WO2021204626A1 - Composés hétéroaryle substitués par aryle et hétéroaryle-carboxamide utiles en tant qu'inhibiteurs de tyk2 - Google Patents

Composés hétéroaryle substitués par aryle et hétéroaryle-carboxamide utiles en tant qu'inhibiteurs de tyk2 Download PDF

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WO2021204626A1
WO2021204626A1 PCT/EP2021/058465 EP2021058465W WO2021204626A1 WO 2021204626 A1 WO2021204626 A1 WO 2021204626A1 EP 2021058465 W EP2021058465 W EP 2021058465W WO 2021204626 A1 WO2021204626 A1 WO 2021204626A1
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amino
group
methyl
carboxamide
methoxy
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PCT/EP2021/058465
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Carlos Puig Duran
Elena Gomez Castillo
Juan Francisco Caturla Javaloyes
Lluis Miquel Pages Santacana
Montserrat Erra Sola
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Almirall, S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention deals with compounds and methods able to inhibit the TYK2 receptor by binding to its pseudokinase domain and with pharmaceutical formulations of such compounds useful in the treatment of related disorders.
  • Protein kinases constitute a very relevant and large family of enzymes responsible for several transduction processes within the cells. The main function of such enzymes is to transfer phosphate groups from ATP to specific substrates of very broad nature: carbohydrates, proteins or lipids. Protein kinases direct phosphorylation processes towards threonine, serine, tyrosine and other amino acid residues present in the structure of the proteins. Such phosphorylation results in a functional change of the target protein giving rise to a modification of enzymatic activity, cellular location or modification of its signalling pathway. A huge sub-family of the protein kinases includes tyrosine kinases, those kinases able to phosphorylate tyrosine residues of different proteins.
  • the receptor-associated tyrosine kinases include a tyrosine-kinase domain recruited to a receptor and are involved in a number of signalling cascades (cytokine signalling, growth hormone and others).
  • the Janus kinase (JAK) family belongs to the later family and catalyses the phosphorylation of STAT proteins through a complex structure known as the JAK-STAT signalling pathway. This structure includes the cytokine receptor, the associated JAK proteins and the STAT protein able, once activated by phosphorylation/dimerization, to translocate into the cell nucleus and to induce transcription of target genes.
  • the JAK family members are JAK1, JAK2, JAK3 and TYK2, which are associated to different cytokine receptors and catalyse the phosphorylation of the different STAT family members.
  • Seven different STAT members STAT members (ST ATI, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6) have been described (Shuai, 2006).
  • the binding of cytokines (such as interleukins or interferons) to its corresponding receptors causes the receptors dimerization and further phosphorylation through the JAK proteins. STAT then binds to the phosphorylated receptors and are in turn phosphorylated by JAKs.
  • JAK JAK1-receptor complexes
  • TYK2 pairs with JAK2 and interact with IL-12 and IL-23 cytokine receptors that are associated with Thl and Thl7 differentiation, respectively (Minegishi, 2006) and with JAK1 for type I interferons.
  • JAK1 JAK1 for type I interferons.
  • inhibitors for this kinase may exert selective inhibitory effects on the mentioned cytokines signaling without broad-based immunosuppression.
  • PI 104A substitution of a highly conserved proline with an alanine at position 1104 in the kinase domain of the TYK2 protein
  • PI 104A substitution of a highly conserved proline with an alanine at position 1104 in the kinase domain of the TYK2 protein
  • Homozygous individuals show impaired responses to type I IFN, IL-12 and IL-23 and was not associated with increased viral or mycobacterium infections (Dendrou, 2016).
  • the structure of the JAK family includes several homology regions being the most significant the JH1 or kinase domain, which accommodates the ATP substrate and catalyses the phosphate transferences. There is also a JH2 or pseudokinase domain, structurally similar to the JH1 domain and essential for normal kinase activity, but lacking enzymatic activity.
  • the pseudokinase domain is involved in the regulation of the kinase or catalytic domain and presents lower sequence homology among the different JAK proteins.
  • TYK2 has a key role on the activation of this axis by transduction of the signals of IL12, IL23 and IFNa.
  • the inhibition of TYK2 shows thus a great potential in the management of psoriasis and other autoimmune diseases like Crohn’s disease, Rheumatoid Arthritis or Lupus Erythematosus.
  • JAK inhibitors have been introduced as therapeutic agents but most of them lack isoform selectivity and, in addition to TYK2, inhibit other family kinases as JAK1. Such promiscuity could give raise to unwanted side effects that could be potentially avoided by use of TYK2 selective inhibitors.
  • a carboxamide substituted derivative which carboxamide substituted derivative is a compound of Formula (I), or a pharmaceutically acceptable salt, or a solvate, or a /V-oxidc, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof: wherein:
  • R 1 is selected from the group consisting of a hydrogen atom, a linear or branched C 1-4 alkyl group, a linear or branched C 1-4 deuterioalkyl group and a monocyclic C 3-6 cycloalkyl group,
  • R 2 is selected from the group consisting of a phenyl group, a monocyclic C 5-7 cycloalkyl group or a monocyclic or bicyclic 5- to 9- membered heteroaryl group containing at least one heteroatom selected from O, N and S, wherein the phenyl, cycloalkyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched Ci- 4 alkyl group, a linear or branched C1-4 deuterio alkyl group, a linear or branched C1-4 alkoxy group, a cyano group, a -S(0) n CH 3 group, a linear or branched Ci-4haloalkyl group, a -P(0)(Ci- 4 alkyl) group, a linear or branched C1-3 haloalkoxy group, a linear or branched Ci-4hydroxyalky
  • R 4 is selected from the group consisting of a linear or branched Ci-4 alkyl group, linear or branched Ci-4 hydroxyalkyl group, a phenyl group, a -(CthVi-monocyclic C3-6 cycloalkyl group and a -(CH2V1- monocyclic 5- to 6- membered heterocyclyl group containing at least one heteroatom selected from the group consisting of O, N and S, wherein the phenyl, cycloalkyl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a linear or branched C 1-4 alkyl group, a hydroxyl group and a -(CthVi-monocyclic or bicyclic 5- to 6- membered heteroaryl group containing at least one heteroatom selected from the group consisting of O, N and S,
  • G 1 represents a phenyl group, a monocyclic or bicyclic 5- to 9- membered heteroaryl group containing at least one heteroatom selected from the group consisting of O, N and S or a monocyclic 5 -to 6-membered heterocyclyl group containing one heteroatom selected from O, N and S, wherein the phenyl, heteroaryl and heterocyclyl groups can be unsubstituted or substituted by one or more substituents selected from a linear or branched C1-4 alkyl group, a halogen atom, a cyano group, a hydroxyl group, an oxo group, a linear or branched C1-4 alkoxy group, a linear or branched C1-3 haloalkyl group, a linear or branched C1-3 haloalkoxy group, a linear or branched (C1-4 alkoxy)-(Ci-4 alkyl)- group, a -(CH 2 ) O-I C(0)NHCH 3 group
  • W represents a nitrogen atom or a CH group
  • R a and R d each independently represent a hydroxyl group, a linear or branched C1-3 alkoxy group and a 5- to 6- membered heterocyclyl group containing at least one heteroatom selected from N, O and S,
  • R b and R c each independently represent a hydrogen atom or a linear or branched C 1-4 alkyl group
  • n an integrer selected from 0, 1 and 2.
  • the invention further provides synthetic processes and intermediates described herein, which are useful for preparing said carboxamide substituted derivatives.
  • the invention is also directed to a carboxamide substituted derivative of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the carboxamide substituted derivatives of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention is also directed to the carboxamide substituted derivatives of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Tyrosine kinase 2 (Tyk2), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder.
  • Tyk2 Tyrosine kinase 2
  • the pathological condition or disease is selected from plaque psoriasis, scalp psoriasis, genital psoriasis, pustular psoriasis, psoriatic erythroderma, acrodermatitis continua, pityriasis rubra pilaris, lichen planus, hidradenitis suppurativa, bullous pemphigoid, pyoderma gangrenousm (PASH), ichthyosis, atopic dermatitis, psoriatic arthritis, ankylosing spondylitis, systemic sclerosis, primary biliary cholangitis, asthma and human multiple myeloma.
  • the invention is also directed to use of the carboxamide substituted derivatives of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Tyrosine Kinase 2 (Tyk2), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder.
  • Tyk2 Tyrosine Kinase 2
  • the pathological condition or disease is selected from plaque psoriasis, scalp psoriasis, genital psoriasis, pustular psoriasis, psoriatic erythroderma, acrodermatitis continua, pityriasis rubra pilaris, lichen planus, hidradenitis suppurativa, bullous pemphigoid, pyoderma gangrenousm (PASH), ichthyosis, atopic dermatitis, psoriatic arthritis, ankylosing spondylitis, systemic sclerosis, primary biliary cholangitis, asthma and human multiple myeloma.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Tyrosine Kinase 2 (Tyk2), in particular wherein the pathological condition or disease is selected from a dermatological disease, an inflammatory or autoimmune-mediated disease and a metabolism/endocrine function disorder.
  • Tyk2 Tyrosine Kinase 2
  • the pathological condition or disease is selected from plaque psoriasis, scalp psoriasis, genital psoriasis, pustular psoriasis, psoriatic erythroderma, acrodermatitis continua, pityriasis rubra pilaris, lichen planus, hidradenitis suppurativa, bullous pemphigoid, pyoderma gangrenousm (PASH), ichthyosis, atopic dermatitis, psoriatic arthritis, ankylosing spondylitis, systemic sclerosis, primary biliary cholangitis, asthma and human multiple myeloma.
  • the invention also provides a combination product comprising (i) the carboxamide substituted derivatives of the invention as described herein; and (ii) one or more additional active substances.
  • C1-4 alkyl embraces linear or branched radicals having 1 to 4 carbon atoms.
  • C1-2 alkyl embraces unsubstituted linear or branched radicals having 1 to 2 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl.
  • C1-4 deuterioalkyl embraces linear or branched radicals having 1 to 4 carbon atoms.
  • C1-2 deuterioalkyl embraces linear or branched radicals having 1 to 2 carbon atoms. Examples of such radicals include monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, trideuterioethyl, pentadeuteriopropyl and trideuteriobutyl.
  • C3-6 cycloalkyl embraces saturated monocyclic carbocyclic radicals having from 3 to 6 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cycobutyl, cyclopentyl and cyclohexyl.
  • a monocyclic C5-7 cycloalkyl group is a saturated monocyclic carbocyclic group having from 5 to 7 carbon atoms.
  • Examples of monocyclic C5-7 cycloalkyl groups include cyclopentyl, cyclohexyl and cycloheptyl.
  • monocyclic or bicyclic 5- to 9-membered heteroaryl group is a 5- to 9- membered ring system, comprising at least one heteoaromatic ring and containing at least one heteroatom selected from O, N and S.
  • a 5- to 9- membered heteroaryl radical may be a single ring (i.e monocyclic) or two fused rings wherein at least one ring contains a heteroatom.
  • a 5- to 6-membered heteroaryl group is a 5 to 6 membered heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
  • radicals examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, oxadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzimidazolyl, indazolyl, indolyl, benzotriazolyl, pyrrolopyridinyl, pyrazoloxazinyl, benzothiophenyl or benzofuranyl.
  • Such heteroaryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • a bicyclic group can contain one or two fused rings that form a fused bicyclic ring structure, whereby the two rings are linked by two adjacent atoms.
  • a bicyclic group can contain a bridged bicyclic ring structure, whereby the two rings are linked by two non-adjacent atomsAltematively, a bicyclic group can contain a spirocyclic bicyclic ring structure, whereby the two rings are connected through a single common atom.
  • C1-4 alkoxy (or alkyloxy) embraces a linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • alkoxy radicals include methoxy, ethoxy, n-propxy, i-propoxy, n-butoxy, sec-butoxy or t-butoxy.
  • C1-3 alkoxy (or alkyloxy) embraces a linear or branched oxy- containing radicals each having alkyl portions of 1 to 3 carbon atoms.
  • Ci-2 alkoxy embraces a linear or branched oxy-containing radicals having alkyl portion of 1 to
  • alkoxy radicals include methoxy, ethoxy, n-propxy or i-propoxy.
  • Ci-4 haloalkyl embraces a linear or branched alkyl group, which is substituted by one or more, preferably 1, 2 or 3 halogen atoms.
  • haloalkyl groups include CCb, CF 3 , CHF 2 , CH2CF3, CH2CHF2, CH2CHFCH3, CH2CH2CH2CI or CH2CH2CH2CHF2.
  • C1-3 haloalkyl embraces linear or branched alkyl groups, which are substituted by one or more, preferably 1, 2 or 3 halogen atoms.
  • C1-2 haloalkyl embraces linear or branched alkyl groups, which are substituted by one or more, preferably 1, 2 or 3 halogen atoms Examples of haloalkyl groups include CCb, CF3, CHF2, CH2CF3, CH2CHF2, CH2CHFCH3 or CH2CH2CH2CI.
  • C1-3 haloalkoxy embraces linear or branched alkoxyl groups in which one or more hydrogen radicals are replaced by a halo group.
  • haloalkoxy groups include trifluoromethoxy, bromomethoxy, 1,2-dichloroethoxy and 3-iodopropoxy.
  • Ci-4hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals.
  • C1-3 hydroxyakyl embraces linear or branched alkyl radicals having 1 to
  • C1-2 hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 2 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals.
  • examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2,3- dihydroxypropyl and l,3-dihydroxypropan-2-yl.
  • C1-4 alkylamino embraces amino groups which are substituted by one or more alkyl groups having 1 to 4 carbon atoms.
  • C1-2 alkylamino embraces amino groups which are substituted by one or more alkyl groups having 1 to 2 carbon atoms. Examples of such radicals include methylamine, dimethylamino, ethylamine, propylamine, methylpropylamine and butylamine.
  • (Ci- 6 alkoxy)-(Ci- 6 alkyl)- embraces linear or branched radicals having 1 to 6 carbon atoms substituted with a Ci- 6 alkoxy group.
  • the term (C1-4 alkoxy)- (C1-4 alkyl)- embraces linear or branched radicals having 1 to 4 carbon atoms substituted with a Ci- 4 alkoxy group and the term (C1-2 alkoxy)-(Ci-2 alkyl)- embraces linear or branched radicals having 1 to 2 carbon atoms substituted with a C1-2 alkoxy group.
  • radicals include methoxy-methyl, ethoxy-methyl, methoxy-ethyl, ethoxy-ethyl, methoxy-propyl, propoxy-methyl, ethoxy-propyl, propoxy-ethyl, propoxy-propyl, methoxy-butyl, ethoxy-butyl, methoxy-pentyl, ethoxy-pentyl and methoxy-hexyl.
  • monocyclic 5- to 7- membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C5-7 carbocyclic ring system in which one or more, for example, 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • radicals include piperinyl, pyrroldyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro-oxazolyl, l,3-dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl, azepanyl, 2-oxa-6-azaspiro[3.3]heptanyl or oxepanyl.
  • monocyclic 5- to 6- membered heterocyclic radical embraces typically a non-aromatic, saturated or unsaturated C5-6 carbocylic ring system in which one or more, for example, 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • Examples of 5- to 6- membered heterocyclyl radicals include piperinyl, pyrroldyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, 4,5-dihydro- oxazolyl, l,3-dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl.
  • halogen atom embraces fluorine, chlorine, bromine and iodine.
  • a halogen atom is typically a fluorine, chlorine or bromine atom.
  • halo when used as a prefix has the same meaning.
  • atoms, radicals, moieties, chains and cycles present in the general structures of the invention are “unsubstituted or substituted”. This means that these atoms, radicals, moieties, chains and cycles can be either unsubstituted or substituted in any position by one or more, for example 1, 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
  • Compounds containing one or more chiral centers may be used in enantiomerically or diastereomerically pure form, in the form of a racemic mixtures and in the form of mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers and stereoisomer-enriched mixtures.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20% and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. “Stereochemistry of Organic Compounds” by Ernest L. Eliel (Wiley, New York, 1994).
  • terapéuticaally effective amount refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • pathological condition or disease susceptible to amelioration by inhibiton of Tyk2 includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with an increased Tyk2 activity.
  • disease states include, but are not limited to, dermatological diseases, inflammatory or autoimmune-mediated diseases and a metabolism/endocrine function disorders.
  • salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • a N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • the carboxamide substituted derivatives of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules.
  • hydrate is employed when said solvent is water.
  • solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • the invention also includes isotopically-labelled carboxamide substituted derivatives of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 1 H and 3 H, carbon, such as U C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Preferred isotopically-labelled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium D or 2 H is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar
  • Isotopically-labelled carboxamide substituted derivatives of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.
  • tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond.
  • tautomerism The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.
  • deuterated derivatives embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015% molar.
  • Hydrogen deuterium exchange (deuterium incorporation)- is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
  • Prodrugs of the carboxamide substituted derivatives described herein are also within the scope of the invention.
  • certain derivatives of the carboxamide substituted derivatives of the present invention which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Biorev ersible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • R 1 is selected from the group consisting of a hydrogen atom, a methyl group or a trideuteriomethyl group.
  • R 1 represents a methyl group or a trideuteriomethyl group.
  • R 2 represents a phenyl group or a monocyclic or bicyclic 5- to 9- membered heteroaryl group containing at least one N atom, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear C1-2 alkyl group, a linear C1-2 deuterioalkyl group, a linear C1-2 haloalkyl group, a linear C1-2 alkoxy group, a - S(0)I- 2 CH 3 group, a halogen atom, a hydroxyl group, a linear C1-2 alkylamino group, a linear Ci-2 hydroxyalkyl group, a cyano group, a NHSO2CH3 group and a 5-membered heteroaryl group containing at least one N atom, said heteroaryl group being optionally substituted by a methyl group.
  • substituents selected from a linear C1-2 alkyl group, a linear C1-2 deuterioalkyl group, a linear
  • R 2 represents a phenyl group or an indolyl group wherein the phenyl and indolyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a hydroxyl group, a linear C1-2 hydroxyalkyl group and a triazolyl group optionally substituted by a methyl group.
  • n is an integer selected from 0, 1 and 2.
  • n 1 or 2.
  • R 3 represents a -C(0)-R 4 group.
  • R 4 is selected from the group consisting of a linear or branched Ci- 4 hydroxyalkyl group and a C 3-6 cycloalkyl group, wherein the cycloalkyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom and a hydroxyl group.
  • R 4 represents a cyclopropyl group unsubstituted or substituted by a fluorine atom.
  • R 3 represents a G 1 group.
  • G 1 represents a monocyclic 5- to 6- membered heteroaryl group containing at least one N atom, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents selected from the group consisting of a linear C 1-2 alkyl group, a cyano group, a linear or branched C 1-3 hydroxyalkyl group, a linear or branched (C 1-2 alkoxy)-(Ci- 2 alkyl)- group and a 6- membered heterocyclyl group containing at least one heteroatom selected from the group consisting of N and O, wherein the heterocyclyl group is optionally substituted by one or more substituents selected from a linear or branched (C 1-2 alkoxy)-(Ci- 2 alkyl)- group, a linear C 1-2 hydroxyalkyl group and a linear C 1-2 alkyl group.
  • substituents selected from the group consisting of a linear C 1-2 alkyl group, a cyano group,
  • G 1 represents a pyridine, a pyrimidine or a pyrazolyl group, wherein the pyridine, pyrimidine and pyrazolyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a methyl group, a linear or branched C 1-3 hydroxyalkyl group and a 6-membered heterocyclyl containing at least one heteroatom selected from the group consisting of N and O group, said heterocyclyl group being optionally substituted by one or more substituents selected from a methyl group, a hydroxyethyl group and a methoxyethyl group.
  • W is a CH group.
  • R 1 represents a hydrogen atom, a methyl group or a trideuteriomethyl group, preferably a methyl group or a trideuteriomethyl group,
  • R 2 represents a phenyl group or a monocyclic or bicyclic 5- to 9- membered heteroaryl group containing at least one N atom, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear C 1-2 alkyl group, a linear C 1-2 deuterioalkyl group, a linear C 1-2 haloalkyl group, a linear C 1-2 alkoxy group, a -S(0)I- 2 CH 3 group, a halogen atom, a hydroxyl group, a linear C 1-2 alkylamino group, a linear Ci- 2 hydroxyalkyl group, a cyano group, aNHSCkCHs group and a 5-membered heteroaryl group containing at least one N atom, said heteroaryl group being optionally substituted by a methyl group,
  • R 3 represents a -C(0)-R 4 group
  • R 4 is selected from the group consisting of a linear or branched C 1-4 hydroxy alkyl group and a C 3-6 cycloalkyl group, wherein the cycloalkyl group is unsubstituted or substituted by one or more substituents selected from a halogen atom and a hydroxyl group, and
  • R 1 represents a hydrogen atom, a methyl group or a trideuteriomethyl group, preferably a methyl group or a trideuteriomethyl group,
  • R 2 represents a phenyl group or a monocyclic or bicyclic 5- to 9- membered heteroaryl group containing at least one N atom, wherein the phenyl and heteroaryl groups are unsubstituted or substituted by one or more substituents selected from a linear C 1-2 alkyl group, a linear C 1-2 deuterioalkyl group, a linear C 1-2 haloalkyl group, a linear C 1-2 alkoxy group, a -S(0) I-2 CH 3 group, a halogen atom, a hydroxyl group, a linear C 1-2 alkylamino group, a linear Ci- 2 hydroxyalkyl group, a cyano group, aNHSCkCtb group and a 5-membered heteroaryl group containing at least one N atom, said heteroaryl group being optionally substituted by a methyl group,
  • R 3 represents a G 1 group
  • G 1 represents a monocyclic 5- to 6- membered heteroaryl group containing at least one N atom, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents selected from the group consisting of a linear C 1-2 alkyl group, a cyano group, a linear or branched C 1-3 hydroxyalkyl group, a linear or branched (C 1-2 alkoxy)- (C 1-2 alkyl)- group and a 6- membered heterocyclyl group containing at least one heteroatom selected from the group consisting of N and O, wherein the heterocyclyl group is optionally substituted by one or more substituents selected from a linear or branched (C 1-2 alkoxy)-(Ci- 2 alkyl)- group, a linear C 1-2 hydroxyalkyl group and a linear Ci - 2 alkyl group, and
  • W represents a CH group.
  • R 2 represents a phenyl group or an indolyl group, wherein the phenyl and indolyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a hydroxyl group, a linear C1-2 hydroxyalkyl group and a triazolyl group optionally substituted by a methyl group,
  • R 4 represents a cyclopropyl group unsubstituted or substituted by a fluorine atom
  • G 1 represents a pyridine, pyrimidine or a pyrazolyl group, wherein the pyridine, pyrimidine and pyrazolyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a methyl group, a linear or branched Ci- 3 hydroxyalkyl group or a 6-membered heterocyclyl containing at least one heteroatom selected from the group consisting of N and O group, optionally substituted by one or more substituents selected from a methyl group, a hydroxyethyl group and a methoxyethyl group.
  • R 1 represents a hydrogen atom, a methyl group, a trideuteriomethyl group or a cyclopropyl group
  • R 2 is selected from the group consisting of a phenyl group, a cyclohexyl group, a pyridinyl group, a benzimidazolyl group, an imidazolpyridinyl group, an indolyl group, a pyrrolopyridinyl group, a benzotriazolyl group, a pyrazolyl group and an indazolyl group, wherein the phenyl, pyridinyl, indolyl, pyrrolopyridinyl, benzotriazolyl, pyrazolyl, imidazolpyridinyl and benzimidazolyl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of a methyl group, a fluorine atom, a chlorine atom, a methoxy group, a cyano group, a -S(0)i- 2CH3 group, a trifluoromethyl group,
  • R 4 is selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, phenyl group, a -CH(CH3)2 group, a -C(CH3)3 group, a - C(CH 3 ) 2 0H group, a -(CH2)-morpholinyl group, a -(CH2)-cyclohexyl group and a - (CH 2 )I-2-OH group, wherein the cyclopropyl, cyclobutyl, phenyl and cyclohexyl groups are unsubstituted or substituted by one or more substituents selected from a fluorine atom, a methyl group, a hydroxyl group and a -(CH2)-triazole group,
  • G 1 is selected from the group consisting of a phenyl group, pyrazolyl group, pyridinyl group, a pyrimidinyl group, a pyridazinyl group, a indazolyl group, an imidazolyl group, a pyrazyl group, a triazolyl group, a tetrahydropyranyl group and a pyrazoloxazinyl group, wherein the phenyl, pyrazolyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazyl and triazolyl groups are unsubstituted or substituted by one or more substituents selected from a fluorine atom, methyl group, a methoxy group, a trifluoromethyl group, a -CH2CF3 group, a -OCH2CF3 group, a cyano group, an oxo group, a hydroxyl group, a methoxymethyl
  • W represents a nitrogen atom or a -CH group.
  • the R 2 and R 3 groups of formula I are unsubstituted or substituted by one, two, three or four substituents.
  • the substituents are the same.
  • the substituents are different.
  • the substituents can be present at the ortho, meta or para positions, preferably the ortho and meta positions.
  • Particular individual compounds of the invention include: 4-[(2-chloro-6-fluoro-benzoyl)amino]-6-(cyclopropanecarbonylamino)-N-methyl-pyridine-3- carboxamide
  • N-methylnicotinamide N-(2-(cyclopropanecarboxamido)-5-(methylcarbamoyl)pyridin-4-yl)-3-methoxy-l -methyl- lH-pyrrolo[2,3-b]pyridine -2-carboxamide
  • the compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • the intermediate amine IV can be in turn obtained from haloderivatives VI directly by carefully controlled reaction with ammonia or by reaction with a benzybc amine and a further de- benzylation process by well-known methods such as hydrogenation in the presence of a metal catalyst as palladium.
  • the amide haloderivatives VI can be obtained from well-known carboxylic derivatives VII through the corresponding acyl halides obtained by conventional methods such as treatment with oxalyl chloride and further reaction with an amine R1-NH2 in the presence of an acid scavenger as a tertiary amine.
  • Method B can also be used to reach the target structures
  • Reaction products were purified, when necessary, by flash chromatography on silica gel (40- 63 pm) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a Cl 8 column and using a gradient, unless otherwise stated, of water-acetonitrile/MeOH (1:1) (0.1% v/v ammonium formate both phases) from 0% to 100% acetonitrile/MeOH (1:1) in 40 column volumes.
  • the conditions “formic acid buffer” refer to the use of 0.1% v/v formic acid in both phases. The appropriate fractions were collected and the solvents evaporated under reduced pressure and/or liofilized.
  • Preparative HPLC-MS were performed on a Waters instrument equipped with a 2767 injector/collector, a 2525 binary gradient pump, a 2996 PDA detector, a 515 pump as a makeup pump and a ZQ4000 Mass spectrometer detector or on a Agilent 1200 Series coupled to an Agilent 6120 Mass spectrometer detector. Both systems were equipped with a Symmetry Prep Cl 8 (19 x 300 mm, 7 pm) column or a XBridge Prep C18 (19 x l00 mm, 5 pm) column.
  • the mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A), the specific gradients used are specified in each particular case.
  • the flow rate was 20 ml/min.
  • the UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector.
  • the system was equipped with an ACQUITY UPLC BEH C-18 (2.1x50 mm, 1.7 mm) column.
  • the mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A).
  • a gradient between 0 to 95% of B was used.
  • the run time was 3 or 6 minutes.
  • the injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.
  • the HPLC chromatographic separations were obtained using a Waters Alliance HT HPLC system coupled to a ZQ mass spectrometer detector.
  • the system was equipped with an YMC- Pack ODS-AQ C-18 (4-6x50 mm, 3 pM) column.
  • the mobile phase was formic acid (1.0 mL) and acetonitrile (1000 mL) (B), formic acid (1.0 mL) and water (1000 mL) (A).
  • a gradient between 5 to 100% of B was used.
  • the run time was 3.5 minutes.
  • the injection volume was 5 microliter.
  • Chromatograms were processed from 210 nM to 400 nM. Mass spectra of the chromatograms were acquired using positive electrospray ionization.
  • DIPEA Diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxyde
  • THF Tetrahydrofuran
  • AcOEt Ethyl acetate
  • DCM Dichloromethane
  • HATU 1 -(bis(dimethylamino)methylene)- 1 H-[ 1 ,2 ,3 ] triazolo [4,5 -bjpyridine- 1 -ium 3 -oxide hexafluorophosphate(V)
  • the starting material (Intermediate 5; 90 mg, 0.21 mmol) was suspended in 2 mL of anh. DMA. Under an Ar flushing the reactants were added, zinc cyanide (11.3 mg, 0.096 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.95 mg, 0.02 mmol), 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (2.47 mg, 0.04 mmol). The mixture was heated at 130 °C. After 30 min. the proportion of starting material is 45 % (55 % of final product). The reaction was left for 1 h 30 min.
  • Interemdiate 20 4-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-methoxy-benzoic acid
  • Interemdiate 21 4-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-methoxy-benzoyl chloride
  • 6-chloropyridine-3-carbonyl chloride hydrochloride (Intermediate 25; 47 mg, 0.22 mmol). The mixture was stirred at room temperature (orange dispersion). After 3 h the reaction is complete. Water was added and the mixture extracted with AcOEt (x 1). The organic fraction was washed with LiCl (5 % solution, x 2) and brine (x 1), dried over anh. MgS04, fdtered and evaporated to have a white solid which was precipitated in EtOH to have a white solid which is 80 % by HPLC-MS. The solid was washed with acetonitrile (x 2) to have the final product as a slightly yellow solid (25 mg, 33 %).
  • Staring material is present in 13 % by HPLC-MS, however the solid was used for the next step without further purification.
  • THF was added (partially soluble, heating with a gun improves the solubility) dropwise (during the addition the crude is clear but at the end, a brown suspension is observed).
  • the mixture was stirred at room temperature (brown suspension) After 40 min. the conversion is about 50 %.
  • the temperature was lowered to 0 °C andNH4Cl sat. was added.
  • a little of water was added (in order to improve the solubility of the aqueous phase) and the mixture was extracted with AcOEt (x 1) and was washed with NaHC03 sat. (x 1) and brine; dried over anh.
  • the reaction shows a 45 % of final product and a 31 % of proportion of starting material. Reduction of Cl is observed in a 14 %.
  • the mixture was heated again after adding more quantities of reactants (3 mg Pd, 4 mg Xantphos, 30 mg of cesium carbonate and 6 mg of dimethylpyrimidine) and the mixture was heated again. After two additional hours the expected product is around 75 % and starting material is 5 % (reduction of chlorine is 15 % and seems stable with the time).
  • the reaction was left heating for one more hour and left cool down to room temperature (4 h 30 min total). The mixture was cooled down to room temperature and NH4C1 sat. was added. AcOEt was added and water in order to improve the separation of phases.
  • the title compound was prepared from methyl 3-(methanesulfonamido)benzoate via methyl 3- [tert-butoxycarbonyl(methylsulfonyl)amino]benzoate according to the method described in J.Med:Chem. 57 (3), 793 (2014).
  • the crude was purified by flash chromatography (biotage, SNAP 40g) by using DCM/DCM-MeOH (10%).
  • a second purification was requiered (Biotage, SNAP 12g GOLD) using DCM/DCM-MeOH (5%). There were obtained 72 (20%) mg of a stereoisomeric mixture (93/7).
  • Methyl 4-carbamoyl-2-methoxy-benzoate (Intermediate 57; 545 mg) was suspended in 2 mL of l,l-dimethoxy-N,N-dimethyl-methanamine (DMF-DMA) and the reaction was heated at 90 °C under argon gas in a sealed flask. After 60 min, the starting material has disappeared and the volatiles were removed, co-evaporated with toluene, to give a yellowish solid (625 mg). The product was used in the next step without further purification.
  • DMF-DMA l,l-dimethoxy-N,N-dimethyl-methanamine
  • Methyl 3-carbamoyl-2-methoxy-benzoate (Intermediate 79; 1.5 g, 7.17 mmol) was slurred in DMF -DMA (9.5 ml, 71.75 mmol) and the mixture was heated at 95°C for lh. Then the reaction was concentrated and to the resulting yellow oil was added toluene and concentrated again. It was repeated twice. The crude oil thus obtained was dissolved in EtOH (5 ml) and used immediately in the following step. In a separate flask was prepared a mixture of EtOH (20 ml) and AcOH (6.7 ml) and the resulting solution was cooled in an ice bath.
  • the aqueous phase was further extracted with EtOAc, then the organic phases were washed with brine (2x), dried, fdtered and solvent removed.
  • the crude was purified by flash chromatography (biotage, SNAP Gold 12g) by using DCM/DCM-MeOH (5%). 128 g (59%) of title compound were thus obtained.
  • reaction mixture was cooled down to room temperature and filtered over a pad with Celite and anh. MgS04, washing with AcOEt.
  • the filtrate was removed under reduced pressure to have a black residue which was purified to have via flash chromatography in DCM/DCM with 5 % MeOH to have a slightly brown oil (152 mg, 37 %).
  • the crude was purified by flash chromatography (100% DCM to 5 % MeOH in DCM gradient) to obtain an oil.
  • the oil has DMF, so it was treated with water/AcOEt.
  • the organic phase was dried and concentrated to afford a white solid (308 mg 93%).
  • Methyl 4,6-dichloropyridine-3-carboxylate (2g, 9.70mmol) was solved in DMF (25mL) and (4-methoxyphenyl)methanamine (1.4mL, 10.71mmol) and triethylamine (4mL, 28.70mmol) were added and stirred at room temperature overnight. Excess water was added and the mixture was extracted with AcOEt (x2). The organic phase was washed with water and brine. The organic phase was dried over MgS04, fdtered and evaporated to dryness. The crude was purified by flash chromatography (Biotage Telos40g) using hexane/AcOEt (up to 10%) (254nm) to give the title compound (2.36g, 79%) as a white solid.
  • the mixture was acidified and extracted with AcOEt, but the carboxylic acid is too polar and remains in the aqueous phase.
  • the aqueous phase was concentrated and the solid was filtered and washed with methanol.
  • the methanolic filtrates were concentrated and purified by flash chromatography (reverse phase, water 0.1% formic acid to acetonitrile 0.1% formic acid) to get a white solid (31 mg, 20%).
  • 6-chloro-4-[(2-methoxy-4-nitro-benzoyl)amino]-N-methyl-pyridine-3-carboxamide (Intermediate 112; 60mg, 0.16mmol), iron (6mg, 0.82mmol) and ammonium chloride (9mg, 0.17mmol) were heated in EtOH/THF/water (0.9mL, 4:4:1) at 80°C for 2 hr. The mixture was filtered and washed with EtOH, then evaporated. The solid was washed with water and filtered. The precipitate was dried in oven overnight (45 mg, 82%) as a white solid.
  • 6-fluoropyridin-2- amine 89 mg, 0.79 mmol
  • Tris(dibenzylideneaeetone)dipalladium(0) 48 mg, 0.052 mmol
  • 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene 61 mg, 0.10 mmol
  • cesium carbonate 513 mg, 1.57 mmol
  • Zinc (242 mg, 3.7 mmol) was added to a vial equipped with a stir bar, the vial was heated at 80°C under high vacuum for lh. After back-filling with nitrogen, iodine chips (31 mg, 0.122 mmol) were added to the vial. DMA (2 ml) was added to the vial and the mixture was stirred at room temperature for 30min. Next, 3-(bromomethyl)tetrahydropyran (441 mg, 2.46 mmol) was added and the mixture was was stirred at 80°C overnight.
  • the aqueous phase was further extracted with more EtOAc, then the organic phase was washed with brine (2x), dried (MgS04), fdtered and solvent removed to give a dark oil.
  • the residue was purified by flash chromatography (Biotage, SNAP 12g) by using hexane/EtOAc from 0 to 75%. 45 mg (41%) of the title compound were obtained as a yellow oil.

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Abstract

L'invention concerne de nouveaux composés substitués par carboxamide de formule (I), ainsi que des procédés pour leur préparation, des compositions pharmaceutiques les comprenant et leur utilisation en thérapie en tant qu'inhibiteurs de la Tyrosine Kinase 2 (Tyk2).
PCT/EP2021/058465 2020-04-06 2021-03-31 Composés hétéroaryle substitués par aryle et hétéroaryle-carboxamide utiles en tant qu'inhibiteurs de tyk2 WO2021204626A1 (fr)

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WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations
WO2023205226A1 (fr) * 2022-04-19 2023-10-26 Blueprint Medicines Corporation Inhibiteurs de kit

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