2,2- dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-oxo-1H- pyridin-3-yl)-2-hydroxy-30 ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxadia zole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-fluoro-2-oxo-1H- pyridin-3-yl)-2-methoxy- ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxadia zole-3-carboxamide or a35 phamaceutically acceptable salt thereof; 952-WO 246 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-methyl-2-oxo-1H- pyridin-3-yl)ethyl]pyrazol- 4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxa mide or a phamaceutically acceptable salt thereof; 5 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[1-(6-oxo-1H-pyr idazin-5-yl)ethyl]pyrazol-4- yl]amino]ethyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[1-(6-oxo-1H-pyr idazin-5-yl)ethyl]pyrazol-4-10 yl]amino]ethyl]-3-isopropyl-isoxazole-4-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyraz in-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide or a phamaceutically acceptable15 salt thereof; N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methox y-ethyl]pyrazol-4- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-4-ethyl-1,2,5-oxadiaz ole-3-carboxamide or a phamaceutically acceptable salt thereof; 20 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[3,3-difluoro-1-(2-oxo -1H-pyridin-3- yl)propyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyraz ole-3-carboxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(6-oxo-1H-pyrid azin-5-yl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-2,2-dicyclopropyl-1-[[1-[(3-cyclopropyl-6-oxo-1H-pyr idazin-5-yl)methyl]pyrazol-4-30 yl]carbamoyl]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methyl-6-oxo-1H-py ridazin-5-yl)methyl]pyrazol- 4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically 35 acceptable salt thereof; 952-WO 247 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[3-hydroxy-1-(6-oxo-1H -pyridazin-5- yl)propyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyraz ole-3-carboxamide or a phamaceutically acceptable salt thereof; 5 (3,3-difluorocyclobutyl) N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[1-(5-methyl-2-oxo-1H- pyridin-3-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate or a phamaceutically acceptable salt thereof; cyclopropyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyraz in-3-10 yl)methyl]pyrazol-4-yl]amino]ethyl]carbamate or a phamaceutically acceptable salt thereof; tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxopyrrolidi n-3- yl)methyl]pyrazol-3-yl]amino]ethyl]carbamate or a phamaceutically acceptable salt15 thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxopyrrolidi n-3-yl)methyl]pyrazol-3- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 20 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyrid in-3-yl)methyl]pyrazol-3- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(2-oxo-1H-py ridin-3-yl)methyl]pyrazol-4- yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2-oxo-1H-pyridin-3-30 yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazo le-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2-oxo-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-3-(trifluoromethyl )isoxazole-4-carboxamide or a35 phamaceutically acceptable salt thereof; 952-WO 248 N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2-oxo-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-3-isopropyl-isoxaz ole-4-carboxamide or a phamaceutically acceptable salt thereof; 5 N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2-oxo-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-ethyl-1,2,5-oxad iazole-3-carboxamide or a phamaceutically acceptable salt thereof; cyclopropyl N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fl uoro-2-oxo-1H-10 pyridin-3-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]carbamate or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1S)-1-(5-fl uoro-2-oxo-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-ethyl-1,2,5-oxad iazole-3-carboxamide or a15 phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[1-(5-fluoro- 2-oxo-1H-pyridin-3-yl)-2- methoxy-ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2, 5-oxadiazole-3-carboxamide or a phamaceutically acceptable salt thereof; 20 N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methox y-ethyl]-3-fluoro-pyrazol-4- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole- 3-carboxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methox y-ethyl]-3-fluoro-pyrazol-4- yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-4-methyl-1,2,5-oxadia zole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-[di(cyclobutyl)methyl]-2-oxo-2-[[1-[(2-oxo-1H-pyri din-3-yl)methyl]pyrazol-4-30 yl]amino]ethyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-[di(cyclobutyl)methyl]-2-oxo-2-[[1-[(2-oxo-1H-pyri din-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt35 thereof; 952-WO 249 tert-butyl N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxopyrrol idin-3- yl)methyl]pyrazol-4-yl]amino]ethyl]carbamate or a phamaceutically acceptable salt thereof; 5 N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxopyrrol idin-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 2-cyclopropyl-N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1 -[(2-oxopyrrolidin-3-10 yl)methyl]pyrazol-4-yl]amino]ethyl]pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxopyrrol idin-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide or a phamaceutically acceptable15 salt thereof; N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxo-1H-py ridin-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 20 2-cyclopropyl-N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1 -[(2-oxo-1H-pyridin-3- yl)methyl]pyrazol-4-yl]amino]ethyl]pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxo-1H-py ridin-3-yl)methyl]pyrazol-4- yl]amino]ethyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide or a phamaceutically acceptable salt thereof; 2-isopropyl-N-[(1S)-1-(4-methylcyclohexyl)-2-oxo-2-[[1-[(2-o xo-1H-pyridin-3-30 yl)methyl]pyrazol-4-yl]amino]ethyl]pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 4-ethyl-N-[(1S)-1-(4-methylcyclohexyl)-2-oxo-2-[[1-[(2-oxo-1 H-pyridin-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-1,2,5-oxadiazole-3-carbo xamide or a phamaceutically35 acceptable salt thereof; 952-WO 250 N-[(1S)-2-[[1-[(1S)-1-(5-fluoro-2-oxo-1H-pyridin-3-yl)ethyl] pyrazol-4-yl]amino]-1-(4- methylcyclohexyl)-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carbox amide or a phamaceutically acceptable salt thereof; 5 N-[(1S)-2-[[1-[(1S)-1-(5-fluoro-2-oxo-1H-pyridin-3-yl)ethyl] pyrazol-4-yl]amino]-1-(4- methylcyclohexyl)-2-oxo-ethyl]-4-methyl-1,2,5-oxadiazole-3-c arboxamide or a phamaceutically acceptable salt thereof; 10 N-[(1S)-2-[[1-[1-(5-fluoro-2-oxo-1H-pyridin-3-yl)-2-hydroxy- ethyl]pyrazol-4-yl]amino]-1- (4-methylcyclohexyl)-2-oxo-ethyl]-2-isopropyl-pyrazole-3-car boxamide or a phamaceutically acceptable salt thereof; N-[(1S)-2-[[1-[1-(5-fluoro-2-oxo-1H-pyridin-3-yl)-2-hydroxy- ethyl]pyrazol-4-yl]amino]-1-15 (4-methylcyclohexyl)-2-oxo-ethyl]-4-methyl-1,2,5-oxadiazole- 3-carboxamide or a phamaceutically acceptable salt thereof; N-[(1S)-2-[[1-[1-(5-fluoro-2-oxo-1H-pyridin-3-yl)-2-methoxy- ethyl]pyrazol-4-yl]amino]-1- (4-methylcyclohexyl)-2-oxo-ethyl]-4-methyl-1,2,5-oxadiazole- 3-carboxamide or a 20 phamaceutically acceptable salt thereof; N-[(1S)-2-[[1-[1-(5-fluoro-2-oxo-1H-pyridin-3-yl)-2-methoxy- ethyl]pyrazol-4-yl]amino]-1- (4-methylcyclohexyl)-2-oxo-ethyl]-2-isopropyl-pyrazole-3-car boxamide or a phamaceutically acceptable salt thereof; 25 N-[(1S)-2-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]pyr azol-4-yl]amino]-1-(4- methylcyclohexyl)-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carbox amide or a phamaceutically acceptable salt thereof; 30 N-[(1S)-2-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]pyr azol-4-yl]amino]-1-(4- methylcyclohexyl)-2-oxo-ethyl]-4-ethyl-1,2,5-oxadiazole-3-ca rboxamide or a phamaceutically acceptable salt thereof; 2-isopropyl-N-[(1S)-1-(4-methylcyclohexyl)-2-oxo-2-[[1-[1-(6 -oxo-1H-pyridazin-5-35 yl)ethyl]pyrazol-4-yl]amino]ethyl]pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 952-WO 251 4-ethyl-N-[(1S)-1-(4-methylcyclohexyl)-2-oxo-2-[[1-[1-(6-oxo -1H-pyridazin-5- yl)ethyl]pyrazol-4-yl]amino]ethyl]-1,2,5-oxadiazole-3-carbox amide or a phamaceutically acceptable salt thereof; 5 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyrid in-3-yl)methyl]imidazol-4- yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide or a phamaceutically acceptable salt thereof; 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[( 2-oxo-1H-pyridin-3-10 yl)methyl]imidazol-4-yl]amino]ethyl]-1,2,5-oxadiazole-3-carb oxamide or a phamaceutically acceptable salt thereof; N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2,2,2-trifluoro -1-(2-oxo-1H-pyridin-3- yl)ethyl]imidazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-c arboxamide or a 15 phamaceutically acceptable salt thereof; 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[2 ,2,2-trifluoro-1-(2-oxo-1H- pyridin-3-yl)ethyl]imidazol-4-yl]amino]ethyl]-1,2,5-oxadiazo le-3-carboxamide or a phamaceutically acceptable salt thereof; 20 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[( 1R*)-2,2,2-trifluoro-1-(2- oxo-1H-pyridin-3-yl)ethyl]imidazol-4-yl]amino]ethyl]-1,2,5-o xadiazole-3-carboxamide or a phamaceutically acceptable salt thereof; or 25 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[( 1S*)-2,2,2-trifluoro-1-(2- oxo-1H-pyridin-3-yl)ethyl]imidazol-4-yl]amino]ethyl]-1,2,5-o xadiazole-3-carboxamide or a phamaceutically acceptable salt thereof