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WO2025106633A1 - Inhibiteurs de tyk2 - Google Patents

Inhibiteurs de tyk2 Download PDF

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Publication number
WO2025106633A1
WO2025106633A1 PCT/US2024/055863 US2024055863W WO2025106633A1 WO 2025106633 A1 WO2025106633 A1 WO 2025106633A1 US 2024055863 W US2024055863 W US 2024055863W WO 2025106633 A1 WO2025106633 A1 WO 2025106633A1
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Prior art keywords
membered monocyclic
compound
pharmaceutically acceptable
acceptable salt
optionally substituted
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Inventor
Simone SCIABOLA
Tamara Halkina LEVIN
Jeffrey Vessels
Marta Nevalainen
Soma MAITRA
Vatee Pattaropong
Martin HIMMELBAUER
John Howard Jones
Zhili Xin
Lei Zhang
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Biogen MA Inc
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Biogen MA Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • TYK2 INHIBITORS RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63/599,185, filed on November 15, 2023. The entire contents of the foregoing application are expressly incorporated herein by reference.
  • TECHNICAL FIELD Provided are certain agents that target the inhibition of Tyrosine kinase 2 (TYK2), and methods of making and using such agents BACKGROUND Cytokines are small secreted proteins released by cells and have a specific effect on the interactions and communications between cells. Cytokine pathways mediate a broad range of biological functions including many aspects of inflammation and immunity through mostly extracellular signaling.
  • Tyrosine kinase 2 is a member of Janus kinases (JAK) that are cytoplasmic protein kinases associated with cytokine receptors and play a central role in mediating cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; and Yamaoka et al. Genome Biology 2004, 5, 253).
  • the JAK family also includes JAK1, JAK2 and JAK3.
  • cytokines known to activate the JAK family include the interferon (IFN) family (IFN-alpha, IFN-beta, IFN- omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp) 130 family (IL-6, IL-11, OSM, LlF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), the gamma C family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), the single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupled receptors (AT1).
  • IFN interferon
  • gp glycoprotein
  • gp glycoprotein
  • TYK2 is important in the signaling of the type I interferons (e.g., IFN-alpha), IL-6, IL-10, IL-12 and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18,5, 571-580; Kisseleva et al., 2002, Gene 285:1-24; and Watford, W.T. & O’Shea, J.J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL-10, IL-12 and IL-23 signaling.
  • TYK2/JAK1, TYK2/JAK2, TYK2/JAK1/JAK2 Studies have shown that inappropriate JAK activities can arise from mutation, over- expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines, and therefore trigger a variety of biological cellular responses relating to cell growth, cell differentiation, cell function, survival, apoptosis, and cell mobility.
  • the inappropriate JAK activities are implicated in many diseases that include but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease.
  • Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases.
  • all known small molecule JAK inhibitors that have progressed into development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (also referred to as the JH1 or Janus Homology 1 domain) of the JAK protein, which prevents catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and resulting pathway signal transduction (Bryan et al., J. Med. Chem.2018, 61, 9030 ⁇ 9058).
  • ATP adenosine triphosphate
  • JAK inhibitors that have been developed are pan-JAK inhibitors or are modestly selective for one or more JAK family members. While these inhibitors have shown encouraging results in treating autoimmune diseases, undesirable side effects leading to a narrow therapeutic index have been observed and suggest the need for improved treatments.
  • TYK2 has been shown to be important in the differentiation and function of multiple cell types important in inflammatory disease and autoimmune disease including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory conditions.
  • the present disclosure relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R 1 is C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, -C(O)R 1c , -SO 2 R 1c , phenyl, 5-or 6- membered monocyclic heteroaryl, or 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein the C1-6alkyl and C2-6alkenyl are each optionally substituted by one or more R 1a , and wherein the C3-10cycloalkyl, phenyl, 5-or 6-membered monocyclic heteroaryl, and 4- to 10- membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R 1b ; each R 1
  • the present disclosure is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the present disclosure is a method of treating a disease or disorder responsive to inhibition of TYK2 in a subject comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition described herein, for the manufacture of a medicament for inhibiting TYK2 activity.
  • the disclosure also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in inhibiting TYK2 activity. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease or disorder responsive to inhibition of TYK2.
  • the compounds of the present disclosure have low efflux ratio, especially in comparison to similar compounds known in the art.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
  • the alkyl comprises 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • an alkyl comprises from 6 to 20 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.
  • the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).
  • alkoxy refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a --O-- C1-4 alkyl group wherein C1-4 alkyl is as defined herein).
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy and the like.
  • alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons.
  • alkoxy-alkly i.e. C1-3alkoxyC1-3alkyl refers to an alkyl group substituted with an alkoxy group.
  • Cx-xx is an alkyl group which has from 1 to 4 carbon atoms
  • aryl refers to a carbocyclic (all carbon) aromatic monocyclic or bicyclic ring system containing 6-10 carbon atoms. Examples of 6-10 membered aryl groups include phenyl and naphthyl. In some embodiments, the aryl is phenyl.
  • cycloalkyl refers to completely saturated monocyclic or bicyclic or spiro hydrocarbon groups of 3-7 carbon atoms, 3-6 carbon atoms, or 5-7 carbon atoms. In some embodiments, cycloalkyl is a 3- to 6-membered monocyclic cycloalkyl.
  • carbocycle, carbocyclyl and carbocyclic ring refer to saturated or partially unsaturated (i.e., non-aromatic) monocyclic or bicyclic hydrocarbon groups of, for example, 3-10, 3-8, 3-7, 3-5, 3-6, 4-6, 5-7 or 7-10 carbon atoms.
  • Halogen or halo may be fluoro, chloro, bromo or iodo.
  • haloalkyl or halo-substituted alkyl refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom.
  • the haloalkyl group can be monohalo-alkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
  • Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
  • the polyhaloalkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups.
  • haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • a perhaloalkyl group refers to an alkyl group having all hydrogen atoms replaced with halo atoms.
  • heteroaryl refers to an aromatic 5- to 6-membered monocyclic or an 8- to 10- membered bicyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone.
  • Examples of 5- to 6- membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, and the like.
  • Examples of 8- to 10-membered bicyclic heteroaryls include, but are not limited to, imidazolthiazolyl, imidazopyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2 ⁇ 2 -isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl and thieno[3,2-b]pyridinyl.
  • heterocyclyl refers to a saturated or unsaturated, monocyclic or bicyclic (e.g., fused, bridged or spiro ring systems) ring system which has from 3- to 14- ring members, or in particular 3- to 8-ring members, 3- to 7-ring members, 3- to 6- ring members, 5- to 7- ring members, 4- to 10-ring members, 4- to 7- ring members or 4- to 6-ring members, at least one of which is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone.
  • C can be oxidized
  • N can be oxidized
  • S can be optionally oxidized to sul
  • the heterocyclyl group can be attached to the rest of a compound of the invention at a heteroatom or a carbon atom.
  • azacyclic refers to a non-aromatic heterocyclyl, which has at least one nitrogen ring atom.
  • the examples of azacyclic include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and morpholine.
  • Fully saturated heterocyclyl groups include heterocycloalkyl groups.
  • 3- to 7-membered monocyclic heterocyclyl include, but are not limited to, aziridinyl, oxiranyl, thirranyl, oxaziridinyl, oxazepanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl
  • a heterocyclyl is a 5-to 7-membered monocyclic heterocyclyl (saturated or partially unsaturated). Examples include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, oxazepanyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl,
  • a heterocyclyl is a 4 to 6-membered saturated monocyclic heterocyclyl. Examples include, but are not limited to, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, and piperdinyl. In one embodiment, a heterocyclyl is a 5- or 6-membered saturated monocyclic or bicyclic heterocyclyl. Examples include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, and 2- oxabicyclo[2.1.1]hexanyl.
  • bicyclic heterocycle refers to a bicyclic ring which is partially or fully saturated and contains 1 to 2 heteroatoms, independently selected from sulfur, oxygen and/or nitrogen.
  • partially or fully saturated heterocycle refers to a nonaromatic ring that is either partially or fully saturated and may exist as a single ring, bicyclic ring (including fused heterocyclic rings) or a spiro ring.
  • the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • Hydroxyl or Hydroxy refers to the group -OH.
  • fused ring system is a ring system that has two ring structures sharing two adjacent ring atoms. In one embodiment, a fused ring system have from 8 to 12 ring members.
  • bridged ring system is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably from one to three) atoms selected from C, N, O, and S. In one embodiment, a bridged ring system have from 6 to 8 ring members.
  • spiro ring system is a ring system that has two ring structures having one ring atom in common.
  • spiro ring systems have from 5 to 8 ring members.
  • the phrase optionally substituted is used interchangeably with the phrase substituted or unsubstituted.
  • the term optionally substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the description of compounds and examples thereof.
  • an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • Examples include carbonyl, sulfinyl, or sulfonyl groups (--C(O)--, --S(O)-- or --S(O)2--) such as, a ketone, aldehyde, or part of an acid, ester, amide, lactone, or lactam group and the like.
  • compounds of the present disclosure refers to compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), or (IIe-1) as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions).
  • salts are included as well, in particular pharmaceutically acceptable salts.
  • Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Sigma-Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York (1967- 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.
  • salt or salts refers to an acid addition or base addition salt of a compound of the disclosure.
  • Salts include in particular pharmaceutical acceptable salts.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this disclosure and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Salts of compounds of the present disclosure having at least one salt-forming group may be prepared in a manner known to those skilled in the art.
  • acid addition salts of compounds of the present disclosure are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Salts can be converted into the free compounds in accordance with methods known to those skilled in the art. Acid addition salts can be converted, for example, by treatment with a suitable basic agent.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • Lists of additional suitable salts can be found, e.g., in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the disclosure provides deuterated compounds in which any or more positions occupied by hydrogen can include enrichment by deuterium above the natural abundance of deuterium.
  • one or more hydrogen atoms are replaced with deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • hydrogen is present at all positions at its natural abundance.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d6-DMSO. It will be recognized by those skilled in the art that the compounds of the present disclosure may contain chiral centers and as such may exist in different stereoisomeric forms.
  • an optical isomer or a stereoisomer refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • the compounds exist in individual optically active isomeric forms or as mixtures thereof, e.g. as racemic or diastereomeric mixtures.
  • Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of a commercially available chiral HPLC column.
  • any structure that does not designate the stereochemistry is to be understood as embracing all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture).
  • the compounds described herein are isolated stereoisomers wherein each of the compounds has one stereocenter and the stereoisomer is in the R configuration. In other embodiment, the compounds described herein are isolated stereoisomers wherein each of the compounds has one stereocenter and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are isolated stereoisomers wherein each of the compounds has two stereocenters and the stereoisomer is in the R R configuration.
  • the compounds described herein are isolated stereoisomers wherein each of the compounds has two stereocenters and the stereoisomer is in the R S configuration. In one embodiment, the compounds described herein are isolated stereoisomers stereoisomer wherein each of the compounds has two stereocenters and the stereoisomer is in the S R configuration. In one embodiment, the compounds described herein are isolated stereoisomers stereoisomer wherein each of the compounds has two stereocenters and the stereoisomer is in the S S configuration. In one embodiment, the compounds described herein each have one or two stereocenters and are racemic mixtures.
  • stereochemical purity means the weight percent of the desired stereoisomer relative to the combined weight of all stereoisomers.
  • name or structure encompasses one enantiomer of compound in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture of the compound and mixtures enriched in one enantiomer relative to its corresponding optical isomer).
  • the compounds of the present disclosure may contain chiral centers and as such may exist in different stereoisomeric forms.
  • the term an optical isomer or a stereoisomer refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound. Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. The term is used to designate a racemic mixture where appropriate.
  • a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)); a single stereoisomer with known relative configuration but unknown absolute configuration is designated with stars (e.g., (1R*,2R*)); and a racemate with two letters (e.g, (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)).
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • the resolved compounds can be defined by the respective retention times for the corresponding enantiomers/diastereomers via chiral HPLC.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless specified otherwise, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAK RTM and CHIRALCEL RTM available from DAICEL Corp. using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • tautomer or tautomeric form refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine- enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens.
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • II. COMPOUNDS OF THE DISCLOSURE the compound of the present disclosure is represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables are as described in the first aspect above.
  • the compound of the present disclosure is represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R 1 is C1-3alkyl, C3-6cycloalkyl, -C(O)R 1c , -SO2R 1c , phenyl, 5-or 6-membered monocyclic heteroaryl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C 1-3 alkyl is optionally substituted by one or more R 1a , and wherein the C3-6cycloalkyl, phenyl, 5-or 6- membered monocyclic heteroaryl, and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by one or more R 1b ; each R 1a is, independently, halo, cyano, C 1-3 alkoxy, or –OH; each R 1b is, independently, halo, C1-3alkyl, -OH, -NH2, -N(C1-3alkyl)
  • R 2 is C 1-3 alkyl; and the remaining variables are as described in the first embodiment.
  • R 2 is -CH3, -CH2OH, -CH2-cyclopropyl, - CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 CN, or cyclopropyl; and the remaining variables are as described in the first embodiment.
  • R 2 is -CH3; and the remaining variables are as described in the first embodiment.
  • Ring A is a 6-membered monocyclic heteroaryl comprising at least one N atom, or Ring A is a 5-membered monocyclic heteroaryl comprising at least one S atom and one or more N atoms; and the remaining variables are as described in the first or second embodiment.
  • Ring A is a 6-membered monocyclic heteroaryl comprising at least one N atom, or Ring A is a 5-membered monocyclic heteroaryl comprising one or more N atoms and optionally one S atom; and the remaining variables are as described in the first or second embodiment.
  • Ring A is pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, isothiazolyl, or thiadiazolyl, each of which are substituted with 1 to 3 R 3 ; and the remaining variables are as described in the first, second, or third embodiment.
  • Ring A is pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, isothiazolyl, or thiadiazolyl, each of which are substituted with 1 to 3 R 3 ; and the remaining variables are as described in the first, second, or third embodiment.
  • Ring A is: ,
  • each R 3 is, independently, C1-3alkyl, C1-3haloalkyl, -OR 3a , -N(R 3c )2, C 3-6 cycloalkyl, 5- or 6-membered monocyclic or bicyclic heterocyclyl, wherein the C 1-3 alkyl and C1-3haloalkyl are each optionally substituted by -OH or C1-3alkoxy, and wherein the C3- 6cycloalkyl and 5- and 6-membered monocyclic or bicyclic heterocyclyl are optionally substituted by 1 to 3 R 5 ;
  • R 3a is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-C 1-3 alkoxy, or C 3- 4 cycloalkyl, or
  • each R 3 is, independently, C1-3alkyl, C1-3haloalkyl, -OR 3a , C3-4cycloalkyl, 5- or 6- membered monocyclic or bicyclic heterocyclyl, wherein the C 1-3 alkyl is optionally substituted by C 1-3 alkoxy, wherein the C 3-4 cycloalkyl is optionally substituted by 1 or 2 halo, and the 5- or 6-membered monocyclic or bicyclic heterocyclyl is optionally substituted by 1 or 2 C1-3alkoxy;
  • R 3a is C1-3alkyl or C3-4cycloalkyl, provided (i) when R 3 is a substituted 5- or 6-membered monocyclic or bicyclic heterocyclyl , then Ring A is a 5-membered monocyclic heteroaryl; or (ii) when R 3 is tetrahydrofuranyl then Ring A is a 5-member
  • each R 3 is, independently, -CH3, CH2CH3, -CF2CH3, -CF2CH2OH, - CH 2 OCH 3 , CH(OH)CH 3 , -CH(CH 3 ) 2 , -CF(CH 3 ) 2 , -OCH 3 , -CF 2 CH 2 CH 3 , -CF 2 CH 2 OCH 3 , - OCH 3 , -OCHF 2 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 OCH 3 , -O-cyclopropyl, -NHCH 3 , -NHCH 2 CH 3 , - NHCH(CH3)2, -N(CH3)2, -NHCH2CH2OCH3, -NH-cyclopropyl, -NH-cyclobutyl, -O- oxetanyl, -O-pyrrolidinyl, cyclopropyl, -NH-cyclobutyl, -O- oxe
  • each R 3 is, independently, -CH3, CH2CH3, -CF2CH3, -CH2OCH3, - CF(CH3)2, -OCH3, -O-cyclopropyl, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, or 2- oxabicyclo[2.1.1]hexanyl, wherein the cyclopropyl is optionally substituted by 1 or 2 halo, and the tetrahydrofuranyl is optionally substituted by –OCH3, provided that when R 3 is tetrahydrofuranyl, substituted tetrahydropyranyl, or 2-oxabicyclo[2.1.1]hexanyl, then Ring A is a 5-membered monocyclic heteroaryl; and the remaining variables are as described in the seventh embodiment.
  • each R 3 is, independently, -CH3, CH2CH3, -CF2CH3, -CF2CH2OH, - CH 2 OCH 3 , -CH(OH)CH 3 , -CH(CH 3 ) 2 , -CF(CH 3 ) 2 , -CF 2 CH 2 CH 3 , -CF 2 CH 2 OCH 3 , -OCH 3 , - OCHF2, -OCH(CH3)2, -OCH2CH2OCH3, -O-cyclopropyl, -NHCH3, -NHCH2CH3, - NHCH(CH3)2, -N(CH3)2, -NHCH2CH2OCH3, -NH-cyclopropyl, -NH-cyclobutyl, membered monocyclic heteroaryl; or (ii) when R 3 is then Ring A is pyrimidinyl.; and the remaining variables are as described in the first,
  • each R 3 is, independently, -CH 3 , CH 2 CH 3 , - Ring A is a 5-membered monocyclic heteroaryl; and the remaining variables are as described in the first, second, third, fourth, fifth, or sixth embodiment.
  • the compound of the present disclosure is represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y 1 , Y 3 , and Y 5 are each N or CH; Y 2 is CR Y1 ; Y 4 is N or CR Y2 ; provided that no more than 2 of Y 1 , Y 2 , Y 4 , and Y 5 are N; R Y1 is C1-3haloalkyl or C3-4cycloalkyl substituted by one or more halo; R Y2 is H, C 1-3 alkyl, -OR Y2a , or 5-or 6-membered monocyclic heterocyclyl, wherein the C 1-3 alkyl is optionally substituted by C 1-3 alkoxy, provided that R Y2 is not tetrahydrofuranyl; R Y2a is C 1-3 alkyl or C 3-4 cycloalkyl; R 1 is C 1-3 alkyl
  • the compound of the present disclosure is represented by (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or (IIh): or a pharmaceutically acceptable salt thereof, wherein the variables R Y1 , R Y2 , R 1 , and X are as defined in the tenth embodiment.
  • the compound of the present disclosure is represented by (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or (IIh): or a pharmaceutically acceptable salt thereof, wherein the variables R Y1 , R Y2 , R 1 , and X are as defined in the tenth embodiment.
  • R Y1 is -CF2CH3, - ; and the remaining variables are as described in the tenth or eleventh embodiment.
  • R Y2 is H, -CH3, CH2CH3, -CH2OCH3, -OCH3, -O-cyclopropyl, or tetrahydropyranyl; and the remaining variables are as described in the tenth, eleventh, or twelfth embodiment.
  • the compound of the present disclosure is represented by Formula (III): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Z 1 , Z 2 , Z 3 , and Z 4 are each independently N, S, CH, or CR 3 ; provided that no more than 2 of Z 1 , Z 2 , Z 3 , and Z 4 are N and no more than 1 of Z 1 , Z 2 , Z 3 , and Z 4 are S; each R 3 is, independently, C1-3alkyl, C1-3haloalkyl, -OR 3a , C3-6cycloalkyl, 5- or 6- membered monocyclic or bicyclic heterocyclyl, wherein the C 3-6 cycloalkyl is optionally substituted by 1 or 2 halo, and the 5- or 6-membered monocyclic or bicyclic heterocyclyl is optionally substituted by 1 or 2 C1-3alkoxy or halo; R 3a is C 1-3 alkyl or C 3-4 cycloalkyl
  • the compound of the present disclosure is represented by (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh):
  • R 3 is -CF2CH3, -CF(CH3)2, , tetrahydrofuranyl, tetrahydropyranyl, or 2- oxabicyclo[2.1.1]hexanyl, wherein the tetrahydrofuranyl is optionally substituted with – OCH3 or -F; and the remaining variables are as described in the fifteenth embodiment.
  • R 1 is C 1-4 alkyl, C 2-6 alkenyl, -C(O)R 1c , - SO2R 1c , C3-10cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, or 5- to 6- membered monocyclic heteroaryl, wherein the C1-4alkyl and C2-6alkenyl are optionally substituted by one to three R 1a , and the C 3-10 cycloalkyl, 4- to 8-membered monocyclic or bicyclic heterocyclyl, and 5- to 6-membered
  • R 1 is C1-3alkyl, C3- 6 cycloalkyl, -C 1-3 alkyl-C 1-3 alkoxy, or 4- to 6-membered monocyclic heterocyclyl, wherein the C3-6cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted by 1 or 2 R 1b ; each R 1b is, independently, C1-3alkyl, C1-3alkoxy, or cyano; and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twel
  • R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 OCH 3 , cyclopropyl, cyclobutyl, oxetanyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, or piperdinyl, wherein the cyclobutyl, azetininyl, tetrahydropyranyl, pyrrolidinyl, and piperdinyl are each optionally substituted by 1 R 1b
  • the compound of the present disclosure is represented by Formula (IIe-1): or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1-3 alkyl or C 3-4 cycloalkyl; R Y1 is C 1-3 haloalkyl; and R Y2 is C1-3alkyl; and the remaining variables are as described in the first embodiment.
  • R 1 is C 1-3 alkyl or C 3-4 cycloalkyl
  • R Y1 is C 1-3 haloalkyl
  • R Y2 is C1-3alkyl
  • the remaining variables are as described in the first embodiment.
  • R 1 is -CH 2 CH 3 or cyclopropyl
  • the remaining variables are as described in the twentieth embodiment.
  • R Y1 is -CF 2 CH 3 ; and the remaining variables are as described in the twentieth or twenty-first embodiment.
  • R Y2 is -CH2CH3; and the remaining variables are as described in the twentieth, twenty-first, or twenty-second embodiment.
  • the compound of present disclosure is any one of compounds of Examples 1-222, or a pharmaceutically acceptable salt thereof.
  • the compound of present disclosure is any one of compounds of Examples 1-46, or a pharmaceutically acceptable salt thereof.
  • the disclosure also includes both the neutral form and pharmaceutically acceptable salts of the compounds illustrated in the exemplification.
  • the present disclosure is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the phrase pharmaceutically acceptable indicates that the substance, composition or dosage form must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the term pharmaceutically acceptable carrier includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329).
  • GRAS safe
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present disclosure or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)
  • a suitable solvent in the presence of one or more of the excipients described above.
  • the compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration.
  • the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • suitable compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • the parenteral compositions e.g, intravenous (IV) formulation
  • IV intravenous
  • the parenteral compositions are aqueous isotonic solutions or suspensions.
  • the parenteral compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1- 75%, or contain about 1-50%, of the active ingredient.
  • the effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be 10 ⁇ g -500 mg.
  • Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal comprises any suitable delivery method.
  • Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to the mammal.
  • Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal also includes administering topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally or intravitreally to a mammal a compound that metabolizes within or on a surface of the body of the mammal to a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a compound or pharmaceutically acceptable salt thereof as described herein may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the compound or pharmaceutically acceptable salt thereof as described herein may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like.
  • Such compositions and preparations should contain at least about 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions can be such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like can include the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation can be vacuum drying and the freeze drying techniques, which can yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the compounds or pharmaceutically acceptable salts thereof as described herein can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Useful dosages of a compound or pharmaceutically acceptable salt thereof as described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949, which is incorporated by reference in its entirety.
  • the amount of a compound or pharmaceutically acceptable salt thereof as described herein, required for use in treatment can vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and can be ultimately at the discretion of the attendant physician or clinician. In general, however, a dose can be in the range of from about 0.1 to about 10 mg/kg of body weight per day.
  • the compound or pharmaceutically acceptable salt thereof as described herein can be conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some embodiments, a dose of 5 mg/kg or less can be suitable. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals. IV. USE OF COMPOUNDS AND COMPOSITIONS OF THE DISCLOSURE The compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease or inhibit the activity of TYK2 or to otherwise affect the properties and/or behavior of TYK2, e.g., stability, phosphorylation, kinase activity, interactions with other proteins, etc.
  • Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the present disclosure is a method of treating a disease or disorder responsive to inhibition of TYK2 in a subject comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically composition described herein for the manufacture of a medicament for inhibiting TYK2 activity.
  • the disclosure also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein for use in inhibiting TYK2 activity.
  • the term inhibit, inhibition or inhibiting refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term subject and patient may be used interchangeably, and means a mammal in need of treatment, e.g., human, companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • a subject is in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (preferably, a human).
  • the term treat, treating or treatment refers to obtaining desired pharmacological and/or physiological effect.
  • the effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
  • co-administer refers to the presence of two active agents in the blood of an individual. Active agents that are co-administered can be concurrently or sequentially delivered.
  • combination therapy or in combination with or pharmaceutical combination refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.
  • Such administration encompasses co- administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients.
  • administration encompasses co-administration in multiple, or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
  • administration also encompasses use of each type of therapeutic agent being administered prior to, concurrent with, or sequentially to each other with no specific time limits. In each case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • the method described herein treats the disease or disorder responsive to inhibition of TYK2, wherein the disease or disorder includes inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoisosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction , thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration , glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myect
  • autoimmune disorders includes diseases or disorders involving inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease, dermatomyositis, diabetes mellitus type 1, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, and Wegener's granulomatosis.
  • ADAM acute disseminated
  • inflammatory disorders includes diseases or disorders involving acute or chronic inflammation such as allergies, asthma, atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.
  • PID pelvic inflammatory disease
  • IBD inflammatory bowel disease
  • reperfusion injury rheumatoid arthritis
  • transplant rejection transplant rejection
  • vasculitis vasculitis.
  • cancer includes diseases or disorders involving abnormal cell growth and/or proliferation, such as glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g.
  • small- cell lung carcinoma non-small-cell lung carcinoma
  • gastric carcinoma gastric carcinoma
  • gastrointestinal stromal tumors pancreatic carcinoma
  • bile duct carcinoma ovarian carcinoma
  • endometrial carcinoma prostate carcinoma
  • renal cell carcinoma lymphoma (e.g., anaplastic large-cell lymphoma), leukemia (e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g. microsatellite instability-high colorectal cancer).
  • lymphoma e.g., anaplastic large-cell lymphoma
  • leukemia e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia
  • multiple myeloma malignant mesothelioma
  • malignant melanoma malignant melanoma
  • the disclosed method can include a kit comprising a compound or pharmaceutically acceptable salt thereof as described herein and instructional material which can describe administering a compound or pharmaceutically acceptable salt thereof as described herein or a composition comprising a compound or pharmaceutically acceptable salt thereof as described herein to a cell or a subject.
  • instructional material which can describe administering a compound or pharmaceutically acceptable salt thereof as described herein or a composition comprising a compound or pharmaceutically acceptable salt thereof as described herein to a cell or a subject.
  • the subject can be a human.
  • d means doublet; dd means double doublet;
  • DCM means dichloromethane;
  • DEA diethylamine
  • DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine;
  • DMA means N,N-dimethylacetamide;
  • DMF means N,N-dimethylformamide;
  • DMSO means Dimethylsulfoxide; DMSO-d6 means hexadeuterodimethyl sulfoxide; Et means ethyl; EtOH means ethanol; EtOAc means ethyl acetate; Eq.
  • HPLC high pressure liquid chromatography
  • IPA 2-propanol
  • LCMS liquid chromatography mass spectrometry
  • LDA lithium diisopropylamide
  • m multiplet
  • Me means methyl
  • MeCN means acetonitrile
  • MeI means iodomethane
  • MeOH means methanol
  • MeOH-d4 means deutero-methanol
  • MS m/z means mass spectrum peak
  • MsCl methanesulfonyl chloride
  • NBS means N-bromosuccinimide
  • NOE nuclear Overhauser effect spectroscopy
  • PE means petroleum ether
  • Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II)
  • Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium (0)
  • Schemes Scheme 1 (a) : Pd Ligand, bis(pinacolato)diboron, base (b) : Pd Ligand, base (c) : EtOH at 130°C, or hexafluoroisopropanol at 70°C, or acid at rt (d) : R 1 -Br, I,OMs,OTf or SO2Ph and base (e) : oxirane, base (f) : ClCF 2 CO 2 Na, base at 100°C (i) : 1,10-phenanthroline, Iridium catalst, HBPin Scheme 3
  • transformations include, but are not limited to: reductive amination of an aldehyde with a primary or secondary amine to provide respectively, a secondary or tertiary amine fluorination of an alcohol to provide an alkyl fluoride fluorination of an alkyl bromide to provide an alkyl fluoride amination of a heteroaryl chloride to provide a heteroaryl amine
  • Typical protecting groups may comprise, carbamate and preferably Boc for the protection of amines.
  • Preparation 7 4-chloro-2-(1,1-difluoroethyl)-6-ethylpyrimidine
  • ethylboronic acid 520 mg, 7 mmol
  • K2CO3 1.46 g, 10.6 mmol
  • Pd(dppf)Cl2 515 mg, 0.70 mmol
  • Preparation 19 4-chloro-2-(1,1-difluoroethyl)pyrimidine
  • a solution of 2-(1,1-difluoroethyl)pyrimidin-4-ol (Preparation 18, 100 mg, 0.63 mmol) in POCl3 (2 mL) was stirred at 100 °C for 2 h.
  • the reaction mixture was concentrated, the residue diluted with H2O (10 mL) and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated to give 4-chloro-2-(1,1- difluoroethyl)pyrimidine as a yellow oil (85 mg, 76%).
  • reaction mixture was concentrated and purified by silica gel column chromatography (EtOAc in PE from 20% to 80%) to give tert-butyl (3-(5-acetamido-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)- 1H-pyrrolo[2,3-c]pyridin-1-yl)cyclobutyl)carbamate (300 mg, 66.2% yield) as a yellow solid.
  • Example 2 N-[3-[4-(1,1-difluoroethyl)thiazol-2-yl]-1H-pyrrolo[2,3-c]pyridin-5-yl]acetamide
  • Example 3 N-(3-(4-(1,1-difluoroethyl)thiazol-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • N-[3-[4-(1,1-difluoroethyl)thiazol-2-yl]-1H-pyrrolo[2,3-c]pyridin-5- yl]acetamide (Example 2, 40 mg, 124 ⁇ mol) and Cs2CO3 (81 mg, 248 ⁇ mol) in DMF (1.5 mL) was added iodomethane (15 ⁇ L 248 ⁇ mol).
  • Example 5 N-(3-(4-(1,1-difluoroethyl)-5-methylthiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(4-(1,1-difluoroethyl)-5-methylthiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared in the same way as described in Example 2 from tert-butyl 5-acetamido-3-(4- (1,1-difluoroethyl)-5-methylthiazol-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate.
  • Example 7 N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared in the same way as described in Example 2 from tert-butyl 5-acetamido-3-(6-(2- fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate.
  • LCMS m/z 314 [M+H]+.
  • Example 8 N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide was prepared in the same way as described in Example 3 from N-(3-(6-(2- fluoropropan-2-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide.
  • Example 9 N-(1-methyl-3-(4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-
  • the title compound was prepared in the same way as described in Example 3 from N-(3-(4- (tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide to afford N-(1- methyl-3-(4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (3.5 mg, 10% yield) as a brown solid.
  • Example 10 rac-(R)-N-(1-methyl-3-(5-methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide
  • the title compound was prepared in the same way as described in Example 3 from rac-(R)-N- (3-(5-methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide to give rac-(R)-N-(1-methyl-3-(5-methyl-4-(tetrahydrofuran-3-yl)thiazol-2-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (6.6 mg, 24.48% yield) as a yellow solid.
  • Example 11 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide
  • N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Preparation 28, 61.1 mg) in Dioxane (3 mL)
  • H2O 0.5 mL
  • 4-chloro-2-(1,1-difluoroethyl)-6-methylpyrimidine Preparation 6, 100 mg, 317 ⁇ mol
  • K 2 CO 3 88 mg, 635 ⁇ mol
  • Pd(dppf)Cl 2 Pd(dppf)Cl 2 .
  • Example 13 N-(3-(4-(1,1-difluoroethyl)pyrimidin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide
  • N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Preparation 28, 100 mg, 317.28 ⁇ mol) and 2-chloro-4-(1,1- difluoroethyl)pyrimidine (85 mg, 476 ⁇ mol) in Dioxane (2 mL) and H2O (0.2 mL) were added Pd(dppf)Cl2 .
  • Example 14 N-(3-(4-(1,1-difluoroethyl)-6-methylpyrimidin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide
  • 2-chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine Preparation 21, 90 mg, 467.31 ⁇ mol
  • N-(1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide Preparation 28, 221 mg, 701 ⁇ mol) in dioxane (5 mL) and H 2 O (1 mL) were added Pd(dppf)Cl 2 ⁇ DCM (38 mg, 47 ⁇ mol) and K 2 CO 3 (194 mg, 1.4 mmol) at 25 °C and the mixture was stirred at
  • Example 16 Rac-cis/trans-N-(1-((1s,3s)-3-cyanocyclobutyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin- 4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • (rac-cis/trans-3-cyanocyclobutyl)methanesulfonate 52.88 mg, 301.82 ⁇ mol
  • N-[3-[2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1H-pyrrolo[2,3-c]pyridin-5- yl]acetamide Example 34, 100 mg, 301 ⁇ mol) and CsCO3 (148 mg, 453 ⁇ mol) in dry DMF (2 mL) was stirred at 100 °C for 17h.
  • Example 17 rac-(R)-N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(tetrahydrofuran-3-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • [rac-(3R)-tetrahydrofuran-3-yl] methanesulfonate 73 mg, 439 ⁇ mol
  • N-[3- [2-(1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1H-pyrrolo[2,3-c]pyridin-5-yl]acetamide Example 34, 65 mg, 146 ⁇ mol
  • CsCO3 238 mg, 731 ⁇ mol
  • Desired product was obtained as a pale yellow solid, which was triturated with diethyl ether to provide N-[3-[2- (1,1-difluoroethyl)-6-methyl-pyrimidin-4-yl]-1-[rac-(3S)-tetrahydrofuran-3-yl]pyrrolo[2,3- c]pyridin-5-yl]acetamide (15 mg, 38 ⁇ mol, 26% yield) as an off-white solid.
  • Example 18 N-(3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin- 5-yl)acetamide
  • Liquid chromatography was performed using a Waters XSelect CSH C18, 5 ⁇ m, 30 mm ⁇ 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 ⁇ 65 % B (0.2% NH4OH final v/v % modifier) with flow rate at 60 mL/min, affording N-(3-(2- (2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide (10 mg, 6 % yield) as a white solid.
  • LCMS m/z 343.0 [M+ H] + .
  • Example 19 N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide Prepared in a similar manner to Example 18 starting with 2-chloro-6-(1-fluoro-1-methyl- ethyl)pyrazine to afford N-(3-(6-(2-fluoropropan-2-yl)pyrazin-2-yl)-1-methyl-1H- pyrazolo[3,4-c]pyridin-5-yl)acetamide (2 mg) as a white solid.
  • LCMS m/z 329.0 [M+ H] + .
  • Example 20 N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide Prepared in a similar manner to Example 18 starting with 4-chloro-6-ethyl-2-(1- fluorocyclopropyl)pyrimidine (Preparation 25) to afford N-(3-(6-ethyl-2-(1- fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (4 mg) as a white solid.
  • Example 21 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)propionamide Prepared in a similar manner to Example 18 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methyl-pyrimidine (Preparation 11) and N-ethylacetamide to afford N-(3-(2-(1,1- difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)propionamide (15 mg) as a white solid.
  • Example 22 N-(3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide
  • a vial containing 5-chloro-3-(2-(2-fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H- pyrrolo[2,3-c]pyridine 149 mg, 467 umol) (prepared similar to Preparation 32 using 4- chloro-2-(2-fluoropropan-2-yl)-6-methylpyrimidine (Preparation 11)), acetamide (112 mg, 1.9 mmol), cesium carbonate (404 mg, 1.2 mmol), and BrettPhos Pd G3 (80 mg, 89 umol) in anhydrous dioxane (3 mL) was degassed then backfilled with nitrogen then carefully heated to 85 °C.
  • Liquid chromatography was performed using a Waters XSelect CSH C18, 5 ⁇ m, 30 mm ⁇ 100 mm column with mobile phase H2O (A) and MeCN (B) and a gradient of 5 ⁇ 65 % B (0.2% NH4OH final v/v % modifier) with flow rate at 60 mL/min.
  • the desired fractions were pooled then concentrated under reduced pressure to afford N-(3-(2-(2- fluoropropan-2-yl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide (49 mg, 29 % yield) as a white solid.
  • Example 23 N-(3-(2-(1,1-difluoroethyl)thiazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide Prepared in a similar manner to Example 22 starting with 5-bromo-2-(1,1- difluoroethyl)thiazole to afford N-(3-(2-(1,1-difluoroethyl)thiazol-5-yl)-1-methyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (2 mg) as a white solid.
  • LCMS m/z 337 [M+ H] + .
  • Example 24 N-(3-(2-(1,1-difluoroethyl)-6-methoxypyridin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- Prepared in a similar manner to Example 22 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methoxypyridine (Preparation 3) to afford N-(3-(2-(1,1-difluoroethyl)-6-methoxypyridin-4- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (26 mg) as a white solid.
  • LCMS m/z 361 [M+ H] + .
  • Example 26 N-(3-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide Prepared in a similar manner to Example 22 starting with 4-bromo-2-(1,1- difluoroethyl)pyridine to afford N-(3-(2-(1,1-difluoroethyl)pyridin-4-yl)-1-methyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (7 mg) as a white solid.
  • LCMS m/z 331.0 [M+ H] + .
  • Example 26 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)propionamide Prepared in a similar manner to Example 22 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methyl-pyrimidine (Preparation 6) and N-Ethylacetamide to afford N-(3-(2-(1,1- difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)propionamide (51 mg) as a white solid.
  • Example 27 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)propionamide Prepared in a similar manner to Example 22 starting with 4-chloro-2-(1,1-difluoroethyl)-6- methyl-pyrimidine (Preparation 6) and 1-methylurea to afford 1-(3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea (15 mg) as a white solid.
  • Example 28 N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar manner Example 22 using 5-chloro-3-(6-(1,1-difluoroethyl)pyridin-2- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 22 with 2-bromo-6-(1,1- difluoroethyl)pyridine, 55.6 mg, 181 umol) to afford the N-(3-(6-(1,1-difluoroethyl)pyridin- 2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (50 mg, 151 umol, 84 % yield).
  • Example 29 N-(3-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar manner Example 22 using 5-chloro-3-(2-(1,1-difluoroethyl)-6- methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 32 using Preparation 8, 61 mg, 181 umol) to afford the title compound (18 mg, 50 umol, 28 % yield) as a white solid.
  • LCMS m/z 362 [M+ H] + .
  • Example 30 N-(3-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin- 5-yl)acetamide Prepared in a similar manner Example 20 using 5-chloro-3-(2-(1,1-difluoroethyl)-6- methoxypyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridine (Preparation 31 using 4- chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine (Preparation 8), 336 mg, 990 umol) to afford the title compound N-(3-(2-(1,1-difluoroethyl)-6-methoxypyrimidin-4-yl)-1-methyl- 1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (7 mg, 2% yield over 2 steps).
  • Example 31 N-(3-(2-(2-fluoropropan-2-yl)-6-methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide Prepared similar to Example 22 using 5-chloro-3-(2-(2-fluoropropan-2-yl)-6- methoxypyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 32 with 4-chloro- 2-(2-fluoropropan-2-yl)-6-methoxypyrimidine (Preparation 12)) to afford the title compound (40 mg, 112 umol, 61 % yield) as a white solid.
  • Example 32 N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide Prepared in a similar manner as described Example 18 but using 5-chloro-3-(6-ethyl-2-(1- fluorocyclopropyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridine (Preparation 32 starting with 4-chloro-6-ethyl-2-(1-fluorocyclopropyl)pyrimidine (Preparation 25), 59.8 mg, 181 umol) to afford the title compound N-(3-(6-ethyl-2-(1-fluorocyclopropyl)pyrimidin-4- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (9 mg, 25.5 umol
  • Example 45 N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared similar to Example 2 from tert-butyl 5-acetamido-3-(6-(1,1- difluoroethyl)pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate using 2-chloro-6-(1,1- difluoroethyl)pyrazine like Example 1.
  • Example 46 N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was prepared similarly to Example 3, from N-(3-(6-(1,1-difluoroethyl)pyrazin-2-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 45).
  • Example 47 N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5- yl)acetamide
  • N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 36, 10 g, 28.96 mmol) and K2CO3 (10.0 g, 72.39 mmol) in DMF (100 mL) was added ethyl iodide (6.32 g, 40.54 mmol) and the reaction was stirred at 100 °C for 2 h.
  • the aqueous solution was adjusted to pH 6 using saturated NaHCO 3 at 25 °C, the solution heated to 70 °C and the pH adjusted further to 7 and the mixture stirred for 2 h.
  • the mixture was filtered to give N-(3-(2-(1,1-difluoroethyl)-6- ethylpyrimidin-4-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (4.7 g, 43.5% yield) as an off yellow solid.
  • Example 48 N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1-(2-hydroxyethyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide
  • N-(3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide (Example 36, 70 mg, 0.203 mmol) and Cs 2 CO 3 (198 mg, 0.608 mmol) in DMF (3 mL) was added oxirane (44.6 mg, 1.01 mmol) at 20°C.
  • Example 49 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(difluoromethyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide
  • N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 100 mg, 0.302 mmol) and sodium 2-chloro-2,2- difluoroacetate (59.8 mg, 0.392 mmol) in DMF (5 mL) was added Cs2CO3 (148 mg, 0.453 mmol) at 25°C.
  • Example 50 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(trifluoromethyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide
  • N-(1-(bromodifluoromethyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 35, 55.0 mg, 0.120 mmol) in sulfolane (2.0 mL) was added tetramethylammonium fluoride (5.6 mg, 60 ⁇ mol).
  • Example 52 rac-N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-((1R,2R)-2-fluorocyclopropyl)- 1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 80 mg, 0.241 mmol) in DMF (2 mL) was added 2-(2- fluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 37, 100 mg, 0.538 mmol), 2-(2-pyridyl)pyridine (75.4 mg, 0.483 mmol), copper (II) acetate (21.9 mg, 1.21
  • Example 53 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-methyl-1H-pyrazol-3-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide (Example 34, 60.0 mg, 0.181 mmol) in DMF (1 mL) was added 1- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (75.4 mg, 0.362 mmol), copper (II) acetate (32.9 mg, 0.181 mmol), TEA (36.7 mg, 0.362 mmol) and 2-(2- pyridyl)
  • Example 54 N-(1-cyclopropyl-3-(2-(1,1-difluoroethyl)-6-ethylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin- 5-yl)acetamide
  • cyclopropyl boronic acid 9.40 g, 109.5 mmol
  • copper (II) acetate 10.41 g, 57.33 mmol
  • TEA 10.55 g, 104.24 mmol
  • 2-(2-pyridyl) pyridine (8.14 g, 52.12 mmol) and Na 2 CO 3 (11.05 g,
  • Example 55 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-((1r,3r)-3- (dimethylamino)cyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • Example 56 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-((1s,3s)-3- (dimethylamino)cyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • N-(1-(3-aminocyclobutyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)- 1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide Preparation 39, 150 mg, 0.375 m
  • the mixture was concentrated and purified by prep-HPLC (Column: Phenomenex C18150mm*30mm*5 ⁇ m; Condition: Water (NH 4 HCO 3 )-MeCN; Begin B: 23; End B:63; Gradient Time (min): 9; Flow Rate (mL/min): 30) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-methylazetidin-3-yl)- 1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (7.5 mg, 9.4% yield) as a white solid.
  • HATU 70.19 mg, 0.185 mmol
  • N-(3-(2-(1,1-difluoroethyl)-6- methylpyrimidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide trifluoroacetate (Example 34, 89 mg, 0.269 mmol) in anhydrous DMF (0.5 mL) was added dropwise and the reaction was warmed to rt and stirred for 16 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3x 20 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure.
  • Example 60 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1-fluorocyclopropyl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide formate
  • N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-(1- hydroxycyclopropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 42, 80.0 mg, 0.207 mmol) in DCM (3.0 mL) was added Deoxy-Flour (228.5 mg, 1.03 mmol) at 25 °C for 2 h.
  • the mixture was purified by prep-HPLC (Column: Welch Xtimate C18 150*25mm*5um; Condition: water (FA)-MeCN; Begin B: 13; End B: 53; Gradient Time (min): 9; Flow Rate (mL/min): 60) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1-(1-fluorocyclopropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide formate (10.0 mg, 11.4% yield) as a yellow solid.
  • Example 62 N-(3-(2-(1,1-difluoroethyl)-6-(methylamino)pyrimidin-4-yl)-1-isopropyl-1H-pyrrolo[2,3- c]pyridin-5-yl)acetamide
  • N-(3-(6-chloro-2-(1,1-difluoroethyl)pyrimidin-4-yl)-1-isopropyl-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide (Preparation 48, 60.0 mg, 0.152 mmol) in MeCN (1.5 mL) was added methylamine (11.3 mg, 0.168 mmol) and TEA (46.3 mg, 0.457 mmol).
  • Example 63 N-(1-(cyclopropylsulfonyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1H- pyrrolo[2,3-c]pyridin-5-yl)acetamide
  • a mixture of 5-chloro-1-(cyclopropylsulfonyl)-3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4- yl)-1H-pyrrolo[2,3-c]pyridine Preparation 51, 84 mg, 0.203 mmol), acetamide (56 mg, 0.953 mmol), cesium carbonate (171 mg, 0.525 mmol) and BrettPhos Pd G3 (38 mg, 42 ⁇ mol) in anhydrous dioxane (2 mL) was degassed, backfilled with N 2 and heated to 85 °C for 2 h.
  • Example 64 N-(3-(2-(1,1-difluoroethyl)pyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide
  • 2-(1,1-difluoroethyl)-4-(trimethylstannyl)pyrimidine Preparation 52, 200 mg, 0.652 mmol
  • N-(3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide Preparation 54, 130 mg, 0.411 mmol
  • Pd(PPh3)4 75.3 mg, 0.065 mmol
  • CuI 24.8 mg, 0.130 mmol
  • Example 65 N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide
  • N-(1-methyl-3-(trimethylstannyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide Preparation 55, 250 mg, 0.708 mmol
  • 4-chloro-2-(1,1-difluoroethyl)-6- methylpyrimidine Preparation 6, 136.4 mg, 0.708 mmol
  • dioxane (10 mL) was added CuI (40.46 mg, 0.212 mmol) and Pd(PPh3)2Cl2 (49.71 mg, 0.071 mmol) under N2.
  • the reaction was stirred at 100 °C for 2 h under N 2 .
  • the reaction was diluted with aq KF (10 mL) and water (20 mL) and stirred at 25 °C for 0.5 h.
  • the mixture was extracted with EtOAc (30 mL x 3) and the combined organic phase was dried over Na2SO4, filtered and concentrated.
  • the crude was purified by silica gel column chromatography (EtOAc in PE from 20% to 100%) and then purified by prep-HPLC (Column: Phenomenex Gemini NX 150 ⁇ 30mm, 5 ⁇ m; Condition: water (NH4HCO3)-MeCN; Begin B: 28; End B: 58; Gradient Time (min): 11; Flow Rate (mL/min): 25) to give N-(3-(2-(1,1-difluoroethyl)-6-methylpyrimidin-4-yl)-1- methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)acetamide (49 mg, 20.0% yield) as a yellow solid.
  • comparator compounds were synthesized as described in WO 2022/242697 WO 2019/178079, or WO 2024/211708: BIOLOGICAL ASSAYS Compounds of the disclosure were assessed for their ability to inhibit TYK2, JAK1 and JAK2 activity.
  • the inhibitory properties of the compounds of the disclosure described herein can be evidenced by testing in any one of the following protocols. JH2 biochemical assay
  • the inhibitory potency of compounds of the disclosure against the kinase activity of recombinantly generated JH2 domain of human Tyk2 was evaluated in a plate-based assay using a TR-FRET assay platform.
  • TR-FRET signal inversely correlates to the amount of probe displaced by compounds and signal was calculated by taking the ratio of fluorescence at 520 nm and 495 nm. The data was normalized and the percent activity versus log concentration of compound was fitted with a 4-parameter logistic model to generate IC50 curves.
  • pSTAT4 cell assay The inhibitory potency of compounds of the disclosure against the Tyk2 kinase activity on STAT4 was evaluated using an MSD-platform plate-based assay format.
  • NK92 cells natively expressing STAT4 and Tyk2 were serum-starved to reduce background phosphorylation levels, then cells were treated compounds for 1 hr with a 10-point four-fold dilution series starting at 10 ⁇ M. Cells were then stimulated with 30 ng/mL IL2 for 15 minutes. Cells were lysed and pSTAT5 levels were quantitated using an MSD plate-based assay with anti-STAT4 antibodies. The data were normalized and the percent activity versus log concentration of compound were fitted with a 4-parameter logistic model to generate to generate IC50 curves.
  • pSTAT5 cell assay Compounds of the disclosure were assessed for their ability to inhibit the JAK2 kinase activity on STAT5 utilizing an MSD-platform plate-based assay format.
  • TF1 cells natively expressing STAT5 and JAK2 were serum-starved to reduce background phosphorylation levels, then cells were treated with compounds of disclosure for 1 hour with a 10-point four- fold dilution series starting at 10 ⁇ M. Cells were then stimulated with 30 ng/mL IL-3 for 15 minutes. Cells were then lysed and pSTAT5 levels were quantitated using an MSD plate- based assay with anti-STAT5 antibodies.
  • pSTAT3 cell assay The inhibitory potency of compounds of the disclosure against the JAK1 kinase activity on STAT3 was evaluated using an MSD-platform plate-based assay format. TF1 cells natively expressing STAT3 and JAK1 were serum-starved to reduce background phosphorylation levels, then cells were treated with compounds of the disclosure for 1 hour with a 10-point four-fold dilution series starting at 10 ⁇ M. Cells were then stimulated with 30 ng/mL interleukin 6 (IL-6) for 15 minutes.
  • IL-6 interleukin 6
  • T Transmission buffer supplemented with 1% BSA
  • the disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

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Abstract

La présente invention concerne des composés de formule (I), ou des sels pharmaceutiquement acceptables de ceux-ci : Formule (I) ; dans laquelle toutes les variables sont telles que définies dans l'application. Les composés de la présente divulgation sont capables d'inhiber l'activité de la tyrosine kinase 2 (TYK2). L'invention concerne en outre des procédés de préparation des composés de l'invention, et des procédés pour leur utilisation thérapeutique.
PCT/US2024/055863 2023-11-15 2024-11-14 Inhibiteurs de tyk2 Pending WO2025106633A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4938949A (en) 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
WO2019178079A1 (fr) 2018-03-12 2019-09-19 Abbvie Inc. Inhibiteurs de la signalisation à médiation par la tyrosine kinase 2
WO2022242697A1 (fr) 2021-05-19 2022-11-24 南京药石科技股份有限公司 Inhibiteur sélectif de tyk2 et son utilisation
WO2024211708A1 (fr) 2023-04-06 2024-10-10 Myrobalan Therapeutics, Inc. Inhibiteurs de tyk2 pour le traitement du glaucome
WO2024217523A1 (fr) * 2023-04-20 2024-10-24 Myrobalan Therapeutics Nanjing Co. Ltd Inhibiteurs sélectifs de tky2 et leurs utilisations

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Publication number Priority date Publication date Assignee Title
US4938949A (en) 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
WO2019178079A1 (fr) 2018-03-12 2019-09-19 Abbvie Inc. Inhibiteurs de la signalisation à médiation par la tyrosine kinase 2
WO2022242697A1 (fr) 2021-05-19 2022-11-24 南京药石科技股份有限公司 Inhibiteur sélectif de tyk2 et son utilisation
WO2024211708A1 (fr) 2023-04-06 2024-10-10 Myrobalan Therapeutics, Inc. Inhibiteurs de tyk2 pour le traitement du glaucome
WO2024217523A1 (fr) * 2023-04-20 2024-10-24 Myrobalan Therapeutics Nanjing Co. Ltd Inhibiteurs sélectifs de tky2 et leurs utilisations

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H.-D. JAKUBKE, H. JESCHKEIT: "Peptide, Proteine (Amino acids, Peptides, Proteins", 1982, VERLAG CHEMIE
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LIANG, Y. ET AL., EXPERT OPINION ON THERAPEUTIC TARGETS, vol. 18, no. 5, 2014, pages 571 - 580
LOUIS F. FIESERMARY FIESER: "Beilsteins Handbuch der organischen Chemie", vol. 1-19, 1973, SPRINGER-VERLAG
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