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WO2024127363A1 - Tyk2 pseudokinase ligands and uses thereof - Google Patents

Tyk2 pseudokinase ligands and uses thereof Download PDF

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Publication number
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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Prior art keywords
alkyl
compound
formula
heteroaryl
compound according
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PCT/IB2023/062810
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French (fr)
Inventor
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 Limited
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Publication of WO2024127363A1 publication Critical patent/WO2024127363A1/en

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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

Described herein are compounds of formula (I) that are useful in the modulation of inflammation and treating associated disorders by acting on TYK2 to cause TYK2-mediated signal transduction inhibition. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, an endocrine disorder, a neurological disorder, a proliferative disorder, or a disorder associated with transplantation.

Description

TYK2 PSEUDOKINASE LIGANDS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit under 35 U.S.C. § 119(e) to Indian Application No.202221073043, filed December 16, 2022, the entirety of which is incorporated herein by reference. FIELD [0002] 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). 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. BACKGROUND [0003] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and related biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is the protein kinase family that consists of a large family of structurally related enzymes. These enzymes are responsible for the control of a variety of signal transduction processes within the cell. 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 such as environmental and chemical stress signals 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. [0004] Among the protein kinase family, the Janus Kinase (JAK) family has a well- established role in inflammation-related pathologies. Janus kinases (JAKs) 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. [0005] 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. [0006] Cytokine pathways that function through JAK1 activation include γc 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 IFNα/β, IFN-γ, and IL-10. 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 γc cytokines like IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Similarly, TYK2 activation is associated with the signaling cascade of interferons like IFNα/β, IFN-γ 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. [0007] TYK2 has been identified as the signaling messenger common to IFN-α, 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. In mice, TYK2 knockout has been shown to reduce dextran sulfate sodium or 2,4,6- trinitrobenzene sulfonic acid-induced colitis. [0008] 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. Additionally, TYK2 knockout in mice has been observed to reduce methylated BSA injection-induced footpad thickness. [0009] Associations between disease susceptibility for psoriasis and TYK2 was established through a genome-wide association study of 2,622 individuals with psoriasis. Similarly, in mice TYK2 knockout decreased imiquimod-induced psoriasis like skin- inflammation. Further, knockout of TYK2 also significantly reduced both IL-23 and IL- 22-induced dermatitis. [0010] Genome-wide association studies of individuals with systemic lupus erythematosus (SLE), an autoimmune disorder, versus an unaffected cohort showed highly significant correlation between the TYK2 locus and SLE incidence. Joint linkage and association studies of various type I IFN signaling genes with SLE showed a strong and significant correlation between loss of function mutations to TYK2 and decreased prevalence of SLE in families with affected members. [0011] 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. [0012] Additionally, TYK2 plays an important role in maintaining tumor surveillance. TYK2 knockout mice show compromised cytotoxic T cell response and accelerated tumor development. However, since these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, TYK2 inhibitors may also be suitable for the treatment of transplant rejection. [0013] 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. Kinase activity of TYK2 has been reported to be essential for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F), in addition to an activating mutation (E957D), resulted in failure to transform. Thus, 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. [0014] Earlier studies have linked increased TYK2 expression with susceptibility to Multiple Sclerosis (MS). 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-β (Aβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Aβ administration led to decreased neuronal cell death. Not surprisingly, an increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. [0016] Inhibition of JAK-STAT signaling pathways is also implicated in hair growth and the reversal of the hair loss associated with alopecia areata. [0017] Additionally, a key structural feature of the JAK family -- the pseudokinase (JH2) domain -- was identified immediately N-terminal to the catalytic domain (JH1). The JH2 domains of the JAK family are known to regulate the function of the JH1 domains through an auto-inhibitory mechanism. These developments indicated that inhibition of 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. [0018] Particularly for 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. [0019] WO2014074661 discloses amide substituted pyridazine compounds including deucravacitinib as TYK2 modulators. WO2020086616 discloses different TYK2 inhibitors including fused tricyclic compounds. However, there still remains need for developing highly selective TYK2 modulators that have improved efficacy and better toxicological profile. [0020] Accordingly, compounds that inhibit the activity of TYK2 through modulation of the pseudokinase domain and deliver a pharmacological response that favorably treats one or more of the conditions described herein would be advantageous. SUMMARY [0021] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:
Figure imgf000007_0001
wherein: Y and Y’ is independently NR5, CR5R5’, O or S; each X is independently CR6 or N; M is NR3, O, S or Se; Z is NR4, CR4R4’, O, S or a bond; [0022] R1 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, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, alkyl, and haloalkyl; [0023] R2 is selected from the group consisting of hydrogen, halogen, -CN, -OR8, -SR8, - S(=O)R7, -S(=O)2R7, -NO2, -NR9R10, -NHS(=O)2R7, -S(=O)2NR9R10, -C(=O)R7, - OC(=O)R7, -C(=O)OR8, -OC(=O)OR8, -C(=O)NR9R10, -OC(=O)NR9R10, - NR8C(=O)NR9R10, -NR8C(=O)R7, -NR8C(=S)R7, -NR8C(=O)OR8, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, alkyl, or haloalkyl; [0024] R3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, 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, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, alkyl, and haloalkyl; [0025] R4 and R4’ are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, alkyl, or haloalkyl; [0026] R5 and R5’ are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, alkyl, or haloalkyl; or R5 and R5’ are taken together to form an oxo; [0027] R6 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, - ORb, -SRb, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRcRd, -NRcS(=O)2Rd, -S(=O)2NRcRd, - C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRcRd, - OC(=O)NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, or alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl or two adjacent R6 are taken together with the atoms to which they are attached to form a 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, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, alkyl, or haloalkyl, deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. [0028] R7 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, alkyl, or haloalkyl; [0029] R8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, alkyl, or haloalkyl; [0030] R9 and R10 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, alkyl, or haloalkyl; or R9 and R10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, alkyl, or haloalkyl; [0031] each Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, alkyl, or haloalkyl; [0032] each Rb is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, alkyl, or haloalkyl; [0033] each Rc and Rd is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, deuteroalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, alkyl, or haloalkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, alkyl, or haloalkyl. [0034] Also disclosed herein are pharmaceutical 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. [0035] Also disclosed herein are 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. [0036] Also disclosed herein are 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. In some embodiments, 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. In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. INCORPORATION BY REFERENCE [0037] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION Definitions [0038] In the context of this disclosure, a number of terms shall be utilized. [0039] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there is a plurality of definitions for terms herein, those in this section prevail. [0040] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Reactions and purification techniques can be performed, e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification. [0041] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein. [0042] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the agent” includes reference to one or more agents and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between about 1% and about 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0043] Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. 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. [0045] “Aliphatic chain” refers to a linear chemical moiety that is composed of only carbons and hydrogens. In some embodiments, the aliphatic chain is saturated. In some embodiments, the aliphatic chain is unsaturated. In some embodiments, the unsaturated aliphatic chain contains one unsaturation. In some embodiments, the unsaturated aliphatic chain contains more than one unsaturation. In some embodiments, the unsaturated aliphatic chain contains two unsaturations. In some embodiments, the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds. [0046] “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 C1-C6 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, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6 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. In some embodiments, the alkyl is a C1-C10 alkyl, a C1-C9 alkyl, a C1- C8 alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1- C2 alkyl, or a C1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. [0047] “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. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [- C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 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. In some embodiments, the alkenyl is a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, or a C2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. [0048] “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. Whenever it appears herein, a numerical range such as “C2-C6 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. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. [0049] “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, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, - CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [0050] “Alkoxy” refers to a radical of the formula -ORa where Ra 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. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -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. In some embodiments, 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. [0052] “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. In some embodiments, the aryl is a 6- to 10- membered aryl. In some embodiments, 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. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -SMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. [0053] “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. Unless stated otherwise specifically in the specification, 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. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. In some embodiments, cycloalkyl is bridged cycloalkyl. In some embodiments of a compound of Formula (I), bridged cycloalkyl is but not limited to
Figure imgf000016_0001
[0054] The term “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 π electronic system. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of shared spiro atoms between the ring and the ring, 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. In some embodiments, spirocycloalkyl is but not limited to
Figure imgf000016_0002
[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, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. [0056] “Haloalkyl” refers to an alkyl radical, as defined above that is substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, 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. In some embodiments, 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. [0057] “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. In one aspect, a heteroalkyl is a C1-C6 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. -NH-, -N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, - CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, or -CH(CH3)OCH3. Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. [0058] “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. [0059] 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. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms. Examples of 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, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3- oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3- dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. 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. [0060] In some embodiments, bridged heterocycloalkyl is but not limited to
Figure imgf000018_0001
[0061] The term “heterocycloalkyl” also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, 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. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, - OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. [0062] The term “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 π-electron system. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of spiro atoms shared between the ring and the ring, 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. [0063] In some embodiments), spiroheterocycloalkyl is but not limited to
Figure imgf000019_0001
[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. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. [0065] “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. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, 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, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1- oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, 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. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. Compounds [0066] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, or stereoisomer thereof:
Figure imgf000021_0001
wherein: Y and Y’ is independently NR5, CR5R5’, O or S; each X is independently CR6 or N; M is NR3, O, S or Se; Z is NR4, CR4R4’, O, S or a bond; [0067] R1 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; [0068] R2 is selected from the group consisting of hydrogen, halogen, -CN, -OR8, -SR8, - S(=O)R7, -S(=O)2R7, -NO2, -NR9R10, -NHS(=O)2R7, -S(=O)2NR9R10, -C(=O)R7, - OC(=O)R7, -C(=O)OR8, -OC(=O)OR8, -C(=O)NR9R10, -OC(=O)NR9R10, - NR8C(=O)NR9R10, -NR8C(=O)R7, -NR8C(=S)R7, -NR8C(=O)OR8, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; [0069] R3 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; [0070] R4 and R4’ are independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; [0071] R5 and R5’ are independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; or R5 and R5’ are taken together to form an oxo; [0072] R6 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, - ORb, -SRb, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRcRd, -NRcS(=O)2Rd, -S(=O)2NRcRd, - C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl or two adjacent R6 are taken together with the atoms to which they are attached to form a 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, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1- C6haloalkyl, C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. [0073] R7 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; [0074] R8 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; [0075] R9 and R10 are independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, and C1-C6haloalkyl; or R9 and R10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; [0076] each Ra is independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; [0077] each Rb is independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; [0078] each Rc and Rd is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. [0079] In some embodiments of a compound of Formula (I), the compound is of Formula (Ia):
Figure imgf000024_0001
wherein: Y’, M, Z, R1, R6, R9, and R10 are as defined hereinabove for Formula (I). [0080] In some embodiments of a compound of Formula (I), the compound is of Formula (Ib):
Figure imgf000024_0002
wherein: Y’, M, Z, R1, R6, R9, and R10 are as defined hereinabove for Formula (I). [0081] In some embodiments of a compound of Formula (I), the compound is of Formula (Ic):
Figure imgf000025_0001
wherein: Y’, M, Z, R1, R2, and R6 are as defined hereinabove for Formula (I). [0082] In some embodiments of a compound of Formula (I), the compound is of Formula (Id):
Figure imgf000025_0002
wherein: Y’, M, Z, R1, R2, and R6 are as defined hereinabove for Formula (I). [0083] In some embodiments of a compound of Formula (I), the compound is of Formula (Ie):
Figure imgf000025_0003
wherein: Y, M, Z, R1, R6, R9, and R10 are as defined hereinabove for Formula (I). [0084] In some embodiments of a compound of Formula (I), the compound is of Formula (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im):
Figure imgf000026_0001
wherein: Y’, M, Z, R1, R2, R6, R9, and R10 are as defined hereinabove for Formula (I). [0085] In some embodiments of a compound of Formula (I), the compound is represented as below:
Figure imgf000026_0002
Figure imgf000027_0001
wherein: Y, Y’, M, X, R1, R2, R4, R6, and R10 are as defined hereinabove for Formula (I). [0086] In some embodiments of a compound of Formula (I), (Ie) or (Iw)–(Iy), Y is NR5. In some embodiments of a compound of Formula (I), (Ie) or (Iw)–(Iy), R5 is hydrogen. In some embodiments of a compound of Formula (I), (Ie) or (Iw)–(Iy), Y is NH. [0087] In some embodiments of a compound of Formula (I), (Ia)-(Id), (If)-(In), or (Iw)– (Iy), Y’ is NR5 or O. In some embodiments of a compound of Formula (I), (Ia)-(Id), (If)- (In), or (Iw)–(Iy), R5 is hydrogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), (If)-(In), or (Iw)–(Iy), Y’ is NH or O. [0088] In some embodiments of a compound of Formula (I) or (Iv)–(Iy), X is CR6. [0089] In some embodiments of a compound of Formula (I), (Ia)-(Im), or (Ix), M is O. [0090] In some embodiments of a compound of Formula (I) and (Ia)-(Im), Z is NR4 or CR4R4’. In some embodiments of a compound of Formula (I) or (Ia)-(Im), R4 and R4’ are hydrogen. In some embodiments of a compound of Formula (I) and (Ia)-(Im), Z is NH and CH2. [0091] In some embodiments of a compound of Formula (I), (Ia)-(Im), (Io), or (Ir), R1 is hydrogen, C1-C6alkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Im), (Io), or (Ir), R1 is hydrogen, Me, or CD3. [0092] In some embodiments of a compound of Formula (I), (Ic), (Id), (Is), or (It), R2 is selected from the group consisting of hydrogen, halogen, -NR9R10, -NR8C(=O)R7 and heteroaryl. [0093] In some embodiments of a compound of Formula (I), (Ia)-(Id), (If)-(Im), (Iw), or (Iy), R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl, C1- C6deuteroalkyl; with the proviso that when Y’ is CR5R5’, then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. [0094] In some embodiments of a compound of Formula (Ie), (Iq), (Iu), or (Iv), R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl. [0095] In some embodiments of a compound of Formula (I), (Ic), (Id), (Is), or (It), R7 is selected from the group consisting of C1-C6alkyl and cycloalkyl, wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1- C6haloalkyl. [0096] In some embodiments of a compound of Formula (I), (Ic), (Id), (Is), or (It), R8 is hydrogen. [0097] In some embodiments of a compound of Formula (I), (Ia)-(m), (Is), or (It), R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl, wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. [0098] In some embodiments of a compound of Formula (Ip), R10 is selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl, wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1- C6haloalkyl. [0099] In some embodiments of a compound of Formula (I), (Ia)-(Im), (Iq), (Iu)-(Iw), or (Iy), Rb is C1-C6alkyl. [0100] In some embodiments of a compound of Formula (I), (Ia)-(Im), (Iq), (Iu)-(Iw), or (Iy), Rc and Rd is independently hydrogen or C1-C6alkyl, wherein each alkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. [0101] In some embodiments of a compound of Formula (I), (It), (Iu), or (Iw)-(Iy),
Figure imgf000029_0001
[0102] In some embodiments of a compound of Formula (I), (Ic), (Id), (Is), or (It), R2 is heteroaryl. [0103] In some embodiments of a compound of Formula (I), (Ic), (Id), (Is), or (It), R2 is imidazolyl or pyrrolyl. [0104] In some embodiments of a compound of Formula (I), (Ic), (Id), (Is), or (It), R2 is selected from the group consisting of hydrogen, halogen, -NH2, -N(Me)2
Figure imgf000029_0002
, ,
Figure imgf000029_0003
[0105] In some embodiments of a compound of Formula (I), (Ia)-(Id), (If)-(Im), (Iw), or (Iy), R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, - N(Me)2, -C(=O)OMe, -C(=O)NH2, C1-C6alkyl,
Figure imgf000029_0005
, with the proviso that when Y’ is CR5R5’, then R6 is n
Figure imgf000029_0004
[0106] In some embodiments of a compound of Formula (Ie), (Iq), (Iu), or (Iv), R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, -N(Me)2, - C(=O)OMe, -C(=O)NH2, C1-C6alkyl,
Figure imgf000030_0001
[0107] In an embodiment of the invention, wherever applicable, 5,10-dihydropyrido[3,4- b]quinoxaline derivatives of formula (I) also encompasses corresponding pyrido[3,4- b]quinoxaline derivatives.
Figure imgf000030_0002
[0108] 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. [0109] In some embodiments of a compound of Formula (I), the compound, or a pharmaceutically acceptable salt, or stereoisomer thereof, is selected from the group consisting of:
Figure imgf000030_0003
- e
Figure imgf000031_0001
- - 4- -1-
Figure imgf000032_0001
- - - 4- 4- 4- 4- 4- 4- - 4- -
Figure imgf000033_0001
Figure imgf000034_0001
- -
Figure imgf000035_0001
- - de e- 4- 4- e-
Figure imgf000036_0001
- de - e- e 3- 3-
Figure imgf000037_0001
e e e 1-
Figure imgf000038_0001
1- de e e - e e e
Figure imgf000039_0001
de
Figure imgf000040_0001
de de de
Figure imgf000041_0001
e e 4- e - 2-
Figure imgf000042_0001
de -
Figure imgf000043_0001
The IUPAC names for compounds provided herein were obtained using ChemDraw® Professional, version: 19.1.1.21. Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [0110] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, 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. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, 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. In some embodiments, dissociable complexes are preferred. In some embodiments, 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. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labelled compounds as pharmaceutical compositions. Thus, in some embodiments, 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. Examples of 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 2H, 3H, 13C, 14C, l5N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, 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. Certain isotopically-labelled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labelled compound or a pharmaceutically acceptable salt, or stereoisomer thereof is prepared by any suitable method. [0112] In some embodiments, 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. [0114] In some embodiments, 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. In some embodiments, 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. [0115] 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, hydroxybenzoate, g- hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate. [0116] Further, 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, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. [0117] In some embodiments, 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. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. [0118] 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. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Preparation of the Compounds [0120] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “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. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), Wako Chemicals USA, Inc. (Richmond, VA), BLDpharm (Shanghai, China), Avra Labs (Telangana, India), and TCI Chemicals (Tokyo, Japan). [0121] 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. March,“Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional 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, Fuhrhop, J. and Penzlin G.“Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V.“Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471- 19031-4; March, J.“Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor)“Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S.“Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G.“Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C.,“Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes;“Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes. [0122] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on- line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Uses, Formulation and Administration Pharmaceutically acceptable compositions [0123] According to another embodiment, 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. In certain embodiments, 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. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [0124] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human. [0125] The term “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. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the 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. [0126] 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. [0127] As used herein, 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. [0128] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, 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. In some embodiments, the kinase and or kinase mediated signal transduction inhibited by the compounds and methods of the invention is TYK2. [0130] 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. [0131] As used herein, the terms “treatment,” “treat,” and “treating” refer 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. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, 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. [0132] Provided compounds are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with activity of TYK2 or mutants thereof. Thus, in certain embodiments, 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. [0133] As used herein, the term “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. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role. Such TYK2 -mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation. [0134] In some embodiments, 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. [0135] In some embodiments, the disorder is an autoimmune disorder. In some embodiments, 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. [0136] In some embodiments, the disorder is an inflammatory disorder. In some embodiments, 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. [0137] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, and/or essential or thrombocytosis. [0138] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, and/or type 1 diabetes. [0139] In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease. [0140] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, 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. [0141] In some embodiments, 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. In some embodiments, 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. [0143] 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. [0144] 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 pemphigoid, lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, other inflammatory or allergic conditions of the skin, solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, and melanoma), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia, T-cell leukemia, T-cell acute lymphoblastic leukemia (T-ALL), acute myelogenous leukemia (AML), or multiple myeloma, skin cancer such as cutaneous T-cell lymphoma (CTCL) (such as Sezary syndrome and mycosis fungoides), cutaneous B-cell lymphoma, myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), systemic inflammatory response syndrome (SIRS) and septic shock, Takayasu and Giant Cell arteritis, sarcoidosis, polymyositis, pityriasis rubra pilaris, granuloma annulare, morphea, lichen sclerosis, celiac disease, familial adenomatous polyposis, axial Spondylo Arthritis (SpA), thrombocytosis, polycystic ovary syndrome, Crouzon's syndrome, Alzheimer's disease, ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia, polychondritis, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, irritable bowel syndrome, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine opthalmopathy, Grave's disease, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. 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, acid- induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch- Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, vaginitis, vasculitis, or vulvitis, acute and chronic gout, chronic gouty arthritis, juvenile rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS), and/or osteoarthritis. [0145] In some embodiments, 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. [0146] In some embodiments, the inflammatory disease which can be treated according to the methods of this invention is a Thl- or Thl7-mediated disease. In some embodiments, the Thl-mediated disease is selected from Systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis). [0147] In some embodiments, 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. [0148] Furthermore, 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. [0149] According to one embodiment, 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. [0150] According to another embodiment, 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. In certain embodiments, 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. [0151] In another embodiment, the invention provides methods of selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, the one or more compounds is more than 2-fold selective over JAK1/2/3. In some embodiments, 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. [0152] The term “biological sample”, as used herein, 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. [0153] 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. Additionally, the various steps in the synthesis may be performed in an alternate sequence to give the desired compound. Example of compounds of the present invention prepared by methods described in the general schemes is given in the preparations and example section set out hereinafter. [0155] The reactions and techniques described in this section are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. This will sometime require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognised that another major consideration in the planning of any synthetic route in this field is the judicious choice of protecting groups present in the compounds described in this invention. [0156] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “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. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [0157] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. [0158] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. 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. [0159] 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. [0160] 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. For example, 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. Abbreviations and acronyms used herein are as follows: DMF-DMA N,N-dimethylformamide dimethyl acetal EtOH Ethanol HCl hydrochloric acid EtOAc ethyl acetate Na2CO3 sodium carbonate Na2SO4 sodium sulfate NH4Cl ammonium chloride CuBr2 copper(II) bromide t-BuONO tert-butyl nitrite NaOH Sodium hydroxide DCM dichloromethane TEA triethylamine DMF dimethylformamide K2CO3 potassium carbonate BnBr benzyl bromide MeOH methanol Pd(dppf)Cl2.DCM 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane EtMgBr ethylmagnesium bromide Pd(PPh3)4 palladium-tetrakis(triphenylphosphine) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) t-BuOH tert-butyl alcohol DPPA diphenylphosphoryl azide CuI copper(I) iodide DIPEA N,N-diisopropylethylamine THF tetrahydrofuran DMSO dimethyl sulfoxide MgSO4 magnesium sulfate KOAc potassium acetate CH3CN acetonitrile P2S5 phosphorus(V) sulfide Cs2CO3 cesium carbonate DMAc dimethylacetamide NMP N-Methylpyrrolidone NBS N-Bromosuccinimide 1,2-DME 1,2-dimethoxyethane (COCl)2 oxalyl chloride General methods of preparation: [0161] All of the compounds of Formula (I) (and derivatives thereof) may be prepared by the procedures described in the general methods presented below or by routine modifications thereof. 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. General processes for preparing compounds of Formula (I) of present invention are depicted below General Scheme 1: [0162] Unless specified, the definitions of R1, R2, X, Y, Z and M are the same as provided above for the compounds of Formula (I)
Figure imgf000060_0001
In general scheme 1, the compounds of the Formula (I)-2 (where Y=OH, SH, NH2 or NHRp, where Rp is N protecting group like tert-butyloxy carbonyl (“boc”) are reacted with a compound of the Formula (I)-3 (where L = halogen or any suitable leaving group) to give a compound of Formula (I)-1 in the presence of a suitable base, such as but not limited to, Cs2CO3 or Na2CO3, and a suitable solvent, such as, but not limited to, DMSO, DMAc, NMP, DMF, and sulfolane at a suitable temperature, such as but not limited to, from room temperature (25-30°C) to reflux temperature until desired conversion is achieved. 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 PPh3, SPhos, Ruphos, XPhos, and BrettPhos; and 2) suzuki coupling chemistry and the like. Alternatively, a compound of Formula (I) (where R2 = H) is obtained by subjecting compound of Formula (I)-1 to hydrogenation using suitable hydrogenating agent, such as but not limited to, Fe/NH4Cl, H2/Pd/C, and H2/raney nickel in the presence of suitable solvent, such as, but not limited to, methanol, ethanol, isopropanol, at a suitable temperature, such as but not limited to, from room temperature to reflux temperature until the desired conversion is achieved. General Scheme 2 [0163] Unless specified, the definitions of R1, R2, X, Y, Z, and M are the same as provided above for Formula (I).
Figure imgf000061_0001
In General Scheme 2, a compound of the Formula (I)-6 (where Y=OH, SH, NH2 or NHRp, where Rp is N protecting group like tert-butyloxy carbonyl [-boc]) is reacted with a compound of the Formula (I)-7 (where L = halogen or any suitable leaving group) in the presence of a suitable base, such as but not limited to Cs2CO3, and a suitable solvent, such as but not limited to DMSO, DMAc, NMP, DMF, and/or sulfolane to give a compound of Formula (I)-5 (where Y=S, O, NH, or NRp) The compound(s) of Formula (I)-5 is hydrogenated using a suitable hydrogenating agent, such as, but not limited to, Fe/NH4Cl, H2/Pd/C, and H2/raney nickel, in a suitable solvent, such as, but not limited to, ethanol and/or water to give compound of Formula (I)-4 which can be further converted to compound of Formula (I)-1 by intramolecular cyclization using suitable base, such as but not limited to, Cs2CO3 in a suitable solvent, such as but not limited to, DMSO, DMAc, NMP, DMF, and sulfolane. General Schemes 3 and 3’: [0164] Unless specified, the definitions of R1, R2, X, Y, Y’, Z, and M are the same as provided above for Formula (I):
Figure imgf000062_0001
In General Schemes 3 and 3’, a compound of Formula (I)-10 or 1-10’ (where L= halogen or any suitable leaving group, Y and Y’ are each CR5R5’) is reacted with a compound of Formula (I)-11 or (I)-11’ (where L is halogen or a suitable leaving group) to give a compound of Formula (I)-9 or (I)-9’ by employing suzuki coupling using a suitable catalyst, such as, but not limited to, Pd(PPh3)4, in the presence of a suitable base, such as, but not limited to, K2CO3, and a suitable solvent, such as but not limited to, DMSO, DMAc, NMP, DMF, Sulfolane. The compound of Formula (I)-9 or (I)-9’ is hydrogenated using suitable hydrogenating agent, such as, but not limited to, Fe/NH4Cl, H2/Pd/C, and H2/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, Cs2CO3, in a suitable solvent, such as but not limited to, DMSO. General Scheme 4: [0165] Unless specified, the definitions of R1, R2, X, Y, Y’, Z, and M are the same as provided above for Formula (I)
Figure imgf000063_0001
[0166] In General Scheme 4, a compound of the (I)-12 (where Y and Y’=OH, SH, NH2, or NHRp and where Rp is a N protecting group like tert-butyloxy carbonyl (boc) is reacted with a compound of Formula (I)-13 (where L is halogen or any suitable leaving group) to give a compound of Formula (I) wherein the reaction occurs in the presence of a suitable base, such as but not limited to, Cs2CO3, and a suitable solvent, such as but not limited to, DMSO, DMAc, NMP, DMF, and/or sulfolane, at a suitable temperature, such as but not limited to, from room temperature (25-30°C) to reflux temperature, until the desired conversion is achieved. Alternatively, when at least one Y and Y’ is NRp, a compound of Formula (I) can be obtained by deprotection methods using suitable acids, such as, but not limited to hydrochloric acid. [0167] The routes described herein, including those mentioned in the Examples and Preparations, illustrate methods of synthesising compounds of Formula (I). The skilled person will appreciate that the compounds of the invention, and intermediates thereto, could be made by methods other than those specifically described herein, for example by adaptation of the methods described herein, for example by methods known in the art. [0168] In the general synthetic methods described herein, unless otherwise specified, the substituents are as defined above with reference to the compounds of Formula (I) above. [0169] 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. [0170] 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. The following non-limiting Preparations and Examples illustrate the preparation of compounds and salts of the present invention. Examples: [0171] Preparation 1: Synthesis of a Compound of Formula (Int-1) (Intermediate (Int) 1)
Figure imgf000064_0001
Step 1: Synthesis of a Compound of Formula (1b) [0172] To a round bottle flask equipped with a condenser, a compound of Formula (1a) (80 g, 396 mmol) and DMF-DMA (43 ml, 324 mmol) were charged at room temperature. The mixture was warmed to 90°C, stirred for 90 min under removal of EtOH formed during the reaction by distillation. After cooling to 0°C, the mixture was treated with 28% aqueous ammonia (100 ml). The mixture was stirred for 30 minutes at the same temperature. The pH of the mixture was adjusted with aqueous HCl. The resulting solid was filtered off, washed with ice-cold H2O, and dried to provide a compound Formula (1b) (45 g, 46%) as an off-white solid. 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. After completion, the reaction mixture was cooled to 0°C, filtered and the filter cake was washed with ice-cold H2O. The solid was dried to give a compound of Formula (1c) (35 g, 84%) as a light yellow solid. 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. The mixture was extracted with EtOAc and the organic phases were washed with aqueous Na2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product as a brown oil which was purified by column chromatography (eluent: 50% ethyl acetate in hexane) to give a compound of Formula (1d) (23.8 g, 58 %) as a light yellow solid. 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), NH4Cl (19.2 g, 359.2 mmol), EtOH (160 ml), and H2O (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. The combined organic extracts were washed with water and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the compound of Formula (1e( (15 g, 72%) as a yellow solid which was carried on without further purification. 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 CH3CN (200 ml), CuBr2 (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. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 30% ethyl acetate in hexane) to afford the compound of Formula (1f) (11 g, 62 % yield) as a yellow oil. 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 H2O (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 H2O 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. The mixture was cooled and stirred at 0°C for 15 min followed by dropwise addition of TEA (13 ml, 92.6 mmol). The resulting mixture was allowed to warm to room temperature and was stirred overnight. The residue was extracted using DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound Int-1 (5 g, 47 %) as an off-white solid.
Preparation 2: Synthesis of a Compound of Formula (Int-2) (Intermediate 2)
Figure imgf000067_0001
Step 1- Synthesis of a Compound of Formula (2b): [0179] To a solution of a compound of formula (2a) (30.0 g, 191.08 mmol) in 100 ml DMF was added K2CO3 (31.6 g, 229.29 mmol). Then, benzylbromide (32.7 g, 63.7 mmol) was added to the reaction mixture at ambient temperature. The mixture was stirred till completion of the reaction. After completion of reaction, H2O was added and the product was extracted with EtOAc. The organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated to afford a compound of Formula (2b) (26 g, 75 % yield) as a yellow solid, which was used for the next reaction without further purification. 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 H2O. The reaction mixture was neutralised with 2N aqueous HCl and was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the compound of Formula (2c) as a yellow solid (27 g, 100%) which was used for the next reaction without further purification. 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. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to afford a compound of Formula (Int-2) (20 g, 96%) as a brown solid. The mixture was used directly for the next step without further purification. Preparation 3: Synthesis of a Compound of Formula (Int-3) (Intermediate-3)
Figure imgf000068_0001
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. The reaction mixture was diluted with H2O (50 ml). The reaction mixture was neutralised with 2N aqueous HCl and was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford a compound of Formula (3a) as a yellow solid (2.1 g, 95%) which was carried on without further purification. 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%). Preparation 4: Synthesis of a Compound of Formula (Int-4) (Intermediate 4)
Figure imgf000068_0002
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%). Preparation 5: Synthesis of a Compound of Formula (Int-5) (Intermediate 5)
Figure imgf000069_0001
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 K2CO3 (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. H2O was added and the product was extracted with EtOAc. The combined organic layers were washed with H2O, dried over Na2SO4, filtered, and concentrated to afford the compound of Formula (2b) (140 g, 89% yield) as a yellow solid, which was carried on without further purification. 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. H2O was added and the solid precipitate was filtered and dried to afford a compound of Formula (5a) (96 g, 52% yield) as a yellow solid, which was carried on without further purification. 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. H2O was added and the solid precipitate was filtered and dried to afford the compound of Formula (5b) as a yellow solid (84 g, 84%) which was carried on without further purification. 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. Then, Pd(dppf)Cl2.DCM (20.04 g, 24.55 mmol) was added and the reaction mixture was further degassed with nitrogen. Then reaction mixture was heated at 100°C. After completion of reaction, the mixture was passed through a pad of celite and the filtrate was concentrated in under reduced pressure. H2O was added and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude product was further purified by column chromatography to afford the compound of Formula (5c) (35 g, 37%) as yellow solid. 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 K2CO3 (16.6 g, 120.4 mmol) was dissolved in a mixture of H2O (10 ml) and 1,2-DME (30 ml). Reaction mixture was degassed with nitrogen. Then Pd(dppf)Cl2.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 H2O and extracted with DCM. Organic layer was combined, washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. The crude was further purified by column chromatography to afford the compound of Formula (5d) (7 g, 43 %) as brown solid. 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. The mixture was used directly for the next step without further purification. Preparation 6: Synthesis of a Compound of Formula (Int-6) (Intermediate 6)
Figure imgf000071_0001
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)
Figure imgf000072_0001
[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)
Figure imgf000072_0002
[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 Cs2CO3 (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 the compound of Formula (Int-8) (3.5 g, 65%) as a grey solid.1H NMR (400 MHz, DMSO-d6): d 9.82 (s, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 6.75 (dd, J = 8.4 Hz, 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 3.82 (s, 3H) ppm. LCMS: m/z 309.15 (M+H+); HPLC: 98.40%.
Preparation 9: Synthesis of a Compound of Formula (Int-9) (Intermediate 9)
Figure imgf000073_0001
[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 Cs2CO3 (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)
Figure imgf000073_0002
[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)
Figure imgf000074_0001
[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)
Figure imgf000074_0002
[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)
Figure imgf000074_0003
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 NH4Cl, 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. Preparation 14: Synthesis of a Compound of Formula (Int-14) (Intermediate 14)
Figure imgf000075_0001
[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). [0203] 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)
Figure imgf000076_0001
[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 H2O, K2CO3 (0.07 g, 0.487 mmol) and Pd(PPh3)4 (0.04 g, 0.03 mmol). The mixture was degassed by nitrogen and then heated to 110°C till completion of the reaction. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure, before being purified using column chromatography providing Int-15 (0.06 g, 84 % yield). Preparation 16: Synthesis of the Compound of Formula (Int-16) (Intermediate 16)
Figure imgf000076_0002
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)
Figure imgf000077_0001
[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)
Figure imgf000077_0002
[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)
Figure imgf000077_0003
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. 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 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 added methyl amine (0.14 g, 4.46 mmol). The mixture was cooled and stirred at 0°C for 15 min followed by dropwise addition of TEA (2 ml, 9.26 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The residue was extracted using DCM. The organic layer was dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 30% ethyl acetate in hexane) to afford the compound of Formula (Int-19) (0.3 g, 28.5 %) as a yellow solid. Preparation 20: Synthesis of a Compound of Formula (Int-20) (Intermediate 20)
Figure imgf000078_0001
[0210] The compound of Formula (Int-19) (0.3 g, 1.06 mmol), the compound of Formula (Int-2) (0.18 g, 1.28 mmol) and Cs2CO3 (0.61 g, 2.12 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 the compound of Formula (Int-20) (0.400 g, 37%) as a brown solid.1H NMR (400 MHz, DMSO-d6): d 9.81 (s, 1H), 8.69 (s, 1H), 8.14 (s, 1H), 6.76 (t, J = 8.0 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 2.76 (m, 3H) ppm. LCMS: m/z 306.24 (M+H+) Preparation 21: Synthesis of a Compound of Formula (Int-21) (Intermediate 21)
Figure imgf000078_0002
[0211] A compound of Formula (Int-21) (0.15 g, 46 %) as a grey solid, was prepared from the compound of Formula (Int-17) using the procedure described for the compound of Formula (Int-20).1H NMR (400 MHz, DMSO-d6): d 9.90 (s, 1H), 8.19 (s, 2H), 6.76 (t, J = 8.4 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H) ppm. LCMS: m/z 292.27 (M+H+). Preparation 22: Synthesis of a Compound of Formula (Int-22) (Intermediate 22)
Figure imgf000079_0001
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. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude product was further purified by column chromatography to afford the compound of Formula (22b) (1 g, 17 %) as pale yellow solid. 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)
Figure imgf000079_0002
[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+). Preparation 24: Synthesis of Int-24 (Intermediate 24)
Figure imgf000080_0001
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 Na2CO3, H2O, brine, dried over Na2SO4 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 Na2SO4 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] To a solution the compound of Formula (24c) (2.5 g, 13.33 mmol) in DMF (50mL) and benzyl bromide (4.8 mL, 40.10 mmol) was added at room temperature and stirred till completion of the reaction. After completion of reaction, the reaction mixture was poured in to ice water, extracted with EtOAc and the organic phases were washed with brine, dried over Na2SO4 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. Preparation 25: Synthesis of a Compound of Formula (Int-25) (Intermediate 25)
Figure imgf000081_0001
[0219] A compound of Formula (Int-25) (2.9 g, 32 %) as a brown solid, was prepared from the compound of Formulas (Int-1) and (Int-24) using same procedure described for the compound of Formula (Int-8).1H NMR (400 MHz, DMSO-d6): d 9.76 (s, 1H), 8.67 (s, 1H), 8.15 (s, 1H), 6.66 (d, J= 9.2 Hz, 1H), 6.42 (d, J= 8.0 Hz, 1H), 3.92 (s, 3H) ppm. LCMS: m/z 327.45 (M+H+) Preparation 26: Synthesis of a Compound of Formula (Int-26) (Intermediate 26)
Figure imgf000082_0001
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. The reaction mixture was concentrated under reduced pressure to afford the compound of Formula (26b) (4 g, 59 %) as a yellow solid which was carried on without further purification. 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. Preparation 27: Synthesis of a Compound of Formula (Int-27) (Intermediate 27)
Figure imgf000082_0002
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)
Figure imgf000083_0001
[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 Cs2CO3 (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. The residue was purified by column chromatography to afford the desired product the compound of Formula (Int-160) as a green solid (1.7 g, 30.46%) Preparation 29: Synthesis of a Compound of Formula (Int-161) (Intermediate 161)
Figure imgf000084_0001
[0225] The compound of Formula (Int-1) (2.0 g, 6.96 mmol), the compound of Formula (Int-244) (1.6 g, 8.36 mmol) and Cs2CO3 (3.39g, 10.45 mmol), were added to 20 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, extracted into DCM and solvent was concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product Int-161 as a yellow solid (1.8 g, 70.66%) Preparation 30: Synthesis of a Compound of Formula (Int-163) (Intermediate 163)
Figure imgf000084_0002
[0226] A compound of Formula (Int-163) (4.0 g, 30 %) as a brown solid, was prepared from the compound of Formulas (Int-1) and (Int-159) using the same procedure described for the compound of Formula (Int-8).1H NMR (400 MHz, DMSO-d6): d 9.91 (s, 1H), 8.65 (s, 1H), 8.12 (s, 1H), 6.49 (s, 1H), 2.02 (s, 3H), 1.96 (s, 6H) ppm. LCMS: m/z 321.40 (M+H+). Preparation 31: Synthesis of a Compound of Formula (Int-190) (Intermediate 190)
Figure imgf000085_0001
[0227] To a solution of the compound of Formula (Int-25) (0.15 g, 1 mmol) and pyrrole boronic acid (0.29 g, 3.0 mmol) in mixture of 1,4-dioxane (6 ml) and water (0.22 ml) was added Cs2CO3 (0.45 g, 3 mmol). The reaction mixture was degassed by Argon and then charged Pd(dppf)Cl2.DCM (0.033 g, 0.1 mmol). The 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. The crude product was further purified by column chromatography to afford a compound of Formula (Int-190) (0.12 g, 57.14% yield) as a solid.1H NMR (300 MHz, DMSO-d6): 9.70 (s, 1H), 8.66 (s, 1H), 8.35 (s, 1H), 7.39-7.37 (d, 1H), 6.65-6.61 (dd, 1H), 6.46-6.44 (d, 1H), 6.33-6.30 (d, 1H), 6.18-6.14 (dd, 1H), 3.84 (s, 3H), 1.38 (s, 9H) ppm. MS: m/z 458 (M+H+) Preparation 32: Synthesis of a Compound of Formula (Int- 191) (Intermediate 191)
Figure imgf000085_0002
[0228] To a solution of the compound of Formula (Int-23) (0.10 g, 0.31 mmol) and N- Boc-2-pyrroleboronic acid (0.197 g, 0.93 mmol) in 1,4-dioxane (4 ml) was added 3 drops of H2O, K2CO3 (0.13 g, 0.93 mmol) and Pd(PPh3)4 (0.07 g, 0.2 mmol). The mixture was degassed by nitrogen and then heated to 110°C till completion of the reaction. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure, before being purified using column chromatography providing a compound of Formula (Int-191) (0.13 g, 93 %). Preparation 33: Synthesis of a Compound of Formula (Int-212) (Intermediate 212)
Figure imgf000086_0001
[0229] To a solution of the compound of Formula (Int-161) (0.3 g, 1 mmol) and N-Boc- 2-pyrroleboronic acid (0.51 g, 3.0 mmol) in mixture of 1,4-dioxane (12 ml) and water (0.6 ml) ,was added Cs2CO3 (0.78 g, 3 mmol) and Pd(dppf)Cl2.DCM (0.066 g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 25-30 °C, added water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography to afford a compound of Formula (Int-212) (0.3 g, 74.07% yield) as a solid. MS: m/z 498(M-H). Preparation 34: Synthesis of a Compound of Formula (Int-213) (Intermediate 213)
Figure imgf000086_0002
[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 Cs2CO3 (0.28 g, 3 mmol) and Pd(dppf)Cl2.DCM (0.021g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 25-30°C, added water and extracted with Ethylacetate The organic layer was dried over sodium sulfate and concentrated under reduced pressure before being purified using column chromatography providing. The compound of Formula (Int-213) (0.097g, 70.28% yield) was obtained as a solid. HPLC: 90.98%. Preparation 35: Synthesis of Int-220 (Intermediate 220)
Figure imgf000087_0001
[0231] A compound of Formula (Int-220) (0.135 g) as a brown solid, was prepared from the compound of Formula (Int-163) and boronic acid using same procedure described for the compound of Formula (Int-191). Preparation 36: Synthesis of a Compound of Formula (Int-231) (Intermediate 231)
Figure imgf000087_0002
[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 Cs2CO3 (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. The residue was purified by column chromatography to afford a compound of Formula (Int- 231) as a yellow solid (3.10 g, 40.75%) Preparation 37: Synthesis of a Compound of Formula (Int-232) (Intermediate 232)
Figure imgf000088_0001
[0233] To a solution of intermediate the compound of Formula (Int-231) (0.15 g, 1 mmol) and N-Boc-2-pyrroleboronic acid (0.28 g, 3.0 mmol) in mixture of 1,4-dioxane (6 ml) and water (0.3 ml) ,was added Cs2CO3 (0.43 g, 3 mmol) and Pd(dppf)Cl2.DCM (0.032 g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 2530°C, added water and extracted with Ethylacetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography to afford a compound of Formula (Int-232) (0.11g, 53.14% yield) as a solid. Preparation 38: Synthesis of a Compound of Formula (Int-233) (Intermediate 233)
Figure imgf000088_0002
[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 Cs2CO3 (0.8 g, 3 mmol) and Pd(dppf)Cl2.DCM (0.06 g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 2530°C, added water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography to afford a compound of Formula (Int-233) (0.09 g, 26.27% yield) as a solid. Preparation 39: Synthesis of a Compound of Formula (Int-234) (Intermediate 234)
Figure imgf000089_0001
[0235] To a solution of the compound of Formula (Int-23) (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 (0.42 g, 2.0 mmol) in mixture of 1,4-dioxane (12 ml) and water (0.5 ml) ,was added Cs2CO3 (0.75 g, 3 mmol) and Pd(dppf)Cl2.DCM (0.12 g, 0.2 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 2530°C, added water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography to afford a compound of Formula (Int-234) (0.12 g, 35.55% yield) as a solid. Preparation 40: Synthesis of a Compound of Formula (Int-235) (Intermediate 235)
Figure imgf000090_0001
[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 Cs2CO3 (0.2 g, 3 mmol) and Pd(dppf)Cl2.DCM (0.017 g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 25-30°C, added water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography to afford the compound of Formula (Int-235) (0.03 g, 30.53% yield) as a solid. Preparation 41: Synthesis of a Compound of Formula (Int-236) (Intermediate 236) [0237]
Figure imgf000090_0002
[0238] To a solution of the compound of Formula (Int-160) (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 (0.25 g, 1.25 mmol) in mixture of 1,4-dioxane (10 ml) and water (0.5 ml), was added Cs2CO3 (0.72 g, 3 mmol), Pd(dppf)Cl2.DCM (0.054 g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 2530°C, added water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography to afford a compound of Formula (Int-236) (0.065 g, 19.40% yield) as a solid. Preparation 42: Synthesis of a Compound of Formula (Int-237) (Intermediate 237)
Figure imgf000091_0001
[0239] The compound of Formula (Int-1) (1.75g, 6.09 mmol), the compound of Formula (Int-245) (1.1g, 7.31 mmol) and Cs2CO3 (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). [0240] [0241] Preparation 43: Synthesis of a Compound of Formula (Int-238) (Intermediate 238)
Figure imgf000091_0002
[0243] To a solution of the compound of Formula (Int-237) (0.5 g, 1.55 mmol) and N- Boc-2-pyrroleboronic acid (0.49 g, 2.31 mmol) in mixture of 1,4-dioxane (12 ml) and water (0.6 ml), was added K2CO3 (0.64 g, 4.65 mmol), Pd(dppf)Cl2.DCM (0.18 g, 0.1 mmol). The mixture was degassed by nitrogen and heated to 110°C till completion of the reaction. After completion of reaction, the reaction mixture was cooled to 25-30°C, added water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by column chromatography to afford the compound of Formula (Int-238) (0.5 g, 71.01% yield) as a solid. Preparation 44: Synthesis of a Compound of Formula (Int-239) (Intermediate 239)
Figure imgf000092_0001
[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 Cs2CO3 (0.8 g, 3 mmol). The mixture was degassed by Argon and then charged Pd(dppf)Cl2.DCM (0.06 g, 0.1 mmol). The 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 crude. The crude was further purified by column chromatography to afford a compound of Formula (Int-239) (0.25 g, 70.42% yield) as a solid.1H NMR (300 MHz, DMSO-d6): 9.74 (s, 1H), 8.69-8.68 (d, 1H), 8.33 (s, 1H), 7.39-7.37 (d, 1H), 6.72-6.61 (m, 2H), 6.44-6.43 (m, 1H), 6.33-6.31 (t, 1H), 6.20-6.18 (dd, 1H) 3.82 (s, 3H), 2.79-2.78 (d, 3H), 1.36 (s, 9H) ppm. MS: m/z 437 (M+H). Preparation 45: Synthesis of a Compound of Formula (Int-240) (Intermediate 240)
Figure imgf000093_0001
[0245] To a solution of the compound of Formula (Int-231) (0.3 g, 1 mmol) and 1- (tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (0.49 g, 2.0 mmol) in mixture of 1,4-dioxane (12 ml) and water (0.6 ml) was added Cs2CO3 (0.86 g, 3 mmol). The mixture was degassed by Argon and then charged Pd(dppf)Cl2.DCM (0.13 g, 0.2 mmol). The 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. The crude product was further purified by column chromatography to afford a compound of Formula (Int-240) (0.08 g, 19.90% yield) as a solid. HPLC: 91.51%. Preparation 46: Synthesis of a Compound of Formula (Int-246) (Intermediate 246)
Figure imgf000093_0002
[0246] To a solution of the compound of Formula (Int-27) (500 mg, 1.62mmol) and benzylamine (0.27, 2.44 mmol), DIPEA (5 ml, 10 vol.) was added and the reaction mixture was heated to 100oC till completion of the reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography to afford a compound of Formula (Int-246) (350 mg, 57.2% yield) as a red solid.1H NMR (400 MHz, DMSO- d6) δ 10.33 (s, 1H), 9.50 (t, J=8.0Hz1H), 8.90 (s, 1H), 7.90 (t, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.44 (t, J=6.8Hz, 3H), 7.31 (t, J=7.6Hz, 2H), 7.23 (t, J=7.2Hz, 1H), 4.89 (d, J=6.0 Hz, 2H), 4.12 (s, 3H). m/z [M+H]+ = 377.87 Preparation 47: Synthesis of a Compound of Formula (Int-247) (Intermediate 247)
Figure imgf000094_0001
[0247] To a solution of the compound of Formula (Int-20) (1g, 3.28 mmol), benzylamine (0.54 ml, about 4.92 mmol) in 1,4-dioxane (10ml, 10 vol.) was added Cs2CO3 (1.59g, 4.92 mmol) at room temperature and the reaction mixture was de-gassed using argon. Xantphos (0.758 g, 1.31 mmol) and Pd2dba3.CH2Cl2 (300 mg, 10 mol %) was added and the reaction mixture was heated to 120°C till completion of the reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain crude. The crude was further purified by column chromatography to afford a compound of Formula (Int-247) (650 mg, about 52.7 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.22 (d, J=4.4Hz, 1H), 7.96 (s, 1H), 7.28 (d, J=4Hz, 4H), 7.21- 7.18 (m, 1H), 6.81 (t, J=6.4Hz, 1H), 6.68 (t, J=8.4Hz, 1H), 6.60 (d, J=7.6Hz, 1H), 6.36 (d, J=7.6Hz, 1H), 4.54 (d, J=6.4Hz, 2H), 3.79 (s, 3H), 2.69 (d, J=4.4Hz, 3H) MS: m/z 377.46 (M+H+);
Preparation 48: Synthesis of a Compound of Formula (Int-248) (Intermediate 248)
Figure imgf000095_0001
[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 Cs2CO3 (530 mg, 1.63mmol) at room temperature and the reaction mixture was de-gassed using argon. Xantphos (252mg, 0.43mmol) and Pd2dba3.CH2Cl2 (99mg, 10 mol %) was added and the reaction mixture was heated to 120°C till completion of the reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain crude. The crude was further purified by column chromatography to afford a compound of Formula (Int-248) (300 mg, 70.3 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.28 (d, J=4.4Hz, 4H), 7.21- 7.18 (m, 1H), 6.76 (t, J=6.4Hz, 1H), 6.44 (s, 1H), 6.20 (s, 1H), 4.54 (d, J=6.0Hz, 2H), 3.78 (s, 3H), 2.15 (s, 3H) m/z (M+H+) 394.49 Preparation 49: Synthesis of a Compound of Formula (Int-249) (Intermediate 249)
Figure imgf000095_0002
[0249] To a solution of the compound of Formula (Int-163) (1 g, 3.12 mmol), benzylamine (68 ml, 6.25 mmol) in 1,4-dioxane (10ml, 10 vol.) was added Cs2CO3 (1.52g, 4.68 mmol) at room temperature and the reaction mixture was de-gassed using argon. Xantphos (0.72g, 1.25mmol) and Pd2dba3.CH2Cl2 (286mg, 10 mol %) was added and the reaction mixture was heated to 120°C till completion of the reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography to afford a compound of Formula (Int-249) (900 mg, 73.8 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.23 (bs, 1H), 7.98 (s, 1H), 7.29 (d, J=4.8Hz, 4H), 7.21-7.18 (m, 1H), 6.63 (t, J=6Hz, 1H), 6.50 (s, 1H), 4.60 (d, J=6.4Hz, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.97 (s, 3H) m/z [M+H]+ = 392.56 Preparation 50: Synthesis of a Compound of Formula (Int-250) (Intermediate 250)
Figure imgf000096_0001
[0250] To a solution of the compound of Formula (Int-25) (1 g, 3.07 mmol), benzylamine (0.67 ml, 6.13 mmol) in 1,4-dioxane (10ml, 10 vol.) was added Cs2CO3 (1.49g, 4.60mmol) at room temperature and the reaction mixture was de-gassed using argon. Xantphos (0.71g, 1.23mmol) and Pd2dba3.CH2Cl2 (280 mg, 10 mol %) was added and the reaction mixture was heated to 120°C till completion of the reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography to afford a compound of Formula (Int-250) (830 mg, 68.1 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.29 (d, J=4.4Hz, 4H), 7.22-7.18 (m, 1H), 6.81 (t, J=6Hz, 1H), 6.59 (dd, J=10.4, 2.4Hz, 1H), 6.22 (dd, J=9.2, 2.4Hz, 1H), 4.55 (d, J=6Hz, 2H), 3.81 (s, 3H) m/z [M+H]+ = 398.48 HPLC: 96.13% Preparation 51: Synthesis of a Compound of Formula (Int-251) (Intermediate 251)
Figure imgf000096_0002
[0251] To a solution of the compound of Formula (Int-163) (0.25 g, 1 mmol) and SM-2 (0.40 g, 2.0 mmol) in mixture of 1,4-dioxane (10 ml) and water (0.5 ml) was added Cs2CO3 (0.72 g, 3 mmol). The mixture was degassed by Argon and then charged Pd(dppf)Cl2.DCM (0.12 g, 0.2 mmol). The 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. The crude product was further purified by column chromatography to afford a compound of Formula (Int-251) (0.15 g, 44.11% yield) as a solid. Preparation 52: Synthesis of a Compound of Formula (Int-252) (Intermediate 252)
Figure imgf000097_0001
[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 Cs2CO3 (0.3 g, 3 mmol). The mixture was degassed by Argon and then charged Pd(dppf)Cl2.DCM (0.045 g, 0.2 mmol). The 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 crude. The crude was further purified by column chromatography to afford a compound of Formula (Int-252) (0.032 g, 23.52% yield) as a solid. [0253] The following intermediates may be prepared according to methods described herein or by conventional methods known in art by using appropriate starting materials: [0254]
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
N
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0002
[0255] The corresponding non-deuterated intermediates may be prepared by using methyl amine instead of CD3NH2. Example 1: Synthesis of a Compound of Formula (15)
Figure imgf000104_0001
[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), Cs2CO3 (1.6 g, 4.92 mmol) and (Pd2dba3) (0.15 g, 0.16 mmol), The mixture was degassed by nitrogen and then heated to 130°C 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 and purified using neutral alumina column chromatography, providing a compound of Formula (15) (0.015 g, 3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 9.47 (s, 1H), 8.57 (br-s, 1H), 8.32 (s, 1H), 8.24 (d, J=3.2 Hz, 1H), 8.18 (s, 1H), 8.10 (dd, J=9.2, 4.0 Hz, 1H), 7.67-7.72 (m, 1H), 6.73 (t, J = 8.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 3.82 (s, 3H), 2.76 (d, J = 4.4 Hz, 3H) ppm. LCMS: m/z 382.32 (M+H+); HPLC: 98.95%. Example 2: Synthesis of a Compound of Formula (21)
Figure imgf000105_0001
[0257] A compound of Formula (21) (0.01 g, 5.3%) as a yellow solid, was prepared from the compound of Formula (Int-21) (0.15 g, 1 mmol) and 5-fluoropyridin-2-amine (0.115 g, 2 mmol) using similar procedure as described for the compound of Formula (15).1H NMR (400 MHz, DMSO-d6): d 9.55 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 8.11 (dd, J = 9 Hz, 4 Hz, 1H), 8.020 (m, J = 1H), 7.69 (m, 1H), 7.42 (m, 1 H), 6.73 (t, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H) 3.81 (s, 3H) ppm. LCMS: m/z 368.42 (M+H+); HPLC: 98.28%. Example 3: Synthesis of a Compound of Formula (22)
Figure imgf000105_0002
[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), Cs2CO3 (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. After completion of reaction, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure, and purified using neutral alumina column chromatography, providing a compound of Formula (22) (0.050 g, 20 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): 9.57 (s, 1H), 9.12 (s, 1H), 8.64 (d, J = 2.0 Hz, 1H), 8.53 (s, 1H), 8.08 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 6.73 (dd, J = 8.4 Hz, 8.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H) ppm. LCMS: m/z 385.24 (M+H+); HPLC: 98.95%. Example 4: Synthesis of example a Compound of Formula (24):
Figure imgf000106_0001
[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).1H NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 8.46 (s, 1H), 8.23-8.24 (m, 1H), 8.16 (s, 1H), 8.13 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.70-7.77 (m, 1H), 6.95-6.98 (m, 1H), 6.73 (t, J = 6.4 Hz, 1H), 6.65 (d, J = 6.4 Hz, 1H), 6.53 (d, J= 6.4 Hz, 1H), 3.82 (s, 3H) ppm. LCMS: m/z 367 (M+H+); HPLC: 98.01%. Example 5: Synthesis of a Compound of Formula (27)
Figure imgf000106_0002
[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. 1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 8.24 (d, J = 3.2 Hz, 1H), 8.14 (s, 1H), 8.09 (dd, J = 9.2 Hz, 4.0 Hz, 1H), 7.68 (dt, J = 8.8 Hz, 3.2 Hz, 1H), 6.73 (dd, J = 8.4 Hz, 8.0 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H) ppm. LCMS: m/z 392.23 (M+H+); HPLC: 97.70%. Example 6: Synthesis of a Compound of Formula (28)
Figure imgf000107_0001
[0261] A compound of Formula (28) (0.18 g, 50.3%) as a yellow solid, was prepared from the compound of Formula (Int-8) (0.309 g, 1 mmol) and cyclopropanecarboxamide (11) (0.170 g, 2 mmol) using similar procedure as described for the compound of Formula (22).1H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 9.66 (s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 6.72 (dd, J = 8.4 Hz, 8.0 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 1.89-1.86 (m, 1H), 0.79-0.78 (m, 4H) ppm. LCMS: m/z 358.23 (M+H+); HPLC: 97.98%. Example 7: Synthesis of a Compound of Formula (77)
Figure imgf000107_0002
[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. LCMS: m/z 372.38 (M+H+); HPLC: 99.99%. Example 8: Synthesis of a Compound of Formula (387)
Figure imgf000108_0001
[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 Cs2CO3 289 mg, 0.89 mmol) at room temperature and the reaction mixture was de-gassed using argon. Xantphos (137 mg, 0.23 mmol) and Pd2dba3.CH2Cl2 (54 mg, 10 mol %) was added and the reaction mixture was heated to 120°C till completion of the reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography to afford a compound of Formula (387) as a yellow solid (26 mg, 13.78 %).1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.18 (bs, 1H), 7.93 (s, 1H), 6.44 (s, 1H), 5.89 (bs, 2H), 3.74 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H) m/z [M+H]+ = 318.27 HPLC (purity): 96.23% Example 9: Synthesis of a Compound of Formula (388)
Figure imgf000108_0002
[0264] To a solution of the compound of Formula (Int-231) (200 mg, 0.59 mmol), tert- butyl carbonate (139 mg, 1.19 mmol) in 1,4-dioxane (10ml, 10 vol.) was added Cs2CO3 (289 mg, 0.89 mmol) at room temperature and the reaction mixture was de-gassed using argon. Xantphos (137 mg, 0.23 mmol) and Pd2dba3.CH2Cl2 (54 mg, 10 mol %) was added and the reaction mixture was heated to 120°C till completion of the reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was further purified by column chromatography to afford a compound of Formula (388) as a yellow solid (42 mg, 22.45 %).1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.23 (bs, 1H), 7.96 (s, 1H), 6.33 (s, 1H), 5.97 (bs, 2H), 3.64 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H) m/z [M+H]+= 318.41 HPLC (purity): 98.12% [0265] The following compounds were prepared analogously according to procedure described in Example 1-9 by using corresponding intermediate and starting material as provided in following table:
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Example 10: Synthesis of a Compound of Formula (31)
Figure imgf000115_0002
[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.1H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 7.75 (s, 1H), 6.72 (dd, J = 8.4 Hz, 8.0 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H) ppm. LCMS: m/z 275.14 (M+H+); HPLC: 99.15%. Example 11: Synthesis of a Compound of Formula (32) (Intermediate 8)
Figure imgf000115_0003
[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 Cs2CO3 (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.1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 6.75 (dd, J = 8.4 Hz, 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 3.82 (s, 3H) ppm. LCMS: m/z 309.15 (M+H+); HPLC: 98.40%. Example 12: Synthesis of a Compound of Formula (44)
Figure imgf000116_0001
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%).1H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 9.84 (s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 6.92 (s, 2H), 6.76 (m, 1H), 6.63 (m, 2H), 6.20 (s, 1H), 3.84 (s, 3H) ppm. LCMS: m/z 340.18 (M+H+); HPLC: 96.87% Example 13: Synthesis of a Compound of Formula (165):
Figure imgf000117_0001
[0269] To a solution of the compound of Formula (Int-190) (0.12 g, 0.12 mmol) in methanol (2.4 ml) was added Conc. HCl (1.2 ml) and stirred for 5 hours at 45°C. After completion of reaction, the solid was filtered and washed with minimum methanol. The solid was stirred in IPA (1.2 ml) and filtered and washed with minimum IPA. The solid was dried under vacuum at 50 °C to give HCl salt of a compound of Formula (165) (0.058 g, 56.20% yield).1H NMR (500 MHz, DMSO-d6): 11.61 (s, 1H), 10.74 (s, 1H), 9.06 (s, 1H), 8.46 (s, 1H), 7.27 (s, 1H), 7.20 (s, 1H), 6.83-6.81 (d, 1H), 6.67-6.66 (d, 1H), 6.33 (s, 1H), 3.82 (s, 3H) ppm. MS: m/z 358 (M+H+); HPLC: 97.31% Example 14: Synthesis of a Compound of Formula (166):
Figure imgf000117_0002
[0270] To a solution of the compound of Formula (Int-191) (0.13 g, 0.29 mmol) in methanol, concentrated HCl solution (1 ml) was added and the mixture was stirred at 40°C. After completion of reaction, mixture was concentrated under vacuum and resulting residue was washed with diethyl ether to give the HCl salt of a compound of Formula (166) as a brown solid (0.14 g, 14%).1H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H), 9.76 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 6.91 (m, 2H), 6.49 (m, 2H), 6.19 (m, 1H), 3.81 (s, 3H), 2.19 (s, 3H) ppm. LCMS: m/z 354.29 (M+H+); HPLC: 98.00% Example 15: Synthesis of a Compound of Formula (199)
Figure imgf000118_0001
[0271] A compound of Formula (199) (0.010 g) as a brown solid, was prepared from the compound of Formula (Int-220) using same procedure described for the compound of Formula (166).1H NMR (400 MHz, DMSO-d6): d 11.68 (br-s, 1H), 10.67 (br-s, 1H), 8.88 (s, 1H), 8.41 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.54 (s, 1H), 6.30 (s, 1H), 2.05 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H) ppm. LCMS: m/z 352 (M+H+); HPLC: 95.15% Example 16: Synthesis of a Compound of Formula (187):
Figure imgf000118_0002
[0272] To a solution of the compound of Formula (Int-212) (0.25 g, 0.50 mmol) in DCM: Methanol (1:1) (4 ml); was added methanolic HCl (10 ml) and stirred at 45°C. After completion of reaction, the solid was filtered, washed with methanol followed by Ethyl acetate and dried to give the HCl salt of a compound of Formula (187) (0.17 g, 78.16% yield). In a stirred saturated solution of sodium bicarbonate (4 ml) was added portion wise obtained HCl salt of a compound of Formula (187) (0.17 g, 1 mmol) and the reaction mixture was stirred at room temperature and then solid was filtered, washed with water and dried to give a compound of Formula (187) (0.14 g, 90.49% yield) as free base solid.1H NMR (500 MHz, DMSO-d6): 11.32 (s, 1H), 10.24 (bs, 1H), 8.67 (s, 1H), 8.34 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 6.96-6.95 (d, J = 8.5 Hz, 2H), 6.22 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H) ppm. MS: m/z 398 (M+H); HPLC: 95.39% Example 17: Synthesis of a Compound of Formula (188)
Figure imgf000119_0001
[0273] To a solution of the compound of Formula (Int-213) (0.097 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 (188) (0.060 g, 71.92% yield). In a stirred saturated solution of sodium bicarbonate (1 ml) was added portion wise obtained HCl salt of a compound of Formula (188) (0.060 g, 1 mmol) and the reaction mixture was stirred at room temperature and then solid was filtered, washed with water and dried to give a compound of Formula (188) (0.045 g, 83.33% yield).1H NMR (300 MHz, DMSO-d6): 11.53 (s, 1H), 10.21 (bs, 1H), 8.70 (s, 1H), 8.34 (s, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.47 (m, 1H), 6.27-6.26 (m, 1H), 3.75 (s, 3H), 2.10 (s, 3H), 2.02 (s, 3H) ppm. MS: m/z 368 (M+H); HPLC: 86.88%. Example 18: Synthesis of a Compound of Formula (316)
Figure imgf000119_0002
[0274] To a solution of the compound of Formula (Int-239) (0.25 g, 0.57 mmol) in methanol (2.5 ml) was added Conc. HCl (10 ml) and stirred for 5 hours at 50°C. After completion of reaction, the solid was filtered and washed with minimum methanol followed by diethyl ether. The solid was dried under vacuum at 50°C to give a compound of Formula (316) (0.19 g, 83.41% yield) as an HCl salt.1H NMR (300 MHz, DMSO-d6): 11.59 (s, 1H), 10.62 (bs, 1H), 8.99 (s, 1H), 8.44 (s, 1H), 7.17 (s, 2H), 6.90-6.85 (m, 1H), 6.78-6.73 (m, 2H), 6.34-6.33 (m, 1H) 3.85 (s, 3H), 2.78-2.77 (d, J = 4.5 Hz, 3H), ppm. MS: m/z 337 (M+H); HPLC: 99.27%. Example 19: Synthesis of a Compound of Formula (385)
Figure imgf000120_0001
[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. After completion of reaction the reaction mixture was, filtered and filtrate was concentrated under reduced pressure and purified using preparative HPLC to give a compound of Formula (385) (0.120 g, 31 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6): d 11.50 (s, 1H), 11.31 (s, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.39 (s, 1H), 7.25 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 6.93 (m, 2H), 6.75 (t, J = 8 Hz, 1H), 6.20 (s, 1H) ppm. LCMS: m/z 340.18 (M+H+); HPLC: 99.90.
Example 20: Synthesis of a Compound of Formula (386)
Figure imgf000121_0001
[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). In a stirred saturated solution of sodium bicarbonate (1 ml) was added portion wise obtained the HCl salt of a compound of Formula (386) (0.072 g, 1 mmol) and the reaction mixture was stirred at room temperature and then solid was filtered, washed with water and dried to give a compound of Formula (386) (0.037 g, 57.09% yield).1H NMR (300 MHz, DMSO-d6): 11.31 (s, 1H), 9.98 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 6.95-6.90 (m, 2H), 6.66 (s, 1H), 6.21-6.18 (m, 1H), 3.68 (s, 3H), 2.10 (s, 3H), 2.02 (s, 3H) ppm. MS: m/z 368 (M+H); HPLC: 94.30%.
Example 21: Synthesis of a Compound of Formula (390)
Figure imgf000122_0001
[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. In a stirred saturated solution of sodium bicarbonate (2 ml) was added portion wise a compound of Formula (390) (HCl salt) (0.05 g, 1 mmol). Stirred for 2 hours and then solid was filtered and washed with water. The solid obtained was dried at 50°C for 6 hours, providing a compound of Formula (390) (0.036 g, 80.0% yield) as a yellow solid.1H NMR (500 MHz, DMSO-d6): 10.07 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 6.75 (s, 1H), 3.68 (s, 3H), 2.09 (s, 3H), 2.01 (s, 3H) ppm. MS: m/z 369 (M+H); HPLC: 95.06%. Example 22: Synthesis of a Compound of Formula (167)
Figure imgf000123_0001
[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). In a stirred saturated solution of sodium bicarbonate (3.4 ml) was added portion wise obtained the HCl salt of a compound of Formula (167) (0.2 g, 1 mmol) and stirred at 25-30°C for 2 hours and then solid was filtered and washed with water to give a crude product. The crude product was purified using silica gel column chromatography, to give a compound of Formula (167) (0.11 g, 61.11% yield) as a solid.1H NMR (500 MHz, DMSO-d6): 12.62 (s, 1H), 9.86 (s, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 6.78-6.75 (m, 1H), 6.70-6.66 (m, 2H), 3.83 (s, 3H) ppm. MS: m/z 341 (M+H+); HPLC: 96.66%.
Figure imgf000124_0001
[0279] To a solution of the compound of Formula (Int-234) (0.12 g, 0.27 mmol) in DCM (3 ml) was added HCl in dioxane (1 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 compound of Formula (169) (0.09 g, 84.26% yield). In a stirred saturated solution of sodium bicarbonate (3.4 ml) was added portion wise the HCl salt of compound of Formula (169) (0.09 g, 1 mmol) and stirred at 25-30°C for 2 hours and then solid was filtered and washed with water to give crude. The crude product was purified using silica gel column chromatography, to give the compound of Formula (169) (0.04 g, 49.38% yield) as a solid.1H NMR (500 MHz, DMSO-d6): 12.62 (s, 1H), 9.78 (s, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 3.81 (s, 3H), 2.19 (s, 3H) ppm. MS: m/z 355 (M+H); HPLC: 93.98%.
Example 24: Synthesis of a Compound of Formula (193)
Figure imgf000125_0001
[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). In a stirred saturated solution of sodium bicarbonate (3.4 ml) was added portion wise the HCl salt of a compound of Formula (193) (0.04 g, 1 mmol) and stirred at 25-30°C for 2 hours and then solid was filtered and washed with water to give crude. The crude product was purified using silica gel column chromatography, to give a compound of Formula (193) (0.02 g, 54.94% yield) as a yellow solid.1H NMR (500 MHz, DMSO-d6): 12.62 (s, 1H), 10.17 (s, 1H), 8.82 (s, 1H), 8.46 (s, 1H), 7.75 (d, 2H), 7.25 (s, 1H), 7.17 (s, 1H), 3.89 (s, 3H), 3.82 (s, 3H) ppm. MS: m/z 399 (M+H); HPLC: 95.11%.
Figure imgf000126_0001
[0281] To a solution of the compound of Formula (Int-236) (0.06 g, 0.13 mmol) in DCM (2 ml) was added HCl in dioxane (1 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 (194) (0.037 g, 69.28% yield). In a stirred saturated solution of sodium bicarbonate (2 ml) was added portion wise the HCl salt of a compound of Formula (194) (0.037 g, 1 mmol) and stirred for 2 hours and then solid was filtered and washed with water to give crude. The crude product was purified using silica gel column chromatography, to give a compound of Formula (194) (0.025 g, 75.07% yield) as a yellow solid.1H NMR (500 MHz, DMSO-d6): 12.66 (s, 1H), 9.83 (s, 1H), 8.60 (s, 1H), 8.37 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 6.53 (s, 1H),3.79 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H) ppm. MS: m/z 369 (M+H); HPLC: 91.07%. Example 26: Synthesis of a Compound of Formula (215)
Figure imgf000126_0002
[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. 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 (215) as a yellow solid (150mg, 78.99%).1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.78 (bs, 1H), 8.08 (s, 1H), 7.39 (bs, 2H), 6.81 (t, J=8.4Hz, 1H), 6.67 (d, J=7.6Hz, 1H), 6.34 (d, J=8.0Hz, 1H), 3.81 (s, 3H), 2.72 (d, J=4.4Hz, 3H) MS: m/z (M+H+) = 287.42, HPLC: 99.55%. Example 27: Synthesis of a Compound of Formula (380)
Figure imgf000127_0001
[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. 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 (380) as a yellow solid (170mg, 73.53%).1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.33 (bs, 2H), 6.51 (s, 1H), 6.17 (s, 1H), 3.80 (s, 3H), 2.16 (s, 3H) m/z [M+H]+ 304.51 HPLC: 96.72%. Example 28: Synthesis of a Compound of Formula (381)
Figure imgf000127_0002
[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. After 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 (381) (180 mg, 97.55 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 7.24 (bs, 2H), 6.53 (s, 1H), 2.03 (s, 6H), 1.98 (s, 3H) m/z [M+H]+ = 302.45 HPLC: 98.42%. Example 29: Synthesis of a Compound of Formula (382)
Figure imgf000128_0001
[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. After 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 (382) (230 mg, 85.0% yield) as a grey solid.1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.78 (s, 1H), 8.12 (s, 1H), 7.39 (bs, 2H), 6.67 (dd, J=10.8, 2.4Hz, 1H), 6.19 (dd, J=8.8, 2.4Hz, 1H), 3.75 (s, 3H) m/z [M+H]+ = 308.37. Example 30: Synthesis of a Compound of Formula (383)
Figure imgf000128_0002
[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. After 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 (383) (110 mg, 41.7 % yield) as a red solid.1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.88 (s, 1H), 8.38 (bs, 2H), 7.89 (t, J=8.8Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.45 (d, J=6.8Hz, 1H), 4.12 (s, 3H). m/z [M+H]+ = 287.35 HPLC (purity): 96.44%. Example 31: Synthesis of a Compound of Formula (201)
Figure imgf000129_0001
[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. The solid obtained was dried at 50°C for 6 hours, providing a compound of Formula (201) (0.06 g, 55.55% yield) as a solid.1H NMR (500 MHz, DMSO-d6): 12.64 (s, 1H), 10.07 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 6.51 (s, 1H), 2.09 (s, 3H), 2.04 (s, 3H), 1.97 (s, 3H) ppm. MS: m/z 353 (M+H); HPLC: 93.83%. Example 32: Synthesis of a Compound of Formula (391)
Figure imgf000130_0001
[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. In a stirred saturated solution of sodium bicarbonate (2 ml) was added portion wise above obtained HCl salt (0.046 g, 1 mmol). Stirred for 2 hours and then solid was filtered and washed with water. The solid obtained was dried at 50°C for 6 hours, providing a compound of Formula (391) (0.037 g, 89.37% yield) as a solid.1H NMR (500 MHz, DMSO-d6): 12.62 (s, 1H), 11.56 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.74-7.71 (d, 2H), 7.42 (s, 1H), 7.28-7.26 (d, J= 10 Hz, 1H), 7.16-7.14 (d, J= 10 Hz, 1H), 6.78-6.75 (t, 1H) ppm. MS: m/z 354 (M+H); HPLC: 96.04%.
Figure imgf000131_0001
[0289] 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
Figure imgf000131_0002
[0290] 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)
Figure imgf000131_0003
[0291] A compound of Formula (34) may be prepared from the compound of Formula (Int-8) using palladium based catalyst and boronic acid. [0292] The following compounds may be prepared according to methods described herein by using appropriate intermediates:
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0002
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
BIOLOGICAL ASSAYS TYK2 JH2 Binding Assay ASSAY PROCEDURE [0293] Binding to TYK2 JH2 domain for test compounds was determined using the KINOMEscan™ platform by DiscoverX, which is a comprehensive high-throughput system for screening compounds against large numbers of human kinases. KINOMEscan™ 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. [0294] 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. 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. [0295] The binding reaction was assembled by combining 15.75 μl of DNA-tagged kinase extract, 3.75 μl liganded affinity beads, and 0.18 μl 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. [0297] The washed beads were re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μΜ 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 μL of kinase eluate to 7.5 μL of qPCR master mix containing 0.15 μΜ amplicon primers and 0.15 μΜ 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. [0298] Binding constants (Kds) were calculated with a standard dose-response curve using the Hill equation: [0299] Response = Background + Signal – Background/ 1 + (KdHill Slope / DoseHill Slope) [0300] The Hill Slope was set to -1; Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm.’ [0301] The Kd values for example compounds are reported in Table 1. Table 1: TYK2 JH2 Binding Assay (Kd; nM) Kd: A = <100nM, B = >100<1000nM, C = >1000<3000nM, D = >3000nM.
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
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 KINOMEscan™ platform by DiscoverX. Assay protocol followed was similar to that of TYK2 JH2. The Kd values for example compounds are reported in Table 2. Table 2: JAK1 JH2, JAK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, TYK2 JH1 Binding Assay (Kd; nM) Kd: A = <100nM, B = >100<1000nM, C = >1000<3000nM, D = >3000nM<10000nM, E = >10000<30000nM, F = >30000nM. )
Figure imgf000150_0002
Kd
Figure imgf000151_0001
Figure imgf000152_0001
* indicates not performed JAK1 JH1, JAK2 JH1, JAK3 JH1, TYK2 JH1 Kinase activity assays Assay Procedure [0303] Kinase activity assays were performed using the LANCE™ 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 ULight™, a small molecular weight acceptor dye with a red-shifted fluorescent emission. The binding of the Eu-labeled anti-phospho tyrosine PT66 antibody to the JAK-1 peptide substrate phosphorylated at Tyr1023 brings the Eu donor and ULight acceptor dye molecules into close proximity. Upon irradiation at 320 or 340 nm, the energy from the Eu donor is transferred to the ULight acceptor dye which, in turn, generates light at 665 nm. The intensity of the light emission is proportional to the level of ULight substrate phosphorylation. [0304] Enzymes were diluted in kinase buffer containing 50mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT and 0.01% Tween-20. 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-light™ 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 2.5µL of 4X kinase enzyme and 2.5µL of 4X test compound were added. Further, 5µL of 2X ATP-substrate mixture was added to initiate the reaction and incubated for respective durations at room temperature.10µL of a 4X STOP solution and detection mixture containing 40mM EDTA (for terminating kinase reactions) and 8nM Eu-anti-phospho-tyrosine antibody (PT66) was added to all wells and further incubated at room temperature for 1 hour. At the end of the incubation period, the plate was read to determine TR-FRET signal at excitation wavelength at 320 nm and emission at 625 nm and 665 nm on a plate reader with TR-FRET capabilities. The TR-FRET signal observed was normalized to that of blank wells and percent inhibition was calculated by comparison to a control without inhibitor. Data was fitted to non-linear regression fit with variable slope (four parameters) for IC50 calculations. The IC50 values for example compounds are reported in Table 4. Table 3: Enzyme, substrate concentrations and incubation times e
Figure imgf000153_0001
Table 4: JAK1 JH1, JAK2 JH1, JAK3 JH1, TYK2 JH1 Activity Assay (IC50; nM) Kinase activity assays IC50: A = <100nM, B = >100<1000nM, C = >1000<3000nM, D = >3000nM<10000nM, E = >10000<30000nM, F = >30000<100000nM, G = >100000nM. y
Figure imgf000153_0002
Figure imgf000154_0001
[0305] In addition to the various embodiments described herein, the present disclosure includes the following embodiments numbered E1 through E61. This list of embodiments is presented as an exemplary list and the application is not limited to these embodiments. E1. A compound having the following formula (I),
Figure imgf000155_0001
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y and Y’ is independently NR5, CR5R5’, O or S; each X is independently CR6 or N; M is NR3, O, S or Se; Z is NR4, CR4R4’, O, S or a bond; R1 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R2 is selected from the group consisting of hydrogen, halogen, -CN, -OR8, -SR8, - S(=O)R7, -S(=O)2R7, -NO2, -NR9R10, -NHS(=O)2R7, -S(=O)2NR9R10, -C(=O)R7, - OC(=O)R7, -C(=O)OR8, -OC(=O)OR8, -C(=O)NR9R10, -OC(=O)NR9R10, - NR8C(=O)NR9R10, -NR8C(=O)R7, -NR8C(=S)R7, -NR8C(=O)OR8, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R3 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R4 and R4’ are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R5 and R5’ are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; or R5 and R5’ are taken together to form an oxo; R6 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -ORb, - SRb, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRcRd, -NRcS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Ra, - OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRcRd, - OC(=O)NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl or two adjacent R6 are taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1- C6haloalkyl, C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. R7 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; R8 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or R9 and R10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; each Ra is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, - C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; each Rb is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, - C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; each Rc and Rd is independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. E2. A compound according to E1, wherein Y is NR5. E3. A compound according to E1 or E2, wherein Y’ is NR5 or O. E4. A compound according to any one of E1-E3, wherein each X is CR6. 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 NR4 or CR4R4’. E7. A compound according to any one of E1-E6, wherein R1 is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6deuteroalkyl. E8. A compound according to any one of E1-E7, wherein R2 is selected from the group selected from hydrogen, halogen, -NR9R10, -NR8C(=O)R7, and heteroaryl. E9. A compound according to any one of E1-E8, wherein R4 and R4’ are independently hydrogen. E10. A compound according to any one of E1-E9, wherein R5 is hydrogen. E11. A compound according to any one of E1-E10, wherein R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl, C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. E12. A compound according to any one of E1-E11, wherein R7 is selected from the group consisting of C1-C6alkyl and cycloalkyl, wherein each alkyl and cycloalkyl, is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. E13. A compound according to any one of E1-E12, wherein R8 is hydrogen. E14. A compound according to any one of E1-E13, wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. E15. A compound according to any one of E1-E14, wherein Rb is C1-C6alkyl. E16. A compound according to any one of E1-E15, wherein each Rc and Rd is independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein each alkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1- C6haloalkyl. E17. A compound according to E1-E16, wherein
Figure imgf000159_0001
E18. A compound according to any one of E1-E17, wherein R2 is heteroaryl. E19. A compound according to E18, wherein R2 is imidazolyl or pyrrolyl. E20. A compound according to any one of E1-E17, wherein R2 is selected from the group consisting of hydrogen, halogen, -NH2, -N(Me)2,
Figure imgf000159_0002
Figure imgf000159_0003
E21. A compound according to any one of E1-E20, wherein R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, -N(Me)2, -C(=O)OMe, -C(=O)NH2, C1-C6alkyl,
Figure imgf000159_0004
, a d ; with the proviso that when Y’ is CR5R5’, then R6 is not
Figure imgf000159_0005
E22. A compound according to any E1, wherein the compound is represented by formula (Ic):
Figure imgf000160_0001
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y’, M, Z, R1, R2, and R6 are as defined in E1. E23. A compound according to E22, wherein Y’ is NR5 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 NR4 or CR4R4’. E26. A compound according to any one of E22-E25, wherein R1 is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6deuteroalkyl. E27. A compound according to any one of E22-E26, wherein R2 is selected from the group consisting of hydrogen, halogen, -NR9R10, -NR8C(=O)R7, and heteroaryl. E28. A compound according to any one of E22-E27, wherein R4 and R4’ are each hydrogen. E29. A compound according to any one of E22-E28, wherein R5 is hydrogen. E30. A compound according to E22-E29, wherein R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. E31. A compound according to any one of E22-E30, wherein R7 is selected from the group consisting of C1-C6alkyl and cycloalkyl, wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. E32. A compound according to any one of E22-E31, wherein R8 is hydrogen. E33. A compound according to any one of E22-E32, wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. E34. A compound according to any one of E22-E33, wherein Rb is C1-C6alkyl. E35. A compound according to any one of E22-E34, wherein each Rc and Rd is independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein each alkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1- C6haloalkyl. E36. A compound according to any one of E22-E35, wherein R2 is heteroaryl. E37. A compound according to E36, wherein R2 is imidazolyl or pyrrolyl. E38. A compound according to any one of E22-E35, wherein R2 is selected from the group consisting of hydrogen, halogen, -NH2, -N(Me)
Figure imgf000161_0001
E39. A compound according to any one of E22-E39, wherein R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, -N(Me)2, -C(=O)OMe, -C(=O)NH2,
Figure imgf000161_0002
E40. A compound according to E1, wherein the compound is represented by formula (Ia):
Figure imgf000162_0001
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y’, M, Z, R1, R6, R9, and R10 are as defined in E1. E41. A compound according to E40, wherein Y’ is NR5 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 NR4 and CR4R4’. E44. A compound according to any one of E40-E43, wherein R1 is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6deuteroalkyl. E45. A compound according to any one of E40-E44, wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, - C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl. E46. A compound according to any one of E40-E45, wherein R4 and R4’ are independently hydrogen. E47. A compound according to any one of E40-E46, wherein R5 is hydrogen. E48. A compound according to any one of E40-E47, wherein R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. E49. A compound according to any one of E40-E48, wherein Rb is C1-C6alkyl. E50. A compound according to any one of E40-E49, wherein –NR9R10 is selected from the group consisting of -NH2, -N(Me)2,
Figure imgf000163_0001
and
Figure imgf000163_0002
E51. A compound according to any one of E40-E50, wherein R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, -N(Me)2, -C(=O)OMe, -C(=O)NH2, C1-C6alkyl
Figure imgf000163_0003
, , nd
Figure imgf000163_0005
; with the proviso that when Y’ is CR5R5’ then R6 is not
Figure imgf000163_0004
E52. A compound according to E1, wherein the compound is represented by formula (Is):
Figure imgf000163_0006
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is heteroaryl. E53. A compound according to E52, wherein R2 is imidazolyl or pyrrolyl. E54. A compound according to E52, wherein R 2 is
Figure imgf000163_0007
E55. A compound according to E1, wherein the compound is Formula (It):
Figure imgf000164_0002
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is heteroaryl and X is CR6. E56. A compound according to E55, wherein R6 is hydrogen. E57. A compound according to E55, wherein R2 is imidazolyl or pyrrolyl. E58. A compound according to E55, wherein R
Figure imgf000164_0001
E59. A compound selected from the group consisting of:
Figure imgf000164_0004
Figure imgf000164_0003
Figure imgf000165_0002
Figure imgf000165_0001
Figure imgf000166_0002
Figure imgf000166_0001
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.

Claims

We Claim: 1. A compound having the following formula (I),
Figure imgf000167_0001
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y and Y’ is independently NR5, CR5R5’, O or S; each X is independently CR6 or N; M is NR3, O, S or Se; Z is NR4, CR4R4’, O, S or a bond; R1 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R2 is selected from the group consisting of hydrogen, halogen, -CN, -OR8, -SR8, - S(=O)R7, -S(=O)2R7, -NO2, -NR9R10, -NHS(=O)2R7, -S(=O)2NR9R10, -C(=O)R7, - OC(=O)R7, -C(=O)OR8, -OC(=O)OR8, -C(=O)NR9R10, -OC(=O)NR9R10, - NR8C(=O)NR9R10, -NR8C(=O)R7, -NR8C(=S)R7, -NR8C(=O)OR8, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2- C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R3 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R4 and R4’ are independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl; R5 and R5’ are independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl; or R5 and R5’ are taken together to form an oxo; R6 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, - ORb, -SRb, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRcRd, -NRcS(=O)2Rd, -S(=O)2NRcRd, - C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRcRd, - OC(=O)NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl or two adjacent R6 are taken together with the atoms to which they are attached to form a cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1- C6haloalkyl, C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. R7 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; R8 is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; R9 and R10 are independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or R9 and R10 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; each Ra is independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; each Rb is independently selected from the group consisting of hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; each Rc and Rd is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl.
2. A compound according to claim 1, wherein Y is NR5.
3. A compound according to claim 1 or 2, wherein Y’ is NR5 or O.
4. A compound according to any one of claims 1-3, wherein each X is CR6.
5. A compound according to any one of claims 1-4, wherein M is O.
6. A compound according to any one of claims 1-5, wherein Z is NR4 or CR4R4’.
7. A compound according to any one of claims 1-6, wherein R1 is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6deuteroalkyl.
8. A compound according to any one of claims 1-7, wherein R2 is selected from the group selected from hydrogen, halogen, -NR9R10, -NR8C(=O)R7, and heteroaryl.
9. A compound according to any one of claims 1-8, wherein R4 and R4’ are independently hydrogen.
10. A compound according to any one of claims 1-9, wherein R5 is hydrogen.
11. A compound according to any one of claims 1-10, wherein R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl, C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
12. A compound according to any one of claims 1-11, wherein R7 is selected from the group consisting of C1-C6alkyl and cycloalkyl, wherein each alkyl and cycloalkyl, is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl.
13. A compound according to any one of claims 1-12, wherein R8 is hydrogen.
14. A compound according to any one of claims 1-13, wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1- C6alkyl, or C1-C6haloalkyl.
15. A compound according to any one of claims 1-14, wherein Rb is C1-C6alkyl.
16. A compound according to any one of claims 1-15 wherein each Rc and Rd is independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein each alkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1- C6haloalkyl.
17. A compound according to any one of claims 1-16, where
Figure imgf000171_0001
18. A compound according to any one of claims 1-17, wherein R2 is heteroaryl.
19. A compound according to claim 18, wherein R2 is imidazolyl or pyrrolyl.
20. A compound according to any one of claims 1-18, wherein R2 is selected from the group
Figure imgf000172_0001
21. A compound according to any one of claims 1-20, wherein R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, -N(Me)2, -C(=O)OMe, -C(=O)NH2, C1- with the proviso that when Y’ is CR5R5’, then R6 is not
Figure imgf000172_0002
22. A compound according to any one of claims 1-21, wherein the compound is represented by formula (Ic):
Figure imgf000172_0003
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y’, M, Z, R1, R2, and R6 are as defined in claim 1.
23. A compound according to claim 22, wherein Y’ is NR5 or O.
24. A compound according to claim 22 or 23, wherein M is O.
25. A compound according to any one of claims 22-24, wherein Z is NR4 or CR4R4’.
26. A compound according to any one of claims 22-25, wherein R1 is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6deuteroalkyl.
27. A compound according to any one of claims 22-26, wherein R2 is selected from the group consisting of hydrogen, halogen, -NR9R10, -NR8C(=O)R7, and heteroaryl.
28. A compound according to any one of claims 22-27, wherein R4 and R4’ are each hydrogen.
29. A compound according to any one of claims 22-28, wherein R5 is hydrogen.
30. A compound according to any one of claims 22-29, wherein R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
31. A compound according to any one of claims 22-30, wherein R7 is selected from the group consisting of C1-C6alkyl and cycloalkyl, wherein each alkyl and cycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, - OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl.
32. A compound according to any one of claims 22-31, wherein R8 is hydrogen.
33. A compound according to any one of claims 22-32, wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1- C6alkyl, or C1-C6haloalkyl.
34. A compound according to any one of claims 22-33, wherein Rb is C1-C6alkyl.
35. A compound according to any one of claims 22-34, wherein each Rc and Rd is independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein each alkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1- C6haloalkyl.
36. A compound according to any one of claims 22-35, wherein R2 is heteroaryl.
37. A compound according to claim 36, wherein R2 is imidazolyl or pyrrolyl.
38. A compound according to any one of claims 22-35, wherein R2 is selected from the group
Figure imgf000174_0001
39. A compound according to any one of claims 22-38, wherein R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, -N(Me)2, -C(=O)OMe, -C(=O)NH2, C1- C6alkyl and with the proviso that when Y’ is CR5R5’, then R6 is not
Figure imgf000174_0002
Figure imgf000174_0003
40. A compound according to claim 1, wherein the compound is represented by formula (Ia):
Figure imgf000175_0001
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y’, M, Z, R1, R6, R9, and R10 are as defined in claim 1.
41. A compound according to claim 40, wherein Y’ is NR5 or O.
42. A compound according to claim 40 or 41, wherein M is O.
43. A compound according to any one of claims 40-42, wherein Z is selected from the group consisting of NR4 and CR4R4’.
44. A compound according to any one of claims 40-43, wherein R1 is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6deuteroalkyl.
45. A compound according to any one of claims 40-44, wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1- C6alkyl, or C1-C6haloalkyl.
46. A compound according to any one of claims 40-45, wherein R4 and R4’ are independently hydrogen.
47. A compound according to any one of claims 40-46, wherein R5 is hydrogen.
48. A compound according to any one of claims 40-47, wherein R6 is selected from the group consisting of hydrogen, halogen, -ORb, -SRb, -NRcRd, -C(=O)ORb, -C(=O)NRcRd, C1- C6alkyl, and heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -ORb, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; with the proviso that when Y’ is CR5R5’ then R6 is not cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
49. A compound according to any one of claims 40-48, wherein Rb is C1-C6alkyl.
50. A compound according to any one of claims 40-49, wherein –NR9R10 is selected from the
Figure imgf000176_0001
51. A compound according to any one of claims 40-50, wherein R6 is selected from the group consisting of hydrogen, halogen, -OMe, -SMe, -N(Me)2, -C(=O)OMe, -C(=O)NH2, C1-
Figure imgf000176_0002
52. A compound according to claim 1, wherein the compound is represented by formula (Is):
Figure imgf000177_0001
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is heteroaryl. 53. A compound according to claim 52, wherein R2 is imidazolyl or pyrrolyl. 54. A compound according to claim 52, wherein R
Figure imgf000177_0002
55. A compound according to claim 1, wherein the compound is Formula (It):
Figure imgf000177_0003
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is heteroaryl and X is CR6. 56. A compound according to claim 55, wherein R6 is hydrogen. 57. A compound according to claim 55 or 56, wherein R2 is imidazolyl or pyrrolyl. 58. A compound according to claim 55 or 56, wherein R
Figure imgf000177_0004
59. A compound selected from the group consisting of:
Figure imgf000178_0001
Figure imgf000179_0001
60. A pharmaceutical composition comprising one or more compounds according to any one of claims 1-59 and a pharmaceutically acceptable carrier or diluent. 61. A method of treating a TYK2-mediated disorder comprising administering to a patient in need thereof a compound of any one of claims 1-59, or a pharmaceutically acceptable salt or stereoisomer thereof.
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