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WO2025162425A1 - Composés de pyrazolopyrimidine utilisés en tant qu'inhibiteur de tyk2 - Google Patents

Composés de pyrazolopyrimidine utilisés en tant qu'inhibiteur de tyk2

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Publication number
WO2025162425A1
WO2025162425A1 PCT/CN2025/075385 CN2025075385W WO2025162425A1 WO 2025162425 A1 WO2025162425 A1 WO 2025162425A1 CN 2025075385 W CN2025075385 W CN 2025075385W WO 2025162425 A1 WO2025162425 A1 WO 2025162425A1
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Prior art keywords
alkyl
haloalkyl
alkynyl
alkenyl
cycloalkyl
Prior art date
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Pending
Application number
PCT/CN2025/075385
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English (en)
Chinese (zh)
Inventor
邓代国
钟文和
卢杰联
雷曾荣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Fermion Technology Co Ltd
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Guangzhou Fermion Technology Co Ltd
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Publication of WO2025162425A1 publication Critical patent/WO2025162425A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a pyrazolopyrimidine compound, a composition containing the same, a preparation method thereof, and use thereof as a TYK2 inhibitor.
  • the Janus kinase family is an intracellular, non-receptor tyrosine kinase that mediates signaling and activation of various cytokines. Gain-of-function expression or mutations in JAKs are associated with numerous autoimmune diseases, inflammation, and cancer. This family includes JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are widely present in various tissues and cells throughout the body, while JAK3 is primarily found in bone marrow cells, thymocytes, natural killer (NK) cells, and activated B and T cells.
  • NK natural killer
  • the JAK-mediated signaling pathway includes three key components: cytokine receptors on the cell surface, JAKs, and downstream proteins.
  • Cytokines such as various interferons (IFNs) and interleukins (ILs)
  • IFNs interferons
  • ILs interleukins
  • cytokine receptors on the cell surface bringing JAKs bound to the intracellular domain of the receptor close.
  • the tyrosine residues of the JAKs are then phosphorylated, increasing the activity of the kinase domain.
  • the activated JAKs phosphorylate the tyrosine residues of the receptors, creating binding sites for proteins with SH2 domains.
  • STATs signal transducers and activators of transcription
  • the dimers then translocate to the nucleus to induce transcription of target genes.
  • other proteins with SH2 domains can also bind to activated JAKs, thereby cross-linking with other signaling pathways, such as PI3K/AKT and MAPK/ERK.
  • TYK2 is a non-receptor tyrosine kinase that mediates immune signals, primarily regulating signaling pathways driven by IL-23, IL-12, and type I interferon (IFN ⁇ ). It is used as an IL-12, IL-23, and/or IFN ⁇ regulator by inhibiting TYK2-mediated signal transduction.
  • TYK2 plays an important role in transmitting inflammatory and immune response signals and is involved in the pathophysiology of various immune-related diseases, such as psoriasis (PS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD).
  • PS psoriasis
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • IBD inflammatory bowel disease
  • TYK2 does not mediate cytokine responses driven by other kinases (such as IL-6, hematopoietic growth factors, and IL-2). Therefore, TYK2 inhibitors can avoid the adverse reactions of currently marketed JAK inhibitors by not acting on other subtypes.
  • JAK inhibitors are active-site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (JH1) of the JAK protein. Due to the high homology of the ATP sites of JAK family kinases and the similarity of the ATP-binding regions of the human kinase group, they generally suffer from low selectivity.
  • ATP adenosine triphosphate
  • JH2 pseudokinase domain
  • BMS-986165 is currently known to selectively bind to JH2 of TYK2, inhibiting TYK2 kinase function through an allosteric effect.
  • the "blood-brain barrier” refers to the interface between the blood and the brain.
  • the BBB and its penetration by neurotherapeutics are major topics in how central nervous system drugs are effective.
  • TYK2 inhibitors with brain-penetrating properties could be used to treat relapsing and progressive neurological diseases such as Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis. From a medicinal chemistry perspective, the ability to design drugs that can penetrate the BBB and achieve the desired biological response is a huge challenge, and drugs that can achieve this goal are currently needed.
  • the present invention provides a pyrazolopyrimidine compound that has excellent selective inhibition of TYK2 activity and can treat a variety of TYK2-mediated diseases.
  • the compound of the present invention can penetrate the BBB.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.
  • the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising said compound, for use in treating and/or preventing TYK2 kinase-mediated diseases.
  • the present invention provides a method for treating and/or preventing a TYK2 kinase-mediated disease in a subject using a compound as defined herein, comprising administering to the subject said compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.
  • the method involves the TYK2 kinase-mediated disease being selected from rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.
  • Suitable examples include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), and 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ).
  • alkenyl is an alkyl group as defined herein that contains at least one carbon-carbon double bond.
  • the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms.
  • alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, or 4-decenyl.
  • Alkynyl is an alkyl group as defined herein that contains at least one carbon-carbon triple bond.
  • the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms.
  • Non-limiting examples of alkynyl groups include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, or 4-decynyl.
  • Carbocyclyl or “cycloalkyl” refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 3-6-membered, 4-6-membered, 5-6-membered, 3-4-membered, 3-5-membered, or 4-5-membered saturated carbocyclic ring or a partially unsaturated carbocyclic ring.
  • the cycloalkyl is C3-6 cycloalkyl, C4-6 cycloalkyl, C5-6 cycloalkyl, C3-4 cycloalkyl, C3-5 cycloalkyl, or C4-5 cycloalkyl.
  • the carbocyclyl is a 3- to 4- membered monocyclic ring, a 3- to 5-membered monocyclic ring, a 3- to 6-membered monocyclic ring, a 3- to 7-membered monocyclic ring, a 3- to 8-membered monocyclic ring, a 3- to 10-membered monocyclic ring, a 5- to 8-membered monocyclic ring, a 5- to 6-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system.
  • Carbocyclic rings include bridged rings or spirocyclic rings.
  • carbocyclic radical examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo [3.2.1] octyl, bicyclo [5.2.0] nonyl, tricyclo [5.3.1.1] dodecyl, adamantyl or spiro [3.3] heptyl etc.
  • Carbocyclic radical can be optionally substituted.
  • halogen refers to -F, -Cl, -Br or -I.
  • haloalkyl refers to an alkyl group substituted with a halogen group, wherein alkyl is as defined above, preferably C 1-6 haloalkyl, C 1-5 haloalkyl, C 1-4 haloalkyl, C 1-3 haloalkyl and C 1-2 haloalkyl.
  • aryl refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom. It can be a monocyclic aryl, a condensed ring aryl, or a polycyclic aryl, preferably a 6-10 membered aryl group. In polycyclic rings, at least one is an aromatic ring system. Phrases containing this term, for example, "6-membered aryl” refers to an aromatic ring system containing 6 ring atoms.
  • the aryl group is a phenyl group.
  • heteroaryl refers to an aromatic group containing heteroatoms, which may be monocyclic or fused rings, wherein the heteroatoms are independently selected from N, O, and S, and are preferably 5-12 membered heteroaryls, preferably 5-10 membered heteroaryls, preferably 5-8 membered heteroaryls, preferably 5-6 membered heteroaryls, and preferably 5 membered heteroaryls.
  • Heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, triazolyl, tetrahydropyrrolyl, and thiadiazolyl.
  • a 5-6 membered monocyclic heteroaryl group typically contains one or more, preferably one to three, and preferably one to two, heteroatoms independently selected from N, O, and S.
  • exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl; exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, thiadiazolyl, and triazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing heteroatoms, wherein the heteroatoms are selected from N, O and S. Furthermore, the term “heterocyclyl” refers to a group of a stable 3-10 membered saturated heterocyclic ring system in which one or more atoms constituting the non-aromatic ring are heteroatoms and the rest are carbon atoms. The heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms and sulfur atoms.
  • the heterocyclyl is preferably a 3-7 membered heterocyclyl, a 3-6 membered heterocyclyl, a 3-5 membered heterocyclyl, a 3-4 membered heterocyclyl, a 4-7 membered heterocyclyl, a 4-6 membered heterocyclyl, a 4-5 membered heterocyclyl, a 5-6 membered heterocyclyl or a 6-7 membered heterocyclyl, each of which contains 1 to 4, preferably 1 to 3, and preferably 1 to 2 heteroatoms selected from N, O or S.
  • the heterocyclyl group can be a 3- to 7-membered monocyclic ring, a 5- to 8-membered monocyclic ring, a 5- to 6-membered monocyclic ring, a 4- to 12-membered bicyclic ring or a 10- to 15-membered tricyclic ring system, preferably a 3- to 10-membered heterocyclyl group, and contains at least 1, preferably 1 to 4, heteroatoms selected from N, O or S.
  • a 3- to 7-membered heterocyclyl group is preferred, which contains 1 to 3, preferably 1 to 2, heteroatoms selected from N, O or S.
  • a 5- to 6-membered heterocyclyl group is preferred, which contains 1 to 3, preferably 1 to 2, heteroatoms selected from N, O or S.
  • a heterocyclic group can be monocyclic ("monocyclic heteroalkyl"), or a bicyclic, tricyclic or higher ring system, which can include fused, bridged or spiro ring systems (e.g., bicyclic systems ("bicyclic heteroalkyl").
  • the ring system of a bicyclic heteroalkyl group can include one or more heteroatoms in one or both rings; and is saturated.
  • Exemplary 3-membered heterocyclic groups include, but are not limited to, aziridine, oxiranyl and thiirane, or stereoisomers thereof;
  • exemplary 4-membered heterocyclic groups include, but are not limited to, azetidinyl, oxiranyl, thiirane, or isomers and stereoisomers thereof;
  • exemplary 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiolanyl, , dithiolanyl, or isomers and stereoisomers thereof.
  • Exemplary 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thiolanyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl, or isomers and stereoisomers thereof;
  • exemplary 7-membered heterocyclic groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, and diazepanyl, or isomers and stereoisomers thereof. Stereoisomers.
  • a typical heterocyclyl is a 3-7 membered monocyclic heterocyclyl containing 1 or more, preferably 1-4, more preferably 1-3 heteroatoms independently selected from N, O and S.
  • a "heterocyclyl” is a 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S.
  • a "heterocyclyl” is a 5-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S.
  • CN refers to a cyano group
  • aromatic includes aryl and heteroaryl groups as defined above.
  • non-aromatic includes cycloalkyl and heterocyclyl groups as defined above.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood to be a linking group.
  • the alkyl group represents the linked alkylene group or arylene group, respectively.
  • the alkyl group represents the linked alkylene group.
  • the alkyl group in the group " -C1 - C3 haloalkyl” should be understood to be an alkylene group.
  • the term "pharmaceutically acceptable salt” means that the compound can be converted into a corresponding salt by conventional methods, which is chemically or physically compatible with the other ingredients constituting a certain pharmaceutical dosage form and physiologically compatible with the receptor.
  • the salt can be an acidic and/or basic salt formed by the compound with an inorganic and/or organic acid and/or an inorganic and/or organic base, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts.
  • These salts can be obtained directly during the final separation and purification of the compound. They can also be obtained by appropriately mixing the compound of the present invention or its stereoisomers or solvates with a certain amount of acid or base.
  • the salt is preferably a water-soluble, pharmaceutically acceptable, non-toxic acid addition salt, examples of which are salts formed between an amino group and an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other conventional methods in the art (e.g., ion exchange).
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid
  • salts formed using other conventional methods in the art e.g., ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • additional pharmaceutically acceptable salts may also include salts derived from appropriate bases, including alkali metal salts, alkaline earth metal salts, and ammonium salts.
  • Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like.
  • additional pharmaceutically acceptable salts include salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates with non-toxic ammonium, quaternary ammonium, and amine cations.
  • solvate may also be referred to as “solvate” or “solvate”, and refers to a compound containing solvent molecules, wherein the solvent molecules can be combined with the compound molecules in ways including coordination bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bonds, etc.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc.
  • the compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates in the solution state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is used to determine the compound. Therefore, the hydrate of a compound can be represented by the general formula R ⁇ xH 2 O, for example, where R is the compound and x is a number greater than 0.
  • a given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5H 2 O)), and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • prodrug refers to any compound that, when administered to an organism, produces a drug, i.e., an active ingredient, as a result of a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and/or metabolic chemical reaction.
  • Prodrugs are therefore covalently modified analogs or latent forms of therapeutically active compounds. Suitable examples include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo compound, phosphoramide, glucoside, ether, acetal, etc. forms of the compound.
  • the present invention also includes isotopically labeled compounds (isotopic variants), which are equivalent to those general formulas or specific compounds described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that commonly found in nature.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively, preferably 2 H (i.e., deuterium, D).
  • isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the processes disclosed in the following schemes and/or the Examples and Preparations.
  • the compounds of the present invention include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.
  • Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • aryl is optionally substituted with alkyl means that the alkyl group may but need not be present, and the term includes instances where the aryl group is substituted with alkyl and instances where the aryl group is not substituted with alkyl.
  • a “pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • pharmaceutically acceptable excipient includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with drug administration.
  • Each excipient must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient.
  • Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltose.
  • sugars such as lactose, glucose, and sucrose
  • starches such as corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrins
  • cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate
  • Rice oil and soybean oil (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical formulations.
  • glycols such as propylene glycol
  • polyols such as glycerol, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • (13) agar (14) buffers such as magnesium hydroxide and aluminum hydroxide
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to one crystalline form being dominant. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • the present invention uses conventional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to conventional operating steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques for analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light-emitting device performance testing.
  • the term “respectively and independently” used in this disclosure should be broadly interpreted to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term “respectively and independently” can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.
  • the present invention relates to the following technical solutions.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof:
  • R 1 is selected from H, halogen, -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 2 is -L 2 –R 2A ;
  • R 3 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, -SR, halogen, -CN, -NO 2 , -N(R 3A )(R 3B ), -NHC(O)R 3A , C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, -SR, halogen, -CN, -NO 2 , -N(R 4A )(R 4B ), -NHC(O)R 4A , C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • L 2 is a covalent bond or a C 1-6 alkylene group, wherein one or two methylene units in the alkylene group are optionally and independently replaced by: -C(R 2B ) 2 -, -CH(R 2B )-, -N(R 2B )-, -N(R 2B )C(O)-, -C(O)N(R 2B )-, -N(R 2B )S(O) 2 -, -S(O) 2 N(R 2B )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) 2 -;
  • R 1A is independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;
  • R 1B is independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;
  • R 2A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 2B is selected from C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, which is optionally substituted with 1-5 R 2b 'substituents;
  • R 2b ' is selected from hydrogen, halogen, oxo, -CN, -NO 2 , -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 3A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 3B is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 3A and R 3B together form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl;
  • R 4A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 4B is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 4A and R 4B together form a 3-7 membered heterocyclyl or a 5-10 membered heteroaryl;
  • R is independently selected at each occurrence from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 0, 1, 2, 3, 4, 5 or 6
  • the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is formula (II),
  • X is C(R 2b1 ), O, S, N or N(R 2b1 );
  • Y is C(R 2b2 ), O, S, N or N(R 2b2 );
  • Z is C(R 2b3 ), O, S, N or N(R 2b3 );
  • R 2b1 is selected from H, halogen, oxo, -CN, -NO 2 , -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b2 is selected from H, halogen, oxo, -CN, -NO 2 , -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 2b3 is selected from H, halogen, oxo, -CN, -NO 2 , -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b4 is selected from H, halogen, oxo, -CN, -NO 2 , -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b5 is selected from H, halogen, oxo, -CN, -NO 2 , -OR, -SR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R is independently selected at each occurrence from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, oxo, and CN;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • the present invention provides a compound of formula (I) or formula (II) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R 1 is selected from -OMe, -OEt,
  • the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is formula (III),
  • R 1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 2A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 2b1 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b2 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b3 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b4 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b5 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 3 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 3A )(R 3B );
  • R 4 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 4A )(R 4B );
  • R 3A is H or C 1-6 alkyl
  • R 3B is H or C 1-6 alkyl
  • R 4A is H or C 1-6 alkyl
  • R 4B is H or C 1-6 alkyl
  • R is independently C 1-6 alkyl or C 3-6 cycloalkyl at each occurrence;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 0, 1, 2, 3 or 4;
  • n is not 0.
  • the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R 1 is selected from -OR and C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1-2 substituents selected from the following: C 1-4 alkyl, -OR, oxo and CN;
  • R 2A is H
  • R 2b1 is selected from H, halogen and -OR;
  • R 2b2 is a 5-6 membered heteroaryl group, which is optionally substituted with a C 1-4 alkyl group;
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H or C 1-4 alkyl
  • R 4B is H or C 1-4 alkyl
  • R is independently C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R1 is -OR
  • R 2A is H
  • R 2b1 is halogen or -OR
  • R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is substituted by a C 1-4 alkyl group.
  • R 2b2 is
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H
  • R 4B is a C 1-4 alkyl group, preferably a methyl group
  • R is independently C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence, preferably methyl or cyclopropyl;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R1 is -OR
  • R 2A is H
  • R 2b1 is -OR
  • R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is substituted by a C 1-4 alkyl group.
  • R 2b2 is
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H
  • R 4B is a C 1-4 alkyl group, preferably a methyl group
  • R is independently C 1-4 alkyl
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (III) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R1 is -OR
  • R 2A is H
  • R 2b1 is halogen
  • R 2b2 is a 5-6 membered heteroaryl group, such as a triazolyl group, which is substituted by a C 1-4 alkyl group.
  • R 2b2 is
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H
  • R 4B is a C 1-4 alkyl group, preferably a methyl group
  • R is a C 3-4 cycloalkyl group, preferably a cyclopropyl group
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (IV), preferably formula (IV-1):
  • R 1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 2A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 2b2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 2b3 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b4 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b5 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -OR, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 3 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 3A )(R 3B );
  • R 4 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 4A )(R 4B );
  • R 3A is H or C 1-6 alkyl
  • R 3B is H or C 1-6 alkyl
  • R 4A is H or C 1-6 alkyl
  • R 4B is H or C 1-6 alkyl
  • R is independently C 1-6 alkyl or C 3-6 cycloalkyl at each occurrence;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 0, 1, 2, 3 or 4;
  • n is not 0.
  • the present invention provides a compound of formula (IV) or formula (IV-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R 1 is selected from -OR and 5-6 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with 1-2 substituents selected from the following: C 1-4 alkyl, -OR, oxo and CN;
  • R 2A is H
  • R 2b2 is a 5-6 membered heteroaryl group, which is optionally substituted with a C 1-4 alkyl group;
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H or C 1-4 alkyl
  • R 4B is H or C 1-4 alkyl
  • R is independently C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (IV) or formula (IV-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R1 is selected from -OR and 5-6 membered heterocyclic group, preferably, the 5-6 membered heterocyclic group is oxacyclopentyl, preferably
  • R 2A is H
  • R 2b2 is a 5-6 membered heteroaryl group, which is optionally substituted with a C 1-4 alkyl group;
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H
  • R 4B is a C 1-4 alkyl group, preferably a methyl group
  • R is a C 1-4 alkyl group
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is of formula (V), preferably (V-1):
  • R 1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 2A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 2b1 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b3 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b4 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b5 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 3 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 3A )(R 3B );
  • R 4 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 4A )(R 4B );
  • R 3A is H or C 1-6 alkyl
  • R 3B is H or C 1-6 alkyl
  • R 4A is H or C 1-6 alkyl
  • R 4B is H or C 1-6 alkyl
  • R is independently C 1-6 alkyl or C 3-6 cycloalkyl at each occurrence;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 0, 1, 2, 3 or 4;
  • n is not 0.
  • the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R 1 is selected from -OMe, -OEt,
  • the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R 1 is selected from -OR, C 3-4 cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl and heteroaryl are optionally substituted with 1-2 substituents selected from the following: C 1-4 alkyl, -OR, oxo and CN;
  • R 2A is H
  • R 2b1 is -OR
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H or C 1-4 alkyl
  • R 4B is H or C 1-4 alkyl
  • R is independently C 1-4 alkyl or C 3-4 cycloalkyl at each occurrence;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 0, 1, or 2;
  • n is not 0.
  • the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R1 is -OR
  • R 2A is H
  • R 2b1 is -OR
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H
  • R 4B is a C 1-4 alkyl group, preferably a methyl group
  • R is independently C 1-4 alkyl at each occurrence, preferably methyl or ethyl
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (V) or formula (V-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R1 is -OR, wherein R is C1-4 alkyl, preferably methyl;
  • R 2A is H
  • R 2b1 is -OR, wherein R is a C 3-4 cycloalkyl group, preferably a cyclopropyl group;
  • R 2b3 is H
  • R 2b4 is H
  • R 2b5 is H
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H
  • R 4B is a C 1-4 alkyl group, preferably a methyl group
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, which is formula (VI), preferably formula (VI-1),
  • R 1 is selected from H, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1-3 substituents selected from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo and CN;
  • R 2A is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;
  • R 2b2 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b3 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b4 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 2b5 is selected from H, halogen, -OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halogen, -OR, oxo, and CN;
  • R 3 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 3A )(R 3B );
  • R 4 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and -N(R 4A )(R 4B );
  • R 3A is H or C 1-6 alkyl
  • R 3B is H or C 1-6 alkyl
  • R 4A is H or C 1-6 alkyl
  • R 4B is H or C 1-6 alkyl
  • R is independently C 1-6 alkyl or C 3-6 cycloalkyl at each occurrence;
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 0, 1, 2, 3 or 4;
  • n is not 0.
  • the present invention provides a compound of formula (VI) or formula (VI-1) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof,
  • R1 is -OR
  • R 2A is H
  • R 2b2 is -OR
  • R 2b3 is H
  • R 2b4 is H or a 5-6 membered heteroaryl group, which is optionally substituted with a C 1-4 alkyl group;
  • R 2b5 is H or halogen
  • R3 is H
  • R 4 is -N(R 4A )(R 4B );
  • R 4A is H
  • R 4B is H or C 1-4 alkyl, preferably methyl
  • R is independently C 1-4 alkyl
  • Each carbon-bonded hydrogen may optionally and independently be replaced with deuterium
  • n 1.
  • the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, wherein the compound is selected from the following: wherein the compound is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it further comprises other therapeutic agents.
  • the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and use of a pharmaceutical composition comprising the same in the preparation of a medicament for treating and/or preventing TYK2 kinase-mediated diseases.
  • the present invention provides a compound as defined herein or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising said compound, for use in treating and/or preventing TYK2 kinase-mediated diseases.
  • the present invention provides a method for treating and/or preventing a TYK2 kinase-mediated disease in a subject using a compound as defined herein, comprising administering to the subject said compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition comprising the same.
  • the TYK2 kinase-mediated disease of the present invention is selected from the group consisting of a neurological disease, an autoimmune disease, a skin disease, an allergic disease, an organ rejection, a cancer, dry eye disease, myelofibrosis, and polycythemia.
  • the neurological disease is Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis;
  • the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease;
  • the skin disease is psoriasis, rash, or atopic dermatitis;
  • the allergic condition is asthma or rhinitis;
  • the organ transplant rejection is allogeneic rejection or graft-versus-host disease; and
  • the cancer is renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma, or leukemia.
  • the method involves the TYK2 kinase-mediated disease being selected from Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus, amyotrophic lateral sclerosis, or multiple sclerosis.
  • the compound (I) of the present invention can be administered by any means suitable for the disease state to be treated, which may depend on the need for site-specific treatment or the amount of drug to be delivered. Although other modes of delivery are contemplated, topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for cancerous or precancerous disease states.
  • the compound can be delivered in the following ways: oral, for example, in the form of tablets, capsules, granules, powders, or liquid preparations (including syrups); topical, for example, in the form of solutions, suspensions, gels, or ointments; sublingual; buccal; parenteral, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (for example, in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, for example, by inhalation spray; topical, for example, in the form of creams or ointments; rectal, for example, in the form of suppositories; or liposomes.
  • oral for example, in the form of tablets, capsules, granules, powders, or liquid preparations (including syrups); topical, for example, in the form of solutions, suspensions, gels, or ointments; sublingual; buccal; parenteral, for example, by
  • a unit dose formulation containing a non-toxic pharmaceutically acceptable carrier or diluent can be administered.
  • the compound can be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved using suitable pharmaceutical compositions or, particularly in the case of extended release, using, for example, subcutaneous implants or osmotic pump devices.
  • compositions for topical administration include a topical carrier.
  • compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity increasing agent, and sweeteners or flavorings, such as those known in the art; and immediate release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and/or lactose, and/or other excipients, binders, extenders, disintegrants, diluents, and lubricants, such as those known in the art.
  • suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity increasing agent, and sweeteners or flavorings, such as those known in the art
  • immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and
  • compositions may include rapidly dissolving diluents, such as mannitol, lactose, sucrose, and/or cyclodextrins.
  • formulations may also include high molecular weight excipients, such as cellulose (AV1CEL ) or polyethylene glycol (PEG); excipients to aid mucoadhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymers (e.g., GANTREZ ); and agents for controlled release, such as polyacrylic acid copolymers (e.g., CARBOPOL 934 Lubricants, glidants, flavoring agents, coloring agents and stabilizers may also be added to facilitate preparation and use.
  • HPC hydroxypropyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • SCMC sodium carboxymethyl cellulose
  • GANTREZ maleic anhydride copolymers
  • agents for controlled release such as polyacrylic acid copolymers (e.g., CARBOPOL 934 Lubricants, glidants, flavoring agents, coloring
  • compositions for nasal aerosol or inhalation administration include solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents, such as those known in the art.
  • compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides and fatty acids, including oleic acid.
  • suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides and fatty acids, including oleic acid.
  • compositions for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
  • suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
  • Therapeutically effective amounts of the compounds of the present invention can be determined by one skilled in the art and include exemplary doses of about 0.05-1000 mg/kg, 1-1000 mg/kg, 1-50 mg/kg, 5-250 mg/kg, 250-1000 mg/kg body weight of active compound per day for mammals, which can be administered as a single dose or in individual divided doses (e.g., 1 to 4 times per day). It should be understood that the specific dose level and frequency of administration for any particular individual may vary and will depend on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the species, age, weight, general health, sex and diet of the individual, the mode and timing of administration, the rate of excretion, the drug combination, and the severity of the particular disease state.
  • Preferred individuals for treatment include animals, most preferably mammalian species, such as humans and domestic animals, such as dogs, cats, horses, etc. Therefore, when the term "patient” is used herein, this term is meant to include all individuals, most preferably mammalian species, who suffer from TYK2 kinase-mediated diseases.
  • NBS N-bromosuccinimide
  • ACN acetonitrile
  • DIEA N,N-diisopropylethylamine
  • IPA Isopropyl alcohol
  • DMAP 4-dimethylaminopyridine (Boc) 2 O: Di-tert-butyl dicarbonate nBu-Li: n-butyllithium
  • THF Tetrahydrofuran
  • TEA triethylamine
  • TEP Tri(2-furyl)phosphine
  • Pd(OAc) 2 Palladium acetate
  • Cs 2 CO 3 Cesium carbonate
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • SOCl 2 thionyl chloride
  • MTBE Methyl tert-butyl ether
  • PBr 3 Phosphorus tribromide EtOH: ethanol NaCN: sodium cyanide
  • DMF N,N-dimethylformamide
  • DCC
  • Step 4 (7-((tert-Butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidin-3-yl)boronic acid
  • the aqueous phase was extracted with ethyl acetate (60 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (60 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step 4 tert-Butyl (5-chloro-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) 107 mg, 0.460 mmol
  • copper(I) thiophene-2-carboxylate CuTC
  • tris(dibenzylideneacetone)dipalladium 140 mg, 0.153 mmol
  • the reaction mixture was stirred in an oil bath at 50°C for 2 hours.
  • the reaction was stopped and the reaction mixture was poured into water (50 mL).
  • the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (50 mL ⁇ 3) and dried over anhydrous sodium sulfate.
  • Step 5 Tert-butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was stirred in an oil bath at 110°C for 1 hour.
  • the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 6 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(tetrahydrofuran-2-yl)ethan-1-one (Compound 1)
  • Step 3 tert-Butyl (5-((tert-butoxycarbonyl)(2-methoxypyridin-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(tetrahydrofuran-3-yl)ethan-1-one (Compound 2)
  • the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (8.67 mg, yield: 36.1%) as a white solid.
  • the pH of the aqueous phase was adjusted to 1-2 with 1M HCl aqueous solution and extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (50 mL ⁇ 3) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (2.477 g, yield: 63.2%, white solid).
  • Step 7 tert-Butyl (5-chloro-3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) 64 mg, 0.276 mmol
  • copper(I) thiophene-2-carboxylate CuTC
  • tris(dibenzylideneacetone)dipalladium 84 mg, 0.092 mmol
  • the reaction solution was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 8 tert-Butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • tert-butyl (5-chloro-3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (80 mg, 0.198 mmol) in dioxane (10 mL), and add 2-methoxypyridin-3-amine (30 mg, 0.237 mmol), palladium acetate (9 mg, 0.040 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46 mg, 0.079 mmol), and cesium carbonate (193 mg, 0.593 mmol).
  • Step 9 1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)ethan-1-one (Compound 3)
  • the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (13.87 mg, yield: 49.7%) as a white solid.
  • Step 2 tert-Butyl (5-chloro-3-(tetrahydro-2H-pyran-4-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 3 tert-Butyl (5-((2-methoxypyridin-3-yl)amino)-3-(tetrahydro-2H-pyran-4-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)(tetrahydro-2H-pyran-4-yl)methanone (Compound 4)
  • reaction solution was poured into water (100 mL), and the aqueous phase was extracted with dichloromethane (60 mL ⁇ 3). The combined organic phases were washed with saturated brine (80 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 4 tert-Butyl (5-chloro-3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) (128 mg, 0.551 mmol), copper(I) thiophene-2-carboxylate (CuTC) (560 mg, 2.937 mmol), and tris(dibenzylideneacetone)dipalladium (168 mg, 0.183 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3).
  • Step 5 Tert-butyl (3-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to give the title compound (50 mg, yield: 29.4%, white solid).
  • Step 6 1-(2-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (Compound 5)
  • Step 2 tert-Butyl (5-chloro-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 3 tert-Butyl (3-(2-methoxyacetyl)-5-((2-methylpyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 4 2-methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 6)
  • Step 2 tert-Butyl (5-chloro-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 3 tert-Butyl (3-(2-ethoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 2-ethoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 7)
  • Step 2 tert-Butyl (5-chloro-3-(3-methoxypropionyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 3 tert-Butyl (3-(3-methoxypropionyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 4 3-methoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)propan-1-one (Compound 8)
  • the combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product.
  • the crude product is purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to yield the title compound (9.58 mg, yield: 18.6%) as a white solid.
  • Step 4 tert-Butyl (5-chloro-3-(2-(2-oxooxazolidin-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) (90 mg, 0.388 mmol), copper(I) thiophene-2-carboxylate (CuTC) (392 mg, 2.056 mmol), and tris(dibenzylideneacetone)dipalladium (118 mg, 0.129 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3).
  • Step 5 tert-Butyl (5-((2-methoxypyridin-3-yl)amino)-3-(2-(2-oxooxazolidin-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 6 3-(2-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-oxoethyl)oxazolidin-2-one (Compound 9)
  • Step 2 tert-Butyl (5-chloro-3-(2-(1-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) 100 mg, 0.431 mmol
  • copper(I) thiophene-2-carboxylate 439 mg, 2.302 mmol
  • tris(dibenzylideneacetone)dipalladium 132 mg, 0.144 mmol
  • the reaction mixture was stirred in an oil bath at 50°C for 2 hours.
  • the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 3 tert-Butyl (3-(2-(1-methoxycyclobutyl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 2-(1-methoxycyclobutyl)-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 10)
  • the pH of the aqueous phase is adjusted to 1-2 with 1M hydrochloric acid solution, and the mixture is extracted with ethyl acetate (50 mL x 3).
  • the combined organic phases are washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound (3.45 g, yield: 82.1%) as a yellow oil.
  • Step 3 tert-Butyl (5-chloro-3-(2-cyclopropyloxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) 256 mg, 1.104 mmol
  • copper(I) thiophene-2-carboxylate CuTC
  • tris(dibenzylideneacetone)dipalladium 337 mg, 0.368 mmol
  • the reaction mixture was stirred in an oil bath at 50°C for 2 hours.
  • the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 4 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 5 2-cyclopropyloxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 11)
  • the combined organic phases are washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product.
  • the crude product is purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to yield the title compound (25.12 mg, yield: 49.9%) as a white solid.
  • Step 3 (5-((2-cyclopropyloxypyridin-3-yl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamic acid tert-butyl ester
  • reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 4 1-(5-((2-cyclopropyloxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 12)
  • Step 1 tert-Butyl (5-((2-cyclopropyloxypyridin-3-yl)amino)-3-(2-ethoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 2 1-(5-((2-cyclopropyloxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-ethoxyethane-1-one (Compound 13)
  • Step 1 tert-Butyl (3-(2-methoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 2 2-methoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 14)
  • Step 1 tert-Butyl (3-(2-ethoxyacetyl)-5-((6-methoxypyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 2 2-Ethoxy-1-(5-((6-methoxypyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 15)
  • the aqueous phase was extracted with ethyl acetate (100 mL x 3).
  • the combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product.
  • Step 2 tert-butyl methyl(5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)-3-(2-(tetrahydrofuran-3-yl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate
  • the aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (72.75 mg, yield: 63.2%) as a white solid.
  • Step 2 3-((7-(methylamino)-3-(2-(tetrahydrofuran-2-yl)acetyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2′-bipyridyl]-2-one (Compound 17)
  • the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.11 mg, yield: 13.2%) as a white solid.
  • Step 1 tert-Butyl (3-(2-methoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 2 3-((3-(2-methoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 18)
  • the aqueous phase was extracted with dichloromethane (40 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by slurrying with N,N-dimethylformamide and acetonitrile to obtain the title compound (13.74 mg, yield: 7.4%) as a yellow solid.
  • Step 1 tert-Butyl (3-(2-ethoxyacetyl)-5-((2-oxo-2H-[1,2'-bipyridyl]-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 2 3-((3-(2-ethoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2H-[1,2'-bipyridyl]-2-one (Compound 19)
  • Step 2 tert-Butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate
  • reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 5 tert-Butyl (5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 6 1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 20)
  • Step 1 tert-Butyl (2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate
  • reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 3 tert-butyl (5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 1-(5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyethane-1-one (Compound 21)
  • the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (15.34 mg, yield: 19.1%) as a white solid.
  • Step 2 tert-Butyl (2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate
  • Step 3 tert-Butyl (2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)carbamate
  • Step 5 tert-Butyl (5-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-3-(2-methoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 6 2-methoxy-1-(5-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 22)
  • Step 1 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 2 2-cyclopropyloxy-1-(5-((2-fluoro-3-(pyridin-2-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 23)
  • Step 1 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction mixture was stirred in an oil bath at 110°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product.
  • Step 2 2-cyclopropyloxy-1-(5-((2-fluoro-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 24)
  • the aqueous phase was extracted with chloroform/isopropanol (3/1) (50 mL x 3).
  • the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (130 mg, yield: 33.2%) as a yellow solid.
  • reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • Step 3 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((3-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 2-cyclopropyloxy-1-(5-((3-fluoro-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 25)
  • the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (10.13 mg, yield: 20.7%), as a yellow solid.
  • Step 5 tert-Butyl (5-chloro-3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) (128 mg, 0.552 mmol), copper(I) thiophene-2-carboxylate (CuTC) (562 mg, 2.945 mmol), and tris(dibenzylideneacetone)dipalladium (168 mg, 0.184 mmol) were added. After nitrogen substitution, the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 6 tert-Butyl (3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • tert-butyl (5-chloro-3-(2-((1S,2R)-2-methoxycyclobutyl)acetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.294 mmol) in dioxane (10 mL), and add 2-methoxypyridin-3-amine (44 mg, 0.353 mmol), palladium acetate (13 mg, 0.059 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (68 mg, 0.118 mmol), and cesium carbonate (288 mg, 0.882 mmol).
  • Step 7 2-((1S,2R)-2-methoxycyclobutyl)-1-(5-(((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 26)
  • Step 2 tert-Butyl 5-chloro-3-(2-cyclobutylacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Tri(2-furyl)phosphine (TFP) 149 mg, 0.644 mmol
  • copper(I) thiophene-2-carboxylate CuTC
  • tris(dibenzylideneacetone)dipalladium 196 mg, 0.215 mmol
  • the reaction mixture was stirred in an oil bath at 50°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 3 tert-Butyl (3-(2-cyclobutylacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 2-cyclobutyl-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 27)
  • the reaction mixture is quenched with water (50 mL), the aqueous phase is extracted with ethyl acetate (50 mL ⁇ 2), the pH of the aqueous phase is adjusted to 1-2 with 1M HCl aqueous solution, and extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined organic phases are washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the title compound (1.6 g, yield: 85.6%, yellow oil).
  • Step 3 tert-Butyl (5-chloro-3-(2-cyclobutoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 tert-Butyl (3-(2-cyclobutoxyacetyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (40 mL), and the aqueous phase was extracted with ethyl acetate (40 mL ⁇ 3). The combined organic phases were washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step 5 2-cyclobutoxy-1-(5-((2-methoxypyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 28)
  • Step 1 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 2 2-cyclopropyloxy-1-(5-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 29)
  • Step 3 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-fluoro-3-morpholinophenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step 4 2-cyclopropyloxy-1-(5-((2-fluoro-3-morpholinophenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 30)
  • Step 2 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 3 2-cyclopropyloxy-1-(7-(methylamino)-5-(quinoxalin-5-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 31)
  • 3-Nitropyridin-2(1H)-one (1.5 g, 10.714 mmol) was dissolved in triethylene glycol dimethyl ether (43 mL). After nitrogen replacement, the temperature was lowered to -15°C and sodium tert-butoxide (2.3 g, 23.571 mmol) was added. The reaction mixture was stirred in a -15°C dry ice bath for 10 minutes. Difluorobromomethyltrimethylsilane (2.6 g, 12.857 mmol) was added dropwise, and the reaction mixture was stirred in a -15°C dry ice bath for 1 hour.
  • Step 3 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 32)
  • the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (11.85 mg, yield: 32.9%) as a white solid.
  • N-(2-Hydroxyphenyl)acetamide (3 g, 19.845 mmol) was dissolved in acetonitrile (20 mL), and deuterated iodomethane (4.89 g, 33.733 mmol) and potassium carbonate (5.49 g, 39.725 mmol) were added. After nitrogen substitution, the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3).
  • Step 3 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-(methoxy-d3)phenyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • reaction solution was poured into water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step 4 2-cyclopropyloxy-1-(5-((2-(methoxy-d3)phenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 33)
  • Step 3 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 4 3-((3-(2-cyclopropyloxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-cyclopropylpyridin-2(1H)-one (Compound 34)
  • Step 1 tert-Butyl (3-(2-cyclobutoxyacetyl)-5-((1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • tert-butyl (5-chloro-3-(2-cyclobutoxyacetyl)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate (120 mg, 0.305 mmol) in dioxane (10 mL), and add 3-amino-1-(difluoromethyl)pyridin-2(1H)-one (58 mg, 0.365 mmol), palladium acetate (14 mg, 0.061 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (70 mg, 0.122 mmol), and cesium carbonate (298 mg, 0.914 mmol).
  • Step 2 3-((3-(2-cyclobutoxyacetyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)-1-(difluoromethyl)pyridin-2(1H)-one (Compound 35)
  • the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3).
  • the combined organic phases were washed with saturated brine (20 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the crude product was purified by preparative HPLC (elution system: water, formic acid, acetonitrile) to obtain the title compound (23.77 mg, yield: 25.6%) as a white solid.
  • Step 1 tert-Butyl 3-(2-cyclopropyloxyacetyl)-5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate
  • Step 2 2-cyclopropyloxy-1-(5-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidin-3-yl)ethan-1-one (Compound 36)
  • Step 2 tert-Butyl (3-(2-cyclopropyloxyacetyl)-5-((2-oxo-1-(pyrazin-2-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(methyl)carbamate

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  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Otolaryngology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de pyrazolopyrimidine de formule générale (I), ou des sels pharmaceutiquement acceptables, des énantiomères, des diastéréoisomères, des racémates, des solvates, des hydrates, des polymorphes, des promédicaments ou des variants isotopiques de ceux-ci. L'invention concerne également une composition pharmaceutique comprenant les composés, son procédé de préparation et son utilisation dans la préparation de médicaments pour le traitement ou la prévention de maladies médiées par la kinase TYK2.
PCT/CN2025/075385 2024-02-01 2025-01-27 Composés de pyrazolopyrimidine utilisés en tant qu'inhibiteur de tyk2 Pending WO2025162425A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780840A (zh) * 2003-02-28 2006-05-31 帝人制药株式会社 吡唑并[1,5－a]嘧啶衍生物
CN101321760A (zh) * 2005-10-06 2008-12-10 先灵公司 作为蛋白激酶抑制剂的吡唑并嘧啶
CN103119045A (zh) * 2010-08-20 2013-05-22 和记黄埔医药（上海）有限公司 吡咯并嘧啶化合物及其用途
CN103313987A (zh) * 2010-11-19 2013-09-18 弗·哈夫曼-拉罗切有限公司 吡唑并吡啶化合物、吡唑并吡啶化合物以及它们作为tyk2抑制剂的用途
CN112334471A (zh) * 2018-04-11 2021-02-05 奎利恩特有限公司 具有药物活性的吡唑并-三嗪和/或吡唑并-嘧啶衍生物
US20240124440A1 (en) * 2020-12-23 2024-04-18 Sudo Biosciences Limited Tyk2 inhibitors and uses thereof
US20240190883A1 (en) * 2021-06-16 2024-06-13 Biotheryx, Inc. Kras protein degraders, pharmaceutical compositions thereof, and their therapeutic applications

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1780840A (zh) * 2003-02-28 2006-05-31 帝人制药株式会社 吡唑并[1,5－a]嘧啶衍生物
CN101321760A (zh) * 2005-10-06 2008-12-10 先灵公司 作为蛋白激酶抑制剂的吡唑并嘧啶
CN103119045A (zh) * 2010-08-20 2013-05-22 和记黄埔医药（上海）有限公司 吡咯并嘧啶化合物及其用途
CN103313987A (zh) * 2010-11-19 2013-09-18 弗·哈夫曼-拉罗切有限公司 吡唑并吡啶化合物、吡唑并吡啶化合物以及它们作为tyk2抑制剂的用途
CN112334471A (zh) * 2018-04-11 2021-02-05 奎利恩特有限公司 具有药物活性的吡唑并-三嗪和/或吡唑并-嘧啶衍生物
US20240124440A1 (en) * 2020-12-23 2024-04-18 Sudo Biosciences Limited Tyk2 inhibitors and uses thereof
US20240190883A1 (en) * 2021-06-16 2024-06-13 Biotheryx, Inc. Kras protein degraders, pharmaceutical compositions thereof, and their therapeutic applications

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