WO2023111181A1 - Modulateurs à petites molécules d'il-17 - Google Patents

Modulateurs à petites molécules d'il-17 Download PDF

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Publication number
WO2023111181A1
WO2023111181A1 PCT/EP2022/086153 EP2022086153W WO2023111181A1 WO 2023111181 A1 WO2023111181 A1 WO 2023111181A1 EP 2022086153 W EP2022086153 W EP 2022086153W WO 2023111181 A1 WO2023111181 A1 WO 2023111181A1
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Prior art keywords
ethyl
oxo
pyrazol
carboxamide
amino
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PCT/EP2022/086153
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English (en)
Inventor
Jimmi Gerner Seitzberg
Kevin Neil Dack
Mark Andrews
Mogens Larsen
Xifu Liang
Peter Andersen
Mia NOERRESKOV BURHARDT
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Leo Pharma A/S
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Publication of WO2023111181A1 publication Critical patent/WO2023111181A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • IL-17 is a significant therapeutic target.
  • 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).
  • 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.
  • 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.
  • small molecule modulators of IL-17 particularly small molecules suitable for oral administration.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • the invention relates to a pharmaceutical composition
  • 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).
  • 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.
  • (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.
  • n-alkyl normal 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.
  • (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.
  • cyano is intended to indicate a –CN group attached to the parent molecular moiety through the carbon atom.
  • (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.
  • (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.
  • (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.
  • 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.
  • 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.
  • 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.
  • fluoro(C1-C3)alkoxy is intended to indicate a (C1-C3)alkylalkoxy group substituted with one or more fluoro atoms, e.g. trifluoromethoxy.
  • 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.
  • 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]pyridin
  • (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.
  • 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.
  • 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- azaspir
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • a molecular drawing of a substituent contains an arrow – the arrow indicates the bond attaching the substituent to the rest of the molecule.
  • 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.
  • a suitable inorganic or organic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric,
  • 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)
  • 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-.1 ⁇ 2Q 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.
  • alkali metal ions such as for example sodium (Na + ), potassium (K + )
  • 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+ ).
  • 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.
  • treatment 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.
  • 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.
  • the invention relates to a compound of formula (I) as described above, wherein R 2 is trans 4-methylcyclohexyl.
  • 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.
  • R 4 and R 5 each independently represent hydrogen, phenyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, and (C3-C7)cycloalkyl(C1-C6)alky
  • 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.
  • 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.
  • R 1 is selected from pyrazolyl, isoxazolyl and oxadiazolyl
  • said pyrazolyl, isoxazolyl and oxadiazolyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, (C1-C4)alkyl, (C3-
  • 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.
  • 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.
  • the invention relates to a compound of formula (I) as described above, wherein R 3 is methyl, methoxymethyl or hydroxymethyl.
  • the invention relates to a compound of formula (I) as described above, wherein R 3 is methoxymethyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the invention relates to any compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) as described herein for use in therapy.
  • 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.
  • 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.
  • 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).
  • the invention relates to a pharmaceutical composition
  • 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).
  • 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.
  • said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chiral pure starting materials.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • autoimmune diseases such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis.
  • 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 autoimmune
  • 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.
  • autoimmune diseases such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis
  • compositions of the 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.
  • the active ingredient comprises from 0.0001-99.9% by weight of the formulation.
  • 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.
  • 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.
  • 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 administration include 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.
  • RESULTS 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.
  • reaction conditions 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.
  • 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 1.8 ⁇ m; 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 ⁇ l 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
  • 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).
  • a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC
  • a base such as DIPEA or triethylamine
  • suitable solvents such as DMF or acetonitrile
  • 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).
  • a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC
  • a base such as DIPEA or triethylamine
  • suitable solvents such as DMF or acetonitrile
  • 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).
  • 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).
  • a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC
  • a base such as DIPEA or triethylamine
  • suitable solvents such as DMF or acetonitrile
  • 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).
  • 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).
  • a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC
  • a base such as DIPEA or triethylamine
  • a suitable solvents such as DMF or acetonitrile
  • 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 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.
  • 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.
  • a suitable solvent such as MeCN or DMF
  • 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).
  • 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).
  • reagents such as phosgene, diphosgene, triphosgene, CD
  • 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).
  • reagents such as phosgene, diphosgene, triphosgene, CDI, 4-nitrophenyl chloroformate or bis(2,5-dioxopyrrolidin-1-yl) carbonate
  • a suitable base such as TEA
  • MeCN or DCM a
  • 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).
  • reagents such as phosgene, diphosgene, triphosgene, CDI, 4-nitrophenyl chloroformate or bis(2,5-dioxopyrrolidin-1-yl) carbonate
  • a suitable base such as TEA
  • MeCN or DMF a suitable solvent
  • 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.
  • 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
  • compounds of general formula (Int 1) can be prepared, as shown in Scheme 13.
  • 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).
  • 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 ⁇ -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.
  • 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.
  • 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.
  • a base such as Cs2CO3 or K2CO3
  • a suitable15 solvent such as DMSO, DMF or MeCN.
  • 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.
  • a metal catalyst such as Pd/C or Pt/C
  • solvent such as20 MeOH, EtOH or EtOAc.
  • 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).
  • 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.
  • 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.
  • a metal catalyst such as Pd/C or Pt/C
  • a solvent such as MeOH, EtOH or EtOAc.
  • 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.
  • Preparation 3 2-(benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoic acid.
  • Ammonium carbonate 100 g, 1.04 mol
  • KCN 17.9 g, 275 mmol
  • EtOH:H2O 200 mL:200 mL
  • Preparation 7 (2S)-2-(tert-butoxycarbonylamino)-3,3-di(cyclobutyl)propanoic 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).
  • 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.
  • 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.
  • 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.
  • Boc anhydride (474 mg, 2.17 mmol) dissolved in THF (5 mL).
  • 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.
  • Preparation 13 N-[(S)-cyano-(4-methylcyclohexyl)methyl]-4-methyl-benzenesulfinamide.
  • 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.
  • a solution of the compound of 5 Preparation 12 (3.49 g, 13.2 mmol) in THF (130 mL) was cooled to -75°C.
  • 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.
  • Preparation 28 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[[2-methoxy-5-(trifluoromethyl)-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).
  • 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).
  • 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.
  • 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).
  • Preparation 49 tert-butyl (3S,5S)-3-[[4-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole- 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.
  • Preparation 62 (2S)-2-amino-3,3-dicyclopropyl-N-[1-[2,2,2-trifluoro-1-(2-methoxy-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.
  • 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.
  • Preparation 74 1-(5-fluoro-2-methoxy-3-pyridyl)-2-triisopropylsilyloxy-ethanol. 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.
  • Preparation 75 [2-(5-fluoro-2-methoxy-3-pyridyl)-2-(4-nitropyrazol-1-yl)ethoxy]- 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).
  • 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).
  • Preparation 80 2-(5-fluoro-2-methoxy-3-pyridyl)-2-(4-nitropyrazol-1-yl)ethanol. 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.
  • Preparation 81 5-fluoro-2-methoxy-3-[2-methoxy-1-(4-nitropyrazol-1-yl)ethyl]pyridine.
  • NaH 50% mass, 150 mg, 3.75 mmol
  • MeI 0.3 mL, 5.0 mmol
  • 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.
  • 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]carbamate.
  • the compound of Preparation 5 100 mg, 0.33 mmol
  • the compound of Preparation 82 85.8 mg, 0.32 mmol
  • 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.
  • 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.
  • 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).
  • Preparation 101 (2S)-2-amino-3,3-dicyclopropyl-N-[1-[(3-methoxypyrazin-2-10 yl)methyl]pyrazol-4-yl]propanamide.
  • 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.
  • Preparation 102 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxypyrazin-2- yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide.
  • 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).
  • 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).
  • Preparation 104 3-[2,2-difluoro-1-(4-nitropyrazol-1-yl)ethyl]-5-fluoro-2-methoxy-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).
  • Preparation 114 5-fluoro-2-methoxy-3-[(1S)-1-(4-nitropyrazol-1-yl)ethyl]pyridine.
  • Preparation 116 2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid.
  • 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 21 ⁇ 2 hours the reaction mixture was filtered and evaporated.
  • 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]carbamate. 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).
  • 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).
  • 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]carbamate. 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).
  • Preparation 128 3-methoxy-6-(trifluoromethyl)pyridazine.
  • Preparation 130 3-methoxy-4-[1-(4-nitropyrazol-1-yl)ethyl]-6-(trifluoromethyl)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).
  • 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]carbamate. 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).
  • 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).
  • 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-ethyl]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).
  • Preparation 142 (6-chloro-3-methoxy-pyridazin-4-yl)methanol and (3-chloro-6-methoxy- pyridazin-4-yl)methanol.
  • 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.
  • Preparation 143 6-chloro-3-methoxy-4-[(4-nitropyrazol-1-yl)methyl]pyridazine.
  • 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).
  • 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-oxadiazole-3-carboxamide.
  • 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).
  • 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).
  • Preparation 153 3-[3,3-difluoro-1-(4-nitropyrazol-1-yl)propyl]-2-methoxy-pyridine.
  • 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.
  • Preparation 154 1-[3,3-difluoro-1-(2-methoxy-3-pyridyl)propyl]pyrazol-4-amine. 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 CeliteTM. The filtrate was 10 concentrated to afford the crude title compound (12.0 mg, 71% yield).
  • 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 CeliteTM and the filtrate was purified directly by prep.
  • 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.
  • 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.
  • 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).
  • Preparation 175 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(3-methoxy-6-methyl-pyridazin- 4-yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide.
  • 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).
  • Preparation 177 4-[3-benzyloxy-1-(4-nitropyrazol-1-yl)propyl]-6-chloro-3-methoxy- 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).
  • Preparation 179 tert-butyl N-[(1S)-1-[[1-[3-benzyloxy-1-(6-chloro-3-methoxy-pyridazin-15 4-yl)propyl]pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate.
  • 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).
  • 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).
  • 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.
  • Preparation 196 tert-butyl N-[5-fluoro-1-[(1S)-1-(5-fluoro-2-methoxy-3-25 pyridyl)ethyl]pyrazol-4-yl]carbamate SelectfluorTM (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.
  • Preparation 199 (2S)-2-amino-3,3-dicyclopropyl-N-[5-fluoro-1-[(1S)-1-(5-fluoro-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.
  • Preparation 200 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1R)-1-(2-methoxy-3- pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide.
  • the compound of Preparation 199 36 mg, 0.08810 mmol
  • 2-isopropylpyrazole-3-carboxylic acid (30 mg, 0.19 mmol)
  • Preparation 201 N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(1S)-1-(5-fluoro-2- methoxy-3-pyridyl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-3-(trifluoromethyl)isoxazole-4-20 carboxamide.
  • 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.
  • Preparation 207 3-[(1S)-1-(4-bromo-3-fluoro-pyrazol-1-yl)ethyl]-5-fluoro-2-methoxy- 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).
  • Preparation 208 N-[3-fluoro-1-[(1S)-1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]pyrazol-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).
  • 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 .
  • Preparation 221 6-chloro-4-[1-(3-fluoro-4-nitro-pyrazol-1-yl)-2-methoxy-ethyl]-3- methoxy-pyridazine.
  • 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).
  • 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-dicyclopropyl-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).
  • Preparation 224 (2S)-2-amino-N-[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methoxy-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.
  • Preparation 233 2-cyclopropyl-N-[(1S)-1-(4,4-difluorocyclohexyl)-2-[[1-[(2-methoxy-3- pyridyl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]pyrazole-3-carboxamide.
  • 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).
  • Preparation 240 (2S)-2-amino-N-[1-[1-(5-fluoro-2-oxo-1H-pyridin-3-yl)-2-hydroxy- 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.
  • Preparation 242 (2S)-2-amino-N-[1-[1-(5-fluoro-2-methoxy-3-pyridyl)-2-methoxy- 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).
  • 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.
  • 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-ethyl]carbamate.
  • 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).
  • Preparation 252 4-cyclopropyl-N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(2-methoxy-3- 5 pyridyl)methyl]imidazol-4-yl]amino]-2-oxo-ethyl]-1,2,5-oxadiazole-3-carboxamide.
  • Preparation 254 1-[2,2,2-trifluoro-1-(2-methoxy-3-pyridyl)ethyl]imidazol-4-amine. 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).
  • 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]ethyl]-1,2,5-oxadiazole-3- carboxamide.
  • 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).
  • 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.
  • Preparation 283 4-(1-bromo-3,3-difluoro-propyl)-6-chloro-3-methoxy-pyridazine.
  • 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).
  • Preparation 288 6-chloro-4-[3,3-difluoro-1-(3-fluoro-4-nitro-pyrazol-1-yl)propyl]-3- methoxy-pyridazine 20
  • the compound of Preparation 283 0.5 g, 1.7 mmol
  • 3-fluoro-4-nitro-1H-pyrazole 0.33 g, 2.5 mmol
  • Preparation 292 6-chloro-4-[3,3-difluoro-1-(3-fluoro-4-nitro-pyrazol-1-yl)propyl]-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 293 1-[1-(6-chloro-3-methoxy-pyridazin-4-yl)-3,3-difluoro-propyl]-3-fluoro- pyrazol-4-amine, Enantiomer 2.
  • 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]carbamate.
  • 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).
  • 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)acetamide; hydrochloride, 10 Diastereomer 1.
  • 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).
  • 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).
  • 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.
  • the compound of Preparation 310 250 mg, 0.61 mmol
  • 4-methyl-1,2,5-oxadiazole-3-carboxylic acid 77.7 mg, 0.61 mmol
  • 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).
  • Preparation 318 tert-butyl N-[1-[1-(5-fluoro-2-methoxy-3-pyridyl)ethyl]triazol-4- yl]carbamate.
  • DPPA 0.247 mL, 315 mg, 1.14 mmol
  • 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.
  • 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.
  • Preparation 324 2,2,2-trifluoro-N-[2-[(5-fluoro-2-methoxy-3-pyridyl)methyl]thiazol-5-10 yl]acetamide.
  • TFA 1.0 g, 0.673 mL
  • 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.
  • 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.
  • 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.
  • Preparation 331 3-[1-(6-chloro-3-methoxy-pyridazin-4-yl)ethyl]isoxazol-5-amine. 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.
  • 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.
  • Preparation 333 benzyl N-[(1S)-1-[[3-[1-(6-chloro-3-methoxy-pyridazin-4- yl)ethyl]isoxazol-5-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate. 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.
  • Example 3 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-3- piperidyl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-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).
  • Example 14 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- 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).
  • Example 17 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[[(3R,5R)-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl]methyl]pyrazol-4-yl]amino]ethyl]-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).
  • Example 26 N-[(1S)-1-(dicyclopropylmethyl)-2-[[1-[(1S)-1-(5-fluoro-2-oxo-1H-pyridin-3- yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3-carboxamide.
  • Example 48 cyclopropyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyrazin- 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.
  • Example 49 tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxopyrrolidin-3-10 yl)methyl]pyrazol-3-yl]amino]ethyl]carbamate.
  • the compound of Preparation 118 54 mg, 0.20 mmol
  • the compound of Preparation 186 48 mg, 0.22 mmol
  • 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-oxopyrrolidin-3- yl)methyl]pyrazol-3-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide.
  • 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).
  • Example 51 N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[1-[(2-oxo-1H-pyridin-3- yl)methyl]pyrazol-3-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide.
  • 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).
  • Example 52 N-[(1S)-1-(dicyclopropylmethyl)-2-[[5-fluoro-1-[(2-oxo-1H-pyridin-3- yl)methyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-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.
  • 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-ethyl]-4-methyl-1,2,5-15 oxadiazole-3-carboxamide.
  • the compound of Preparation 220 5.0 mg, 0.009 mmol
  • acidic HPLC 1.5 mg, 31% yield).
  • Example 60 N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methoxy-ethyl]-3- fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-2-isopropyl-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.
  • Example 61 N-[(1S)-1-[[1-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)-2-methoxy-ethyl]-3- fluoro-pyrazol-4-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]-4-methyl-1,2,5-oxadiazole-3- carboxamide.
  • the compound of Preparation 224 22 mg, 0.046 mmol
  • 4-methyl-1,2,5-oxadiazole-3-carboxylic acid 3.6 mg, 0.028 mmol
  • Example 62 N-[(1S)-1-[di(cyclobutyl)methyl]-2-oxo-2-[[1-[(2-oxo-1H-pyridin-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).
  • Example 63 N-[(1S)-1-[di(cyclobutyl)methyl]-2-oxo-2-[[1-[(2-oxo-1H-pyridin-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide. 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).
  • Example 65 N-[(1S)-1-(4,4-difluorocyclohexyl)-2-oxo-2-[[1-[(2-oxopyrrolidin-3- yl)methyl]pyrazol-4-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide.
  • 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).
  • 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).
  • 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-carboxamide.
  • 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.
  • Example 86 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 5 ⁇ ) % 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).
  • Example 88 Peak 2: (10.8 mg, 72% recovery).
  • 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-oxo- 1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-2-isopropyl-pyrazole-3- carboxamide and N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-oxo-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.
  • Examples 106 and 107 N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-oxo- 1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxadiazole-3- carboxamide and N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-oxo-3- triethylsilyl-1H-pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5- oxadiazole-3-carboxamide.
  • Example 106 N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-oxo-1H- pyridazin-5-yl)ethyl]pyrazol-4-yl]amino]-2-oxo-ethyl]-4-methyl-1,2,5-oxadiazole-3- 20 carboxamide : 11 mg, 84% yield as a colourless solid.
  • Example 107 N-[(1S)-1-(dicyclopropylmethyl)-2-[[3-fluoro-1-[(1RS)-1-(6-oxo-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.
  • 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.
  • 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-isopropyl-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.
  • 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-isopropyl-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).
  • 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-oxadiazole-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-oxadiazole-3-carboxamide, 15 diastereomer 2.
  • Example 137 Peak 2: (7.0 mg, 23% recovery).
  • 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-isopropyl-pyrazole-3-carboxamide,20 diastereomer 1 and
  • Example 139 N-[(1S)-2-[[1-[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-isopropyl-pyrazole-3-carboxamide, diastereomer 2.
  • Example 139 Peak 2: (9.0 mg, 30% recovery).
  • 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-[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.
  • Example 141 Peak 2: (4.0 mg, 16% recovery).
  • Example 147 N-[(1S)-1-[[3-[1-(3-chloro-6-oxo-1H-pyridazin-5-yl)ethyl]isoxazol-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).
  • 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 ⁇ l 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 ⁇ L of human TH-17 supernatant corresponding to 2 ng/mL IL-17A final concentration (measured by IL-17A AlphaLisa® SureFire®, Perkin Elmer). Finally, 45 ⁇ l 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 ⁇ l of the supernatant was transferred from the cell plate to a new Viewplate and 45 ⁇ l 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 ⁇ L 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.
  • 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,
  • 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.
  • 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 .
  • 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 substitu
  • 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 substitu
  • 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 .
  • 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 substitu
  • 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.
  • 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)
  • 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.
  • 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.
  • 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 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.
  • 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
  • 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.
  • 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 optional
  • 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-C
  • 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 (
  • 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)
  • 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-C
  • 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.
  • 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.

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Abstract

La présente invention concerne un composé selon la formule (I) et des sels, hydrates ou solvates pharmaceutiquement acceptables de celui-ci. L'invention concerne en outre lesdits composés destinés à être utilisés en thérapie, des compositions pharmaceutiques comprenant lesdits composés, des procédés de traitement de maladies, par exemple des maladies dermiques, avec lesdits composés, et l'utilisation desdits composés dans la fabrication de médicaments.
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