WO2021255086A1 - Modulateurs à petites molécules d'il-17 - Google Patents

Modulateurs à petites molécules d'il-17 Download PDF

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WO2021255086A1
WO2021255086A1 PCT/EP2021/066226 EP2021066226W WO2021255086A1 WO 2021255086 A1 WO2021255086 A1 WO 2021255086A1 EP 2021066226 W EP2021066226 W EP 2021066226W WO 2021255086 A1 WO2021255086 A1 WO 2021255086A1
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alkyl
independently selected
cycloalkyl
halogen
phenyl
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PCT/EP2021/066226
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English (en)
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Mark Andrews
Kevin Neil Dack
Mia Nørreskov BURHARDT
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Leo Pharma A/S
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Publication of WO2021255086A1 publication Critical patent/WO2021255086A1/fr

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    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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

Definitions

  • IL-17 also known as IL-17A or CTLA8
  • IL-17A is a pro-inflammatory cytokine involved in anti- microbial defense at epithelial surfaces.
  • IL-17 is comprised of two covalently joined IL-17A subunits (IL-17AA) with an approximate mass of 32 kDa, and signals through a receptor comprising IL17RA and IL17RC subunits. This receptor is predominantly expressed in epithelial and mesenchymal cells.
  • the IL17RA/IL17RC receptor is also used by IL-17 variants IL-17AF and IL-17FF, which both are successively weaker, partial agonists on this receptor (Monin, L., Gaffen, S.L.; 2018, Cold Spring Harb. Perspect. Biol. 10. doi:10.1101/cshperspect.a028522).
  • Crucial for signaling is the assembly of signaling complexes containing the multifunctional protein ACT1/CIKS, which in turn can recruit TRAF and other proteins. Via these signaling complexes IL-17 induces cytokines, chemokines, antimicrobial peptides and growth factors via activation of transcription factor NFkB or via MAP kinase-dependent pathways (e.g.
  • IL-17 acts in concert with IL-1beta, IL-22 and IFNgamma (Amatya, N. et al., Trends in Immunology, 2017, 38, 310-322. doi:10.1016/j.it.2017.01.006; Onishi, R.M., Gaffen, S.L. Immunology, 2010, 129, 311–321. doi:10.1111/j.1365-2567.2009.03240.x).
  • IL-17 is secreted by a variety of immune cells, such as Th17 helper cells, Tc17 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.
  • WO2013116682 discloses Macrocyclic Compounds for Modulating IL-17; WO2014066726 discloses Compounds for Modulating IL-17; WO2018229079 discloses Compounds for Modulating IL-17; WO2019223718 discloses Compounds for Modulating IL-17; WO2019138017 discloses Compounds for Modulating IL-17; WO2020011731 discloses Compounds for Modulating IL-17; WO2020120140 discloses Compounds for Modulating IL-17; WO2020120141 discloses Compounds for Modulating IL-17; WO2020260426 discloses Compounds for Modulating IL-17; WO2020260425 discloses Compounds for Modulating IL-17; WO2020261141 discloses Compounds for Modulating IL-17; WO2020146194 discloses IL-17A inhibitors.
  • Orally available, highly efficacious small molecule IL-17 modulators which bind to IL-17 to decrease its functional ability to activate the IL-17 receptor complex may have a number of advantages compared to monoclonal antibodies.
  • Oral administration and flexible treatment regimen may be two significant aspects in favor of patient convenience and the compounds may exhibit improved safety due to the possibility of faster withdrawal of the drug should adverse events occur. Therefore, there is a continuous need to develop small molecule modulators of IL-17, particularly small molecules suitable for oral administration.
  • some patients may be treated by topical application of small molecule modulators of IL-17. This can be particularly suitable for patients with skin lesions that are readily accessible and limited in body surface area.
  • Topical treatment may also be prescribed for certain patients who could benefit from avoiding systemic modulation of the IL-17 pathway, for example when undergoing treatment for infections or gastrointestinal problems.
  • SUMMARY OF THE INVENTION The inventors have surprisingly found that novel compounds of the present invention exhibit modulating effects on the IL-17 signalling pathway.
  • Compounds of the present invention may have advantageous properties such as high metabolic stability and/or membrane permeability, properties that make them suitable for oral administration.
  • Other compounds of the present invention may have advantageous properties for local topical therapy, such as high skin permeability and high metabolic instability.
  • Compounds of the present invention may be beneficial in preventing, treating or ameliorating a variety of diseases which involve up-regulation or de-regulation of IL-17, such as for example psoriasis, ankylosing spondylitis and psoriatic arthritis.
  • the present invention relates to a compound according to formula (I) wherein A, B, D and E are independently selected from N and C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C(R 4 ); R 1 is selected from the group consisting of -CHR 5 R 6 , (C 3 -C 10 )cycloalkyl and G, wherein said (C 3 - C 10 )cycloalkyl and G are optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 -C 4 )alkyl; G is R 5 and R 6 each independently represent hydrogen, phenyl, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl , wherein said phenyl,
  • the present invention relates to compounds of formula (Ia) wherein A, B, D, E, X, Y, Z, V, R 1 and R 2 are as defined in claim 1 or pharmaceutically acceptable salts, hydrates and solvates thereof.
  • the present invention relates to compounds of formula (Ib)
  • the invention relates to a pharmaceutical composition comprising a compound of general formula (I) 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 I 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.
  • (C a -C b )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.
  • (C a -C b )alkoxy is intended to indicate a radical of the formula –OR’, wherein R’ is (C a -C b )alkyl as indicated herein, wherein the (C a -C b )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.
  • (C a -C b )cycloalkyl is intended to indicate a saturated (C a -C b )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.
  • (C a -C b )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.
  • (C a -C b )cycloalkyl(C a -C b )alkyl is intended to indicate a (C a -C b )alkyl group as defined herein substituted with one or more (C a -C b )cycloalkyl groups as defined herein.
  • the (C a -C b )alkyl group is substituted with one (C a -C b )cycloalkyl group.
  • halo(C a -C b )alkyl is intended to indicate an (C a -C b )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.
  • halogen is intended to indicate a substituent from the 7th 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]pyridinyl, pyrazolo[1,5- a]pyridinyl, pyrazolo[1,5-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, and imidazo[1,2]pyridazinyl.
  • the term (5- or 6-membered heteroaryl)-(C a -C b )alkyl is intended to indicate a 5- or 6- membered heteroaryl appended to the parent molecular moiety through a (C a -C b )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]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
  • 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.
  • (a-b membered heterocycloalkyl)-(C c -C d )alkyl is intended to indicate a a-b membered heterocycloalkyl radical appended to the parent molecular moiety through an (C c - C d )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(C a -C b )alkyl is intended to indicate an (C a -C b )alkyl group as defined above substituted with one or more hydroxy, e.g.
  • phenyl-(C a -C b )alkyl is intended to indicate a phenyl group appended to appended to the parent molecular moiety through an (C a -C b )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.
  • 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.
  • pharmaceutically acceptable salt is intended to indicate salts prepared by reacting a compound of formula I, which comprise a basic moiety, with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroacetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-1, 2-disulfonic, 2-hydroxyethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid.
  • a suitable inorganic or organic acid such as hydrochloric, hydrobromic, hydroi
  • 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, lH-imidazole, 4-(2-hydroxyethyl)-morpholine, piperazine, l-(2-hydroxyethyl)
  • R 2 contains -L-PO(OH)2
  • the phosphoric acid group may form a salt with a monovalent cation M + or divalent cation Q 2+ to form a group selected from -L-PO(OH)O-.M + ,-L- PO(OH)O-.1/ 2 Q 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 NH 4 + , dialkylammonium (NH 2 ((C 1 -C 4 )alkyl) 2 ) + , trialkylammonium (NH((C 1 - C 4 )alkyl) 3 ) + , or tetraalkylammonium (N((C 1 -C 4 )alkyl) 4 ) + , alkylammonium (H 3 N(C 1 -C 4 )alkyl) + or hydroxyalkylammonium (H 3 N-hydroxy(C 1 -C 4 )alkyl) + , the protonated forms of L-arginine, L- lysine or the protonated forms of any pharmaceutically acceptable bases such as those mentioned above.
  • 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+ ).
  • alkaline earth metal ions such as calcium (Ca 2+ ), Magnesium (Mg 2+ ), barium (Ba 2+ ), or Zinc (Zn 2+ ).
  • the term 'prodrug' is intended to indicate compounds which are drug- precursors which, upon administration, are converted to the parent drug in vivo by enzymatic and/or chemical reactions. Generally, the pro-drug is less biologically active than its parent drug.
  • the prodrug may have improved physical-chemical properties compared to the parent drug, such as improved aqueous solubility, thereby facilitating the absorption and consequently the bioavailability of the parent compound upon administration.
  • the term ‘parent drug’ or ‘parent compound’ is intended to indicate the biologically active compound which is released from the prodrug via enzymatic and/or chemical processes following administration of the prodrug. The parent drug is frequently the starting material for the preparation of the corresponding prodrug.
  • prodrugs according to the invention are prodrugs that are attached to a nitrogen or oxygen of the parent molecule.
  • the parent molecule contains a 5- membered heteroaryl containing nitrogen substituted with hydrogen as a ring atom said hydrogen may be replaced with a substituent selected from -L-PO(OH)2, wherein L is selected from the group consisting of a bond or - CHR g O- and R g is selected from hydrogen and (C 1 -C 6 )alkyl to form a prodrug.
  • 5-membered heteroaryls such as pyrrole, imidazole, pyrazole, triazole and tetrazole when attached to the reminder of the molecule via a carbon ring atom are moieties that may contain a nitrogen ring atom substituted by hydrogen.
  • solvate is intended to indicate a species formed by interaction between a compound, e.g. a compound of formula I, 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.
  • treatment means 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. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference, regardless of any separately provided incorporation of particular documents made elsewhere herein.
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A, B, D and E are each independently selected from N or C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C(R 4 ); R 1 is selected from -CHR 5 R 6 , and wherein R 5 and R 6 each independently represent hydrogen, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, wherein said phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A, B, D and E are each independently selected from N or C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C(R 4 ); R 1 is selected from -CHR 5 R 6 , and wherein R 5 and R 6 each independently represent (C 3 - C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl wherein said (C 3 -C 7 )cycloalkyl and (C 3 - C 7 )cycloalkyl(C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C 1 -C 4 )alkyl; R 2 is selected from the group consisting of 5- or 6-membered heteroaryl, wherein said 5-or 6- membered heteroaryl is optionally
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A, B, D and E are each independently selected from is N or C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C(R 4 ); R 1 is selected from cyclohexyl, cycloheptyl, cyclooctanyl, adamantyl, spiro[2.3]hexanyl, bicyclo[3,1,0]hexanyl, bicyclo[4,1,0]heptanyl, bicyclo[2,2,2]octanyl or spiro[2.5]octanyl, wherein said cyclohexyl, cycloheptyl, cyclooctanyl, adamantyl, spiro[2.3]hexanyl, bicyclo[3,1,0]hexanyl, bicyclo[4,1,0]heptanyl,bicyclo[2,2,2,
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A, B, D and E are each independently selected from N or C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C( R 4 ); R 1 is selected from G, wherein G is wherein said G is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 -C 4 )alkyl R 2 is selected from the group consisting of 5- or 6-membered heteroaryl, wherein said 5-or 6- membered heteroaryl is optionally substituted with one or more substituents independently selected from R a , wherein said 5- or 6-membered heteroaryl may optionally contain -CO- as a ring member and wherein when said 5 membered heteroaryl contains nitrogen as a ring atom said nitrogen may optionally be substituted with -L-
  • the invention relates to a compound of formula (I), (Ia) or (Ib), wherein, R 2 is selected from pyrazolyl and imidazolyl, wherein said pyrazolyl or imidazolyl is optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl.
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, R 2 is 3,5-di(C 1 -C 6 )alkyl-pyrazol-4-yl or 3,5-di(C 1 -C 6 )alkyl-imidazol-4-yl.
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, R 2 is selected from 3,5-di(C 1 -C 6 )alkyl-pyrazol-4-yl and 3,5-di(C 1 -C 6 )alkyl-imidazol-4-yl, wherein said 3,5-di(C 1 -C 6 )alkyl-pyrazol-4-yl or 3,5-di(C 1 -C 6 )alkyl-imidazol-4-yl contains a nitrogen ring atom substituted by a substituent selected from -L-PO(OH) 2.
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A is C-R 3 and R 3 is selected from hydrogen, halogen, hydroxy, cyano, -NR c R d , (C 1 -C 6 )alkyl, (C 1 - C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7-membered heterocycloalkyl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7- membered heterocycloalkyl is optionally substituted with one or more substituent
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, B is C-R 3 and R 3 is selected from hydrogen, halogen, hydroxy, cyano, -NR c R d , (C 1 -C 6 )alkyl, (C 1 - C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7-membered heterocycloalkyl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7- membered heterocycloalkyl is optionally substituted with one or more substituent
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A is N, two of B, D and E are CH and one of B, D and E is C-R 3 wherein R 3 is independently selected from hydrogen, halogen, cyano, -NR c R d , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7-membered heterocycloalkyl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 - C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7-membered hetero
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, B is N, two of A, D and E are CH and one of A, D and E is C-R 3 , wherein R 3 is selected from hydrogen, halogen, cyano -NR c R d , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 - C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7-membered heterocycloalkyl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 - C 7 )cycloalkoxy, phenyl, phenoxy, 5-6-membered heteroaryl, and 4-7-membered hetero
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, X, Y, Z and V are independently selected from CH and C(R 4 ). In one embodiment, the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, X is N, Y is C(R 4 ) and V and Z are CH.
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A, B, D and E are each independently selected from N or C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C(R 4 ); R 1 is selected from -CHR 5 R 6 , and wherein R 5 and R 6 each independently represent (C 3 - C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl wherein said (C 3 -C 7 )cycloalkyl and (C 3 - C 7 )cycloalkyl(C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C 1 -C 4 )alkyl; R 2 is selected from the group consisting of 5- or 6-membered heteroaryl, wherein said 5-or 6- membered heteroaryl is optionally
  • the invention relates to a compound of formula (I), (Ia) or (Ib) above wherein, R 3 is tetrahydropyran-4-yl.
  • the invention relates to a compound of formula (I), (Ia) or (Ib) wherein, A, B, D and E are each independently selected from N or C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C(R 4 ); R 1 is selected from -CHR 5 R 6 , and wherein R 5 and R 6 each independently represent (C 3 - C 7 )cycloalkyl or (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl wherein said (C 3 -C 7 )cycloalkyl and (C 3 - C 7 )cycloalkyl(C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C
  • the invention relates to a compound of formula (I), (Ia) or (Ib) above wherein, A and E are C- R 3 , wherein R 3 is fluoro and B and D are C-R 3 , wherein R 3 is hydrogen.
  • the compounds of general formula I have an (EC 50 ) value in an IL-8 release 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 cosolvent 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 formula (I), (Ia) and (Ib) includes all tautomers and all mixtures thereof.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number found in nature.
  • the present invention includes all suitable isotopic variations of the compounds of general Formula I.
  • different isotopic forms of hydrogen include 1 H, 2 H and 3 H
  • different isotopic forms of carbon include 12 C, 13 C and 14 C
  • different isotopic forms of nitrogen include 14 N and 15 N.
  • Enriching for deuterium (2H) may for example increase in vivo half-life or reduce dosage regiments, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically enriched compounds within general formula I can be prepared by conventional techniques well known to a person skilled in the art or by processes analogous to those described in the general procedures and examples herein using appropriate isotopically enriched reagents and/or intermediates. Some compounds have lower aqueous solubility which may affect the absorption and consequently the bioavailability of the compounds. Such compounds may advantageously be administered in the form of prodrugs improving the aqueous solubility of the parent compound.
  • prodrugs which, upon administration, are converted to their parent compounds may be less active in vitro compared to their parent compounds, but because of the improved aqueous solubility, facilitating the absorption and consequently the bioavailability of the parent compounds upon administration, such prodrugs have improved in vivo activity compared to their parent compounds.
  • Prodrugs of the compounds of formula (I) form part of the invention claimed. Solvates and hydrates form part of the invention claimed.
  • the compounds of the present invention may be useful for preventing, treating or ameliorating any of the following diseases: psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, lichen planus, lupus nephritis, Sjögren’s syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides 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 pemph
  • 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, Sjögren’s syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides LN and DLE), multiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum, hidradenitis suppurativa, discoid lupus erythematosus, Papulopus
  • 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, Sjögren’s syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides 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 administer
  • 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 to 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.
  • the compounds of the present invention may also be useful for veterinary treatment of animals including mammals such as horses, cattle, sheep, pigs, dogs, and cats.
  • 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.
  • the compound may be administered one or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner.
  • a dosage unit of a formulation contain between 0.001 mg and 1000 mg, preferably between 0.01 mg and 300 mg of a compound of formula I.
  • a suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician.
  • the compound may be administered either orally, parenterally, topically, transdermally or intradermally and other routes according to different dosing schedules, e.g. daily, weekly or with monthly intervals. In general a single dose will be in the range from 0.001 to 400 mg/kg body weight.
  • 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.
  • formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier, semisolid 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 the form of discrete units as capsules, sachets, tablets, chewing gum or lozenges, each containing 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 compressing, 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 the 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 the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. Liposomal formulations 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 systems 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.
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of synthesis.
  • the compounds of the invention could for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art.
  • the organic solvents used were usually anhydrous.
  • the solvent ratios indicated refer to vol:vol unless otherwise noted.
  • Thin layer chromatography was performed using Merck 6OF254 silica-gel TLC plates. Visualisation of TLC plates was performed using UV light (254 nm) or by an appropriate staining technique. Proton nuclear magnetic resonance spectra were obtained at the stated frequencies in the solvents indicated. Tetramethylsilane was used as an internal standard for proton spectra. The value of a multiplet, either defined doublet (d), triplet (t), quartet (q) or (m) at the approximate midpoint is given unless a range is quoted. (br) indicates a broad peak, whilst (s) indicates a singlet.
  • LCMS Method 1 Column: Acquity UPLC HSS T31.8 ⁇ 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 Injection volume: 1 ⁇ l Gradient: UPLC (inlet method): XEV Metode 1 CM MS – method: Pos_50_1000 or Neg_50_1000 Instruments: Waters Acquity UPLC, Waters XEVO G2-XS QTof, Waters PDA (Photodiode Array).
  • Compounds of general formula (I) can be prepared, as shown in Scheme 1.
  • Compounds of general formula (Int 1) which are either commercially available or are synthesised, are coupled with amines of general formula (Int 2), which are either commercially available or synthesised, in the presence of a coupling reagent such as 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 solvent, such as DMF or MeCN to form compounds of formula (Int 3).
  • a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC
  • a base such as DIPEA or triethylamine
  • Compounds of general formula (Int 4) are coupled with diamines 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 solvent, such as DMF or MeCN to form compounds of formula (Int 6).
  • a coupling reagent such as HATU, HBTU, CDI, T3P, PyBOP, BOP, DCC or EDC
  • a base such as DIPEA or triethylamine
  • a suitable solvent such as DMF or MeCN
  • Compounds of formula (Int 7) can react with 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (PdCl2(dppf)), in the presence of an aqueous base, such as K 2 CO 3 or Na2CO3, in a suitable solvent, such as DMF or 1,4-dioxane to form compounds of formula (Int 8).
  • a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (PdCl2(dppf)
  • an aqueous base
  • Compounds of general formula (Int 15) can be synthesised as outlined in Scheme 3.
  • Compounds of general formula (Int 11) which are either commercially available or can be synthesised according to methods known to those skilled in the art, can be reacted with an appropriate 1,3-diketone to give compounds of general formula (Int 12).
  • a compound of general formula (Int 11) can be reacted with an appropriate 1,3- diketone in the presence of a suitable base, such as K 2 CO 3 or Cs 2 CO 3 , in a suitable solvent, such as DMF or DMSO, at an elevated temperature, for example 50-100°C.
  • a suitable base such as K 2 CO 3 or Cs 2 CO 3
  • a suitable solvent such as DMF or DMSO
  • Compounds of general formula (Int 13) can be prepared by reaction of compounds of general formula (Int 12) with hydrazine hydrate in a suitable solvent, such as EtOH, at an appropriate temperature, for example from room temperature to 80°C.
  • the compounds of formula (Int 14) can be synthesised by methods known to those skilled in the art using, for example, SEM chloride or Boc anhydride, to give compounds of general formula (Int 14). Reduction of the nitro group in compounds of general formula (Int 14) can be carried out by many methods known to those skilled in the art to give anilines of general formula (Int 15). For example, by catalytic hydrogenation, using a suitable catalyst, such as Pd on carbon, in a suitable solvent, such as EtOAc, MeOH or EtOH, under a suitable pressure of hydrogen.
  • Scheme 4 Preparation of compounds of formula (Int 21), wherein R 5 and R 6 are as previously defined and Q is a suitable halogen:
  • Compounds of general formula (Int 20) can be prepared by the addition of Grignard reagents (Int 19), which are either commercially available or can be synthesised, in the presence of copper iodide, to compounds of general formula (Int 18) in suitable solvents at a suitable temperature such as THF at a temperature of -78°C.
  • Compounds of general formula (Int 20) can be hydrolysed with an appropriate base such as LiOH, KOH or NaOH in a suitable solvent such as MeOH, EtOH or THF, to give compounds of general formula (Int 21).
  • reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, eluting with 5% EtOAc in petroleum ether) to give the title compound (1.8 g, 40% yield) as a yellow solid.
  • Preparation 9 4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]aniline 10% Pd/C (188 mg) was added to a solution of the compound of Preparation 8 (1.88 g, 5.41 mmol) in MeOH (30 mL) and placed under hydrogen at atmospheric pressure. After 1 hour the catalyst was filtered off, washing with MeOH, and the filtrate was concentrated in vacuo to give the title compound (1.67 g, 97%) as a colourless solid.
  • Preparation 10 tert-butyl 4-[4-[[2-(dicyclopropylmethyl)-3-ethoxy-3-oxo- propanoyl]amino]phenyl]-3,5-dimethyl-pyrazole-1-carboxylate HATU (188 mg, 0.494 mmol) was added to a solution of the compound of Preparation 3 (112 mg, 0.494 mmol), the compound of Preparation 7 (142 mg, 0.494 mmol) and DIPEA (0.258 mL, 1.48 mmol) in MeCN (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo.
  • HATU (18.7 mg, 0.049 mmol) was added to a solution of the compound of Preparation 11 (40 mg, 0.049 mmol), benzene-1,2-diamine (10.6 mg, 0.098 mmol) and DIPEA (0.051 mL, 0.295 mmol) in DMF (1 mL) and stirred at room temperature for 18 hours.
  • the reaction mixture was filtered through a PTFE filter, then purified directly by prep. acidic HPLC to afford the title compound (16.1 mg, 71% yield).
  • LCMS (Method 2) (ES): m/z 458.3 [M+H] + , RT 0.70 min.
  • Preparation 15 N-(2-amino-3-methyl-phenyl)-2-(dicyclopropylmethyl)-N'-[4-(3,5-dimethyl- 1H-pyrazol-4-yl)phenyl]propanediamide.
  • the product of Preparation 11 (18 mg, 0.022 mmol) was reacted with 3-methylbenzene-1,2-diamine (5.4 mg, 0.044 mmol) to afford the title compound after prep. acidic HPLC (10 mg, assume 100% yield).
  • LCMS (METHOD 2) (ES): m/z 472.3 [M+H] + , RT 0.74 min.
  • Preparation 16 N-(2-amino-4-fluoro-phenyl)-2-(dicyclopropylmethyl)-N'-[4-(3,5-dimethyl-1H- pyrazol-4-yl)phenyl]propanediamide.
  • the product of Preparation 11 (18 mg, 0.022 mmol) was reacted with 4-fluorobenzene-1,2-diamine (5.6 mg, 0.044 mmol) to afford the title compound after prep. acidic HPLC (10 mg, assume 100% yield).
  • LCMS (METHOD 2) (ES): m/z 476.2 [M+H] + , RT 0.72 min.
  • Preparation 17 N-(2-amino-4-bromo-phenyl)-2-(dicyclopropylmethyl)-N'-[4-(3,5-dimethyl- 1H-pyrazol-4-yl)phenyl]propanediamide.
  • the product of Preparation 11 38 mg, 0.046 mmol
  • 4-bromobenzene-1,2-diamine 17.5 mg, 0.093 mmol
  • acidic HPLC 25 mg, assume 100% yield.
  • LCMS (METHOD 2) (ES): m/z 538.2 [M+H] + , RT 0.78 min.
  • Preparation 18 N-(2-amino-3-pyridyl)-2-(dicyclopropylmethyl)-N'-[4-(3,5-dimethyl-1H- pyrazol-4-yl)phenyl]propanediamide.
  • the product of Preparation 11 23 mg, 0.028 mmol
  • pyridine-2,3-diamine 6.1 mg, 0.056 mmol
  • acidic HPLC 13 mg, assume 100% yield.
  • LCMS (METHOD 2) (ES): m/z 459.2 [M+H] + , RT 0.56 min.
  • Preparation 19 N-(2-amino-4-fluoro-phenyl)-2-(dicyclopropylmethyl)-N'-[4-(3,5-dimethyl-1H- pyrazol-4-yl)phenyl]propanediamide.
  • the product of Preparation 11 (18 mg, 0.022 mmol) was reacted with 3-fluorobenzene-1,2-diamine (5.6 mg, 0.044 mmol) to afford the title compound after prep. acidic HPLC (10 mg, assume 100% yield).
  • LCMS (METHOD 2) (ES): m/z 476.2 [M+H] + , RT 0.73 min.
  • Preparation 20 N-(2-amino-4-methyl-phenyl)-2-(dicyclopropylmethyl)-N'-[4-(3,5-dimethyl- 1H-pyrazol-4-yl)phenyl]propanediamide.
  • the product of Preparation 11 (18 mg, 0.022 mmol) was reacted with 4-methylbenzene-1,2-diamine (5.4 mg, 0.044 mmol) to afford the title compound after prep. acidic HPLC (10 mg, assume 100% yield).
  • LCMS (METHOD 2) (ES): m/z 472.3 [M+H] + , RT 0.73 min.
  • Preparation 21 N-(2-amino-4-bromo-phenyl)-2-(dicyclopropylmethyl)-N'-[4-[3,5-dimethyl-1- (2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanediamide.
  • the product of Preparation 13 50 mg, 0.10 mmol
  • 4-bromobenzene-1,2-diamine 37.6 mg, 0.20 mmol
  • acidic HPLC 67 mg, assume 100% yield.
  • LCMS (METHOD 2) (ES): m/z 668.2 [M+H] + , RT 1.01 min.
  • Preparation 22 2-(6-bromo-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-[3,5-dimethyl-1-(2- trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanamide.
  • the compound of Preparation 21 (67 mg, 0.1 mmol) was dissolved in acetic acid (2 mL) and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was purified directly by acidic prep. HPLC to afford the title compound (45 mg, 69% yield).
  • Preparation 24 3,3-dicyclopropyl-N-[4-[3,5-dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol- 4-yl]phenyl]-2-(6-tetrahydropyran-4-yl-1H-benzimidazol-2-yl)propanamide.
  • 10% Pd/C (5 mg, 0.0047 mmol) was added to a solution of the compound of Preparation 23 (17.0 mg, 0.067 mmol) in EtOH (3.5 mL) and the reaction mixture was degassed with nitrogen for 10 minutes.
  • Triethylsilane (0.03 ml, 0.184 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours.
  • Preparation 29 2-(6-bromo-7-fluoro-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propanamide.
  • the compound of Preparation 28 (95 mg, 0.14 mmol) was dissolved in acetic acid (5 mL) and the reaction mixture was stirred at 90°C for 6 hours. The reaction mixture was purified directly by acidic prep. HPLC to afford the title compound (90 mg, 79% yield).
  • Preparation 30 2-(6-cyano-7-fluoro-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propenamide.
  • the compound of Preparation 29 (22 mg, 0.034 mmol), zinc cyanide (7.8 mg, 0.066 mmol), davephos (3.9 mg, 0.0099 mmol) and tris(dibenzylideneacetone)dipalladium (9.1 mg, 0.0099 mmol) were dissolved in DMF (1.5 mL) under nitrogen and heated to 80°C for 18 hours.
  • Preparation 32 2-(5-bromo-7-fluoro-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propenamide.
  • the compound of Preparation 31 (103 mg, 0.15 mmol) was dissolved in acetic acid (5 mL) and the reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was purified directly by acidic prep. HPLC to afford the title compound (64 mg, 64% yield).
  • Preparation 33 2-(5-cyano-7-fluoro-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propenamide.
  • the compound of Preparation 32 22 mg, 0.034 mmol
  • zinc cyanide 4.7 mg, 0.040 mmol
  • tetrakis(triphenylphosphine) palladium 3.9 mg, 0.0034 mmol
  • the reaction mixture was filtered through a PTFE filter and purified directly by acidic prep.
  • Preparation 35 2-(4-bromo-7-fluoro-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-[3,5- dimethyl-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]phenyl]propenamide.
  • the compound of Preparation 34 (67 mg, 0.17 mmol) was dissolved in acetic acid (5 mL) and the reaction mixture was stirred at 90°C for 18 hours and 110°C for another 2 hours. The reaction mixture was purified directly by acidic prep. HPLC to afford the title compound (75 mg, 66% yield).
  • Example 2 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(7-methyl-1H- benzimidazol-2-yl)propanamide. According to the method of Example 1 the product of Preparation 15 (10 mg, 0.022 mmol) was reacted to afford the title compound after prep. acidic HPLC (6.4 mg, 64% yield).
  • Example 3 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(6-fluoro-1H- benzimidazol-2-yl)propanamide.
  • the product of Preparation 16 (10.5 mg, 0.022 mmol) was reacted to afford the title compound after prep. acidic HPLC (3.7 mg, 37% yield).
  • Example 4 2-(6-bromo-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H- pyrazol-4-yl)phenyl]propanamide. According to the method of Example 1 the product of Preparation 17 (25 mg, 0.046 mmol) was reacted to afford the title compound after prep. acidic HPLC (16.5 mg, 68% yield).
  • Example 5 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(3H-imidazo[4,5- b]pyridin-2-yl)propanamide. According to the method of Example 1 the product of Preparation 18 (13 mg, 0.028 mmol) was reacted to afford the title compound after prep. acidic HPLC (2.8 mg, 23% yield).
  • Example 6 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(7-fluoro-1H- benzimidazol-2-yl)propanamide. According to the method of Example 1 the product of Preparation 19 (10.5 mg, 0.022 mmol) was reacted to afford the title compound after prep. acidic HPLC (5.8 mg, 58% yield).
  • Example 7 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(6-methyl-1H- benzimidazol-2-yl)propanamide.
  • the product of Preparation 19 (10 mg, 0.022 mmol) was reacted to afford the title compound after prep. acidic HPLC (6.0 mg, 60% yield).
  • Example 8 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(6- tetrahydropyran-4-yl-1H-benzimidazol-2-yl)propanamide.
  • Example 9 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(3H-imidazo[4,5- c]pyridin-2-yl)propanamide.
  • the compound of Preparation 25 (11.9 mg, 0.022 mmol) was dissolved in acetic acid (2 mL) and the reaction mixture was stirred at 140°C for 18 hours. The reaction mixture was purified directly by acidic prep. HPLC to afford the title compound (1.9 mg, 19% yield).
  • Example 10 3,3-dicyclopropyl-N-[4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-(7-hydroxy-1H- benzimidazol-2-yl)propanamide. According to the method of Example 8 the product of Preparation 27 (23 mg, 0.04 mmol) was reacted to afford the title compound after prep. acidic HPLC (10.0 mg, 54% yield).
  • Example 11 2-(6-bromo-7-fluoro-1H-benzimidazol-2-yl)-3,3-dicyclopropyl-N-[4-(3,5- dimethyl-1H-pyrazol-4-yl)phenyl]propenamide.
  • the product of Preparation 29 (6.0 mg, 0.009 mmol) was reacted to afford the title compound after prep. acidic HPLC (3.7 mg, 77% yield).
  • Example 24 IL-8 release assay in human epithelial keratinocytes adult (HEKa) Keratinocytes were seeded at 3500 cells/well in 384-well ViewPlates (Perkin Elmer) in Epilife medium (Thermo Fisher) containing human keratinocyte growth supplement (HKGS) without hydrocortisone and incubated in a humid incubator at 37°C, 5% CO 2 , overnight. The following day growth medium was removed and 25 ⁇ l fresh Epilife medium was added. 75 nL test compound in 100% DMSO was added into each well reserved for test compounds, by the use of acoustic pipetting.
  • HEKa human epithelial keratinocytes adult
  • HKGS human keratinocyte growth supplement
  • Cells were incubated for 68-72 hours in the incubator.
  • IL-8 released from the cells was measured by the use of a commercial homogenous time-resolved fluorescence (HTRF) assay (CisBio). 2 ⁇ L cell culture supernatant was transferred to a 384-well Proxiplate. 5 ⁇ L HTRF reagent was added and the plates were incubated sealed in the dark for 3-22 hours at room temperature.
  • HTRF time-resolved fluorescence
  • Time-resolved fluorescence was read at 665 vs 620 nm, with excitation at 320 nm, and IL-8 levels were calculated as percent of controls. Reduction of the amount of secreted IL-8 indicates decreased IL-17 signaling. Concentration response curves were fitted by the use of a four-parameter logistic equation. Relative IC50 and Emax were reported from curves showing acceptable fit (r2>0.9). Cytotoxicity was measured in the cell-containing Viewplates 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 535 nm). Fluorescence was directly proportional to the amount of metabolic activity.
  • Embodiment 1 A Compound having the formula (I) wherein A, B, D and E are independently selected from N or C-R 3 ; X, Y, Z and V are each independently selected from N, CH and C(R 4 ); R 1 is selected from the group consisting of -CHR 5 R 6 , (C 3 -C 10 )cycloalkyl and G, wherein said (C 3 - C 10 )cycloalkyl and G are optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 -C 4 )alkyl; G is R 5 and R 6 each independently represent hydrogen, phenyl, (C 1 -C 6 )alky
  • Embodiment 2 The compound according to embodiment 1 having the formula (Ia) wherein A, B, D, E, X, Y, Z, V, R 1 and R 2 are as defined in embodiment 1 or pharmaceutically acceptable salts, hydrates and solvates thereof.
  • Embodiment 3. The compound according to embodiment 1 having the formula (Ib) ( ) wherein A, B, D, E, X, Y, Z, V, R 1 and R 2 are as defined in claim 1 or pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R 1 is selected from -CHR 5 R 6 , and wherein R 5 and R 6 each independently represent hydrogen, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, wherein said phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, methyl or ethyl, is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C 1 -C 4 )alkyl; with the proviso that at least one of R 5 and R 6 are different from hydrogen.
  • Embodiment 5 The compound according to any one of embodiments 1-3, wherein R 1 is - CHR 5 R 6 wherein R 5 and R 6 each independently represent (C 3 -C 7 )cycloalkyl, or (C 3 - C 7 )cycloalkyl(C 1 -C 6 )alkyl wherein said (C 3 -C 7 )cycloalkyl and C 7 )cycloalkyl(C 1 -C 6 )alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C 1 -C 4 )alkyl.
  • R 1 is selected from cyclohexyl, cycloheptyl, cyclooctanyl, adamantyl, spiro[2.3]hexanyl, bicyclo[3,1,0]hexanyl, bicyclo[4,1,0]heptanyl, bicyclo[2,2,2]octanyl or spiro[2.5]octanyl, wherein said cyclohexyl, cycloheptyl, cyclooctanyl, adamantyl, spiro[2.3]hexanyl, bicyclo[3,1,0]hexanyl, bicyclo[4,1,0]heptanyl, bicyclo[2,2,2]octanyl or spiro[2.5]octanyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and
  • R 1 is selected from G, wherein G is wherein said G is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 -C 4 )alkyl.
  • R 1 is selected from G
  • G is wherein said G is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 -C 4 )alkyl.
  • R 1 is (C 3 -C 7 )cycloalkyl, wherein said (C 3 -C 7 )cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 - C 4 )alkyl; or R 1 is -CHR 5 R 6 wherein R 5 and R 6 each independently are (C 3 -C 7 )cycloalkyl, or (C 3 - C 7 )cycloalkyl(C 1 -C 6 )alkyl, wherein said (C 3 -C 7 )cycloalkyl and (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl are optionally substituted with one or more substituents independently selected from halogen, cyano, and (C 1 -C 4 )alkyl; with the proviso
  • Embodiment 9 The compound according to embodiment 8, wherein R 1 is (C 3 -C 7 )cycloalkyl wherein said (C 3 -C 7 )cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 -C 4 )alkyl.
  • Embodiment 10 The compound according to embodiment 9 wherein R 1 is cyclohexyl substituted with one or more substituents selected from (C 1 -C 4 )alkyl.
  • Embodiment 11 The compound according to embodiment 8, wherein R 1 is (C 3 -C 7 )cycloalkyl wherein said (C 3 -C 7 )cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, (C 1 -C 4 )alkyl and halo(C 1 -C 4 )al
  • R 1 is -CHR 5 R 6, and wherein R 5 and R 6 each independently are (C 3 -C 4 )cycloalkyl-(C 1 -C 2 )alkyl, wherein said (C 3 - C 4 )cycloalkyl-(C 1 -C 2 )alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C 1 -C 4 )alkyl.
  • R 5 and R 6 each independently are (C 3 -C 4 )cycloalkyl-(C 1 -C 2 )alkyl, wherein said (C 3 - C 4 )cycloalkyl-(C 1 -C 2 )alkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, and (C 1 -C 4 )alkyl.
  • R 2 is selected from pyrazol-4-yl or imidazol-4-yl, wherein said pyrazol-4-yl or imidazol-4-yl contains a nitrogen ring atom substituted by a substituent selected from -L-PO(OH)2 and the other ring atoms of said pyrazol-4-yl or imidazole-4-yl are substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl.
  • R 2 is selected from pyrazol-4-yl or imidazol-4-yl, wherein said pyrazol-4-yl or imidazol-4-yl contains a nitrogen ring atom substituted by a substituent selected from -L-PO(OH)2 and the other ring atoms of said pyrazol-4-yl or imidazole-4-yl are substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl.
  • Embodiment 19
  • Embodiment 30 The compound according to any one of embodiments 1-29, wherein A is C-R 3 , B is C-R 3 , D is C-R 3 and E is C-R 3 .
  • Embodiment 31 The compound according to any one of embodiments 1-29, wherein A is N, B is C-R 3 , D is C-R 3 and E is C-R 3 .
  • Embodiment 32 The compound according to any one of embodiments 1-29, wherein A is C-R 3 , B is N, D is C-R 3 , and E is C-R 3 .
  • Embodiment 33 The compound according to any one of embodiments 1-29, wherein A is N, B is C-R 3 , D is N, and E is C-R 3 .
  • Embodiment 34 The compound according to any one of embodiments 1-29, wherein A is N, B is N, D is C-R 3 , and E is C-R 3 .
  • Embodiment 35 The compound according to any one of embodiments 1-29, wherein A is N, B is C-R 3 , E is N, and D is C-R 3 .
  • Embodiment 36 The compound according to any one of embodiments 1-29, wherein A is C-R 3 , B is N, E is C-R 3 , and D is N.
  • Embodiment 37 The compound according to any one of embodiments 1-29, wherein A is C-R 3 , B is N, E is C-R 3 , and D is N.
  • R 3 is selected from hydrogen, halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy and 4-7-membered heterocycloalkyl.
  • R 3 is selected from hydrogen, halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 - C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy and 4-7-membered heterocycloalkyl.
  • Embodiment 38 The compound according to any one of embodiments 1-36 wherein each R 3 is hydrogen.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023025783A1 (fr) 2021-08-23 2023-03-02 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023111181A1 (fr) 2021-12-16 2023-06-22 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17

Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121103A1 (fr) * 2004-06-08 2005-12-22 Boehringer Ingelheim International Gmbh Benzimidazoles, procede de production et d'utilisation desdits benzimidazoles en tant que medicaments
WO2013116682A1 (fr) 2012-02-02 2013-08-08 Ensemble Therapeutics Corporation Composés macrocycliques pour une modulation d'il-17
WO2014066726A2 (fr) 2012-10-26 2014-05-01 Ensemble Therapeutics Corporation Composés pour la modulation d'il-17
WO2018229079A1 (fr) 2017-06-14 2018-12-20 Ucb Biopharma Sprl Indolines spirocycliques utilisées comme modulateurs d'il-17
WO2019138017A1 (fr) 2018-01-15 2019-07-18 Ucb Biopharma Sprl Dérivés d'imidazole fusionnés utilisés en tant qu'inhibiteurs d'il-17
WO2019223718A1 (fr) 2018-05-22 2019-11-28 成都先导药物开发股份有限公司 Immunomodulateur
WO2020011731A1 (fr) 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2020120140A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés de benzimidazolone, et analogues de ceux-ci, en tant que modulateurs d'il-17
WO2020120141A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés d'amine fonctionnalisés utiles en tant que modulateurs d'il-17
WO2020146194A1 (fr) 2019-01-07 2020-07-16 Eli Lilly And Company Inhibiteurs imidazo [1,2-b]pyridazine il-17 a
WO2020260425A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
WO2020261141A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazopyridine en tant que modulateurs d'il-17
WO2020260426A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
CN112341450A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341446A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341440A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341519A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341439A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341435A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341441A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341429A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂的中间体化合物
CN112341451A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341442A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121103A1 (fr) * 2004-06-08 2005-12-22 Boehringer Ingelheim International Gmbh Benzimidazoles, procede de production et d'utilisation desdits benzimidazoles en tant que medicaments
WO2013116682A1 (fr) 2012-02-02 2013-08-08 Ensemble Therapeutics Corporation Composés macrocycliques pour une modulation d'il-17
WO2014066726A2 (fr) 2012-10-26 2014-05-01 Ensemble Therapeutics Corporation Composés pour la modulation d'il-17
WO2018229079A1 (fr) 2017-06-14 2018-12-20 Ucb Biopharma Sprl Indolines spirocycliques utilisées comme modulateurs d'il-17
WO2019138017A1 (fr) 2018-01-15 2019-07-18 Ucb Biopharma Sprl Dérivés d'imidazole fusionnés utilisés en tant qu'inhibiteurs d'il-17
WO2019223718A1 (fr) 2018-05-22 2019-11-28 成都先导药物开发股份有限公司 Immunomodulateur
WO2020011731A1 (fr) 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2020120140A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés de benzimidazolone, et analogues de ceux-ci, en tant que modulateurs d'il-17
WO2020120141A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés d'amine fonctionnalisés utiles en tant que modulateurs d'il-17
WO2020146194A1 (fr) 2019-01-07 2020-07-16 Eli Lilly And Company Inhibiteurs imidazo [1,2-b]pyridazine il-17 a
WO2020260425A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
WO2020261141A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazopyridine en tant que modulateurs d'il-17
WO2020260426A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
CN112341450A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341446A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341440A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341519A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341439A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341435A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341441A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341429A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂的中间体化合物
CN112341451A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂
CN112341442A (zh) 2019-08-09 2021-02-09 成都先导药物开发股份有限公司 一种免疫调节剂

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Goodman & Gilman's The Pharmacological Basis of Therapeutics", 1995, MCGRAW-HILL
"Remington, The Science and Practice of Pharmacy", 2005
AMATYA, N ET AL., TRENDS IN IMMUNOLOGY, vol. 38, 2017, pages 310 - 322
BERGE, S.M, J. PHARM. SCI., vol. 66, no. 1, 1977, pages 1 - 19
GAFFEN, S.L. ET AL., NAT REV IMMUNOL., vol. 14, 2014, pages 585 - 600
LESLIE DAKIN: "Hit Identification, binding site elucidation and structure guided design of novel macrocyclic IL-17A antagonists", SWISS COURSE ON MEDICINAL CHEMISTRY, 9 October 2016 (2016-10-09)
MONIN, L.GAFFEN, S.L., COLD SPRING HARB. PERSPECT. BIOL., vol. 10, 2018
ONISHI, R.MGAFFEN, S.L, IMMUNOLOGY, vol. 129, 2010, pages 311 - 321
STAHL, P.H.WERMUTH, C.G: "Handbook of Pharmaceutical Salts, Properties, Selection and Use", 2011, WILEY-VCH
W. AMAREGOC. CHAIBUTTERWORTH-HEINEMANN: "Purification of Laboratory Chemicals", 2009

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023025783A1 (fr) 2021-08-23 2023-03-02 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023111181A1 (fr) 2021-12-16 2023-06-22 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17

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