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WO2024127363A1 - Ligands de pseudokinase tyk2 et leurs utilisations - Google Patents

Ligands de pseudokinase tyk2 et leurs utilisations Download PDF

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WO2024127363A1
WO2024127363A1 PCT/IB2023/062810 IB2023062810W WO2024127363A1 WO 2024127363 A1 WO2024127363 A1 WO 2024127363A1 IB 2023062810 W IB2023062810 W IB 2023062810W WO 2024127363 A1 WO2024127363 A1 WO 2024127363A1
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alkyl
compound
formula
heteroaryl
compound according
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Abishek Venkatasubramanian IYER
Jeevak Sopanrao KAPURE
Suresh KURHADE
Garima PRIYADARSHANI
Shailendra SISODIYA
Jissy Akkarapattiakal KURIAPPAN
Sanchari Basu MALLIK
Mahesh HALLE
Snehal Dhol
Amol TANDON
Praveer GUPTA
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Alembic Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • the present invention relates to compounds and methods of making such compounds useful for inhibiting non-receptor tyrosine-protein kinase 2, also known as Tyrosine kinase 2 (TYK2).
  • TYK2 non-receptor tyrosine-protein kinase 2
  • the invention also relates to pharmacologically acceptable compositions and medicaments comprising such compounds and methods of using said compounds and compositions in the treatment of various disorders.
  • Protein kinases mediate intracellular signalling by effecting the transfer of a phosphoryl group to a protein acceptor and may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • a variety of extracellular and other stimuli can trigger these phosphorylation events.
  • An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
  • Many diseases are associated with abnormal cellular responses triggered by kinase- mediated events. Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.
  • the Janus Kinase (JAK) family has a well- established role in inflammation-related pathologies.
  • Janus kinases are a family of intracellular, non-receptor tyrosine kinases, and the mammalian JAK family consist of four members namely Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2).
  • JAKs mediate downstream signalling of cytokine-mediated effects through the JAK-STAT pathway.
  • the activated JAK phosphorylates downstream signaling proteins such as members of the STAT family leading to transcription and further translation of inflammatory mediators.
  • Cytokine pathways regulated by JAK1, JAK2, JAK3 and TYK2 have been implicated in the pathology of various diseases. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancers, cardiovascular diseases, allergies and asthma, Alzheimer's disease, hormone-related diseases, and many other disorders.
  • Cytokine pathways that function through JAK1 activation include ⁇ c cytokines like IL-2, IL-4, IL-7, IL-9 IL-15, IL-21, and IL-13; gp130 cytokines like IL-6, IL- 11,ciliary neurotrophic factor (CNTF), oncostatin M (OSM), leukemia inhibitory factor (LIF), and cardiotrophin-1 (CT-1); and type I interferons (IFNs) like IFN ⁇ / ⁇ , IFN- ⁇ , and IL-10.
  • ⁇ c cytokines like IL-2, IL-4, IL-7, IL-9 IL-15, IL-21, and IL-13
  • gp130 cytokines like IL-6, IL- 11,ciliary neurotrophic factor (CNTF), oncostatin M (OSM), leukemia inhibitory factor (LIF), and cardiotrophin-1 (CT-1); and type I interferons (IFNs) like IFN ⁇ / ⁇ , IFN- ⁇ , and
  • JAK2 activation is involved in the downstream signaling of IL-3, IL-5, IL-12, IL- 23 and GM-CSF, erythropoietin (EPO), thrombopoietin (TPO), granulocyte-colony stimulating factor (G-CSF), growth hormone (GH), leptin, type II cytokines like IL-10, and gp130 cytokines like IL-6, IL-11,CNTF, OSM, LIF, and CT-1.
  • JAK3 activation is involved in the signalling of ⁇ c cytokines like IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
  • TYK2 activation is associated with the signaling cascade of interferons like IFN ⁇ / ⁇ , IFN- ⁇ and interleukins like IL-12 and IL-23. Therefore, inhibition of signal transduction mediated by the JAK class of enzymes, including TYK2, represents a target for treating various inflammatory, autoimmune and related disorders.
  • TYK2 has been identified as the signaling messenger common to IFN- ⁇ , IL-12 and IL-23. Receptor mediated signal transduction and activation by these cytokines has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.
  • TYK2 knockout has been shown to reduce dextran sulfate sodium or 2,4,6- trinitrobenzene sulfonic acid-induced colitis.
  • Decreased TYK2 activity is reported to result in protection of joints from collagen antibody-induced arthritis in a pre-clinical model of human rheumatoid arthritis. This is possibly due to the decreased production of Th1/Th17-related cytokines and matrix metalloproteases, and other key markers of inflammation.
  • TYK2 knockout in mice has been observed to reduce methylated BSA injection-induced footpad thickness.
  • TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis (CF). Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.
  • COPD chronic obstructive pulmonary disease
  • CF cystic fibrosis
  • GCH Goblet cell hyperplasia
  • mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.
  • STAT6 cystic fibrosis
  • TYK2 plays an important role in maintaining tumor surveillance. TYK2 knockout mice show compromised cytotoxic T cell response and accelerated tumor development.
  • T-cell acute lymphoblastic leukemia (T-ALL) is known to be highly dependent on IL-10 and is modulated by TYK2 through STAT1-mediated signal transduction. This pathway is important for maintenance of cancer cell survival through upregulation of anti- apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, is known to reduce cell growth in T-ALL.
  • TYK2 enzymes featuring kinase-dead mutations M978Y or M978F
  • E957D activating mutation
  • selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and/or BCL -addicted tumors, such as 70% of adult T-cell leukemia cases.
  • MS Multiple Sclerosis
  • TYK2 knockout mice show complete resistance in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.
  • TYK2 knockout mice show no infiltration of CD4+ T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS. Additionally, loss of function mutation in TYK2 leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders. [0015] TYK2 mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid- ⁇ (A ⁇ ) peptide. Decreased TYK2 phosphorylation of STAT3 following A ⁇ administration led to decreased neuronal cell death.
  • a ⁇ amyloid- ⁇
  • JAK-STAT signaling pathways are also implicated in hair growth and the reversal of the hair loss associated with alopecia areata.
  • JH2 domains of the JAK family are known to regulate the function of the JH1 domains through an auto-inhibitory mechanism.
  • JAKs 1-3 and TYK2 may be achieved through targeting either the kinase domain through competitive inhibition to binding of ATP or the JH2 of JAKs.
  • TYK2 JH2 it has been reported that the domain is auto-inhibitory and stabilizes the inactivated state of the kinase domain. It has also been reported that small molecule ligands can stabilize this auto-inhibitory conformation thereby preventing protein function in an allosteric manner.
  • WO2014074661 discloses amide substituted pyridazine compounds including deucravacitinib as TYK2 modulators.
  • WO2020086616 discloses different TYK2 inhibitors including fused tricyclic compounds.
  • R 1 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, hal
  • compositions comprising a therapeutically effective amount of one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt, stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • methods of inhibiting a TYK2 enzyme in a patient or biological sample comprising contacting said patient or biological sample with one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof.
  • methods of treating a TYK2-mediated disorder comprising administering to a patient in need thereof one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, thereof.
  • the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.
  • Cis- and trans-geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • the present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. [0044] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
  • “Aliphatic chain” refers to a linear chemical moiety that is composed of only carbons and hydrogens.
  • the aliphatic chain is saturated.
  • the aliphatic chain is unsaturated.
  • the unsaturated aliphatic chain contains one unsaturation.
  • the unsaturated aliphatic chain contains more than one unsaturation.
  • the unsaturated aliphatic chain contains two unsaturations.
  • the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about twenty carbon atoms, or from one to ten carbon atoms or from one to six carbon atoms, containing the indicated number of carbon atoms, for example, a C 1 -C 6 alkyl group may have from 1 to 6 (inclusive) carbon atoms in it.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1- propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl-2- pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octy
  • C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 - C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 - C 2 alkyl, or a C 1 alkyl.
  • an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • C 2 -C 6 alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2- butynyl, 1,3-butadiynyl and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkylene is optionally substituted with oxo, halogen, - CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -NO 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [0051] “Aminoalkyl” refers to an alkyl radical, as defined above that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine.
  • the alkyl is substituted with one, two, or three amines.
  • Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10- membered aryl.
  • the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -SMe, -NH 2 , or -NO 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon ring system.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, most preferably 3 to 6 carbon atoms
  • Monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or - OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • cycloalkyl is bridged cycloalkyl.
  • bridged cycloalkyl is but not limited to [0054]
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4- membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5- membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl is but not limited to [0055] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms.
  • Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 .
  • the deuteroalkyl is CD 3 .
  • “Haloalkyl” refers to an alkyl radical, as defined above that is substituted by one or more halogen atoms.
  • the alkyl is substituted with one, two, or three halogen atoms.
  • the alkyl is substituted with one, two, three, four, five, or six halogen halogens.
  • Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3- bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • the haloalkyl is trifluoromethyl.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, - N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, - CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , or -CH(CH 3 )OCH 3 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls.
  • Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • the terms “heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, or “heterocyclyl” may be used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon ring system which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon.
  • heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups through a single bond, or through a ring any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
  • bridged heterocycloalkyl is but not limited to [0061]
  • the term “heterocycloalkyl” also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , - OH, -OMe, -NH 2 , or -NO 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between 3 to 20 membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 3-membered/5-membered, 4-membered/5- membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6- membered monospiro heterocyclic group.
  • spiroheterocycloalkyl is but not limited to [0064] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl.
  • a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a 5- to 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or - NO 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl,
  • the compound is of Formula (Ia): wherein: Y’, M, Z, R 1 , R 6 , R 9 , and R 10 are as defined hereinabove for Formula (I).
  • the compound is of Formula (Ib): wherein: Y’, M, Z, R 1 , R 6 , R 9, and R 10 are as defined hereinabove for Formula (I).
  • the compound is of Formula (Ic):
  • Y’, M, Z, R 1 , R 2 , and R 6 are as defined hereinabove for Formula (I).
  • the compound is of Formula (Id): wherein: Y’, M, Z, R 1 , R 2 , and R 6 are as defined hereinabove for Formula (I).
  • the compound is of Formula (Ie): wherein: Y, M, Z, R 1 , R 6 , R 9 , and R 10 are as defined hereinabove for Formula (I).
  • the compound is of Formula (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im):
  • Y, Y’, M, X, R 1 , R 2 , R 4 , R 6 , and R 10 are as defined hereinabove for Formula (I).
  • Y is NR 5 .
  • R 5 is hydrogen.
  • Y is NH.
  • Y’ is NR 5 or O.
  • R 5 is hydrogen.
  • Y’ is NH or O.
  • X is CR 6 .
  • M is O.
  • Z is NR 4 or CR 4 R 4’ .
  • R 4 and R 4’ are hydrogen.
  • Z is NH and CH 2 .
  • R 1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Im), (Io), or (Ir), R 1 is hydrogen, Me, or CD 3 .
  • R 8 is hydrogen.
  • R b is C 1 -C 6 alkyl.
  • R 2 is heteroaryl.
  • R 2 is imidazolyl or pyrrolyl.
  • R 2 is selected from the group consisting of hydrogen, halogen, -NH 2 , -N(Me) 2 , , [0105]
  • R 6 is selected from the group consisting of hydrogen, halogen, -OM
  • the 5,10-dihydropyrido[3,4-b]quinoxaline derivatives of the present invention may be oxidized to form the corresponding pyrido[3,4-b]quinoxaline derivatives owing to the unstable nature of 5,10-dihydropyrido[3,4-b]quinoxaline derivatives.
  • the oxidizing agents used for this purpose would be conventional oxidizing agents known to a person skilled in the art and also include air, oxygen, etc.
  • the compound, or a pharmaceutically acceptable salt, or stereoisomer thereof is selected from the group consisting of: - e - - 4- -1- - - - 4- 4- 4- 4- 4- 4- - 4- -
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z isomers as well as the corresponding mixtures thereof.
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. [0111] In some embodiments, the compounds described herein exist in their isotopically- labelled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labelled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labelled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically- labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein, , or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms, are within the scope of this disclosure.
  • isotopically-labelled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the isotopically labelled compound or a pharmaceutically acceptable salt, or stereoisomer thereof is prepared by any suitable method.
  • the compounds described herein are labelled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts [0113] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p- toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1 -4 alkyl)4, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Tautomers [0119] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond.
  • Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al.,“Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House,“Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist,“Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit a TYK2 protein kinase, or a mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit a TYK2 protein kinase, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a TYK2 protein kinase, or a mutant thereof.
  • Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
  • Uses of Compounds and Pharmaceutically Acceptable Compositions [0129] Compounds and compositions described herein are generally useful for the inhibition of kinase activity and or kinase mediated signal transduction of one or more enzymes.
  • the kinase and or kinase mediated signal transduction inhibited by the compounds and methods of the invention is TYK2.
  • the activity of a compound utilized in this invention as an inhibitor of TYK2, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of activated TYK2, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TYK2.
  • Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/TYK2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with TYK2 bound to known radioligands.
  • Representative in vitro and in vivo assays useful in assaying a TYK2 inhibitor include those described and disclosed in, e.g., each of which is herein incorporated by reference in its entirety. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of TYK2, or a mutant thereof, are set forth in the Examples below.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the present invention provides a method for treating a TYK2- mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • TYK2-mediated disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role.
  • TYK2 -mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.
  • the present invention provides a method for treating one or more disorders, wherein the disorders are selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • the disorder is an autoimmune disorder.
  • the disorder is one or more selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin changes (“POEMS”) syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.
  • POEMS Skin changes
  • Crohn's disease Crohn's disease
  • ulcerative colitis and inflammatory bowel disease.
  • the inflammatory disorder is one or more of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.
  • the disorder is a proliferative disorder.
  • the proliferative disorder is a hematological cancer.
  • the proliferative disorder is a leukemia.
  • the leukemia is a T-cell leukemia.
  • the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).
  • the proliferative disorder is polycythemia vera, myelofibrosis, and/or essential or thrombocytosis.
  • the disorder is an endocrine disorder.
  • the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, and/or type 1 diabetes.
  • the disorder is a neurological disorder.
  • the neurological disorder is Alzheimer's disease.
  • the proliferative disorder is associated with one or more activating mutations in TYK2.
  • the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V73 II, E957D, and R1027H.
  • the disorder is associated with transplantation. In some embodiments, the disorder associated with transplantation is transplant rejection, or graft versus host disease. [0142] In some embodiments, the disorder is associated with type I interferon, IL-10, IL- 12, or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling.
  • the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.
  • Compounds disclosed herein are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and/or other inflammatory or allergic conditions of the skin.
  • Compounds disclosed herein may also be used for the treatment of diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and/or inflammatory diseases in which autoimmune reactions are implicated or having an autoimmune component or etiology, such as systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, rheumatoid arthritis, chronic obstructive pulmonary disease, hepatomegaly, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria bullous pemphigoi
  • idiopathic nephrotic syndrome or minal change nephropathy including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, silica induced diseases, pulmonary disease, cystic fibrosis
  • the inflammatory disease which can be treated according to the methods of this invention is one or more of acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.
  • the inflammatory disease which can be treated according to the methods of this invention is a Thl- or Thl7-mediated disease.
  • the Thl-mediated disease is selected from Systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).
  • the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, and/or diseases affecting the nose such as allergic rhinitis.
  • the invention provides the use of a compound described herein, or a pharmaceutically acceptable salt, thereof for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, and/or a disorder commonly occurring in connection with transplantation.
  • the invention relates to methods of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with one or more compounds described herein or a composition comprising the one or more compounds.
  • the invention relates to methods of inhibiting TYK2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with one or more compounds described herein, or a composition comprising the one or more compounds.
  • methods of irreversibly inhibiting TYK2, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with one or more compounds described herein, or a composition comprising the one or more compounds are contemplated.
  • the invention provides methods of selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3.
  • the one or more compounds is more than 2-fold selective over JAK1/2/3.
  • the one or more compounds is more than 5-fold selective over JAK 1/2/3. In some embodiments, the one or more compounds is more than 10-fold selective over JAK 1/2/3. In some embodiments, the one or more compounds is more than 50-fold selective over JAK 1/2/3. In some embodiments, the one or more compounds is more than 100-fold selective over JAKl/2/3.
  • biological sample includes, without limitation, cell cultures or extracts thereof, biopsied material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of TYK2 (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • EXAMPLES AND METHODS OF PREPARATION Synthetic scheme and procedure [0154] The compounds of the present invention may be synthesised by many methods available to those skilled in the art of organic chemistry. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein.
  • “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc.
  • Groups such as trityl, dimethoxytrityl, acetal and t- butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with benzyl chlorocarbonate (“Cbz”) groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
  • Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pd- catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • the present invention also encompasses any one or more of these processes for preparing the compounds of Formula (I) (or derivatives thereof), in addition to any novel intermediates used therein.
  • the person skilled in the art will appreciate that the following reactions may be heated thermally or under microwave irradiation. The course of reaction is monitored through an analytical technique known to the person such as for example using TLC, HPLC, NMR and the like.
  • the compound(s) of Formula (I)-1 can be further converted to a compound of Formula (I) by various methods, including but not limited to, 1) palladium-mediated Buchwald coupling of a compound of Formula (I)-1 with substituted amino-heterocycles or substituted primary amides, optionally in the presence of ligands PPh 3 , SPhos, Ruphos, XPhos, and BrettPhos; and 2) suzuki coupling chemistry and the like.
  • suitable hydrogenating agent such as but not limited to, Fe/NH 4 Cl, H 2 /Pd/C, and H 2 /raney nickel
  • suitable solvent such as, but not limited to, methanol, ethanol, isopropanol
  • the compound of Formula (I)-9 or (I)-9’ is hydrogenated using suitable hydrogenating agent, such as, but not limited to, Fe/NH 4 Cl, H 2 /Pd/C, and H 2 /raney nickel in a suitable solvent, such as, but not limited, to ethanol and/or water to give a compound of Formula (I)-8 or (I)-8’, which is further converted to a compound of Formula (I)-1 or (I)-1’ by intramolecular cyclization using a suitable base, such, as but not limited to, Cs 2 CO 3 , in a suitable solvent, such as but not limited to, DMSO.
  • suitable hydrogenating agent such as, but not limited to, Fe/NH 4 Cl, H 2 /Pd/C, and H 2 /raney nickel
  • a suitable solvent such as, but not limited, to ethanol and/or water
  • a compound of Formula (I) can be obtained by deprotection methods using suitable acids, such as, but not limited to hydrochloric acid.
  • suitable acids such as, but not limited to hydrochloric acid.
  • the suitable solvent used for the above scheme is selected from the one which does not affect the course of the reaction, that includes but is not limited to DMSO, DMAc, NMP, DMF, sulfolane, diglyme, ketone, alcohol, halogenated hydrocarbon, ether, and/or ester and the like or mixtures thereof.
  • the suitable base used for the above scheme(s) is an alkali metal hydroxide, such as sodium or potassium hydroxide, or an alkali metal carbonate, such as a sodium or potassium carbonate or caesium carbonate or sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butoxide or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide or amines such as triethylamine, diisopropylethylamine, diisopropylamine, 4-N, N-dimethylaminopyridine or pyridine.
  • alkali metal hydroxide such as sodium or potassium hydroxide
  • an alkali metal carbonate such as a sodium or potassium carbonate or caesium carbonate or sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butoxide or amides
  • amides such as sodium amide, lithium bis (trimethylsilyl)
  • Step 2- Synthesis of a Compound of Formula (1c): [0173] To a solution of a compound of Formula (1b) (45 g, 246 mmol) in 150 ml of acetic acid, 65% of nitric acid (15.5 g, 246 mmol) was added drop wise at 60°C. The mixture was stirred at 90°C till completion of the reaction.
  • Step 3- Synthesis of a Compound of Formula (1d): [0174] To a suspension of a compound of Formula (1c) (35 g, 154 mmol), phosphorus oxychloride (140 ml, 1535 mmol) was added and the mixture was stirred at a temperature of 80°C till completion of the reaction. After completion of the reaction, approximately half volume of the phosphorus oxychloride was removed in vacuo and the remaining mixture was poured onto ice.
  • Step 4- Synthesis of a Compound of Formula (1e): [0175] To a suspension of a compound of Formula (1d) (23.8 g, 89.8 mmol), iron powder (20 g, 359.2 mmol), NH 4 Cl (19.2 g, 359.2 mmol), EtOH (160 ml), and H 2 O (60 ml) were added and heated at 60°C for 2 h. The mixture was passed through a pad of celite and the filtrate was concentrated in vacuo to remove EtOH. The residual solution was extracted with EtOAc.
  • Step 5- Synthesis of a Compound of Formula (1f): [0176] To a solution of containing a compound of Formula (1e) (13.8 g, 59.22 mmol) in CH 3 CN (200 ml), CuBr 2 (19.8 g, 88.8 mmol) and t-butyl nitrite (12.2 g, 118.44 mmol) were added and the mixture was stirred at 0°C for 15 minutes (after degassing in N2) and then heated at 55°C till completion of the reaction.
  • Step 6- Synthesis of a Compound of Formula (1g): [0177] To a solution of a compound of Formula (1f) (13 g, 43.62 mmol) in THF (200 ml), MeOH (100 ml and H 2 O (50 ml), 6 N NaOH (50 ml) was added at room temperature and the mixture was stirred for 1 h. After reducing the solvent concentration, the mixture was acidified with conc.HCl and then filtered. The filter cake was washed with ice-cold H 2 O and the solid was dried to give the compound of Formula (1g) (11 g, 87 % yield) as a white solid.
  • Step 7- Synthesis of a Compound of Formula (Int-1): [0178] To a solution of 1g (10 g, 37.03 mmol) in DCM (100 ml) at room temperature, oxalyl chloride (6.1 g, 48.15 mmol) was added. The mixture was stirred at room temperature for 15 minutes, followed by addition of 4 drops of DMF (check effervescence). After stirring for 2 h reaction mixture became a clear solution. The reaction was concentrated under reduced pressure and the residue was dissolved in DCM and concentrated again. The resulting crude was dissolved in DCM and then methyl-d3- amine hydrochloride (3.15 g, 44.43 mmol) was added.
  • Step 2- Synthesis of a Compound of Formula (2c): [0180] To a solution containing a compound of Formula (2b) (26 g, 105.16 mmol) in MeOH (100 ml) at 0°C was added 25% of sodium methoxide in MeOH (28.4 g, 525.8 mmol) dropwise for 15 minutes. The reaction mixture was stirred at 50°C until the reaction was complete. After completion of the reaction, the reaction mixture was diluted with H 2 O.
  • Step 3- Synthesis of the Compound of Formula (Int-2): [0181] A suspension of a compound of Formula (2c) (27 g, 104.2 mmol) in MeOH and 10% palladium on charcoal (5 g) was stirred in a hydrogen atmosphere at room temperature till completion of the reaction.
  • Step-1 Synthesis of a Compound of Formula (3a) [0182] To a solution containing a compound of Formula (2b) (2 g, 8.09 mmol) in MeOH (100 ml) at 0°C was added sodium thiomethoxide (2.8 g, 40.5 mmol) slowly. The reaction mixture was stirred at 50°C until the reaction was complete.
  • Step-2 Synthesis of a Compound of Formula (Int-3) [0183] A compound of Formula (Int-3) was prepared from a compound of Formula (3a) using the procedure described for the synthesis of the compound of Formula (Int-2) (0.5 g, 37%).
  • Step 4 Synthesis of a Compound of Formula (Int-4) (Intermediate 4)
  • Step-1 Synthesis of a Compound Formula (4a) [0184] The compound of Formula (4a) was prepared from the compound of Formula (2b) using the procedure described for the synthesis of the compound of Formula (3a) (1.9 g, 86%).
  • Step-2 Synthesis of a Compound of Formula (Int-4) [0185] A compound of Formula (Int-4) was prepared from a compound of Formula (4a) using the procedure described for the synthesis of the compound of Formula (Int-2) (0.8 g, 78%).
  • Step-1 Synthesis of a Compound of Formula (2b) [0186] To a solution containing a compound of Formula (2a) (100 g, 636.9 mmol) in 300 ml DMF was added K 2 CO 3 (105.5 g, 764.3 mmol) followed by benzyl bromide (108.9 g, 636.9 mmol) and the mixture was stirred till completion of the reaction at ambient temperature. The reaction mixture was concentrated under reduced pressure. H 2 O was added and the product was extracted with EtOAc.
  • Step-2 Synthesis of a Compound of Formula (5a) [0187] To a solution containing a compound of Formula (2a) (140 g, 566.8 mmol) and trimethylsilyl chloride (12.3 g, 113.3 mmol) in 300 ml DMF, NBS was added dropwise (111 g, 623.4 mmol) at 0°C. After the addition mixture was stirred at room temperature till completion of the reaction, the reaction mixture was concentrated under reduced pressure.
  • Step-3 Synthesis of a Compound of Formula (5b) [0188] To a solution of a compound of Formula (5a) (96 g, 294.47 mmol) in MeOH (300 ml) at 0°C, 30% of sodium methoxide in MeOH (79.5 g, 1427.39 mmol) was added dropwise for 15 minutes. The reaction mixture was stirred at 50°C till completion of the reaction and then concentrated under reduced pressure.
  • Step-4 Synthesis of a Compound of Formula (5c) [0189] To a solution of a compound of Formula (5b) (84 g, 245.52 mmol), bis- pinacolato-diboron (74.8 g, 294.62 mmol) in 1,4-dioxane (200 ml) potassium acetate (60.2 g, 613.8 mmol) was added under nitrogen atmosphere. Reaction mixture was degassed with nitrogen.
  • Step-5 Synthesis of a Compound of Formula (5d) [0190]
  • a compound of Formula (5c) (18.5 g, 48.15 mmol), 3-bromo-1-methyl-1H-1,2,4- triazole (6.5 g, 40.12 mmol) and K 2 CO 3 (16.6 g, 120.4 mmol) was dissolved in a mixture of H 2 O (10 ml) and 1,2-DME (30 ml). Reaction mixture was degassed with nitrogen. Then Pd(dppf)Cl 2 .DCM (3.3 g, 4.012 mmol) was added. Reaction mixture was stirred at 110°C. After completion of reaction, reaction mixture was transferred into H 2 O and extracted with DCM.
  • Step-6 Synthesis of a Compound of Formula (Int-5) [0191] A suspension of a compound of Formula (5d) (7 g, 20.59 mmol) in MeOH and 10% palladium on charcoal (1 g) was stirred in a hydrogen atmosphere at room temperature till the completion of reaction. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford the compound of Formula (Int-5) (4.5 g, 99 %) as a brown solid.
  • Step 6 Synthesis of a Compound of Formula (Int-6) (Intermediate 6)
  • Step-1 Synthesis of a Compound of Formula (6b) [0192]
  • a compound of Formula (6b) was prepared from the compound of Formula (6a) and 2-bromo-5-fluoropyrimidine using the procedure described in for synthesis of the compound of Formula (5d) (14 g, 18 %) as a yellow solid.
  • Step-2 Synthesis of a Compound of Formula (Int-6) [0193] A compound of Formula (Int-6) was prepared from the compound of Formula (6b) using the procedure described for the synthesis of the compound of Formula (Int-5) (14 g, 76 %) as a yellow solid.
  • Preparation 7 Synthesis of the Compound of Formula (Int-7) (Intermediate 7) [0194] A compound of Formula (Int-7) was prepared from the compound of Formula (1g) using the procedure described for the synthesis of the compound of Formula (Int-1) (2.5 g, 59%).
  • Preparation 8 Synthesis of a Compound of Formula (Int-8) (Intermediate 8/example 32) [0195] The compound of Formula (Int-1) (5 g, 17.42 mmol), The compound of Formula (Int-2) (2.9 g, 20.9 mmol) and Cs 2 CO 3 (11.3 g, 34.84 mmol), were added to 5 ml of DMSO under an inert atmosphere.
  • Preparation 9 Synthesis of a Compound of Formula (Int-9) (Intermediate 9) [0196]
  • the compound of Formula (Int-1) (5 g, 17.42 mmol), the compound of Formula (Int-5) (3.84 g, 17.42 mmol) and Cs 2 CO 3 (8.51 g, 26.14 mmol), were added to 20 ml of DMSO under an inert atmosphere.
  • the reaction was heated to 120°C till the completion of reaction.
  • the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by column chromatography to afford the compound of Formula (Int-9) (4 g, 65 %) as a grey solid.
  • Preparation 10 Synthesis of a Compound of Formula (Int-10) (Intermediate 10) [0197] A compound of Formula (Int-10) was prepared from the compound of Formulas (Int-1) and (Int-6) using the procedure described for synthesis of the compound of Formula (Int-9) (0.5 g, 7 %) as a yellow solid.
  • Preparation 11 Synthesis of Int-11 (Intermediate 11) [0198] A compound of Formula (Int-11) was prepared from the compound of Formulas (Int-1) and (Int-3) using the procedure described for synthesis of the compound of Formula (Int-9) (0.5 g, 48 %) as a yellow solid.
  • Preparation 12 Synthesis of the Compound of Formula (Int-12) (Intermediate 12) [0199] A compound of Formula (Int-12) was prepared from the compound of Formulas (Int-1) and (Int-4) using the procedure described for synthesis of the compound of Formula (Int-9).
  • Preparation 13 Synthesis of the Compound of Formula (Int-13) (Intermediate 13)
  • Step-1 Synthesis of the Compound of Formula (Int-13a) [0200]
  • a compound of Formula (Int-13a) was prepared from the compound of Formulas (Int-7) and (Int-4) using the procedure described for synthesis of the compound of Formula (Int-8) (0.23 g, 44 %) as a yellow solid.
  • Step-2 Synthesis of the Compound of Formula (Int-13) [0201] To a solution of the compound of Formula (Int-13a) (0.23 g, 0.68 mmol) in 4 ml anhydrous THF was added 1 M EtMgBr (2 ml, 2.04 mmol) at -10°C. The reaction mixture was stirred at room temperature till the completion of reaction, quenched with sat NH 4 Cl, and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the compound of Formula (Int-13) (0.045 g, 22 %) as a yellow solid.
  • Step 14 Synthesis of a Compound of Formula (Int-14) (Intermediate 14) [0202]
  • Step-1 A compound of Formula (Int-14a) (0.43 g, 32%) was prepared from the compound of Formulas (Int-7) and (Int-5) using the procedure described for synthesis of the compound of Formula (Int-13a).
  • Step-2 A compound of Formula (Int-14) (0.06 g, 16%) was prepared from the compound of Formula (Int-14a) using the procedure described for synthesis of the compound of Formula (Int-13) as a yellow solid.
  • Preparation 15 Synthesis of a Compound of Formula (Int-15) (Intermediate 15) [0204] To a solution of the compound of Formula (Int-8) (0.05 g, 0.162 mmol) and N- Boc-2-pyrroleboronic acid (0.103 g, 0.49 mmol) in 1,4-dioxane (4 ml) was added 3 drops of H 2 O, K 2 CO 3 (0.07 g, 0.487 mmol) and Pd(PPh 3 ) 4 (0.04 g, 0.03 mmol). The mixture was degassed by nitrogen and then heated to 110°C till completion of the reaction.
  • Step-1 Synthesis of a Compound of Formula (16b) [0205] A compound of Formula (16b) was prepared from the compound of Formula (16a) using the procedure described for the synthesis of the compound of Formula (Int-1) (0.5g, 37% yield) as a brown solid.
  • Step-2 synthesis of Int-16 [0206] A compound of Formula (Int-16) was prepared from the compound of Formula (16b) using the procedure described for the synthesis of the compound of Formula (Int-5) (0.300 g, 72 %). Preparation 17: Synthesis of a Compound of Formula (Int-17) (Intermediate 17) [0207] A Compound of Formula (Int-17) was prepared from the Compound of Formula (1g) using the procedure described for the synthesis of the Compound of Formula (Int-1) (0.6 g, 60%) as a white solid.
  • Preparation 18 Synthesis of a Compound of Formula (Int-18) (Intermediate 18) [0208] A compound of Formula (Int-18) was prepared from the compound of Formulas (Int-17) and (Int-16) using the procedure described for synthesis of the compound of Formula (Int-8).
  • Preparation 19 Synthesis of a Compound of Formula (Int-19) (Intermediate 19) g [0209] To a solution of the Compound of Formula (Int-1g) (1 g, 3.72 mmol) in DCM (100 ml) at room temperature, oxalyl chloride (0.61 g, 4.83 mmol) was added.
  • Step-1 Synthesis of a Compound of Formula (22b) [0212] To a solution of the compound of Formula (22a) (4.5 g, 32.60 mmol) in DCM (150 ml), fuming nitric acid, (2.0 ml, 48.91 mmol) was added drop wise at 0°C. The mixture was stirred at 0°C till completion of the reaction. The reaction mixture was poured in to ice-cold water and extracted with ethyl acetate.
  • Step-2 synthesis of a Compound of Formula (Int-22) [0213] A compound of Formula (Int-22) was prepared from the compound of Formula (22b) using the procedure described for the synthesis of the compound of Formula (Int-5) (1 g, 17 %).
  • Preparation 23 Synthesis of a Compound of Formula (Int-23) (Intermediate 23) [0214] A compound of Formula (Int-23) was prepared from the compound of Formulas (Int-1) and (Int-22) using the procedure described for synthesis of the compound of Formulas (Int-8) (0.27 g, 48%) as a yellow solid.1H NMR (400 MHz, DMSO-d6): d 9.75 (s, 1H), 8.64 (s, 1H), 8.13 (s, 1H), 6.52 (s, 1H), 6.29 (s, 1H), 3.81 (s, 3H), 2.16 (s, 3H) ppm. LCMS: m/z 323.20 (M+H+).
  • Step-1 Synthesis of a Compound of Formula (24b) [0215] To a solution of the compound of Formula (24a) (2 g, 11.29 mmol) in DMF (50 mL), NaOMe (1.098 g, 20.33 mmol) was added at 0 °C for 10 min, the reaction mixture was stirred at 50°C till completion of the reaction. After completion, the reaction mixture was cooled to room temperature, diluted with cold water.
  • the reaction mixture was extracted with EtOAc and the organic phases were washed with aqueous Na 2 CO 3 , H 2 O, brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product
  • the crude compound was purified by column chromatography by using gradient mixture of 10% to 25 % ethyl acetate in pet ether as an eluent to afford the compound of Formula (24b) (1.1 g) as a colourless thick mass.
  • Step-2 Synthesis of a Compound of Formula (24c) [0216] To a solution of the compound of Formula (24b) (1 g, 5.29 mmol) in DMSO (40 mL); 2% NaOH solution (5 mL) was added at room temperature and reaction mixture was stirred at room temperature till completion of the reaction. After completion of reaction, the reaction mixture was neutralized with 1N HCl solution. The reaction mixture was extracted with EtOAc and the organic phases were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by column chromatography by using gradient mixture of 25% ethyl acetate/pet ether eluent to afford of the compound of Formula (24c) (450 mg) as a colourless liquid.
  • Step-3 Synthesis of a Compound of Formula (24d) [0217]
  • DMF 50mL
  • benzyl bromide 4.8 mL, 40.10 mmol
  • the reaction mixture was poured in to ice water, extracted with EtOAc and the organic phases were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was washed with 5% ethyl acetate in pet ether and dried under vacuum to afford of the compound of Formula (24d) (about 3.2 g) as a thick mass.
  • Step-4 Synthesis of a Compound of Formula (Int-24) [0218] To a solution the compound of Formula (24d) (3 g, 10.83 mmol) in EtOAc/MeOH (1:1) (100mL), 5% Pd/C (600 mg, 20% of substrate) was added at room temperature and stirred under Hydrogen pressure at room temperature till completion of the reaction. After completion of reaction, Pd/C was removed by celite filtration and filtrate was concentrated under reduced pressure. The residue was washed with pet ether and dried under vacuum to afford of the compound of Formula (Int-24) (1.9 g) as an off-white solid.
  • Step-1 Synthesis of a Compound of Formula (26b) [0220] To a solution of the compound of Formula (26a) (5 g, 25.38 mmol) in t-BuOH (50 ml), DPPA (8.4 g, 30.45 mmol) and TEA (4 g, 38.07 mmol) were added and the mixture was stirred at 0°C for 15 minutes. Then heated at 80°C till completion of the reaction.
  • Step-2 Synthesis of a Compound of Formula (Int-26) [0221] A compound of Formula (Int-26) was prepared from the compound of Formula (26b) using the procedure described for the synthesis of the compound of Formula (Int-5) (3 g, 86 % yield) as off-white solid.
  • Step-1 Synthesis of a Compound of Formula (27a) [0222]
  • a compound of Formula (27a) was prepared from the compound of Formulas (Int-1) and (Int-26), CuI (0.13 g, 0.69 mmol) and 1,10-phenonthrline (0.18 g, 1.34 mmol) using the procedure described for synthesis of the compound of Formulas (Int-8) (0.6 g, 21 %) as a brown solid.
  • Step-2 Synthesis of a Compound of Formula (Int-27) [0223] 4 N HCl solution in dioxane (2 ml) was added to a solution of the compound of Formula (27a) (0.6 g, 1.47 mmol) in DCM (5 ml) and the mixture was stirred till completion of the reaction at room temperature. The reaction mixture was concentrated under reduced pressure and the crude compound was purified by column chromatography to afford the compound of Formula (Int-27) (0.4 g, 88 %) as a brown solid.
  • Preparation 28 Synthesis of a Compound of Formula (Int-160) (Intermediate 160) [0224] The compound of Formula (Int-1) (4.7 g, 16.61 mmol), the compound of Formula (Int-242) (3.3 g, 19.93 mmol), and Cs 2 CO 3 (8.10g, 24.9mmol), were added to 47 ml of DMSO under an inert atmosphere. The reaction was heated to 100 °C till completion of the reaction. After completion of the reaction, the reaction was quenched with ice cold water, extracted into DCM and solvent was concentrated under reduced pressure.
  • reaction mixture was heated to 110 °C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to room temperature, Water was added to reaction mixture and the product was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product.
  • Preparation 34 Synthesis of a Compound of Formula (Int-213) (Intermediate 213) [0230] To a solution of the compound of Formula (Int-160) (0.1 g, 1 mmol) and N-Boc- 2-pyrroleboronic acid (0.19 g, 3.0 mmol) in mixture of 1,4-dioxane (4 ml) and water (0.2 ml) , was added Cs 2 CO 3 (0.28 g, 3 mmol) and Pd(dppf)Cl 2 .DCM (0.021g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction.
  • Preparation 36 Synthesis of a Compound of Formula (Int-231) (Intermediate 231) [0232] The compound of Formula (Int-1) (6.5 g, 22.64 mmol), the compound of Formula (Int-243) (4.54 g, 27.18 mmol) and Cs 2 CO 3 (10.02 g, 33.97 mmol), were added to 65 ml of DMSO under an inert atmosphere. The reaction was heated to 100°C till completion of the reaction. After completion of the reaction, reaction was quenched with ice cold water and extracted into DCM and solvent was concentrated under reduced pressure.
  • Preparation 38 Synthesis of a Compound of Formula (Int-233) (Intermediate 233) [0234] To a solution of the compound of Formula (Int-8) (0.25 g, 1 mmol) and 1- (tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (0.28 g, 3.0 mmol) in mixture of 1,4-dioxane (10 ml) and water (0.5 ml) , was added Cs 2 CO 3 (0.8 g, 3 mmol) and Pd(dppf)Cl 2 .DCM (0.06 g, 0.1 mmol).
  • Preparation 40 Synthesis of a Compound of Formula (Int-235) (Intermediate 235) [0236] To a solution of intermediate a compound of Formula (Int-161) (0.075 g, 1 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- imidazole (0.07 g, 2.0 mmol) in mixture of 1,4-dioxane (3 ml) and water (0.15 ml) , was added Cs 2 CO 3 (0.2 g, 3 mmol) and Pd(dppf)Cl 2 .DCM (0.017 g, 0.1 mmol).
  • Preparation 42 Synthesis of a Compound of Formula (Int-237) (Intermediate 237) [0239] The compound of Formula (Int-1) (1.75g, 6.09 mmol), the compound of Formula (Int-245) (1.1g, 7.31 mmol) and Cs 2 CO 3 (2.97g, 9.14 mmol), were added to 17.5 ml of DMSO under an inert atmosphere. The reaction was heated to 100°C till completion of the reaction. After completion of the reaction, reaction was quenched with ice cold water and extracted into DCM and solvent was concentrated under reduced pressure. The residue was purified by column chromatography to afford a compound of Formula (Int- 237) as a brown solid (1.2 g, 61.38% yield).
  • Preparation 44 Synthesis of a Compound of Formula (Int-239) (Intermediate 239) [0244] To a solution of the compound of Formula (Int-20) (0.25 g, 1 mmol) and pyrroleboronic acid (0.52 g, 3.0 mmol) in mixture of 1,4-dioxane (10 ml) and water (0.5 ml) was added Cs 2 CO 3 (0.8 g, 3 mmol). The mixture was degassed by Argon and then charged Pd(dppf)Cl 2 .DCM (0.06 g, 0.1 mmol). The reaction mixture was heated to 110 °C till completion of the reaction.
  • Preparation 48 Synthesis of a Compound of Formula (Int-248) (Intermediate 248) [0248] To a solution of the compound of Formula (Int-23) (350mg, 1.09 mmol), benzylamine (0.24 ml, 2.17 mmol) in 1,4-dioxane (3.5ml, 10 vol.) was added Cs 2 CO 3 (530 mg, 1.63mmol) at room temperature and the reaction mixture was de-gassed using argon. Xantphos (252mg, 0.43mmol) and Pd2dba3.CH 2 Cl 2 (99mg, 10 mol %) was added and the reaction mixture was heated to 120°C till completion of the reaction.
  • Preparation 52 Synthesis of a Compound of Formula (Int-252) (Intermediate 252) [0252] To a solution of the compound of Formula (Int-237) (0.1 g, 1 mmol) and 1- (tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (0.21 g, 2.5 mmol) in mixture of 1,4-dioxane (4 ml) and water (0.2 ml) was added Cs 2 CO 3 (0.3 g, 3 mmol).
  • Example 1 Synthesis of a Compound of Formula (15) [0256] To a solution of the compound of Formula (Int-20) (0.5 g, 1.64 mmol) and 5- fluoropyridin-2-amine (0.37 g, 3.23 mmol) in 1,4-dioxane (4 ml) was added xanthphos (0.19 g, 0.33 mmol), Cs 2 CO 3 (1.6 g, 4.92 mmol) and (Pd 2 dba 3 ) (0.15 g, 0.16 mmol), The mixture was degassed by nitrogen and then heated to 130°C till completion of the reaction.
  • Example 3 Synthesis of a Compound of Formula (22) [0258] To a solution of the compound of Formula (Int-8) (0.200 g, 1 mmol) and 5- fluoropyridin-2-amine (0.146 g, 2 mmol) in 1,4-dioxane (4 ml) was added xanthphos (0.075 g, 0.2 mmol), Cs 2 CO 3 (0.636 g, 3 mmol) and Pd2(dba)3 (0.059 g, 0.1 mmol), The mixture was degassed by nitrogen and then heated to 130°C till completion of the reaction.
  • Example 4 Synthesis of example a Compound of Formula (24): [0259] A compound of Formula (24) (0.010 g) as a yellow solid, was prepared from the compound of Formula (Int-8) and pyridin-2-amine using similar procedure as described for the compound of Formula (22).
  • Example 5 Synthesis of a Compound of Formula (27) [0260] A compound of Formula (27) was prepared from the compound of Formula (Int- 8) and 6-aminonicotinonitrile using similar procedure as described for 22 (0.05 g, 19.7%) as a yellow solid.
  • Example 7 Synthesis of a Compound of Formula (77) [0262] A compound of Formula (77) (0.04 g, 6.9%) as a yellow solid, was prepared from the compound of Formula (Int-23) (0.05 g, 0.155 mmol) and cyclopropanecarboxamide (0.026 g, 0.31 mmol) using similar procedure as described for the compound of Formula (22).1H NMR (400 MHz, DMSO-d6): d 9.99 (s, 1H), 9.81 (s, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 6.36 (s, 1H), 6.11 (s, 1H), 3.65 (s, 3H), 2.06 (s, 3H), 1.89-1.92 (m, 1H), 0.78-0.79 (m, 4H) ppm.
  • Example 8 Synthesis of a Compound of Formula (387) [0263] To a solution of the compound of Formula (Int-160) (200 mg, 0.59 mmol), tert- butyl carbonate (139 mg, 1.19 mmol) in 1,4-dioxane (10ml, 10 vol.) was added Cs 2 CO 3 289 mg, 0.89 mmol) at room temperature and the reaction mixture was de-gassed using argon.
  • Example 10 Synthesis of a Compound of Formula (31) [0266] A suspension of the compound of Formula (Int-8) (0.04 g, 0.162 mmol) in MeOH and 10% palladium on charcoal (0.03 g) was stirred in a hydrogen atmosphere at room temperature till completion of the reaction. After completion of reaction, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford a compound of Formula (31) (0.02 g, 57%) as a white solid.
  • Example 11 Synthesis of a Compound of Formula (32) (Intermediate 8) [0267]
  • the compound of Formula (Int-1) (5 g, 17.42 mmol), the compound of Formula (Int-2) (2.9 g, 20.9 mmol) and Cs 2 CO 3 (11.3 g, 34.84 mmol), were added to 5 ml of DMSO under an inert atmosphere.
  • the reaction was heated to 120°C till completion of the reaction.
  • the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by column chromatography (eluent: 50% ethyl acetate in hexane) to afford compound the compound of Formula (32) (3.5 g, 65%) as a grey solid.
  • Example 12 Synthesis of a Compound of Formula (44) Int15 [0268] To a solution of the compound of Formula (Int-15) (0.35 g, 0.79 mmol) in methanol, concentrated HCl solution (2 ml) was added and the mixture was stirred till completion of the reaction at 40°C. After completion of reaction, mixture was concentrated under vacuum and resulting residue was triturated with diethyl ether to give HCl salt of a compound of Formula (44) as a brown solid (0.20 g, 74%).
  • Example 19 Synthesis of a Compound of Formula (385) [0275] To a solution of the compound of Formula (Int-238) (0.5 g, 1.1 mmol) in methanol, concentrated HCl in dioxane solution (2 ml) was added and the mixture was stirred till completion of the reaction at 70 °C.
  • Example 20 Synthesis of a Compound of Formula (386) [0276] To a solution of the compound of Formula (Int-232) (0.1 g, 0.21 mmol) in Methanol (2 ml) was added Conc. HCl (1 ml) and stirred at 50-55°C. After completion of reaction, the solid was filtered, washed with methanol and dried to give the HCl salt of a compound of Formula (386) (0.072 g, 83.72% yield).
  • Example 21 Synthesis of a Compound of Formula (390) [0277] To a solution of the compound of Formula (Int-240) (0.08 g.0.17 mmol) in DCM (3 ml) was added HCl in dioxane (0.8 ml) and stirred for 2 hours at RT. After completion of reaction, the solvent was removed under vacuum and residue was stirred in mixture of DCM:MeOH (9:1) (3 ml). The solid was filtered and washed with minimum mixture of DCM:MeOH (9:1), dried under vacuum at 50°C to give a compound of Formula (390) (0.05 g, 70.22% yield) as HCl salt.
  • Example 22 Synthesis of a Compound of Formula (167) [0278] To a solution of the compound of Formula (Int-233) (0.06 g, 0.14 mmol) in DCM (1 ml) was added HCl in dioxane (1 ml) and stirred at 25-30°C. After completion of reaction, the solid was filtered, washed with DCM and dried to give the HCl salt of a compound of Formula (167) (0.03 g, 56.81% yield).
  • Example 24 Synthesis of a Compound of Formula (193) [0280] To a solution of the compound of Formula (Int-235) (0.06 g, 0.12 mmol) in DCM (1.2 ml) was added HCl in dioxane (0.6 ml) and stirred for at 25-30°C. After completion of reaction, the solid was filtered, washed with DCM and dried to give the HCl salt of a compound of Formula (193) (0.04 g, 74.07% yield).
  • Example 26 Synthesis of a Compound of Formula (215) [0282] A suspension of the compound of Formula (Int-247) (250mg, 0.66 mmol) in MeOH:DCM (5 ml, 1:1) and 10% palladium on charcoal (25mg, 10% w/w) was stirred in a hydrogen atmosphere at 60°C till completion of the reaction.
  • Example 27 Synthesis of a Compound of Formula (380) [0283] A suspension of the compound of Formula (Int-248) (300mg, 0.76mmol) in MeOH:DCM (5 ml, 1:1) and 10% palladium on charcoal (30mg, 10% w/w) was stirred in a hydrogen atmosphere at 60°C till completion of the reaction.
  • Example 28 Synthesis of a Compound of Formula (381) [0284] A suspension of the compound of Formula (Int-249) (240mg, 0.61mmol) in MeOH:DCM (5 ml, 1:1) and 10% palladium on charcoal (24 mg, 10% w/w) was stirred in a hydrogen atmosphere at 60°C till completion of the reaction.
  • Example 29 Synthesis of a Compound of Formula (382) [0285] A suspension of the compound of Formula (Int-250) (350mg, 0.88mmol) in MeOH:DCM (5 ml, 1:1) and 10% palladium on charcoal (35 mg, 10% w/w) was stirred in a hydrogen atmosphere at 60°C till completion of the reaction.
  • Example 30 Synthesis of a Compound of Formula (383) [0286] A suspension of the compound of Formula (Int-246) (350mg, 0.92mmol) in MeOH:DCM (5 ml, 1:1) and 10% palladium on charcoal (35mg, 10% w/w) was stirred in a hydrogen atmosphere at 50°C till completion of the reaction.
  • Example 31 Synthesis of a Compound of Formula (201) [0287] To a solution of the compound of Formula (Int-251) (0.15 g) in DCM (1.2 ml) was added HCl in dioxane (0.6 ml) and stirred for 2 hours at RT. After completion of reaction, the solvent was removed under vacuum to afford crude solid which on triturating with ethyl acetate gave a compound of Formula (201) (0.12 g, 89.88% yield) as HCl salt. In a stirred saturated solution of sodium bicarbonate (2.5 ml) was added portion wise above obtained HCl salt (0.12 g, 1 mmol). Stirred for 2 hours and then solid was filtered and washed with water.
  • Example 32 Synthesis of a Compound of Formula (391) [0288] To a solution of the compound of Formula (Int-252) (0.085 g, 0.19 mmol) in DCM (3 ml) was added HCl in dioxane (0.85 ml) and stirred for 2 hours at RT. After completion of reaction, the solvent was removed under vacuum and residue was stirred in mixture of DCM:MeOH (9:1) (2 ml). The solid was filtered and washed with minimum mixture of DCM:MeOH (9:1), dried under vacuum at 50°C to give a compound of Formula (391) (0.046 g, 60.80% yield) as HCl salt.
  • a compound of Formula (92) may be prepared from the compound of Formula (28) by using P2S5 in THF.
  • Example 34 Synthesis of a Compound 33
  • a compound of Formula (33) may be prepared from the compound of Formula (35) by utilizing Olah’s reagent.
  • Example 35 Synthesis of a Compound of Formula (34)
  • a compound of Formula (34) may be prepared from the compound of Formula (Int-8) using palladium based catalyst and boronic acid.
  • the following compounds may be prepared according to methods described herein by using appropriate intermediates:
  • BIOLOGICAL ASSAYS TYK2 JH2 Binding Assay ASSAY PROCEDURE Binding to TYK2 JH2 domain for test compounds was determined using the KINOMEscanTM platform by DiscoverX, which is a comprehensive high-throughput system for screening compounds against large numbers of human kinases.
  • KINOMEscanTM is based on a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized, active-site directed ligand. The assay is performed by combining three components: DNA-tagged kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand is measured via quantitative PCR of the DNA tag.
  • a fusion protein of a partial length construct of human TYK2 JH2domain- pseudokinase (amino acids G556 to D888 based on reference sequence NP 003322.3) and the DNA binding domain of NFkB was expressed in transiently transfected HEK293 cells. From these HEK 293 cells, extracts were prepared in M-PER extraction buffer (Pierce) in the presence of Protease Inhibitor Cocktail Complete (Roche) and Phosphatase Inhibitor Cocktail Set II (Merck) per manufacturers’ instructions.
  • M-PER extraction buffer Pierce
  • the TYK2(JH2domain- pseudokinase) fusion protein was labelled with a chimeric double-stranded DNA tag containing the NFkB binding site (5’-GGGAATTCCC-3’) fused to an amplicon for qPCR readout, which was added directly to the expression extract (the final concentration of DNA-tag in the binding reaction is 0.1 nM).
  • Streptavidin-coated magnetic beads (Dynal M280) were treated with a biotinylated small molecule ligand for 30 minutes at room temperature to generate affinity resins the binding assays.
  • the liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding.
  • the binding reaction was assembled by combining 15.75 ⁇ l of DNA-tagged kinase extract, 3.75 ⁇ l liganded affinity beads, and 0.18 ⁇ l test compound (PBS/0.05% Tween 20/10 mM DTT/0.1% BSA/2 pg/ml sonicated salmon sperm DNA)].
  • Extracts were used directly in binding assays without any enzyme purification steps at a >10,000- fold overall stock dilution (final DNA tagged enzyme concentration ⁇ 0.1 nM). Extracts were loaded with DNA-tag and diluted into the binding reaction in a two-step process. First extracts were diluted 1:100 in 1x binding buffer (PBS/0.05% Tween 20/10 mM DTT/0.1% BSA/2 pg/ml sonicated salmon sperm DNA) containing 10 nM DNA-tag. This dilution was allowed to equilibrate at room temperature for 15 minutes and then subsequently diluted 1:100 in 1x binding buffer. Test compounds were prepared as 111x stocks in 100% DMSO.
  • Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. [0296] All compounds for Kd measurements are distributed by acoustic transfer in the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plates in a final volume of 0.02 mL. Assays were incubated with shaking for 1 hour at room temperature, then the beads were pelleted and washed with wash buffer (1x PBS, 0.05% Tween 20) to remove displaced kinase and test compound.
  • the washed beads were re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 ⁇ non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • the kinase concentration in the eluates was measured by qPCR.
  • qPCR reactions were assembled by adding 2.5 ⁇ L of kinase eluate to 7.5 ⁇ L of qPCR master mix containing 0.15 ⁇ amplicon primers and 0.15 ⁇ amplicon probe.
  • the qPCR protocol consisted of a 10-minute hot start at 95°C, followed by 35 cycles of 95°C for 15 seconds, 60°C for 1 minute. Test compounds were prepared as 111X stocks in 100% DMSO.
  • Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points.
  • Binding assays for JAK1 JH2, JAK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, TYK2 JH1 Binding Assays Assay Procedure [0302] Binding assays for JAK1 JH2, JAK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, TYK2 JH1 for test compounds was determined using the KINOMEscanTM platform by DiscoverX. Assay protocol followed was similar to that of TYK2 JH2. The Kd values for example compounds are reported in Table 2.
  • Kase activity assays were performed using the LANCETM Ultra Kinase Activity Assay platform (Perkin Elmer).
  • LANCE Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) assays use a proprietary europium chelate donor dye, W1024 (Eu), together with ULightTM, a small molecular weight acceptor dye with a red-shifted fluorescent emission.
  • Test compounds were prepared as 10mM stock in 100% DMSO and further diluted to 0.4 mM in kinase buffer. A 3.33- fold series dilution was performed to generate 11 concentrations of each test compound.
  • Kinase enzymes, ATP and substrate (U-lightTM JAK-1) were added as per in-house standardized protocol (details provided in Table 3). The assay was carried out in a 384 well plate, where 2.5 ⁇ L of 4X kinase enzyme and 2.5 ⁇ L of 4X test compound were added.
  • E1 A compound having the following formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y and Y’ is independently NR 5 , CR 5 R 5’ , O or S; each X is independently CR 6 or N; M is NR 3 , O, S or Se; Z is NR 4 , CR 4 R 4’ , O, S or a bond; R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 - C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkoxy,
  • E2 A compound according to E1, wherein Y is NR 5 . E3. A compound according to E1 or E2, wherein Y’ is NR 5 or O. E4. A compound according to any one of E1-E3, wherein each X is CR 6 . E5. A compound according to any one of E1-E4, wherein M is O. E6. A compound according to any one of E1-E5, wherein Z is NR 4 or CR 4 R 4’ . E7. A compound according to any one of E1-E6, wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl. E8.
  • a compound according to any one of E1-E7, wherein R 2 is selected from the group selected from hydrogen, halogen, -NR 9 R 10 , -NR 8 C( O)R 7 , and heteroaryl.
  • R 4 and R 4’ are independently hydrogen.
  • R 5 is hydrogen.
  • R 8 is hydrogen.
  • E15 A compound according to any one of E1-E14, wherein R b is C 1 -C 6 alkyl.
  • E17 A compound according to E1-E16, wherein E18. A compound according to any one of E1-E17, wherein R 2 is heteroaryl.
  • E20. A compound according to any one of E1-E17, wherein R 2 is selected from the group consisting of hydrogen, halogen, -NH 2 , -N(Me) 2 , E21.
  • Y’, M, Z, R 1 , R 2 , and R 6 are as defined in E1.
  • E23. A compound according to E22, wherein Y’ is NR 5 or O.
  • E24. A compound according to E22 or E23, wherein M is O.
  • E25. A compound according to any one of E22-E25 wherein Z is NR 4 or CR 4 R 4’ .
  • E26. A compound according to any one of E22-E25, wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl.
  • a compound according to any one of E22-E26, wherein R 2 is selected from the group consisting of hydrogen, halogen, -NR 9 R 10 , -NR 8 C( O)R 7 , and heteroaryl.
  • E28. A compound according to any one of E22-E27, wherein R 4 and R 4’ are each hydrogen.
  • R 8 is hydrogen.
  • R b is C 1 -C 6 alkyl.
  • E36 A compound according to any one of E22-E35, wherein R 2 is heteroaryl.
  • E41 A compound according to E40, wherein Y’ is NR 5 or O.
  • E42 A compound according to E40 or E41, wherein M is O.
  • E43 A compound according to any one of E40-E42, wherein Z is independently selected from the group consisting of NR 4 and CR 4 R 4’ .
  • E44 A compound according to any one of E40-E43, wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl.
  • E45 A compound according to any one of E40-E43, wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 deuteroalkyl.
  • E46. A compound according to any one of E40-E45, wherein R 4 and R 4’ are independently hydrogen.
  • E49 A compound according to any one of E40-E48, wherein R b is C 1 -C 6 alkyl.
  • E50 A compound according to any one of E40-E49, wherein –NR 9 R 10 is selected from the group consisting of -NH 2 , -N(Me) 2 , and E51.
  • a compound according to E1 wherein the compound is represented by formula (Is): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is heteroaryl.
  • E53. A compound according to E52, wherein R 2 is imidazolyl or pyrrolyl.
  • a compound according to E52, wherein R 2 is E55.
  • E56. A compound according to E55, wherein R 6 is hydrogen.
  • E57. A compound according to E55, wherein R 2 is imidazolyl or pyrrolyl.
  • E 58. A compound according to E55, wherein R E59.
  • E60 A pharmaceutical composition comprising one or more compounds according to any one of E1-E59 and a pharmaceutically acceptable carrier or diluent.
  • E61. A method of treating a TYK2-mediated disorder comprising administering to a patient in need thereof a compound of any one of E1-E59, or a pharmaceutically acceptable salt or stereoisomer thereof.

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Abstract

L'invention concerne des composés de formule (I) qui sont utiles dans la modulation de l'inflammation et le traitement de troubles associés en agissant sur TYK2 pour provoquer une inhibition de transduction de signal médiée par TYK2. Dans certains modes de réalisation, le trouble médié par TYK2 est un trouble auto-immun, un trouble inflammatoire, un trouble endocrinien, un trouble neurologique, un trouble prolifératif, ou un trouble associé à une transplantation.
PCT/IB2023/062810 2022-12-16 2023-12-15 Ligands de pseudokinase tyk2 et leurs utilisations Ceased WO2024127363A1 (fr)

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Citations (3)

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WO2014074661A1 (fr) 2012-11-08 2014-05-15 Bristol-Myers Squibb Company Composés hétérocycliques substitués par amide, utiles comme modulateurs d'il-12, il-23 et/ou de réponses à l'ifnα
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WO2003057676A1 (fr) * 2002-01-04 2003-07-17 Schering Corporation 3,4-di-substitutes pyridazinediones utilises en tant qu'antagonistes du recepteur de chimiokines cxc
WO2014074661A1 (fr) 2012-11-08 2014-05-15 Bristol-Myers Squibb Company Composés hétérocycliques substitués par amide, utiles comme modulateurs d'il-12, il-23 et/ou de réponses à l'ifnα
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