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WO2024257023A1 - Ligands de pseudokinase tyk2 et leurs utilisations - Google Patents

Ligands de pseudokinase tyk2 et leurs utilisations Download PDF

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Publication number
WO2024257023A1
WO2024257023A1 PCT/IB2024/055815 IB2024055815W WO2024257023A1 WO 2024257023 A1 WO2024257023 A1 WO 2024257023A1 IB 2024055815 W IB2024055815 W IB 2024055815W WO 2024257023 A1 WO2024257023 A1 WO 2024257023A1
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alkyl
compound according
compound
cycloalkyl
heteroaryl
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WO2024257023A8 (fr
Inventor
Suresh KURHADE
Garima PRIYADARSHANI
Shailendra SISODIYA
Mahesh HALLE
Jeevak Sopanrao KAPURE
Jissy Akkarapattiakal KURIAPPAN
Sanchari Basu MALLIK
Amol TANDON
Ganesan Subramaniam
Abishek Venkatasubramanian IYER
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Alembic Pharmaceuticals Ltd
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Alembic Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed 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.
  • Cytokines play an important role in the regulation of immunity and inflammation.
  • Janus kinase is an intracellular non-receptor tyrosine kinase that mediates the process of transmitting various cytokine signals from the extracellular to the nucleus.
  • the JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3 and TYK2, each of which mediates different types of cytokine signaling pathways.
  • JAK family members are composed of four JAK homology regions (JH), including a catalytically active kinase domain (JH1), a catalytically inactive kinase-like domain (JH2), and a SH2-like domain (JH3) and four FERM domains (JH4-7).
  • JH1 domain catalytically active kinase domain
  • JH2 domain catalytically inactive kinase-like domain
  • JH3 SH2-like domain
  • JH4-7 FERM domains
  • JH2 domain is the most special structure, which has a high degree of similarity with the amino acid sequence of the JH1 domain, but due to the lack of several key amino acids, it does not have phosphatase activity, so it cannot exert catalytic activity, and therefore is known as the kinase-like domain, and functions to regulate catalytic activity.
  • TYK2 has been shown to be critical in regulating the signal transduction cascade downstream of receptors for IL-12, IL-23 and type I interferons. [0006] Due to high sequence similarity of the kinase domain JH2 among the JAK family (JAK1, JAK2, JAK3, and TYK2), it is challenging to develop a selective inhibitor towards TYK2’s JH2 without inhibiting the JH1 of JAK1, JAK2, JAK3 or TYK2.
  • JAK inhibitors that bind to the kinase domain of JAKs including tofacitinib, ruxolitinib, baricitinib, upadacitinib, etc., are not very selective among the JAK family members and exhibit dose-dependent side effects clinically such as anemia.
  • the development of highly selective TYK2 inhibitors remains attractive among pharmaceutical companies. Based on the structural differences between the ATP binding pockets in TYK2’s JH1 and JH2, Bristol- Myers Squibb Company has developed a highly selective JH2 binder, Deucravacitnib, which only inhibits the physiological functions mediated by TYK2 without binding to the kinase domains (JH1) of JAKs.
  • BMS- 986165 The structure of BMS- 986165 is shown below (WO2014074661) [0007] WO2015069310, WO2019183186, WO2020086616, WO2020092196, WO2020159904, WO2021222153, WO2022105771, and WO2022193499 disclose different compounds as TYK2 inhibitors, however, there remains a need to develop new compounds that selectively binds to the JH2 pseudokinase domain of TYK2, with minimal binding toward kinase domains of the JAK families.
  • SUMMARY [0008] In embodiments, the present disclosure provides a compound of Formula (A):
  • the compound of Formula (A) is a compound of Formula (I), Formula (II) or Formula (III).
  • Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:
  • R 2 is a heteroaryl wherein the carbon atom of heteraryl group is attached with the pyridazine ring; and R 1 , Z, X 1 , X 2 , X 3 , X 4 , G 1 , A 1 , A 2 , m and n are as defined herein above for Formula (I).
  • a compound of Formula (III), or a pharmaceutically acceptable salt, or stereoisomer thereof wherein R 1 , R 2 , Z, X 1 , X 2 , X 3 , X 4 , G 1 , A 1 , A 2 , m and n are as defined herein above for Formula (I).
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • a method of inhibiting a TYK2 enzyme in a patient or biological sample comprising contacting said patient or biological sample with a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof.
  • a method of treating a TYK2-mediated disorder comprising administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, or 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.
  • INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION Definitions [00025] In the context of this disclosure, a number of terms shall be utilized. [00026] 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.
  • Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
  • Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
  • 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. [00028] 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.
  • 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. In some embodiments, 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, oct
  • 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 C1 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. [00038] “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. 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.
  • 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 cycloalkyls 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 [00041]
  • 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 [00042] “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, but does not include the ring part of -OO-, -OS- or -SS-, 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 [00048]
  • 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 [00051] “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.
  • the compound of Formula (A) is a compound of Formula (I), Formula (II) or Formula (III).
  • the compound of Formula (I) is selected from a compound having Formula I-A1, I-A2, I-A3, I-A4, I-A5 or I-A6 wherein: R 1 , R 2 , R 3 , Z, G 1 , A 1 , A 2 , m and n are as defined hereinabove for Formula (I).
  • the compound of Formula (I) is selected from a compound having Formula I-A7 or I-A8
  • R 1 is selected from alkyl and deuteroalkyl
  • R 2 , X 1 , X 2 , X 3 , X 4 , A 1 , A 2 , m and n are as defined hereinabove for Formula (I).
  • the compound of Formula (I) is selected from a compound having Formula I-A9, I-A10, I-A11, I-A12, I-A13 or I-A14 wherein: R 1 is selected from alkyl or deuteroalkyl; Z is selected from NH or CH 2 ; and R 2 , X 1 , X 2 , X 3 , X 4 , A 1 , A 2 , m and n are as defined hereinabove for Formula (I).
  • a compound of Formula (II), or a pharmaceutically acceptable salt, or stereoisomer thereof wherein: R 2 is a heteroaryl wherein the carbon atom of heteraryl group is attached with the pyridazine ring; and R 1 , Z, X 1 , X 2 , X 3 , X 4 , G 1 , A 1 , A 2 , m and n is as defined herein above for Formula (I).
  • the compound of Formula (II) is selected from a compound having Formula II-A1, II-A2, II-A3, II-A4, II-A5, or II-A6
  • R 2 is as defined hereinabove for Formula (II); and R 1 , R 3 , Z, G 1 , A 1 , A 2 , m and n are as defined hereinabove for Formula (I).
  • the compound of Formula (III) is selected from a compound having Formula III-A1, III-A2, III-A3, III-A4, III-A5, or III-A6 wherein: R 1 , R 2 , R 3 , Z, G 1 , A 1 , A 2 , m and n is as defined hereinabove for Formula (I).
  • the compound of Formula (III) is selected from a compound having Formula III-A7, or III-A8
  • R 1 is selected from alkyl or deuteroalkyl
  • R 2 , X 1 , X 2 , X 3 , X 4 , A 1 , A 2 , m and n are as defined hereinabove for Formula (I).
  • the group as defined in Formula (I), (II) and (III) herein above is selected from the following, wherein G 1 , A 1 , A 2 , R 6 , m and n are as defined herein above for Formula (I). [00075] In some embodiments of present invention, the group as defined in Formula (I), (II) and (III) herein above is selected from following,
  • the compound, or a pharmaceutically acceptable salt, or stereoisomer thereof is selected from the group consisting of: C
  • 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,
  • 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.
  • 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.
  • Labeled compounds [00079] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled 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- labeled 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 [00081] 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, 1,2-
  • 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 [00087] 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 (e.g., pharmaceutically acceptable salt) thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a pharmaceutically acceptable derivative e.g., pharmaceutically acceptable salt
  • 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.
  • the term “patient,” as used herein, 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 substantially perturb 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 [00097] 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.
  • 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.
  • 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 autoimmune disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.
  • the disorder is an inflammatory disorder.
  • the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, 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, essential or thrombocytosis.
  • the disorder is an endocrine disorder.
  • the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, 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.
  • the activating mutation in TYK2 is selected from G36D, S47N, R425H, V73 II, E957D, and R1027H.
  • the disorder is associated with transplantation.
  • the disorder associated with transplantation is transplant rejection, or graft versus host disease.
  • the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.
  • Compounds of the invention 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 other inflammatory or allergic conditions of the skin.
  • Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease 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
  • 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
  • the inflammatory disease which can be treated according to the methods of this invention is selected from 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 and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.
  • the invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, thereof for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder, or a proliferative disorder, or a disorder commonly occurring in connection with transplantation.
  • the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting activity of TYK2, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or with a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting activity of TYK2, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or with a composition comprising said compound.
  • the invention provides a method of selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3.
  • a compound of the present invention is more than 2-fold selective over JAK1 or JAK2 or JAK3. In some embodiments, a compound of the present invention is more than 5-fold selective over JAK1 or JAK2 or JAK3. In some embodiments, a compound of the present invention is more than 10-fold selective over JAK1 or JAK2 or JAK3. In some embodiments, a compound of the present invention is more than 50-fold selective over JAK 1/ JAK 2/ JAK 3. In some embodiments, a compound of the present invention is more than 100-fold selective over JAKl or JAK2 or JAK3.
  • 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 activity of TYK2 (or a mutant thereof) 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.
  • Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting activity of TYK2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of reversibly or irreversibly inhibiting activity of one or more of TYK2, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the present invention provides a method for treating a disorder mediated by TYK2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.
  • 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. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds.
  • 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.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • 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 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.
  • 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.
  • a 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 derivatives of Formula (A), 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 (A) of present invention are depicted below in general schemes 1-6.
  • the generic compounds of Formula (A) as described in general procedure encompasses the compounds of Formula (I), Formula (II) and Formula (III); wherein Y 1 , Y 2 and Y 3 of formula (A) is N or CR 3 .
  • the compound of the Formula I-3 is further reacted with compound of formula I-4 in palladium mediated reaction optionally in presence of ligands PPh3, SPhos, Ruphos, XPhos, SPhos and BrettPhos and in presence of suitable base, such as but not limited to, NaOtBu, KOtBu, CS 2 CO 3, triethylamine, and a suitable solvent, such as but not limited to toluene, dioxane, acetonitrile to give compound I-6.
  • Reaction of compound 1-3 with compound 1-4 is also optionally performed without palladium catalyst and ligand.
  • compound 1-6 is also prepared by reacting compound I-1 with compound 1-5 under similar conditions as used for preparing compound 1-3.
  • Compound I-6 is further converted to compound A by various methods, including but not limited to, 1) palladium-mediated Buchwald coupling I-6 with substituted amino-heterocycles or substituted primary amides optionally in the presence of ligands PPh3, SPhos, Ruphos, XPhos, SPhos and BrettPhos; and 2) suzuki coupling chemistry and the like.
  • the protective group is used during the course of the reaction and the said protective group is removed by a conventional methods known in the art
  • Compound I-5 was prepared by reacting compound I-2 with compound I-4 using conventional methods known in the art.
  • Compounds I-2 and I-4 are commercially available.
  • Compound I-10 is converted to compound 1-1 by reacting with grignard or organolithium reagent of formula R 1 -Z-MgBr in presence of suitable base, such as but not limited to,triethylamine and a suitable solvent, such as but not limited to THF. Further, compound I-1 is converted to compound A by following similar procedure as described in general schemes provided herein. Compounds of Formula I-9 are commercially available.
  • Compound I-13 is converted to compound 1-14 by treating with oxalyl chloride in suitable solvent, such as but not limited to DCM or by treating with N,N'-CDI in suitable solvent, such as but not limited to THF, at suitable temperature such as but not limited to, from room temperature to reflux temperature until desired conversion is achieved followed by reacting with N,O - Dimethylhydroxylamine hydrochloride in presence of suitable base, such as but not limited to DIPEA and a suitable solvent, such as but not limited to THF.
  • suitable solvent such as but not limited to DCM
  • N,N'-CDI in suitable solvent, such as but not limited to THF
  • Compound I-14 is converted to compound 1-15 by reacting with grignard or organolithium reagent of formula R 1 -Z-MgBr in presence of suitable base, such as but not limited to,triethylamine and a suitable solvent, such as but not limited to THF.
  • suitable base such as but not limited to,triethylamine
  • a suitable solvent such as but not limited to THF.
  • Compound I-15 is further converted to compound A by following similar procedure as described in scheme 1 for preparing compound A from compound I-6.
  • compound of formula I-14 is converted into compound of formula I-14a by following similar procedure as described for preparing compound A from compound I-16, which is further converted into compound of formula A by following similar procedure as described for preparing compound I-15 from compound I-14.
  • General scheme 5 [000138]
  • the compound of the Formula I-16 (wherein L represents leaving group such as halogen) is reacted with compound of formula I- 2 to give compound I-17 by following similar procedure as described in scheme 1 for preparing compound I-3 from compound I-1.
  • Compound I-17 is further converted to compound I-18 by following similar procedure as described in scheme 1 for preparing compound I-6 from compound I-3.
  • compound I-18 is also be prepared by reacting compound I-16 with compound 1-5 by following similar procedure as described in scheme 1 for preparing compound I-6 from compound I-1 and compound 1-5.
  • compound I-18 is converted to compound I-19 by following similar procedure as described in scheme 1 for preparing compound A from compound 1-6.
  • Compound I-19 is further converted to compound I-20 by treating with halogenating reagent such as N- bromosuccinimide or N-chlorosuccinimide in suitable solvent such as but not limited to DCM, THF, EtOAc, DMF.
  • halogenating reagent such as N- bromosuccinimide or N-chlorosuccinimide in suitable solvent such as but not limited to DCM, THF, EtOAc, DMF.
  • suitable solvent such as but not limited to DCM, THF, EtOAc, DMF.
  • the suitable solvent used for the above schemes may be selected from the one which does not affect the course of the reaction, that includes but not limited to DMSO, DMAc, NMP, DMF, sulfolane, diglyme, ketone, alcohol, halgenated hydrocarbon, ether, ester and the like or mixtures thereof.
  • the suitable base used for the above schemes may be selected from inorganic base or organic base such as but not limited to alkali metal hydroxides such as sodium or potassium hydroxide or alkali metal carbonates such as 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 hydroxides such as sodium or potassium hydroxide or alkali metal carbonates such as sodium or potassium carbonate or caesium carbonate or sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium
  • Step 1 Synthesis of Int-1 (Intermediate 1)
  • Step 1 synthesis of 1b
  • Step 2- synthesis of 1c [000147] A suspension of 1b (22.9 g, 0.135 mol) in POCl 3 (230 mL) was heated to 90 ⁇ C and stirred until completion of reaction. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was cooled to 0 ⁇ C, treated with crushed ice to quench the excess of POCl 3 and treated with additional H 2 O (200 mL).
  • Step 3- synthesis of 1d [000148] To a solution of chloropyridine 1c (28 g, 0.135 mol) in a mixture of THF (480 mL), MeOH (110 mL), and H2O (110 mL); 5N NaOH (50 mL) was added at 25-30°C and the reaction mixture was stirred until completion of reaction.
  • Step 4- synthesis of Int-1: [000149] To a slurry of 1d (5 g, 20.05 mmol, and 1.0 eq.) in DCM (80 mL), Oxalyl chloride (2.96 mL, 33.85 mmol, 1.7 eq.) was added at 25-30°C followed by 10-15 drops of DMF.
  • the reaction mixture was stirred at 25-30°C for 1.5 h to form a nearly clear solution.
  • the reaction mixture was concentrated under nitrogen, the residue was dissolved in DCM (30 mL) and re-concentrated and the process was repeated to ensure complete removal of the excess oxalyl chloride.
  • the resulting crude acid chloride was dissolved in DCM (100 mL) and methyl-d3-ammonium chloride (2.39 g, 33.85 mmol, 1.7 eq.) was added, the reaction mixture was cooled in an ice bath and diisopropylethylamine (13.65 mL, 78.17 mmol, 2.3 eq.) was added dropwise.
  • Step-2 synthesis of 3c [000152] To a stirred solution of 3b (6 g, 32.08 mmol) in t-butanol (200 mL), triethylamine (13.5 mL, 96.25 mmol ) was added, then diphenylphosphoryl azide (10.3 mL, 48.12 mmol) was added subsequently at 25-30°, and reaction mixture was stirred at 80°C until completion of reaction.
  • reaction mixture was concentrated under reduced pressure, basified with saturated NaHCO3 solution, extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution and dried over anhydrous Na 2 SO 4 , concentrated under vacuum to afford semi-pure compound, which was washed with 20% ethyl acetate in pet ether and dried under vacuum to afford 4.9 g of Int-3 as white solid.
  • Step-1 Synthesis of Int-4 (Intermediate 4)
  • Step-1 synthesis of 4b [000154]
  • NaOMe 13.65 g, 252.69 mmol
  • the reaction mixture was diluted with water and extracted with MTBE, the organic layer was washed with cold brine solution, dried over anhydrous Na 2 SO 4 , and evaporated under reduced pressure.
  • the crude compound 4b (off white solid, 35 g, 89.17%) was used for next step without further purification.
  • Step-2 synthesis of 4 [000155]
  • compound 4b 35 g, 150.21 mmol
  • EtOH and water (7:3) 350 mL
  • ammonium chloride 79.61 g, 1502.10 mmol
  • iron powder 42.06 g, 751.05 mmol
  • the reaction mixture was cooled to room temperature, excess iron powder was removed under celite filtration and the organic layer was dried over anhydrous Na 2 SO 4 , and evaporated under vacuum.
  • Step-2 synthesis of Int-6 [000158] To a solution of 6c (0.900, 2.81 mmol) in DCM (5 mL) was added TFA (excess) at 0°C. The reaction mass was stirred at 25-30°C until completion of reaction. After completion of reaction, the reaction mixture was concentrated and purified with silica gel flash column chromatography to give Int-6 (500 mg, 80%) as yellow solid. Preparation 7: Synthesis of Int-7 (Intermediate 7) [000159] Int-7 was prepared from 7a using procedure described for the synthesis of compound Int-6 (300 mg, 59%).
  • Preparation 8 Synthesis of Int-8 (Intermediate 8) [000160] Int-8 was prepared from 8a using procedure described for the synthesis of compound 6c (200 mg, 39%).
  • Preparation 9 Synthesis of Int-9 (Intermediate 9) [000161] To a solution of Int-1 (0.584, 2.81mmol) and Int-6 (0.938, 2.81 mmol) in dry THF, LiHMDS (8.5 mL, 8.43 mmol) solution was added and the mixture was stirred at 25-30°C until completion of reaction. After completion of reaction, the reaction mixture was transferred into water and extracted with ethyl acetate. Aqueous layer was acidified with 1.0 N HCl and extracted with ethyl acetate.
  • Preparation 12 Synthesis of Int-11 (Intermediate 11) [000164] Int-11 (0.800 g, 80 %) as off-white solid was prepared from compound Int-5 and Int-3 using procedure described for synthesis of compound 1
  • Preparation 13 Synthesis of Int-12 (Intermediate 12) [000165] Int-12a was prepared from Int-1 and Int-2, which was converted to Int-12 (0.1 g, 38 %) using procedure described for synthesis of 6c as yellow solid.
  • Preparation 14 Synthesis of Int-13 (Intermediate 13) [000166] Int-13a was prepared from Int-1 and Int-2 which was converted to Int-13 (0.03 g, 27 %) as yellow solid using procedure described for synthesis of 7c.
  • Preparation 15 Synthesis of Int-14 (Intermediate 14) [000167] Int-14 (300 mg, 39%) was prepared from Int-4 and 6a using procedure described for the synthesis of compound 6c.
  • Preparation 16 Synthesis of Int-15 (Intermediate 15) [000168] Int-15 (0.5g, 37%) as brown solid was prepared from int-4 and 7 using procedure described for the synthesis of 6c or 7c.
  • Preparation 17 Synthesis of Int-16a (Intermediate 16a) [000169] Int 16a was prepared from compound Int-1 and Int-14 using procedure described for synthesis of Int-9.
  • Preparation 18 Synthesis of Int-16b (Intermediate 16b) [000170] Int 16b was prepared from compound Int-1 and Int-15 using procedure described for synthesis of Int-9.
  • Preparation 19 Synthesis of Int-17 (Intermediate 17) Step 1: synthesis of 17a [000171] To a slurry of 1d (12 g, 15.6 mmol, 1.0 eq.) in dichloromethane (120 mL) at room temperature was added oxalyl chloride (6 mL, 47.5 mmol, 3 eq.) followed by 10-15 drops of DMF causing some effervescence. The mixture was stirred at room temperature to form a nearly clear solution.
  • Step 5- synthesis of 17e [000175] To a solution of 17d (2.7 g, 10.38 mmol) in AcOH (20 mL) was added cone. HCl (40 mL). The reaction solution was heated at 100 °C till completion of the reaction. The reaction mixture was cooled to 25-30°C, concentrated, diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel flash column chromatography to give 17e (1.1 g, 55%) as a white solid.
  • Step 6- synthesis of Int-17 [000176] To a solution of 17e (1.1 g, 5.85 mmol) in CH 3 CN (15 mL) was added POCl3 (2 mL). The reaction solution was heated at 85°C till the completion of reaction. The reaction mixture was cooled to 25-30°C, concentrated and diluted with EtOAc. The solution was added to a mixed solution of EtOAc and saturated aqueous NaHCO3. After separation, the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash column chromatography to give Int- 17 (0.96 g, 80%) as a white solid.
  • Step 1 Synthesis of Int-18 (Intermediate 18) Step 1: synthesis of 18a [000177] To a solution of Int-17 (0.4 g, 1.94 mmol) and 3-bromo-2- methoxyaniline (0.47 g, 2.33 mmol) in dry THF. LiHMDS (0.97 g, 5.83 mmol) solution was added and the mixture was stirred at 25-30°C till completion of reaction. After completion of reaction, the reaction mixture was transferred into water and extracted with ethyl acetate. Aqueous layer was acidified with 1.0 N HCl and extracted with ethyl acetate. EtOAc layer was, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • Step 2- synthesis of Int-18 [000178] To a solution of 8 (0.25 g, 0.67 mmol) and cyclopropanecarboxamide (0.06 g, 0.67 mmol) in 1,4-dioxane (3 ml) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 0.06 g, 0.100 mmol), cesium carbonate (0.55 g, 1.68 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 0.093 g, 0.100 mmol).
  • Preparation 22 Synthesis of Int-20 (Intermediate 20) [000180] Int 20 was prepared from compound Int-1 and Int-19 using procedure described for synthesis of Int-9 Preparation 23: Synthesis of Int-21 (Intermediate 21) [000181] Int 21a was prepared from Int-1 and Int-10, using procedure described for synthesis of compound 1 which was converted to Int-21 using procedure described for synthesis of Int-9 (0.9 g, 54.55 %) as pink solid.
  • Preparation 24 Synthesis of Int-22 (Intermediate 22) [000182] Int 21a was prepared from Int-1 and Int-10, which was converted to Int-22 using procedure, described for synthesis of compound 1 as pale-yellow solid (1.9 g, 38.99%).
  • Preparation 28 Synthesis of Int-26 (Intermediate 26) [000186] Int-27 was prepared from compound Int-1 and Int-25 using procedure described for synthesis of Int-9 (0.6 g, 29.5%). Preparation 29: Synthesis of Int-21 (Intermediate 21) using Int-27 (Intermediate 27) [000187] Int-27 was prepared from Int-1 and Int-4 using procedure described for synthesis of compound 1, which was converted to Int-21 using procedure described for synthesis of Int-21a (0.04 g, 10.25 %) as light yellow solid.
  • Preparation 30 Synthesis of Int-28 (Intermediate 28) [000188] Int-28a was prepared from Int-1e and 8a, which was converted to Int-28 using procedure described for synthesis of compound 1 (0.8 g, 36.4 %) as off-white solid.
  • Preparation 31 Synthesis of Int-29 (Intermediate 29) [000189] Int-29 was prepared from Int-22 and 29a using procedure described for synthesis of compound 1 (0.180 g, 45.80%) as yellow solid.
  • Preparation 32 Synthesis of Int-30 (Intermediate 30) [000190] Int-30b was prepared from Int-25a and 30a, which was converted to Int-30 using procedure described for synthesis of compound 1 (0.130 g, 21.4 %) as yellow liquid.
  • Preparation 33 Synthesis of Int-31 (Intermediate 31) [000191] Int-31 was prepared from Int-31a and 31b using procedure described for synthesis of compound 1 (0.08 g, 25.64%) as yellow solid.
  • Preparation 34 Synthesis of Int-32 (Intermediate 32) [000192] Int-32 was prepared from Int-26a and 32a using procedure described for synthesis of compound 1.
  • Preparation 35 Synthesis of Int-5a (Intermediate 5a) [000193] Int-32 was 5a was prepared from 1e using procedure described for synthesis of Int-1 (2.9g, 67.88%) off-white solid.
  • Preparation 36 Synthesis of Int-33 (Intermediate 33) [000194] Int-33a was prepared from 5a and Int-3 using procedure described for Int-9, which was converted to Int-33 using procedure described for synthesis of compound 1 (6.0 g, 59.4 %) as light yellow solid. [000195] The following intermediates may be prepared according to methods described herein using appropriate starting materials:
  • reaction mixture was degassed by nitrogen for three times and then heated to 120°C until completion of reaction. After completion of reaction the reaction mixture was, filtered and filtrate was concentrated under reduced pressure and purified using preparative HPLC providing compound 1 (0.120 g, 56 % yield) as yellow solid.
  • Example 2 Synthesis of compound 4 [000199] To the solution of Int-11 (1.0 mmol) and 6b (1.5 mmol) in dioxane (5 mL), was added Pd(OAc) 2 (10 mol%), X-Phos (20 mol%) and Cs 2 CO 3 (3.0 mmol) and the resulting solution was heated at 120°C until completion of reaction. After completion of reaction the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure and purified using flash column chromatography to give compound 4 (0.054g, 18 %) as white solid.
  • Example 3 Synthesis of compound 21 [000201] To a solution of 17 (0.10 g, 0.17 mmol) in dioxane, 4M HCl in dioxane solution (3 ml) was added at 0 °C and the mixture was stirred at 25-30°C until completion of reaction. After completion of reaction the reaction mixture was concentrated under vacuum and resulting residue was purified using preparative HPLC providing compound 21 (0.015 g, 18 % yield) as yellow solid.
  • Example 3a Synthesis of compound 23 [000202] To a solution of 19 (0.09 g, 0.157 mmol) in DCM, 20% TFA/DCM solution (15 mL) was added at 0 °C and the mixture was stirred at 25-30°C till completion of reaction. After completion of reaction the reaction mixture was concentrated under vacuum and resulting residue was purified using preparative HPLC providing compound 23 (0.038 g, 51.35% yield) as white solid.
  • Example 5 Synthesis of compound 25 [000206] To a solution of 23 (0.40 g) in DCM (5 ml) was added TFA (1 ml) dropwise at 0°C and stirred for 6 hours at rt. After completion of reaction the reaction mixture was concentrated under reduced pressure and purified using flash column chromatography to give compound 25 (0.046 g, 14.2 %) as off-white solid.
  • Example 10 Synthesis of Compound 191 [000214] Compound 191 was prepared from 1a and 1b using procedure described for synthesis of compound 4 (0.058 g, 26.36 %) as white solid. [000215] 1 H NMR (400 MHz, DMSO-d6): ⁇ 10.76 (s, 1H), 10.46 (s, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 4.04 (s, 4H), 3.62 (s, 3H), 2.88 (t, 4H), 1.99-1.93 (m, 1H), 0.76-0.75 (m, 4H) ppm.
  • compounds having lower pyrimidine ring such as 41, 42, 43, 44, 89, 90, 91, 92, 93, 94, 104, 105, 107, 108, 109, 110, 119, 120, 156, 162, 163, 185, 186 may be prepared from appropriate starting materials obtained according to procedure as reported in WO2014074670.
  • compounds having lower pyridazine ring such as 155, 164, 165, 166, 167, 169, 183, 187 having may be prepared from appropriate starting materials obtained according to procedure as reported in WO2014074661.
  • BIOLOGICAL ASSAYS TYK2 JH2 Binding Assay Assay Procedure [000219] 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. [000222] 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.
  • Binding assays for JAK1 JH2, JAK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, TYK2 JH1 Binding Assays Assay Procedure [000224] 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.
  • Kd JAK1 JH2, JAK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, TYK2 JH1 Binding Assay (Kd; nM)
  • B >100 and ⁇ 1000nM
  • C >1000 and ⁇ 3000nM
  • D >3000nM and ⁇ 10000nM
  • E >10000 and ⁇ 30000nM
  • F >30000nM.
  • 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.
  • E2 A compound according to E1, wherein Z is NR 4 or CR 4 R 4’ .
  • E3 A compound according to E1or E2, wherein A 1 and A 2 are independently selected from CR 4 R 4’ .
  • E5. A compound according to E1-E4, wherein R 1 is selected from C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl.
  • a compound according to E1-E7, wherein R 4 and R 4’ are independently selected from hydrogen or halogen.
  • R 5 is hydrogen.
  • a compound according to E1-E9, wherein R 6 is selected from hydrogen, C 1 - C 6 alkyl or cycloalkyl.
  • E13. A compound according to E12, wherein Z is NR 4 or CR 4 R 4’ .
  • E14 A compound according to E12 or E13, wherein A 1 and A 2 are independently selected from CR 4 R 4’ .
  • a compound according to E12-E16, wherein R 2 is selected from NR 6 C( O)R 6’ or heteroaryl.
  • E18. A compound according to E12-E17, wherein R 3 is selected from hydrogen or -OR a ; with a proviso that when each of X 1 , X 2 , X 3 , and X 4 represents CR 3 , X 4 represents CR 3 , R 3 not being hydrogen.
  • a compound according to E12-E18, wherein R 4 and R 4’ are independently selected from hydrogen or halogen.
  • E27. A compound according to E23-E26, wherein R 1 is selected from C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl.
  • a compound according to E23-E27, wherein R 2 is selected from NR 6 C( O)R 6’ or heteroaryl.
  • E29. A compound according to E23-E28, wherein R 3 is selected from hydrogen or -OR a ; with a proviso that when each of X 1 , X 2 , X 3 , and X 4 represents CR 3 , X 4 represents CR 3 , R 3 not being hydrogen.
  • R 4 and R 4’ are independently selected from hydrogen or halogen.
  • a compound according to E23-31, wherein R 6 and R 6’ is selected from hydrogen, C 1 -C 6 alkyl or cycloalkyl.
  • E33. A compound according to E23-E32, wherein R a is, C 1 -C 6 alkyl E34.
  • E1 having the following formula:
  • X 1 , X 2 , X 3 , X 4 , A 1 , A 2 , G 1 , R 1 , R 2 , m and n are as defined in E1.
  • E35 A compound according to E34, wherein X 1 , X 2 , X 3 , X 4 are independently selected from N or CR 3 E36.
  • E40. A compound according to E34-E39, wherein R 3 is selected from hydrogen or -OR a ; with a proviso that when each of X 1 , X 2 , X 3 , and X 4 represents CR 3 , X 4 represents CR 3 , R 3 not being hydrogen.
  • E41. A compound according to E34-E40, wherein R 4 and R 4’ are independently selected from hydrogen or halogen.
  • X 1 , X 2 , X 3 , X 4 , Z, R 1 , R 2 are as defined in E1.
  • E46. A compound according to E45, wherein X 1 , X 2 , X 3 , X 4 are independently selected from N or CR 3 E47.
  • E48. A compound according to E45-E47, wherein R 1 is selected from C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl.
  • a compound according to E45-E48, wherein R 2 is selected from NR 6 C( O)R 6’ or heteroaryl.
  • E50. A compound according to E45-E49, wherein R 3 is selected from hydrogen or -OR a ; with a proviso that when each of X 1 , X 2 , X 3 , and X 4 represents CR 3 , X 4 represents CR 3 , R 3 not being hydrogen.
  • R 6 and R 6’ is selected from hydrogen, C 1 -C 6 alkyl or cycloalkyl.
  • E52. A compound according to E45-E51, wherein R a is, C 1 -C 6 alkyl E53.
  • X 1 , X 2 , X 3 , X 4 are independently selected from N or CH R a is C 1 -C 6 alkyl E54.
  • R 2 is a heteroaryl wherein the carbon atom of heteraryl group is attached with the pyridazine ring; and R 1 , Z, X 1 , X 2 , X 3 , X 4 , G 1 , A 1 , A 2 , m and n are as defined in E1.
  • E56. A compound having the following formula (III): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 , R 2 , Z, X 1 , X 2 , X 3 , X 4 , G 1 , A 1 , A 2 , m and n are as defined in E1.
  • a pharmaceutical composition comprising one or more compounds according to E1-E54, and a pharmaceutically acceptable carrier or diluent.
  • E58. A method of treating a TYK2-mediated disorder comprising administering to a patient in need thereof, a compound of any one of E1-E55, or a pharmaceutically acceptable salt or stereoisomer thereof.
  • compound of Formula (A) as described in E59 encompasses the compounds of Formula (I), Formula (II) and Formula (III).

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Abstract

L'invention concerne des composés de formule A qui sont utiles dans la modulation de l'inflammation et le traitement de troubles associés par action sur TYK2 pour provoquer une inhibition de la transduction de signal médiée par TYK2. Dans certains modes de réalisation, le trouble médié par TYK2 est un trouble auto-immun, un trouble inflammatoire, un trouble endocrinien, un trouble neurologique, un trouble prolifératif ou un trouble associé à une transplantation.
PCT/IB2024/055815 2023-06-14 2024-06-14 Ligands de pseudokinase tyk2 et leurs utilisations Pending WO2024257023A1 (fr)

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